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MDedge conference coverage features onsite reporting of the latest study results and expert perspectives from leading researchers.
‘Double-Expresser’ DLBCL: Tucidinostat Improved R-CHOP Outcomes
At the annual meeting of the American Society of Clinical Oncology (ASCO), they announced that combining the histone deacetylase inhibitor tucidinostat with standard R-CHOP chemotherapy in previously untreated “double-expresser” patients improved complete response and event-free survival (EFS) rates over R-CHOP alone.
The trial, dubbed DEB, is the first phase 3 investigation to confirm the benefit of combination treatment with an epigenetic agent for such patients, lead investigator and study presenter Weili Zhao, MD, PhD, a hematologist at the Shanghai Institute of Hematology, told her audience.
“Tucidinostat plus R-CHOP could be a new frontline treatment option in this patient population,” Dr. Zhao said.
However, the agent is not available in the United States, at least for now. It is approved in China for peripheral T-cell lymphoma (PTCL) and HER2-negative breast cancer and in Japan for PTCL and adult T-cell leukemia/lymphoma.
Dr. Zhao said that tucidinostat was also conditionally approved for DLBCL in China recently, based on the strength of the DEB results.
Study discussant Peter Riedell, MD, a hematologist at the University of Chicago, Illinois, was cautious on several points.
First, there’s been no overall survival benefit in the trial, but follow-up so far has been short, at a median of 13.9 months, and Dr. Zhao reported interim, not final, results.
Dr. Riedell also noted that there were more grade 3 or worse adverse events, particularly hematologic side effects, hypokalemia, and pneumonia, with tucidinostat add-on in DEB.
Other outstanding questions include the applicability of the findings to non-Chinese patients and the effect of adding tucidinostat to another common DLCBL chemotherapy regimen, pola-R-CHP, which is being increasingly used in the United States for higher-risk disease, which includes double-expressers of the MYC and BCLC oncogenes.
DEB equally randomized 423 patients at 40 centers in China to either six cycles of R-CHOP with tucidinostat 20 μg twice weekly or R-CHOP with placebo. Complete responders went on to either tucidinostat or placebo maintenance treatment for up to 24 weeks. Subjects had an International Prognostic Index score of at least 2.
Out of a total of 152 EFS events, 64 (30.3%) were in the tucidinostat group and 88 (41.5%) were in the placebo group; 24-month EFS was 58.9% with tucidinostat and 46.2% with R-CHOP alone (hazard ratio, 0.68; P = .018).
Meanwhile, the complete response rate with tucidinostat was 73.0% versus 61.8% (P = .014).
Although there were more higher-grade adverse events in the experimental arm, most patients were able to tolerate and complete the planned treatment cycles.
The study was funded by tucidinostat maker Chipscreen Biosciences. Dr. Zhao reported no disclosures. Dr. Riedell disclosed ties with numerous companies, including BeiGene (a partner of Chipscreen) and Novartis.
At the annual meeting of the American Society of Clinical Oncology (ASCO), they announced that combining the histone deacetylase inhibitor tucidinostat with standard R-CHOP chemotherapy in previously untreated “double-expresser” patients improved complete response and event-free survival (EFS) rates over R-CHOP alone.
The trial, dubbed DEB, is the first phase 3 investigation to confirm the benefit of combination treatment with an epigenetic agent for such patients, lead investigator and study presenter Weili Zhao, MD, PhD, a hematologist at the Shanghai Institute of Hematology, told her audience.
“Tucidinostat plus R-CHOP could be a new frontline treatment option in this patient population,” Dr. Zhao said.
However, the agent is not available in the United States, at least for now. It is approved in China for peripheral T-cell lymphoma (PTCL) and HER2-negative breast cancer and in Japan for PTCL and adult T-cell leukemia/lymphoma.
Dr. Zhao said that tucidinostat was also conditionally approved for DLBCL in China recently, based on the strength of the DEB results.
Study discussant Peter Riedell, MD, a hematologist at the University of Chicago, Illinois, was cautious on several points.
First, there’s been no overall survival benefit in the trial, but follow-up so far has been short, at a median of 13.9 months, and Dr. Zhao reported interim, not final, results.
Dr. Riedell also noted that there were more grade 3 or worse adverse events, particularly hematologic side effects, hypokalemia, and pneumonia, with tucidinostat add-on in DEB.
Other outstanding questions include the applicability of the findings to non-Chinese patients and the effect of adding tucidinostat to another common DLCBL chemotherapy regimen, pola-R-CHP, which is being increasingly used in the United States for higher-risk disease, which includes double-expressers of the MYC and BCLC oncogenes.
DEB equally randomized 423 patients at 40 centers in China to either six cycles of R-CHOP with tucidinostat 20 μg twice weekly or R-CHOP with placebo. Complete responders went on to either tucidinostat or placebo maintenance treatment for up to 24 weeks. Subjects had an International Prognostic Index score of at least 2.
Out of a total of 152 EFS events, 64 (30.3%) were in the tucidinostat group and 88 (41.5%) were in the placebo group; 24-month EFS was 58.9% with tucidinostat and 46.2% with R-CHOP alone (hazard ratio, 0.68; P = .018).
Meanwhile, the complete response rate with tucidinostat was 73.0% versus 61.8% (P = .014).
Although there were more higher-grade adverse events in the experimental arm, most patients were able to tolerate and complete the planned treatment cycles.
The study was funded by tucidinostat maker Chipscreen Biosciences. Dr. Zhao reported no disclosures. Dr. Riedell disclosed ties with numerous companies, including BeiGene (a partner of Chipscreen) and Novartis.
At the annual meeting of the American Society of Clinical Oncology (ASCO), they announced that combining the histone deacetylase inhibitor tucidinostat with standard R-CHOP chemotherapy in previously untreated “double-expresser” patients improved complete response and event-free survival (EFS) rates over R-CHOP alone.
The trial, dubbed DEB, is the first phase 3 investigation to confirm the benefit of combination treatment with an epigenetic agent for such patients, lead investigator and study presenter Weili Zhao, MD, PhD, a hematologist at the Shanghai Institute of Hematology, told her audience.
“Tucidinostat plus R-CHOP could be a new frontline treatment option in this patient population,” Dr. Zhao said.
However, the agent is not available in the United States, at least for now. It is approved in China for peripheral T-cell lymphoma (PTCL) and HER2-negative breast cancer and in Japan for PTCL and adult T-cell leukemia/lymphoma.
Dr. Zhao said that tucidinostat was also conditionally approved for DLBCL in China recently, based on the strength of the DEB results.
Study discussant Peter Riedell, MD, a hematologist at the University of Chicago, Illinois, was cautious on several points.
First, there’s been no overall survival benefit in the trial, but follow-up so far has been short, at a median of 13.9 months, and Dr. Zhao reported interim, not final, results.
Dr. Riedell also noted that there were more grade 3 or worse adverse events, particularly hematologic side effects, hypokalemia, and pneumonia, with tucidinostat add-on in DEB.
Other outstanding questions include the applicability of the findings to non-Chinese patients and the effect of adding tucidinostat to another common DLCBL chemotherapy regimen, pola-R-CHP, which is being increasingly used in the United States for higher-risk disease, which includes double-expressers of the MYC and BCLC oncogenes.
DEB equally randomized 423 patients at 40 centers in China to either six cycles of R-CHOP with tucidinostat 20 μg twice weekly or R-CHOP with placebo. Complete responders went on to either tucidinostat or placebo maintenance treatment for up to 24 weeks. Subjects had an International Prognostic Index score of at least 2.
Out of a total of 152 EFS events, 64 (30.3%) were in the tucidinostat group and 88 (41.5%) were in the placebo group; 24-month EFS was 58.9% with tucidinostat and 46.2% with R-CHOP alone (hazard ratio, 0.68; P = .018).
Meanwhile, the complete response rate with tucidinostat was 73.0% versus 61.8% (P = .014).
Although there were more higher-grade adverse events in the experimental arm, most patients were able to tolerate and complete the planned treatment cycles.
The study was funded by tucidinostat maker Chipscreen Biosciences. Dr. Zhao reported no disclosures. Dr. Riedell disclosed ties with numerous companies, including BeiGene (a partner of Chipscreen) and Novartis.
FROM ASCO 2024
ASCO 2024: An Expert’s Top Hematology Highlights
Research presented at the annual meeting of the American Society of Clinical Oncology (ASCO) has the potential to change practice — and assumptions — about acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and blood cancer as a whole, according to the chief science officer of the American Cancer Society.
In an interview following the conference, Arif H. Kamal, MD, MBA, MHS, who practices hematology-oncology at Duke University, Durham, North Carolina, recapped several landmark studies and discussed their lessons for clinicians.
Question: You’ve highlighted a randomized, multisite clinical trialled by a researcher from Massachusetts General Hospital in Boston. The researchers enrolled 115 adult patients with AML or high-risk myelodysplastic syndrome (MDS) who were receiving non–intensive care to usual care or regular meetings with palliative care clinicians (monthly as outpatients and at least twice weekly as inpatients). Among those who died (61.7%), those in the intervention group had their end-of-life preferences documented much earlier (41 days before death vs. 1.5 days, P < .001). They were also more likely to have documented end-of-life care preferences (96.5% vs. 68.4%, P < .001) and less likely to have been hospitalized within the last month of life (70.6% vs. 91.9%, P = .031). Why did this study strike you as especially important?
Dr. Kamal: A few studies have now shown better outcomes in hematology after the use of early palliative care. This has been shown not only in transplant patients but also in non-transplant patients with hematologic malignancies. As a result, you’re seeing a shift toward regular integration of palliative care.
The historical concern has been that palliative care takes the foot off the gas pedal. Another way to look at it is that palliative care helps keep the foot on the gas pedal.
Q: Should the focus be on all hematologic cancer patients or just on those who are more severe cases or whose illness is terminal?
Dr. Kamal: The focus is on patients with acute progressive leukemias rather than those with indolent, long-standing lymphomas. This a reflection of severity and complexity: In leukemia, you can be someone really sick all of a sudden and require intensive treatment.
Q: What’s new about this kind of research?
Dr. Kamal: We’re learning how palliative care is valuable in all cancers, but particularly in blood cancers, where it has historically not been studied. The groundbreaking studies in palliative care over the last 20 years have largely been in solid tumors such as lung cancers and colorectal cancers.
Q: What is unique about the patient experience in hematologic cancers compared to solid tumor cancers?
Dr. Kamal: Blood cancers are a relatively new place to integrate palliative care, but what we’re finding is that it may be even more needed than in solid tumors in terms of improving outcomes.
In pancreatic cancer, you may not know if something is going to work, but it is going to take you months to figure it out. In leukemia, there can be a lot of dynamism: You’re going to find out in a matter of days. You have to be able to pivot really quickly to the next thing, go to transplant very quickly and urgently, or make a decision to pursue supportive care.
This really compresses the normal issues like uncertainty and emotional anxiety that a pancreatic cancer patient may process over a year. Leukemic patients may need to process that over 2, 3, or 4 weeks. Palliative care can be there to help the patient to process options.
Q: You also highlighted the industry-funded phase 3 ASC4FIRST study into asciminib (Scemblix) in newly diagnosed patients with CML. The trial was led by a researcher from the South Australian Health and Medical Research Institute and the University of Adelaide, Australia. Asciminib, a STAMP inhibitor, is FDA-approved for certain CML indications. In an intention-to-treat analysis, the new study finds better major molecular response at 48 weeks for the drug vs. investigator-selected tyrosine kinase inhibitors (67.7% vs. 49.0%, P < .001). What do these findings tell you?
Dr. Kamal: CML has been a disease where you had Gleevec — imatinib — and additional options that were all in the second-line or third-line setting after failure. Now, you’re seeing durable responses across the board: an expansion of options and potentially new options in the first-line setting.
[Editor’s note: For more about asciminib, check commentaries from physicians who spoke to Medscape and ASCO Daily News.]
Q: What makes this drug unique?
Dr. Kamal: CML was the leader in helping us to understand that if you identify a mutation, you can create a medication against it. Now, what we’re finding out is that there are other ways to work around mutations. Asciminib is not affected by the most common mutations that lend to drug resistance in the classic drugs that target BCR-ABL cells like imatinib.
Q: Finally, you spotlighted a retrospective study led by researchers at Case Western Reserve University that explored rates of obesity-related cancers — including multiple myeloma — in patients with BMI ≥ 35 who took glucagon-like protein-1 receptor agonists (GLP-1 RAs) or underwent bariatric surgery. Both strategies were linked to lower risk of the cancers vs. no intervention (GLP-1 RAs, hazard ratio [HR] = 0.61; 95% CI 0.46-0.81, and bariatric surgery, HR = 0.78; 95% CI 0.67-0.91). What did you learn from this research?
Dr. Kamal: When we think about risk reduction for cancer, we generally think about hormone-driven cancers. Blood cancers are not typically hormone-driven.
This study is hinting at that idea that healthy weight across the board will reduce your cancer risk even in blood cancers, and pharmacologic interventions to reduce your weight may also reduce that cancer risk.
Q: So weight-loss drugs such as Ozempic could potentially lower the risk of hematologic cancer?
Dr. Kamal: We’re going to need more data on this, and you wouldn’t take it for that reason. But there may be a story here that says get to a healthy weight — it doesn’t matter how you do it — and your risk of all cancers goes down.
Dr. Kamal has no disclosures to report.
Research presented at the annual meeting of the American Society of Clinical Oncology (ASCO) has the potential to change practice — and assumptions — about acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and blood cancer as a whole, according to the chief science officer of the American Cancer Society.
In an interview following the conference, Arif H. Kamal, MD, MBA, MHS, who practices hematology-oncology at Duke University, Durham, North Carolina, recapped several landmark studies and discussed their lessons for clinicians.
Question: You’ve highlighted a randomized, multisite clinical trialled by a researcher from Massachusetts General Hospital in Boston. The researchers enrolled 115 adult patients with AML or high-risk myelodysplastic syndrome (MDS) who were receiving non–intensive care to usual care or regular meetings with palliative care clinicians (monthly as outpatients and at least twice weekly as inpatients). Among those who died (61.7%), those in the intervention group had their end-of-life preferences documented much earlier (41 days before death vs. 1.5 days, P < .001). They were also more likely to have documented end-of-life care preferences (96.5% vs. 68.4%, P < .001) and less likely to have been hospitalized within the last month of life (70.6% vs. 91.9%, P = .031). Why did this study strike you as especially important?
Dr. Kamal: A few studies have now shown better outcomes in hematology after the use of early palliative care. This has been shown not only in transplant patients but also in non-transplant patients with hematologic malignancies. As a result, you’re seeing a shift toward regular integration of palliative care.
The historical concern has been that palliative care takes the foot off the gas pedal. Another way to look at it is that palliative care helps keep the foot on the gas pedal.
Q: Should the focus be on all hematologic cancer patients or just on those who are more severe cases or whose illness is terminal?
Dr. Kamal: The focus is on patients with acute progressive leukemias rather than those with indolent, long-standing lymphomas. This a reflection of severity and complexity: In leukemia, you can be someone really sick all of a sudden and require intensive treatment.
Q: What’s new about this kind of research?
Dr. Kamal: We’re learning how palliative care is valuable in all cancers, but particularly in blood cancers, where it has historically not been studied. The groundbreaking studies in palliative care over the last 20 years have largely been in solid tumors such as lung cancers and colorectal cancers.
Q: What is unique about the patient experience in hematologic cancers compared to solid tumor cancers?
Dr. Kamal: Blood cancers are a relatively new place to integrate palliative care, but what we’re finding is that it may be even more needed than in solid tumors in terms of improving outcomes.
In pancreatic cancer, you may not know if something is going to work, but it is going to take you months to figure it out. In leukemia, there can be a lot of dynamism: You’re going to find out in a matter of days. You have to be able to pivot really quickly to the next thing, go to transplant very quickly and urgently, or make a decision to pursue supportive care.
This really compresses the normal issues like uncertainty and emotional anxiety that a pancreatic cancer patient may process over a year. Leukemic patients may need to process that over 2, 3, or 4 weeks. Palliative care can be there to help the patient to process options.
Q: You also highlighted the industry-funded phase 3 ASC4FIRST study into asciminib (Scemblix) in newly diagnosed patients with CML. The trial was led by a researcher from the South Australian Health and Medical Research Institute and the University of Adelaide, Australia. Asciminib, a STAMP inhibitor, is FDA-approved for certain CML indications. In an intention-to-treat analysis, the new study finds better major molecular response at 48 weeks for the drug vs. investigator-selected tyrosine kinase inhibitors (67.7% vs. 49.0%, P < .001). What do these findings tell you?
Dr. Kamal: CML has been a disease where you had Gleevec — imatinib — and additional options that were all in the second-line or third-line setting after failure. Now, you’re seeing durable responses across the board: an expansion of options and potentially new options in the first-line setting.
[Editor’s note: For more about asciminib, check commentaries from physicians who spoke to Medscape and ASCO Daily News.]
Q: What makes this drug unique?
Dr. Kamal: CML was the leader in helping us to understand that if you identify a mutation, you can create a medication against it. Now, what we’re finding out is that there are other ways to work around mutations. Asciminib is not affected by the most common mutations that lend to drug resistance in the classic drugs that target BCR-ABL cells like imatinib.
Q: Finally, you spotlighted a retrospective study led by researchers at Case Western Reserve University that explored rates of obesity-related cancers — including multiple myeloma — in patients with BMI ≥ 35 who took glucagon-like protein-1 receptor agonists (GLP-1 RAs) or underwent bariatric surgery. Both strategies were linked to lower risk of the cancers vs. no intervention (GLP-1 RAs, hazard ratio [HR] = 0.61; 95% CI 0.46-0.81, and bariatric surgery, HR = 0.78; 95% CI 0.67-0.91). What did you learn from this research?
Dr. Kamal: When we think about risk reduction for cancer, we generally think about hormone-driven cancers. Blood cancers are not typically hormone-driven.
This study is hinting at that idea that healthy weight across the board will reduce your cancer risk even in blood cancers, and pharmacologic interventions to reduce your weight may also reduce that cancer risk.
Q: So weight-loss drugs such as Ozempic could potentially lower the risk of hematologic cancer?
Dr. Kamal: We’re going to need more data on this, and you wouldn’t take it for that reason. But there may be a story here that says get to a healthy weight — it doesn’t matter how you do it — and your risk of all cancers goes down.
Dr. Kamal has no disclosures to report.
Research presented at the annual meeting of the American Society of Clinical Oncology (ASCO) has the potential to change practice — and assumptions — about acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and blood cancer as a whole, according to the chief science officer of the American Cancer Society.
In an interview following the conference, Arif H. Kamal, MD, MBA, MHS, who practices hematology-oncology at Duke University, Durham, North Carolina, recapped several landmark studies and discussed their lessons for clinicians.
Question: You’ve highlighted a randomized, multisite clinical trialled by a researcher from Massachusetts General Hospital in Boston. The researchers enrolled 115 adult patients with AML or high-risk myelodysplastic syndrome (MDS) who were receiving non–intensive care to usual care or regular meetings with palliative care clinicians (monthly as outpatients and at least twice weekly as inpatients). Among those who died (61.7%), those in the intervention group had their end-of-life preferences documented much earlier (41 days before death vs. 1.5 days, P < .001). They were also more likely to have documented end-of-life care preferences (96.5% vs. 68.4%, P < .001) and less likely to have been hospitalized within the last month of life (70.6% vs. 91.9%, P = .031). Why did this study strike you as especially important?
Dr. Kamal: A few studies have now shown better outcomes in hematology after the use of early palliative care. This has been shown not only in transplant patients but also in non-transplant patients with hematologic malignancies. As a result, you’re seeing a shift toward regular integration of palliative care.
The historical concern has been that palliative care takes the foot off the gas pedal. Another way to look at it is that palliative care helps keep the foot on the gas pedal.
Q: Should the focus be on all hematologic cancer patients or just on those who are more severe cases or whose illness is terminal?
Dr. Kamal: The focus is on patients with acute progressive leukemias rather than those with indolent, long-standing lymphomas. This a reflection of severity and complexity: In leukemia, you can be someone really sick all of a sudden and require intensive treatment.
Q: What’s new about this kind of research?
Dr. Kamal: We’re learning how palliative care is valuable in all cancers, but particularly in blood cancers, where it has historically not been studied. The groundbreaking studies in palliative care over the last 20 years have largely been in solid tumors such as lung cancers and colorectal cancers.
Q: What is unique about the patient experience in hematologic cancers compared to solid tumor cancers?
Dr. Kamal: Blood cancers are a relatively new place to integrate palliative care, but what we’re finding is that it may be even more needed than in solid tumors in terms of improving outcomes.
In pancreatic cancer, you may not know if something is going to work, but it is going to take you months to figure it out. In leukemia, there can be a lot of dynamism: You’re going to find out in a matter of days. You have to be able to pivot really quickly to the next thing, go to transplant very quickly and urgently, or make a decision to pursue supportive care.
This really compresses the normal issues like uncertainty and emotional anxiety that a pancreatic cancer patient may process over a year. Leukemic patients may need to process that over 2, 3, or 4 weeks. Palliative care can be there to help the patient to process options.
Q: You also highlighted the industry-funded phase 3 ASC4FIRST study into asciminib (Scemblix) in newly diagnosed patients with CML. The trial was led by a researcher from the South Australian Health and Medical Research Institute and the University of Adelaide, Australia. Asciminib, a STAMP inhibitor, is FDA-approved for certain CML indications. In an intention-to-treat analysis, the new study finds better major molecular response at 48 weeks for the drug vs. investigator-selected tyrosine kinase inhibitors (67.7% vs. 49.0%, P < .001). What do these findings tell you?
Dr. Kamal: CML has been a disease where you had Gleevec — imatinib — and additional options that were all in the second-line or third-line setting after failure. Now, you’re seeing durable responses across the board: an expansion of options and potentially new options in the first-line setting.
[Editor’s note: For more about asciminib, check commentaries from physicians who spoke to Medscape and ASCO Daily News.]
Q: What makes this drug unique?
Dr. Kamal: CML was the leader in helping us to understand that if you identify a mutation, you can create a medication against it. Now, what we’re finding out is that there are other ways to work around mutations. Asciminib is not affected by the most common mutations that lend to drug resistance in the classic drugs that target BCR-ABL cells like imatinib.
Q: Finally, you spotlighted a retrospective study led by researchers at Case Western Reserve University that explored rates of obesity-related cancers — including multiple myeloma — in patients with BMI ≥ 35 who took glucagon-like protein-1 receptor agonists (GLP-1 RAs) or underwent bariatric surgery. Both strategies were linked to lower risk of the cancers vs. no intervention (GLP-1 RAs, hazard ratio [HR] = 0.61; 95% CI 0.46-0.81, and bariatric surgery, HR = 0.78; 95% CI 0.67-0.91). What did you learn from this research?
Dr. Kamal: When we think about risk reduction for cancer, we generally think about hormone-driven cancers. Blood cancers are not typically hormone-driven.
This study is hinting at that idea that healthy weight across the board will reduce your cancer risk even in blood cancers, and pharmacologic interventions to reduce your weight may also reduce that cancer risk.
Q: So weight-loss drugs such as Ozempic could potentially lower the risk of hematologic cancer?
Dr. Kamal: We’re going to need more data on this, and you wouldn’t take it for that reason. But there may be a story here that says get to a healthy weight — it doesn’t matter how you do it — and your risk of all cancers goes down.
Dr. Kamal has no disclosures to report.
Significant Benefit with Liver Transplantation in ACLF: CHANCE Study
MILAN —
To date, the results show that 3-month post–liver transplantation mortality rates in patients with ACLF grades 2 and 3 were only 9%, which is not significantly different than that of patients with decompensated cirrhosis, with a mortality of 7%.
“Treatment of ACLF is an unmet medical need,” said Rajiv Jalan, MD, professor of hepatology and honorary consultant in hepatology, University College London Hospitals, London, England.
These findings highlight “the inadequacy of current transplant allocation criteria for patients with ACLF 2 and 3,” which is leading to excess mortality on the wait list, he added.
Dr. Jalan presented the interim results at the European Association for the Study of the Liver (EASL) Congress 2024.
If confirmed in the full analysis, these results argue strongly for increasing access to liver transplantation and changing organ allocation for patients with ACLF 2 and 3, he said.
Organ Allocation Principally Based on MELD Scores
ACLF, which occurs in patients with cirrhosis and acutely decompensated liver disease admitted to hospital, carries a high, short-term risk for death. The risk for 28-day mortality for ACLF 2 and 3 is between 30% and 90% and characterized by multiorgan failure.
As seen in previous data, even patients on the transplant waiting list with a low Model for End-Stage Liver Disease (MELD) score have a risk for death between 20% and 30% if they are ACLF 2 and 3, Dr. Jalan said.
MELD scores do not consider the risk for death because of failure of extrahepatic organs, he added. Existing worldwide organ allocation systems are principally based on patient MELD scores or its variations; therefore, many patients die on the waiting list.
With this in mind, the CHANCE study aimed to compare 1-year graft and patient survival rates after liver transplantation in patients with ACLF 2 or 3 at the time of transplantation with patients with decompensated cirrhosis without ACLF and transplantation-free survival of patients with ACLF 2 or 3 not listed for liver transplantation.
The multicenter observational study comprised 66 liver transplant centers from 21 countries and over 500 investigators. Recruitment was closed after 1000 patients were enrolled.
Patients were aged 54-56 years, 31%-35% were women, 48%-70% had alcohol-related cirrhosis, and 19%-24% had metabolic dysfunction–associated steatohepatitis. MELD scores ranged from 25 to 36.
For the interim results, Dr. Jalan and colleagues assessed mortality on the waiting list and 3-month post–liver transplantation mortality.
Secondary endpoints included quality of life and cost of care.
Of the 823 patients in the study, they were grouped as follows: 376 patients with ACLF 2 or 3 listed for liver transplantation (group 1), 313 patients with ACLF 0 or 1 and MELD score > 20 listed for liver transplantation (group 2), and 134 patients with ACLF 2 or 3 not listed for liver transplantation (group 3).
Overall, patients in group 1 had very severe ACLF; 177 patients with ACLF 3 had three or more organ failures, Dr. Jalan noted.
“It is interesting to note that, in group 3, there is an overrepresentation of alcohol-related cirrhosis, and this might reflect a bias in transplantation,” he added.
Dr. Jalan highlighted geographical points of difference. Patients in the United States were younger, which could be important when interpreting results of post-transplantation outcomes. In Asia, the majority of the patients were men and primarily from India, where living donor transplantation is commonly performed. In Latin America, only 33% of study participants had alcohol-related cirrhosis in contrast to 67% of those in North America.
However, “comorbidities across the world were similar, and MELD scores were also similar,” Dr. Jalan said.
Death or Delisting
Between listing and transplantation, 28% of patients in group 1 either died or were delisted, compared with 16% of those in group 2. In group 3, 85% of patients who were not listed for transplantation in the first place died.
Similar to what has been seen in other studies, nearly 50% of patients with ACLF 3 but a MELD score < 25 on the wait list died or were delisted, Dr. Jalan pointed out, suggesting that these patients are disadvantaged under the current system of waiting list priority.
Geographically, deaths on the wait list were significantly higher in Latin America at 40% than in North America, Europe, and Asia at 20%, 18%, and 13%, respectively.
“This is likely due to low donation rates in Latin America,” Dr. Jalan said.
Turning to 3-month post-transplantation mortality, the rates in groups 1 and 2 were 9% and 7%, respectively.
“This demonstrates very nicely the clear benefit of transplant,” Dr. Jalan said. “The risk of death post transplant, even with ACLF 2 or 3, is not significantly different to those patients with decompensated cirrhosis.”
There was a slightly higher risk for death in patients with ACLF 3 than in those with ACLF 2 at 14% vs 7%, but “the risk of death in these patients if they don’t have transportation is 70%-80%,” he said.
Looking at 3-month post-transplantation mortality by continent, Dr. Jalan highlighted that Latin America showed 16% risk, compared with Asia, Europe, and North America that showed 12%, 7%, and 3% risk, respectively.
“This is probably multifactorial and likely to be influenced by time on the waiting list, quality of organs available, and patient demographics, among other factors,” Dr. Jalan said. When very sick people undergo transplantation, “there is a higher risk of death.”
The patients in this study have waited a long time, “which worsens their situation,” said Dr. Jalan, reinforcing his argument for changing the international organ allocation system to allow earlier access for these patients.
‘The Landscape of Organ Allocation Is Extremely Complex’
Comoderator Ana Lleo, MD, PhD, full professor of internal medicine and hepatology, Humanitas University, Milan, Italy, commented that “the number of patients included in this international study is significant,” and that the issue of mortality on the wait list is of great clinical interest.
“The landscape of organ allocation is extremely complex,” she added.
The system for liver transplantation considers a large number of clinical conditions with very diverse benefit profiles, she explained.
“While we would like to offer liver transplantation for all patients with any range of benefit, the current donations are not sufficient to cover the request,” Dr. Lleo said. “Therefore, prioritization remains key.”
The findings do illustrate the inadequacy of current transplantation allocation criteria for patients with ACLF 2 and 3, said Debbie Shawcross, MBBS, PhD, professor of hepatology and chronic liver failure, King’s College Hospital, London, England, who is also serving as vice-secretary of the EASL Governing Board.
However, “this must be balanced by the recognition that the global donor pool of organs available is a finite resource,” she said, echoing Dr. Lleo’s comments.
This calls for wider ethical discussions to avoid disadvantaging more stable, often younger patients with cirrhosis who are listed for transplantation, she added.
Dr. Jalan declared he is the inventor of Ornithine Phenylacetate, licensed by UCL to Mallinckrodt Pharma; a speaker and grant reviewer for Grifols Research Collaboration: Yaqrit; and the founder of Yaqrit, Hepyx, CyberLiver, and Gigabiome. Dr. Lleo declared that she does not have any conflicts relevant to this work but received lecture fees from Gilead, Advanz Pharma, Alfasigma, GSK, Incyte, Gore, AstraZeneca, and Ipsen and consulted for Advanz Pharma, AstraZeneca, Ipsen, GSK, and Dr Falk. Dr. Shawcross declared advisory board/consultancy for EnteroBiotix, Norgine, Satellite Bio, and MRN Health.
A version of this article first appeared on Medscape.com.
MILAN —
To date, the results show that 3-month post–liver transplantation mortality rates in patients with ACLF grades 2 and 3 were only 9%, which is not significantly different than that of patients with decompensated cirrhosis, with a mortality of 7%.
“Treatment of ACLF is an unmet medical need,” said Rajiv Jalan, MD, professor of hepatology and honorary consultant in hepatology, University College London Hospitals, London, England.
These findings highlight “the inadequacy of current transplant allocation criteria for patients with ACLF 2 and 3,” which is leading to excess mortality on the wait list, he added.
Dr. Jalan presented the interim results at the European Association for the Study of the Liver (EASL) Congress 2024.
If confirmed in the full analysis, these results argue strongly for increasing access to liver transplantation and changing organ allocation for patients with ACLF 2 and 3, he said.
Organ Allocation Principally Based on MELD Scores
ACLF, which occurs in patients with cirrhosis and acutely decompensated liver disease admitted to hospital, carries a high, short-term risk for death. The risk for 28-day mortality for ACLF 2 and 3 is between 30% and 90% and characterized by multiorgan failure.
As seen in previous data, even patients on the transplant waiting list with a low Model for End-Stage Liver Disease (MELD) score have a risk for death between 20% and 30% if they are ACLF 2 and 3, Dr. Jalan said.
MELD scores do not consider the risk for death because of failure of extrahepatic organs, he added. Existing worldwide organ allocation systems are principally based on patient MELD scores or its variations; therefore, many patients die on the waiting list.
With this in mind, the CHANCE study aimed to compare 1-year graft and patient survival rates after liver transplantation in patients with ACLF 2 or 3 at the time of transplantation with patients with decompensated cirrhosis without ACLF and transplantation-free survival of patients with ACLF 2 or 3 not listed for liver transplantation.
The multicenter observational study comprised 66 liver transplant centers from 21 countries and over 500 investigators. Recruitment was closed after 1000 patients were enrolled.
Patients were aged 54-56 years, 31%-35% were women, 48%-70% had alcohol-related cirrhosis, and 19%-24% had metabolic dysfunction–associated steatohepatitis. MELD scores ranged from 25 to 36.
For the interim results, Dr. Jalan and colleagues assessed mortality on the waiting list and 3-month post–liver transplantation mortality.
Secondary endpoints included quality of life and cost of care.
Of the 823 patients in the study, they were grouped as follows: 376 patients with ACLF 2 or 3 listed for liver transplantation (group 1), 313 patients with ACLF 0 or 1 and MELD score > 20 listed for liver transplantation (group 2), and 134 patients with ACLF 2 or 3 not listed for liver transplantation (group 3).
Overall, patients in group 1 had very severe ACLF; 177 patients with ACLF 3 had three or more organ failures, Dr. Jalan noted.
“It is interesting to note that, in group 3, there is an overrepresentation of alcohol-related cirrhosis, and this might reflect a bias in transplantation,” he added.
Dr. Jalan highlighted geographical points of difference. Patients in the United States were younger, which could be important when interpreting results of post-transplantation outcomes. In Asia, the majority of the patients were men and primarily from India, where living donor transplantation is commonly performed. In Latin America, only 33% of study participants had alcohol-related cirrhosis in contrast to 67% of those in North America.
However, “comorbidities across the world were similar, and MELD scores were also similar,” Dr. Jalan said.
Death or Delisting
Between listing and transplantation, 28% of patients in group 1 either died or were delisted, compared with 16% of those in group 2. In group 3, 85% of patients who were not listed for transplantation in the first place died.
Similar to what has been seen in other studies, nearly 50% of patients with ACLF 3 but a MELD score < 25 on the wait list died or were delisted, Dr. Jalan pointed out, suggesting that these patients are disadvantaged under the current system of waiting list priority.
Geographically, deaths on the wait list were significantly higher in Latin America at 40% than in North America, Europe, and Asia at 20%, 18%, and 13%, respectively.
“This is likely due to low donation rates in Latin America,” Dr. Jalan said.
Turning to 3-month post-transplantation mortality, the rates in groups 1 and 2 were 9% and 7%, respectively.
“This demonstrates very nicely the clear benefit of transplant,” Dr. Jalan said. “The risk of death post transplant, even with ACLF 2 or 3, is not significantly different to those patients with decompensated cirrhosis.”
There was a slightly higher risk for death in patients with ACLF 3 than in those with ACLF 2 at 14% vs 7%, but “the risk of death in these patients if they don’t have transportation is 70%-80%,” he said.
Looking at 3-month post-transplantation mortality by continent, Dr. Jalan highlighted that Latin America showed 16% risk, compared with Asia, Europe, and North America that showed 12%, 7%, and 3% risk, respectively.
“This is probably multifactorial and likely to be influenced by time on the waiting list, quality of organs available, and patient demographics, among other factors,” Dr. Jalan said. When very sick people undergo transplantation, “there is a higher risk of death.”
The patients in this study have waited a long time, “which worsens their situation,” said Dr. Jalan, reinforcing his argument for changing the international organ allocation system to allow earlier access for these patients.
‘The Landscape of Organ Allocation Is Extremely Complex’
Comoderator Ana Lleo, MD, PhD, full professor of internal medicine and hepatology, Humanitas University, Milan, Italy, commented that “the number of patients included in this international study is significant,” and that the issue of mortality on the wait list is of great clinical interest.
“The landscape of organ allocation is extremely complex,” she added.
The system for liver transplantation considers a large number of clinical conditions with very diverse benefit profiles, she explained.
“While we would like to offer liver transplantation for all patients with any range of benefit, the current donations are not sufficient to cover the request,” Dr. Lleo said. “Therefore, prioritization remains key.”
The findings do illustrate the inadequacy of current transplantation allocation criteria for patients with ACLF 2 and 3, said Debbie Shawcross, MBBS, PhD, professor of hepatology and chronic liver failure, King’s College Hospital, London, England, who is also serving as vice-secretary of the EASL Governing Board.
However, “this must be balanced by the recognition that the global donor pool of organs available is a finite resource,” she said, echoing Dr. Lleo’s comments.
This calls for wider ethical discussions to avoid disadvantaging more stable, often younger patients with cirrhosis who are listed for transplantation, she added.
Dr. Jalan declared he is the inventor of Ornithine Phenylacetate, licensed by UCL to Mallinckrodt Pharma; a speaker and grant reviewer for Grifols Research Collaboration: Yaqrit; and the founder of Yaqrit, Hepyx, CyberLiver, and Gigabiome. Dr. Lleo declared that she does not have any conflicts relevant to this work but received lecture fees from Gilead, Advanz Pharma, Alfasigma, GSK, Incyte, Gore, AstraZeneca, and Ipsen and consulted for Advanz Pharma, AstraZeneca, Ipsen, GSK, and Dr Falk. Dr. Shawcross declared advisory board/consultancy for EnteroBiotix, Norgine, Satellite Bio, and MRN Health.
A version of this article first appeared on Medscape.com.
MILAN —
To date, the results show that 3-month post–liver transplantation mortality rates in patients with ACLF grades 2 and 3 were only 9%, which is not significantly different than that of patients with decompensated cirrhosis, with a mortality of 7%.
“Treatment of ACLF is an unmet medical need,” said Rajiv Jalan, MD, professor of hepatology and honorary consultant in hepatology, University College London Hospitals, London, England.
These findings highlight “the inadequacy of current transplant allocation criteria for patients with ACLF 2 and 3,” which is leading to excess mortality on the wait list, he added.
Dr. Jalan presented the interim results at the European Association for the Study of the Liver (EASL) Congress 2024.
If confirmed in the full analysis, these results argue strongly for increasing access to liver transplantation and changing organ allocation for patients with ACLF 2 and 3, he said.
Organ Allocation Principally Based on MELD Scores
ACLF, which occurs in patients with cirrhosis and acutely decompensated liver disease admitted to hospital, carries a high, short-term risk for death. The risk for 28-day mortality for ACLF 2 and 3 is between 30% and 90% and characterized by multiorgan failure.
As seen in previous data, even patients on the transplant waiting list with a low Model for End-Stage Liver Disease (MELD) score have a risk for death between 20% and 30% if they are ACLF 2 and 3, Dr. Jalan said.
MELD scores do not consider the risk for death because of failure of extrahepatic organs, he added. Existing worldwide organ allocation systems are principally based on patient MELD scores or its variations; therefore, many patients die on the waiting list.
With this in mind, the CHANCE study aimed to compare 1-year graft and patient survival rates after liver transplantation in patients with ACLF 2 or 3 at the time of transplantation with patients with decompensated cirrhosis without ACLF and transplantation-free survival of patients with ACLF 2 or 3 not listed for liver transplantation.
The multicenter observational study comprised 66 liver transplant centers from 21 countries and over 500 investigators. Recruitment was closed after 1000 patients were enrolled.
Patients were aged 54-56 years, 31%-35% were women, 48%-70% had alcohol-related cirrhosis, and 19%-24% had metabolic dysfunction–associated steatohepatitis. MELD scores ranged from 25 to 36.
For the interim results, Dr. Jalan and colleagues assessed mortality on the waiting list and 3-month post–liver transplantation mortality.
Secondary endpoints included quality of life and cost of care.
Of the 823 patients in the study, they were grouped as follows: 376 patients with ACLF 2 or 3 listed for liver transplantation (group 1), 313 patients with ACLF 0 or 1 and MELD score > 20 listed for liver transplantation (group 2), and 134 patients with ACLF 2 or 3 not listed for liver transplantation (group 3).
Overall, patients in group 1 had very severe ACLF; 177 patients with ACLF 3 had three or more organ failures, Dr. Jalan noted.
“It is interesting to note that, in group 3, there is an overrepresentation of alcohol-related cirrhosis, and this might reflect a bias in transplantation,” he added.
Dr. Jalan highlighted geographical points of difference. Patients in the United States were younger, which could be important when interpreting results of post-transplantation outcomes. In Asia, the majority of the patients were men and primarily from India, where living donor transplantation is commonly performed. In Latin America, only 33% of study participants had alcohol-related cirrhosis in contrast to 67% of those in North America.
However, “comorbidities across the world were similar, and MELD scores were also similar,” Dr. Jalan said.
Death or Delisting
Between listing and transplantation, 28% of patients in group 1 either died or were delisted, compared with 16% of those in group 2. In group 3, 85% of patients who were not listed for transplantation in the first place died.
Similar to what has been seen in other studies, nearly 50% of patients with ACLF 3 but a MELD score < 25 on the wait list died or were delisted, Dr. Jalan pointed out, suggesting that these patients are disadvantaged under the current system of waiting list priority.
Geographically, deaths on the wait list were significantly higher in Latin America at 40% than in North America, Europe, and Asia at 20%, 18%, and 13%, respectively.
“This is likely due to low donation rates in Latin America,” Dr. Jalan said.
Turning to 3-month post-transplantation mortality, the rates in groups 1 and 2 were 9% and 7%, respectively.
“This demonstrates very nicely the clear benefit of transplant,” Dr. Jalan said. “The risk of death post transplant, even with ACLF 2 or 3, is not significantly different to those patients with decompensated cirrhosis.”
There was a slightly higher risk for death in patients with ACLF 3 than in those with ACLF 2 at 14% vs 7%, but “the risk of death in these patients if they don’t have transportation is 70%-80%,” he said.
Looking at 3-month post-transplantation mortality by continent, Dr. Jalan highlighted that Latin America showed 16% risk, compared with Asia, Europe, and North America that showed 12%, 7%, and 3% risk, respectively.
“This is probably multifactorial and likely to be influenced by time on the waiting list, quality of organs available, and patient demographics, among other factors,” Dr. Jalan said. When very sick people undergo transplantation, “there is a higher risk of death.”
The patients in this study have waited a long time, “which worsens their situation,” said Dr. Jalan, reinforcing his argument for changing the international organ allocation system to allow earlier access for these patients.
‘The Landscape of Organ Allocation Is Extremely Complex’
Comoderator Ana Lleo, MD, PhD, full professor of internal medicine and hepatology, Humanitas University, Milan, Italy, commented that “the number of patients included in this international study is significant,” and that the issue of mortality on the wait list is of great clinical interest.
“The landscape of organ allocation is extremely complex,” she added.
The system for liver transplantation considers a large number of clinical conditions with very diverse benefit profiles, she explained.
“While we would like to offer liver transplantation for all patients with any range of benefit, the current donations are not sufficient to cover the request,” Dr. Lleo said. “Therefore, prioritization remains key.”
The findings do illustrate the inadequacy of current transplantation allocation criteria for patients with ACLF 2 and 3, said Debbie Shawcross, MBBS, PhD, professor of hepatology and chronic liver failure, King’s College Hospital, London, England, who is also serving as vice-secretary of the EASL Governing Board.
However, “this must be balanced by the recognition that the global donor pool of organs available is a finite resource,” she said, echoing Dr. Lleo’s comments.
This calls for wider ethical discussions to avoid disadvantaging more stable, often younger patients with cirrhosis who are listed for transplantation, she added.
Dr. Jalan declared he is the inventor of Ornithine Phenylacetate, licensed by UCL to Mallinckrodt Pharma; a speaker and grant reviewer for Grifols Research Collaboration: Yaqrit; and the founder of Yaqrit, Hepyx, CyberLiver, and Gigabiome. Dr. Lleo declared that she does not have any conflicts relevant to this work but received lecture fees from Gilead, Advanz Pharma, Alfasigma, GSK, Incyte, Gore, AstraZeneca, and Ipsen and consulted for Advanz Pharma, AstraZeneca, Ipsen, GSK, and Dr Falk. Dr. Shawcross declared advisory board/consultancy for EnteroBiotix, Norgine, Satellite Bio, and MRN Health.
A version of this article first appeared on Medscape.com.
FROM EASL 2024
‘Dramatic’ Phase 2 Results for Survodutide in MASH, Fibrosis
MILAN — , according to phase 2 results presented here at the European Association for the Study of the Liver (EASL) Congress 2024.
The data were simultaneously published in The New England Journal of Medicine .
The primary endpoint data, reported earlier this year in a press release, showed that up to 83% of participants on survodutide showed a statistically significant improvement in MASH compared with those on placebo (18.2%) based on paired biopsy results.
In addition, 75% of patients treated with survodutide experienced resolution of MASH with no worsening of fibrosis compared with 15% of patients on placebo, and in patients with F2/F3 fibrosis, 64.5% achieved improvement in fibrosis without worsening of MASH, reported Arun J. Sanyal, MD, principal study investigator and director of the Virginia Commonwealth University (VCU) Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, VCU School of Medicine, Richmond, Virginia.
What’s so amazing is that this “exceptional improvement” is after 48 weeks of therapy with a class of molecule that is already known to also have cardiometabolic benefits, Dr. Sanyal said in an interview.
“At the highest dose of survodutide [6.0 mg], two thirds of patients in whom we have biopsy data, at both the beginning and the end, actually showed fibrosis regression within 48 weeks,” he said. “This is pretty dramatic.”
Efficacy and Safety of Survodutide
A total of 293 participants with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned (1:1:1:1) to receive once-weekly subcutaneous injections of survodutide 2.4 mg (n = 73), 4.8 mg (n = 72), or 6.0 mg (n = 74) or placebo (n = 74).
Around half of study participants were women, with mean age around 50 years and a body mass index around 35 kg/m2. Overall, 26%-30% had type 2 diabetes, 24%-36% had F2 fibrosis, and 23%-30% had F3 fibrosis. The total Nonalcoholic Fatty Liver Disease Activity Score was 5.2.
After completing a 24-week rapid-dose-escalation phase, participants followed a 24-week maintenance phase. Histologic improvement (reduction) in MASH without worsening of fibrosis after 48 weeks of treatment comprised the primary endpoint, whereas a reduction in liver fat content by at least 30% and biopsy-assessed reduction in fibrosis by at least one stage were among the secondary endpoints.
The main analyses of the trial were based on two treatment sets: Actual treatment (the actual dose received at the start of the maintenance phase; per protocol) and planned treatment (the maintenance dose assigned to participants at randomization). Dr. Sanyal mainly reported results based on actual treatment, which were used for the primary analysis.
The overall primary endpoint data, including nonresponders, showed a 47% improvement in MASH in the 2.4-mg treatment group, 62% in the 4.8 mg group, and 43% in the 6.0-mg group compared with 13.5% in the placebo group (P < .001).
In addition, 50% of patients on 2.4- and 6-mg doses experienced a statistically significant improvement in fibrosis (F1-F3) without worsening of MASH. In patients with F2/F3 fibrosis, 64.5% of participants in the 6-mg survodutide group showed improvement vs 25.9% in the placebo group.
Reduction in liver fat by at least 30% was achieved by up to 87% in the 6-mg group according to MRI-estimated proton density fat fraction; when nonresponders were included, the percentage was 76.9% of the 6-mg group. Other outcomes included weight loss and reductions in A1c.
The results did not differ markedly between doses, which “is really exciting news,” Dr. Sanyal said.
Patients who are intolerant of the highest dose can switch to a lower dose without a big loss of efficacy, he said, adding that even the low dose was sufficient to get near maximal glucagon effect.
Adverse events were similar between survodutide and placebo, except for gastrointestinal events, including nausea, diarrhea, and vomiting. The occurrence of serious adverse events also was similar between survodutide and placebo.
Discontinuation due to adverse events was 20% across all the survodutide groups (with 16% due to gastrointestinal events) vs 3% in the placebo group.
Dual Agonist vs Monoagonist Therapy
The dual agonist approach may confer clinical advantages over GLP-1 receptor monoagonist pharmacotherapies for MASH.
“GLP has no receptors in the liver, so all its effects are mediated outside the liver, particularly for weight loss and improvement in metabolic status, increase in insulin secretion and sensitivity, and overall systemic glycemia,” Dr. Sanyal explained.
“People with established fibrosis take longer to respond in terms of downstream liver scarring with extrahepatic changes alone,” he added.
With “glucagon directly targeting the liver, we believe this reduces oxidative stress and possibly stimulates FGF-21 secretion [liver-derived factor that regulates lipid and glucose metabolism] in the liver, so there are likely multiple mechanisms driving the antifibrogenic benefits,” Dr. Sanyal said.
In comparison, the study authors highlighted that data on the GLP-1 receptor monoagonist semaglutide suggest a significantly higher proportion of patients on semaglutide achieve MASH resolution than those on placebo but that it does not result in “a significantly higher percentage of patients with improvement in fibrosis stage.
“It might be that it takes longer to get an effect in the liver with semaglutide,” Dr. Sanyal said.
By year-end, we’ll know how the GLP-1 alone approach (eg, semaglutide) and the dual agonist approach work, and we’ll eventually have data on triple agonists, Dr. Sanyal added.
The Burden of Liver Disease
Comoderator Debbie Shawcross, MBBS, PhD, professor of hepatology and chronic liver failure, King’s College, London, England, remarked on the importance of new drugs, including survodutide, in reducing the burden of steatotic liver disease.
Approximately one third of the world’s population and between 7% and 9% of children have steatotic liver disease, she noted. The buildup of fat causes inflammation and scarring of the liver, which may then progress to liver cirrhosis and primary liver cancers.
Survodutide offers much hope “as a drug that will reduce both liver inflammation and scarring, while also providing the benefit of improved diabetic control,” Dr. Shawcross said.
Reflecting on the dual agonism, she said that both the glucagon and GLP-1 receptors are critical to controlling metabolic functions.
Survodutide is currently being investigated in five phase 3 studies for people living with overweight and obesity, both of which are associated with MASH. There is also a trial looking at people with overweight/obesity with confirmed or presumed diagnosis of MASH, according to a company press release.
Dr. Sanyal reported grants, consultancy fees, and speaker fees from a wide range of companies working in the field of liver medicine. Dr. Shawcross reported no conflicts in relation to this drug and advisory board membership/consultancy for EnteroBiotix, Norgine, Satellite Bio, and MRN Health.
A version of this article first appeared on Medscape.com.
MILAN — , according to phase 2 results presented here at the European Association for the Study of the Liver (EASL) Congress 2024.
The data were simultaneously published in The New England Journal of Medicine .
The primary endpoint data, reported earlier this year in a press release, showed that up to 83% of participants on survodutide showed a statistically significant improvement in MASH compared with those on placebo (18.2%) based on paired biopsy results.
In addition, 75% of patients treated with survodutide experienced resolution of MASH with no worsening of fibrosis compared with 15% of patients on placebo, and in patients with F2/F3 fibrosis, 64.5% achieved improvement in fibrosis without worsening of MASH, reported Arun J. Sanyal, MD, principal study investigator and director of the Virginia Commonwealth University (VCU) Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, VCU School of Medicine, Richmond, Virginia.
What’s so amazing is that this “exceptional improvement” is after 48 weeks of therapy with a class of molecule that is already known to also have cardiometabolic benefits, Dr. Sanyal said in an interview.
“At the highest dose of survodutide [6.0 mg], two thirds of patients in whom we have biopsy data, at both the beginning and the end, actually showed fibrosis regression within 48 weeks,” he said. “This is pretty dramatic.”
Efficacy and Safety of Survodutide
A total of 293 participants with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned (1:1:1:1) to receive once-weekly subcutaneous injections of survodutide 2.4 mg (n = 73), 4.8 mg (n = 72), or 6.0 mg (n = 74) or placebo (n = 74).
Around half of study participants were women, with mean age around 50 years and a body mass index around 35 kg/m2. Overall, 26%-30% had type 2 diabetes, 24%-36% had F2 fibrosis, and 23%-30% had F3 fibrosis. The total Nonalcoholic Fatty Liver Disease Activity Score was 5.2.
After completing a 24-week rapid-dose-escalation phase, participants followed a 24-week maintenance phase. Histologic improvement (reduction) in MASH without worsening of fibrosis after 48 weeks of treatment comprised the primary endpoint, whereas a reduction in liver fat content by at least 30% and biopsy-assessed reduction in fibrosis by at least one stage were among the secondary endpoints.
The main analyses of the trial were based on two treatment sets: Actual treatment (the actual dose received at the start of the maintenance phase; per protocol) and planned treatment (the maintenance dose assigned to participants at randomization). Dr. Sanyal mainly reported results based on actual treatment, which were used for the primary analysis.
The overall primary endpoint data, including nonresponders, showed a 47% improvement in MASH in the 2.4-mg treatment group, 62% in the 4.8 mg group, and 43% in the 6.0-mg group compared with 13.5% in the placebo group (P < .001).
In addition, 50% of patients on 2.4- and 6-mg doses experienced a statistically significant improvement in fibrosis (F1-F3) without worsening of MASH. In patients with F2/F3 fibrosis, 64.5% of participants in the 6-mg survodutide group showed improvement vs 25.9% in the placebo group.
Reduction in liver fat by at least 30% was achieved by up to 87% in the 6-mg group according to MRI-estimated proton density fat fraction; when nonresponders were included, the percentage was 76.9% of the 6-mg group. Other outcomes included weight loss and reductions in A1c.
The results did not differ markedly between doses, which “is really exciting news,” Dr. Sanyal said.
Patients who are intolerant of the highest dose can switch to a lower dose without a big loss of efficacy, he said, adding that even the low dose was sufficient to get near maximal glucagon effect.
Adverse events were similar between survodutide and placebo, except for gastrointestinal events, including nausea, diarrhea, and vomiting. The occurrence of serious adverse events also was similar between survodutide and placebo.
Discontinuation due to adverse events was 20% across all the survodutide groups (with 16% due to gastrointestinal events) vs 3% in the placebo group.
Dual Agonist vs Monoagonist Therapy
The dual agonist approach may confer clinical advantages over GLP-1 receptor monoagonist pharmacotherapies for MASH.
“GLP has no receptors in the liver, so all its effects are mediated outside the liver, particularly for weight loss and improvement in metabolic status, increase in insulin secretion and sensitivity, and overall systemic glycemia,” Dr. Sanyal explained.
“People with established fibrosis take longer to respond in terms of downstream liver scarring with extrahepatic changes alone,” he added.
With “glucagon directly targeting the liver, we believe this reduces oxidative stress and possibly stimulates FGF-21 secretion [liver-derived factor that regulates lipid and glucose metabolism] in the liver, so there are likely multiple mechanisms driving the antifibrogenic benefits,” Dr. Sanyal said.
In comparison, the study authors highlighted that data on the GLP-1 receptor monoagonist semaglutide suggest a significantly higher proportion of patients on semaglutide achieve MASH resolution than those on placebo but that it does not result in “a significantly higher percentage of patients with improvement in fibrosis stage.
“It might be that it takes longer to get an effect in the liver with semaglutide,” Dr. Sanyal said.
By year-end, we’ll know how the GLP-1 alone approach (eg, semaglutide) and the dual agonist approach work, and we’ll eventually have data on triple agonists, Dr. Sanyal added.
The Burden of Liver Disease
Comoderator Debbie Shawcross, MBBS, PhD, professor of hepatology and chronic liver failure, King’s College, London, England, remarked on the importance of new drugs, including survodutide, in reducing the burden of steatotic liver disease.
Approximately one third of the world’s population and between 7% and 9% of children have steatotic liver disease, she noted. The buildup of fat causes inflammation and scarring of the liver, which may then progress to liver cirrhosis and primary liver cancers.
Survodutide offers much hope “as a drug that will reduce both liver inflammation and scarring, while also providing the benefit of improved diabetic control,” Dr. Shawcross said.
Reflecting on the dual agonism, she said that both the glucagon and GLP-1 receptors are critical to controlling metabolic functions.
Survodutide is currently being investigated in five phase 3 studies for people living with overweight and obesity, both of which are associated with MASH. There is also a trial looking at people with overweight/obesity with confirmed or presumed diagnosis of MASH, according to a company press release.
Dr. Sanyal reported grants, consultancy fees, and speaker fees from a wide range of companies working in the field of liver medicine. Dr. Shawcross reported no conflicts in relation to this drug and advisory board membership/consultancy for EnteroBiotix, Norgine, Satellite Bio, and MRN Health.
A version of this article first appeared on Medscape.com.
MILAN — , according to phase 2 results presented here at the European Association for the Study of the Liver (EASL) Congress 2024.
The data were simultaneously published in The New England Journal of Medicine .
The primary endpoint data, reported earlier this year in a press release, showed that up to 83% of participants on survodutide showed a statistically significant improvement in MASH compared with those on placebo (18.2%) based on paired biopsy results.
In addition, 75% of patients treated with survodutide experienced resolution of MASH with no worsening of fibrosis compared with 15% of patients on placebo, and in patients with F2/F3 fibrosis, 64.5% achieved improvement in fibrosis without worsening of MASH, reported Arun J. Sanyal, MD, principal study investigator and director of the Virginia Commonwealth University (VCU) Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, VCU School of Medicine, Richmond, Virginia.
What’s so amazing is that this “exceptional improvement” is after 48 weeks of therapy with a class of molecule that is already known to also have cardiometabolic benefits, Dr. Sanyal said in an interview.
“At the highest dose of survodutide [6.0 mg], two thirds of patients in whom we have biopsy data, at both the beginning and the end, actually showed fibrosis regression within 48 weeks,” he said. “This is pretty dramatic.”
Efficacy and Safety of Survodutide
A total of 293 participants with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned (1:1:1:1) to receive once-weekly subcutaneous injections of survodutide 2.4 mg (n = 73), 4.8 mg (n = 72), or 6.0 mg (n = 74) or placebo (n = 74).
Around half of study participants were women, with mean age around 50 years and a body mass index around 35 kg/m2. Overall, 26%-30% had type 2 diabetes, 24%-36% had F2 fibrosis, and 23%-30% had F3 fibrosis. The total Nonalcoholic Fatty Liver Disease Activity Score was 5.2.
After completing a 24-week rapid-dose-escalation phase, participants followed a 24-week maintenance phase. Histologic improvement (reduction) in MASH without worsening of fibrosis after 48 weeks of treatment comprised the primary endpoint, whereas a reduction in liver fat content by at least 30% and biopsy-assessed reduction in fibrosis by at least one stage were among the secondary endpoints.
The main analyses of the trial were based on two treatment sets: Actual treatment (the actual dose received at the start of the maintenance phase; per protocol) and planned treatment (the maintenance dose assigned to participants at randomization). Dr. Sanyal mainly reported results based on actual treatment, which were used for the primary analysis.
The overall primary endpoint data, including nonresponders, showed a 47% improvement in MASH in the 2.4-mg treatment group, 62% in the 4.8 mg group, and 43% in the 6.0-mg group compared with 13.5% in the placebo group (P < .001).
In addition, 50% of patients on 2.4- and 6-mg doses experienced a statistically significant improvement in fibrosis (F1-F3) without worsening of MASH. In patients with F2/F3 fibrosis, 64.5% of participants in the 6-mg survodutide group showed improvement vs 25.9% in the placebo group.
Reduction in liver fat by at least 30% was achieved by up to 87% in the 6-mg group according to MRI-estimated proton density fat fraction; when nonresponders were included, the percentage was 76.9% of the 6-mg group. Other outcomes included weight loss and reductions in A1c.
The results did not differ markedly between doses, which “is really exciting news,” Dr. Sanyal said.
Patients who are intolerant of the highest dose can switch to a lower dose without a big loss of efficacy, he said, adding that even the low dose was sufficient to get near maximal glucagon effect.
Adverse events were similar between survodutide and placebo, except for gastrointestinal events, including nausea, diarrhea, and vomiting. The occurrence of serious adverse events also was similar between survodutide and placebo.
Discontinuation due to adverse events was 20% across all the survodutide groups (with 16% due to gastrointestinal events) vs 3% in the placebo group.
Dual Agonist vs Monoagonist Therapy
The dual agonist approach may confer clinical advantages over GLP-1 receptor monoagonist pharmacotherapies for MASH.
“GLP has no receptors in the liver, so all its effects are mediated outside the liver, particularly for weight loss and improvement in metabolic status, increase in insulin secretion and sensitivity, and overall systemic glycemia,” Dr. Sanyal explained.
“People with established fibrosis take longer to respond in terms of downstream liver scarring with extrahepatic changes alone,” he added.
With “glucagon directly targeting the liver, we believe this reduces oxidative stress and possibly stimulates FGF-21 secretion [liver-derived factor that regulates lipid and glucose metabolism] in the liver, so there are likely multiple mechanisms driving the antifibrogenic benefits,” Dr. Sanyal said.
In comparison, the study authors highlighted that data on the GLP-1 receptor monoagonist semaglutide suggest a significantly higher proportion of patients on semaglutide achieve MASH resolution than those on placebo but that it does not result in “a significantly higher percentage of patients with improvement in fibrosis stage.
“It might be that it takes longer to get an effect in the liver with semaglutide,” Dr. Sanyal said.
By year-end, we’ll know how the GLP-1 alone approach (eg, semaglutide) and the dual agonist approach work, and we’ll eventually have data on triple agonists, Dr. Sanyal added.
The Burden of Liver Disease
Comoderator Debbie Shawcross, MBBS, PhD, professor of hepatology and chronic liver failure, King’s College, London, England, remarked on the importance of new drugs, including survodutide, in reducing the burden of steatotic liver disease.
Approximately one third of the world’s population and between 7% and 9% of children have steatotic liver disease, she noted. The buildup of fat causes inflammation and scarring of the liver, which may then progress to liver cirrhosis and primary liver cancers.
Survodutide offers much hope “as a drug that will reduce both liver inflammation and scarring, while also providing the benefit of improved diabetic control,” Dr. Shawcross said.
Reflecting on the dual agonism, she said that both the glucagon and GLP-1 receptors are critical to controlling metabolic functions.
Survodutide is currently being investigated in five phase 3 studies for people living with overweight and obesity, both of which are associated with MASH. There is also a trial looking at people with overweight/obesity with confirmed or presumed diagnosis of MASH, according to a company press release.
Dr. Sanyal reported grants, consultancy fees, and speaker fees from a wide range of companies working in the field of liver medicine. Dr. Shawcross reported no conflicts in relation to this drug and advisory board membership/consultancy for EnteroBiotix, Norgine, Satellite Bio, and MRN Health.
A version of this article first appeared on Medscape.com.
FROM EASL 2024
Eribulin Similar to Taxane When Paired With Dual HER2 Blockade in BC
The results of this multicenter, randomized, open-label, parallel-group, phase 3 Japanese trial suggest that patients who cannot tolerate the standard taxane-based regimen have a new option for treatment.
“Our study is the first to show the non-inferiority of eribulin to a taxane, when used in combination with dual HER2 blockade as first-line treatment for this population,” lead author Toshinari Yamashita, MD, PhD, from the Kanagawa Cancer Center, in Kanagawa, Japan, said at the annual meeting of the American Society of Clinical Oncology.
“To our knowledge, noninferiority of eribulin to a taxane when used in combination with dual HER2 blockade has not been investigated,” Dr. Yamashita said.
“The combination of trastuzumab, pertuzumab, and taxane is a current standard first-line therapy for recurrent or metastatic HER2-positive breast cancer,” explained Dr. Yamashita. “However, because of taxane-induced toxicity, the development of less toxic but equally effective alternatives are needed.
“Because its efficacy is comparable to that of the current standard regimen, the combination of eribulin, trastuzumab, and pertuzumab is one of the options for first-line treatment of how to fight locally advanced or metastatic breast cancer,” he continued.
Study Results and Methods
The trial enrolled 446 patients, mean age 56 years, all of whom had locally advanced or metastatic breast cancer and no prior use of chemotherapy, excluding T-DM1. Patients who had received hormonal or HER2 therapy alone or the combination, as treatment for recurrence, were also eligible.
They were randomized 1:1 to receive a 21-day chemotherapy cycle of either (i) eribulin (1.4 mg/m2 on days 1 and 8), or (ii) a taxane (docetaxel 75 mg/m2 on day 1 or paclitaxel 80 mg/m2 on days 1, 8 and 15), each being administered in combination with a dual HER2 blockade of trastuzumab plus pertuzumab.
Baseline characteristics of both groups were well balanced, with 257 (57.6%) having ER-positive disease, 292 (65.5%) visceral metastasis, and 263 (59%) with de novo stage 4 disease, explained Dr. Yamashita.
For the primary endpoint, the median progression-free survival (PFS) was 14 versus 12.9 months in the eribulin and taxane group, respectively (hazard ratio [HR] 0.95, P = .6817), confirming non-inferiority of the study regimen, he reported.
The clinical benefit rate was similar between the two groups, with an objective response rate of 76.8% in the eribulin group and 75.2% in the taxane group.
Median OS was 65.3 months in the taxane group, but has not been reached in the study group (HR 1.09).
In terms of side-effects, the incidence of treatment-emergent adverse events was similar between the eribulin and taxane groups (58.9% vs 59.2%, respectively, for grade 3 or higher).
“Skin-related adverse events (62.4% vs 40.6%), diarrhea (54.1% vs 36.6%), and edema (42.2% vs 8.5%) tend to be more common with taxane, whereas neutropenia (61.6% vs 30.7%) and peripheral neuropathy (61.2% vs 52.8%) tend to be more common with eribulin use,” he said.
Overall, “these results suggest that eribulin is less toxic chemotherapeutic partner for dual HER2 blockade and can be used for a longer,” he said.
Findings Are a ‘Clinical Pearl’
Harold Burstein, MD, PhD, a breast cancer expert at Dana-Farber Cancer Institute and professor at Harvard Medical School in Boston, described the findings as “a nice clinical pearl,” because some patients do not tolerate taxane therapy. “In such cases, you can substitute eribulin, which is usually tolerated without allergic hypersensitivity issues,” he said in an interview.
Eribulin has specific properties that “could make it a perfect candidate” as an adjunct to standard treatment regimens across different breast cancer subtypes, observed Wynne Wijaya, MD an oncology researcher at the University of Oxford, England, and Universitas Gadjah Mada, in Yogyakarta, Indonesia, in a recent review (World J Exp Med. 2024;14[2]:92558).
Dr. Wijaya, who was not involved in this study, said in an interview that the findings have important implications.
“This encouraging result adds eribulin as another option in the first line treatment regimen for patients with HER2-positive, locally advanced or metastatic breast cancer, especially in terms of side effects/toxicities,” she said. “As clinicians, we can offer to tailor the choice of therapy between eribulin versus taxane in the regimen based on [which side effects patients are better able to tolerate]. It would also be interesting and worthwhile to conduct similar trials in different types of populations to provide more robust evidence.”
Eisai Co. funded the research. Dr. Yamashita disclosed ties with AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eisai, Kyowa Hakko Kiri, Lilly, MSD, Pfizer, Taiho, Gilead Sciences, Nihonkayaku, Ono Yakuhin, and Seagen. Dr. Burstein disclosed a research grant from National Cancer Institute. Dr. Wijaya had no relevant disclosures.
The results of this multicenter, randomized, open-label, parallel-group, phase 3 Japanese trial suggest that patients who cannot tolerate the standard taxane-based regimen have a new option for treatment.
“Our study is the first to show the non-inferiority of eribulin to a taxane, when used in combination with dual HER2 blockade as first-line treatment for this population,” lead author Toshinari Yamashita, MD, PhD, from the Kanagawa Cancer Center, in Kanagawa, Japan, said at the annual meeting of the American Society of Clinical Oncology.
“To our knowledge, noninferiority of eribulin to a taxane when used in combination with dual HER2 blockade has not been investigated,” Dr. Yamashita said.
“The combination of trastuzumab, pertuzumab, and taxane is a current standard first-line therapy for recurrent or metastatic HER2-positive breast cancer,” explained Dr. Yamashita. “However, because of taxane-induced toxicity, the development of less toxic but equally effective alternatives are needed.
“Because its efficacy is comparable to that of the current standard regimen, the combination of eribulin, trastuzumab, and pertuzumab is one of the options for first-line treatment of how to fight locally advanced or metastatic breast cancer,” he continued.
Study Results and Methods
The trial enrolled 446 patients, mean age 56 years, all of whom had locally advanced or metastatic breast cancer and no prior use of chemotherapy, excluding T-DM1. Patients who had received hormonal or HER2 therapy alone or the combination, as treatment for recurrence, were also eligible.
They were randomized 1:1 to receive a 21-day chemotherapy cycle of either (i) eribulin (1.4 mg/m2 on days 1 and 8), or (ii) a taxane (docetaxel 75 mg/m2 on day 1 or paclitaxel 80 mg/m2 on days 1, 8 and 15), each being administered in combination with a dual HER2 blockade of trastuzumab plus pertuzumab.
Baseline characteristics of both groups were well balanced, with 257 (57.6%) having ER-positive disease, 292 (65.5%) visceral metastasis, and 263 (59%) with de novo stage 4 disease, explained Dr. Yamashita.
For the primary endpoint, the median progression-free survival (PFS) was 14 versus 12.9 months in the eribulin and taxane group, respectively (hazard ratio [HR] 0.95, P = .6817), confirming non-inferiority of the study regimen, he reported.
The clinical benefit rate was similar between the two groups, with an objective response rate of 76.8% in the eribulin group and 75.2% in the taxane group.
Median OS was 65.3 months in the taxane group, but has not been reached in the study group (HR 1.09).
In terms of side-effects, the incidence of treatment-emergent adverse events was similar between the eribulin and taxane groups (58.9% vs 59.2%, respectively, for grade 3 or higher).
“Skin-related adverse events (62.4% vs 40.6%), diarrhea (54.1% vs 36.6%), and edema (42.2% vs 8.5%) tend to be more common with taxane, whereas neutropenia (61.6% vs 30.7%) and peripheral neuropathy (61.2% vs 52.8%) tend to be more common with eribulin use,” he said.
Overall, “these results suggest that eribulin is less toxic chemotherapeutic partner for dual HER2 blockade and can be used for a longer,” he said.
Findings Are a ‘Clinical Pearl’
Harold Burstein, MD, PhD, a breast cancer expert at Dana-Farber Cancer Institute and professor at Harvard Medical School in Boston, described the findings as “a nice clinical pearl,” because some patients do not tolerate taxane therapy. “In such cases, you can substitute eribulin, which is usually tolerated without allergic hypersensitivity issues,” he said in an interview.
Eribulin has specific properties that “could make it a perfect candidate” as an adjunct to standard treatment regimens across different breast cancer subtypes, observed Wynne Wijaya, MD an oncology researcher at the University of Oxford, England, and Universitas Gadjah Mada, in Yogyakarta, Indonesia, in a recent review (World J Exp Med. 2024;14[2]:92558).
Dr. Wijaya, who was not involved in this study, said in an interview that the findings have important implications.
“This encouraging result adds eribulin as another option in the first line treatment regimen for patients with HER2-positive, locally advanced or metastatic breast cancer, especially in terms of side effects/toxicities,” she said. “As clinicians, we can offer to tailor the choice of therapy between eribulin versus taxane in the regimen based on [which side effects patients are better able to tolerate]. It would also be interesting and worthwhile to conduct similar trials in different types of populations to provide more robust evidence.”
Eisai Co. funded the research. Dr. Yamashita disclosed ties with AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eisai, Kyowa Hakko Kiri, Lilly, MSD, Pfizer, Taiho, Gilead Sciences, Nihonkayaku, Ono Yakuhin, and Seagen. Dr. Burstein disclosed a research grant from National Cancer Institute. Dr. Wijaya had no relevant disclosures.
The results of this multicenter, randomized, open-label, parallel-group, phase 3 Japanese trial suggest that patients who cannot tolerate the standard taxane-based regimen have a new option for treatment.
“Our study is the first to show the non-inferiority of eribulin to a taxane, when used in combination with dual HER2 blockade as first-line treatment for this population,” lead author Toshinari Yamashita, MD, PhD, from the Kanagawa Cancer Center, in Kanagawa, Japan, said at the annual meeting of the American Society of Clinical Oncology.
“To our knowledge, noninferiority of eribulin to a taxane when used in combination with dual HER2 blockade has not been investigated,” Dr. Yamashita said.
“The combination of trastuzumab, pertuzumab, and taxane is a current standard first-line therapy for recurrent or metastatic HER2-positive breast cancer,” explained Dr. Yamashita. “However, because of taxane-induced toxicity, the development of less toxic but equally effective alternatives are needed.
“Because its efficacy is comparable to that of the current standard regimen, the combination of eribulin, trastuzumab, and pertuzumab is one of the options for first-line treatment of how to fight locally advanced or metastatic breast cancer,” he continued.
Study Results and Methods
The trial enrolled 446 patients, mean age 56 years, all of whom had locally advanced or metastatic breast cancer and no prior use of chemotherapy, excluding T-DM1. Patients who had received hormonal or HER2 therapy alone or the combination, as treatment for recurrence, were also eligible.
They were randomized 1:1 to receive a 21-day chemotherapy cycle of either (i) eribulin (1.4 mg/m2 on days 1 and 8), or (ii) a taxane (docetaxel 75 mg/m2 on day 1 or paclitaxel 80 mg/m2 on days 1, 8 and 15), each being administered in combination with a dual HER2 blockade of trastuzumab plus pertuzumab.
Baseline characteristics of both groups were well balanced, with 257 (57.6%) having ER-positive disease, 292 (65.5%) visceral metastasis, and 263 (59%) with de novo stage 4 disease, explained Dr. Yamashita.
For the primary endpoint, the median progression-free survival (PFS) was 14 versus 12.9 months in the eribulin and taxane group, respectively (hazard ratio [HR] 0.95, P = .6817), confirming non-inferiority of the study regimen, he reported.
The clinical benefit rate was similar between the two groups, with an objective response rate of 76.8% in the eribulin group and 75.2% in the taxane group.
Median OS was 65.3 months in the taxane group, but has not been reached in the study group (HR 1.09).
In terms of side-effects, the incidence of treatment-emergent adverse events was similar between the eribulin and taxane groups (58.9% vs 59.2%, respectively, for grade 3 or higher).
“Skin-related adverse events (62.4% vs 40.6%), diarrhea (54.1% vs 36.6%), and edema (42.2% vs 8.5%) tend to be more common with taxane, whereas neutropenia (61.6% vs 30.7%) and peripheral neuropathy (61.2% vs 52.8%) tend to be more common with eribulin use,” he said.
Overall, “these results suggest that eribulin is less toxic chemotherapeutic partner for dual HER2 blockade and can be used for a longer,” he said.
Findings Are a ‘Clinical Pearl’
Harold Burstein, MD, PhD, a breast cancer expert at Dana-Farber Cancer Institute and professor at Harvard Medical School in Boston, described the findings as “a nice clinical pearl,” because some patients do not tolerate taxane therapy. “In such cases, you can substitute eribulin, which is usually tolerated without allergic hypersensitivity issues,” he said in an interview.
Eribulin has specific properties that “could make it a perfect candidate” as an adjunct to standard treatment regimens across different breast cancer subtypes, observed Wynne Wijaya, MD an oncology researcher at the University of Oxford, England, and Universitas Gadjah Mada, in Yogyakarta, Indonesia, in a recent review (World J Exp Med. 2024;14[2]:92558).
Dr. Wijaya, who was not involved in this study, said in an interview that the findings have important implications.
“This encouraging result adds eribulin as another option in the first line treatment regimen for patients with HER2-positive, locally advanced or metastatic breast cancer, especially in terms of side effects/toxicities,” she said. “As clinicians, we can offer to tailor the choice of therapy between eribulin versus taxane in the regimen based on [which side effects patients are better able to tolerate]. It would also be interesting and worthwhile to conduct similar trials in different types of populations to provide more robust evidence.”
Eisai Co. funded the research. Dr. Yamashita disclosed ties with AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eisai, Kyowa Hakko Kiri, Lilly, MSD, Pfizer, Taiho, Gilead Sciences, Nihonkayaku, Ono Yakuhin, and Seagen. Dr. Burstein disclosed a research grant from National Cancer Institute. Dr. Wijaya had no relevant disclosures.
FROM ASCO 2024
PFS Benefits Seen With Palbociclib + Endocrine Therapy in Breast Cancer
“The combination of palbociclib plus exemestane plus leuprolide showed a consistent significant improvement in PFS [progression-free survival] compared to the capecitabine arm,” Yeon Hee Park, MD, PhD, from Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea, reported at the annual meeting of the American Society of Clinical Oncology.
Study Methods and Results
Young-PEARL, a prospective, multicenter, open-label, randomized phase 2 study, included 184 patients, median age 44 years, who had relapsed or progressed during previous tamoxifen therapy, with one line of previous chemotherapy for mBC allowed. Patients were randomized to palbociclib plus endocrine therapy (oral palbociclib 125 mg per day for 21 days every 4 weeks, oral exemestane 25 mg per day for 28 days, plus leuprolide 3.75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2, twice daily for 2 weeks every 3 weeks).
Previously published initial results (Lancet Oncol. 2019 Dec;20[12]:1750-1759) for the primary endpoint showed a median PFS of 20.1 months in the palbociclib group versus 14.4 months in the capecitabine group, (hazard ratio [HR] 0.659, P = .0235) after median follow-up of 17 months.
Updated results showed this benefit was maintained after a median of 54 months, with a PFS of 19.5 months in the palbociclib arm, versus 14 months in capecitabine arm (HR 0.744, P = .0357), Dr. Park reported. However, this PFS benefit did not lead to an overall survival (OS) benefit, with median OS being similar: 54.8 versus 57.8 months in the palbociclib and capecitabine groups, respectively (HR = 1.02, P = .92).
To explore why PFS — but not OS — was better in the palbociclib arm, the researchers conducted a multivariate analysis which showed that going on to an additional CDK4/6 inhibitor treatment after the end of the study was as an independent variable favoring OS. Because more patients in the capecitabine arm received a post-study CDK4/6 inhibitor (49.3%) compared with in the palbociclib group (15%), this weighted the OS to the capecitabine arm, Dr. Park explained in an interview.
“In the capecitabine arm, excluding post-study CDK4/6 inhibitor use, the median OS was 38.8 months.” This was inferior to the 49 months OS seen in the palbociclib arm (P = .065), she said.
“As expected, hematologic toxicity was more common in the palbociclib arm compared with in the capecitabine arm,” Dr. Park said (92% vs 86%), with neutropenia topping the list [of all adverse events] (65.2% vs 27.9%, all grades). However, “most [adverse events] were not that serious,” Dr. Park said. Arthralgia was more common in the palbociclib arm (25% vs 7%), and diarrhea and hand-foot syndrome were more common in the capecitabine arm (15.2% vs 39.5% and 79.1% vs 2.2%).
Study Validates Endocrine Therapy + CDK4/6 Inhibitor as First Line
Commenting on Young-PEARL in an interview, Harold Burstein, MD, PhD, said, “The point of this study was to compare whether upfront chemotherapy would be better than upfront hormonal therapy for patients who had metastatic ER positive breast cancer.”
“This is the first study in probably 20 years that has compared these two approaches, and it validated that for the vast majority of patients with ER positive metastatic breast cancer, the appropriate first treatment is endocrine therapy with a CDK4/6 inhibitor,” continued Dr. Burstein, a breast cancer expert at Dana-Farber Cancer Institute, and professor at Harvard Medical School in Boston.
Dr. Park disclosed honoraria from AstraZeneca, Daiichi Sankyo, Eisai, Lilly, MSD, Novartis, Pfizer, and Roche; consulting or advisory roles for AstraZeneca, Boryung, Daiichi Sankyo, Eisai, Gilead Sciences, Lilly, Menarini, MSD, Novartis, Pfizer, and Roche; research funding from AstraZeneca, Gencurix, Genome Insight, NGeneBio, Pfizer; and Roche; and travel/accommodations/expenses from Gilead. Dr. Burstein disclosed a research grant from the National Cancer Institute.
“The combination of palbociclib plus exemestane plus leuprolide showed a consistent significant improvement in PFS [progression-free survival] compared to the capecitabine arm,” Yeon Hee Park, MD, PhD, from Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea, reported at the annual meeting of the American Society of Clinical Oncology.
Study Methods and Results
Young-PEARL, a prospective, multicenter, open-label, randomized phase 2 study, included 184 patients, median age 44 years, who had relapsed or progressed during previous tamoxifen therapy, with one line of previous chemotherapy for mBC allowed. Patients were randomized to palbociclib plus endocrine therapy (oral palbociclib 125 mg per day for 21 days every 4 weeks, oral exemestane 25 mg per day for 28 days, plus leuprolide 3.75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2, twice daily for 2 weeks every 3 weeks).
Previously published initial results (Lancet Oncol. 2019 Dec;20[12]:1750-1759) for the primary endpoint showed a median PFS of 20.1 months in the palbociclib group versus 14.4 months in the capecitabine group, (hazard ratio [HR] 0.659, P = .0235) after median follow-up of 17 months.
Updated results showed this benefit was maintained after a median of 54 months, with a PFS of 19.5 months in the palbociclib arm, versus 14 months in capecitabine arm (HR 0.744, P = .0357), Dr. Park reported. However, this PFS benefit did not lead to an overall survival (OS) benefit, with median OS being similar: 54.8 versus 57.8 months in the palbociclib and capecitabine groups, respectively (HR = 1.02, P = .92).
To explore why PFS — but not OS — was better in the palbociclib arm, the researchers conducted a multivariate analysis which showed that going on to an additional CDK4/6 inhibitor treatment after the end of the study was as an independent variable favoring OS. Because more patients in the capecitabine arm received a post-study CDK4/6 inhibitor (49.3%) compared with in the palbociclib group (15%), this weighted the OS to the capecitabine arm, Dr. Park explained in an interview.
“In the capecitabine arm, excluding post-study CDK4/6 inhibitor use, the median OS was 38.8 months.” This was inferior to the 49 months OS seen in the palbociclib arm (P = .065), she said.
“As expected, hematologic toxicity was more common in the palbociclib arm compared with in the capecitabine arm,” Dr. Park said (92% vs 86%), with neutropenia topping the list [of all adverse events] (65.2% vs 27.9%, all grades). However, “most [adverse events] were not that serious,” Dr. Park said. Arthralgia was more common in the palbociclib arm (25% vs 7%), and diarrhea and hand-foot syndrome were more common in the capecitabine arm (15.2% vs 39.5% and 79.1% vs 2.2%).
Study Validates Endocrine Therapy + CDK4/6 Inhibitor as First Line
Commenting on Young-PEARL in an interview, Harold Burstein, MD, PhD, said, “The point of this study was to compare whether upfront chemotherapy would be better than upfront hormonal therapy for patients who had metastatic ER positive breast cancer.”
“This is the first study in probably 20 years that has compared these two approaches, and it validated that for the vast majority of patients with ER positive metastatic breast cancer, the appropriate first treatment is endocrine therapy with a CDK4/6 inhibitor,” continued Dr. Burstein, a breast cancer expert at Dana-Farber Cancer Institute, and professor at Harvard Medical School in Boston.
Dr. Park disclosed honoraria from AstraZeneca, Daiichi Sankyo, Eisai, Lilly, MSD, Novartis, Pfizer, and Roche; consulting or advisory roles for AstraZeneca, Boryung, Daiichi Sankyo, Eisai, Gilead Sciences, Lilly, Menarini, MSD, Novartis, Pfizer, and Roche; research funding from AstraZeneca, Gencurix, Genome Insight, NGeneBio, Pfizer; and Roche; and travel/accommodations/expenses from Gilead. Dr. Burstein disclosed a research grant from the National Cancer Institute.
“The combination of palbociclib plus exemestane plus leuprolide showed a consistent significant improvement in PFS [progression-free survival] compared to the capecitabine arm,” Yeon Hee Park, MD, PhD, from Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea, reported at the annual meeting of the American Society of Clinical Oncology.
Study Methods and Results
Young-PEARL, a prospective, multicenter, open-label, randomized phase 2 study, included 184 patients, median age 44 years, who had relapsed or progressed during previous tamoxifen therapy, with one line of previous chemotherapy for mBC allowed. Patients were randomized to palbociclib plus endocrine therapy (oral palbociclib 125 mg per day for 21 days every 4 weeks, oral exemestane 25 mg per day for 28 days, plus leuprolide 3.75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2, twice daily for 2 weeks every 3 weeks).
Previously published initial results (Lancet Oncol. 2019 Dec;20[12]:1750-1759) for the primary endpoint showed a median PFS of 20.1 months in the palbociclib group versus 14.4 months in the capecitabine group, (hazard ratio [HR] 0.659, P = .0235) after median follow-up of 17 months.
Updated results showed this benefit was maintained after a median of 54 months, with a PFS of 19.5 months in the palbociclib arm, versus 14 months in capecitabine arm (HR 0.744, P = .0357), Dr. Park reported. However, this PFS benefit did not lead to an overall survival (OS) benefit, with median OS being similar: 54.8 versus 57.8 months in the palbociclib and capecitabine groups, respectively (HR = 1.02, P = .92).
To explore why PFS — but not OS — was better in the palbociclib arm, the researchers conducted a multivariate analysis which showed that going on to an additional CDK4/6 inhibitor treatment after the end of the study was as an independent variable favoring OS. Because more patients in the capecitabine arm received a post-study CDK4/6 inhibitor (49.3%) compared with in the palbociclib group (15%), this weighted the OS to the capecitabine arm, Dr. Park explained in an interview.
“In the capecitabine arm, excluding post-study CDK4/6 inhibitor use, the median OS was 38.8 months.” This was inferior to the 49 months OS seen in the palbociclib arm (P = .065), she said.
“As expected, hematologic toxicity was more common in the palbociclib arm compared with in the capecitabine arm,” Dr. Park said (92% vs 86%), with neutropenia topping the list [of all adverse events] (65.2% vs 27.9%, all grades). However, “most [adverse events] were not that serious,” Dr. Park said. Arthralgia was more common in the palbociclib arm (25% vs 7%), and diarrhea and hand-foot syndrome were more common in the capecitabine arm (15.2% vs 39.5% and 79.1% vs 2.2%).
Study Validates Endocrine Therapy + CDK4/6 Inhibitor as First Line
Commenting on Young-PEARL in an interview, Harold Burstein, MD, PhD, said, “The point of this study was to compare whether upfront chemotherapy would be better than upfront hormonal therapy for patients who had metastatic ER positive breast cancer.”
“This is the first study in probably 20 years that has compared these two approaches, and it validated that for the vast majority of patients with ER positive metastatic breast cancer, the appropriate first treatment is endocrine therapy with a CDK4/6 inhibitor,” continued Dr. Burstein, a breast cancer expert at Dana-Farber Cancer Institute, and professor at Harvard Medical School in Boston.
Dr. Park disclosed honoraria from AstraZeneca, Daiichi Sankyo, Eisai, Lilly, MSD, Novartis, Pfizer, and Roche; consulting or advisory roles for AstraZeneca, Boryung, Daiichi Sankyo, Eisai, Gilead Sciences, Lilly, Menarini, MSD, Novartis, Pfizer, and Roche; research funding from AstraZeneca, Gencurix, Genome Insight, NGeneBio, Pfizer; and Roche; and travel/accommodations/expenses from Gilead. Dr. Burstein disclosed a research grant from the National Cancer Institute.
FROM ASCO 2024
Seladelpar Shows Clinically Meaningful Improvements in PBC
MILAN — according to two interim analyses of the ASSURE long-term extension study.
The first analysis of 337 patients with PBC, with and without cirrhosis, showed that treatment with seladelpar had a durable effect up to 2 years on cholestasis and markers of liver injury, as well as a sustained reduction in pruritus, Palak Trivedi, MD, associate professor at the National Institute for Health Research Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, England, reported in a poster presented at the European Association for the Study of the Liver (EASL) Congress 2024.
The 2-year analysis also showed that seladelpar, a first-in-class, orally active agent, was safe and well tolerated in this patient population, he added.
These “results are consistent with the pivotal phase 3 RESPONSE study,” Dr. Trivedi noted. The RESPONSE study showed that seladelpar significantly improved liver biomarkers of disease activity and symptoms of pruritus at 12 months in patients with PBC who had an inadequate response or intolerance to ursodeoxycholic acid (UDCA), the standard of care, and had no history of hepatic decompensation. Patients with cirrhosis were allowed to enroll.
A total of 158 patients from the RESPONSE trial, both from the placebo and from the active treatment arm, were rolled over into the ASSURE trial. Another subset of 179 patients were drawn from prior seladelpar placebo-controlled studies (referred to as “legacy studies”), including the ENHANCE study. All participants in the current analysis received 10 mg of seladelpar, once daily, for up to 155 weeks.
Of the participants from the legacy studies, 99 completed 24 months of treatment with seladelpar, and 164 completed 12 months of treatment. In the 24-month treatment group, 70% met the composite response endpoint, which included alkaline phosphatase (ALP) levels below 1.67 times the upper limit of normal, a decrease in ALP levels of at least 15%, and total bilirubin levels at or below the upper limit of normal, according to a press release of the study findings. In addition, 42% of these participants achieved ALP normalization at 24 months, a marker of liver disease progression. In the 12-month treatment group, 73% achieved the clinically meaningful composite response endpoint, with 42% experiencing ALP normalization.
For patients rolled over from RESPONSE, 102 received 18 months of treatment with seladelpar, and 29 received 24 months of treatment. A total of 62% of patients in the 18-month group achieved the composite endpoint, and 33% achieved ALP normalization, while 72% of the 24-month group reached the composite endpoint, and 17% had ALP normalization.
Of patients who had received a placebo in the RESPONSE trial and went on to receive treatment with seladelpar, 75% achieved the composite endpoint, 27% had ALP normalization at 6 months, and 94% achieved the composite endpoint and 50% reached ALP normalization at 12 months.
Key secondary endpoints included ALP normalization and changes in liver enzymes (ALP, total bilirubin, gamma-glutamyl transferase [GGT], alanine transaminase [ALT], and aspartate aminotransferase [AST]).
Pruritus Relief Important for Quality of Life
Among study participants who reported a four or more at baseline on the numerical rating scale (NRS) for pruritus, legacy patients at 12 months and 24 months of treatment reported a mean reduction of 3.8 and 3.1, respectively. Participants from RESPONSE also reported a mean reduction of 3.8.
This level of reduction in NRS is “considered clinically significant” and takes patients from a level of moderate to severe itching down to mild, said Carrie Frenette, MD, executive director, Global Medical Affairs, Liver Diseases, Gilead Sciences, Foster City, California, and a former hepatologist of 20 years with a special interest in liver transplantation.
This “is a huge benefit in quality of life for these patients,” Dr. Frenette said in an interview.
Dr. Frenette also noted that UDCA, the current first-line treatment for PBC, is inadequate in up to 40% of patients, and second-line treatments, notably obeticholic acid, can cause itching.
Eleonora De Martin, MD, transplant hepatologist at Centre Hépato-Biliaire, Paul Brousse Hospital, Paris, France, who comoderated the session, pointed out that PBC is a complex disease.
“We need both disease control and symptom control, and they’re not always compatible,” she said. “Sometimes you can control the disease but not the symptoms, and symptomatic control is so important,” especially with pruritus.
Patients With PBC and Cirrhosis
A separate analysis from ASSURE looked at a subset of 17 patients with PBC and cirrhosis who completed 24 months of treatment. The findings were presented by Stuart Gordon, MD, professor of medicine, Wayne State University School of Medicine, and hepatologist at Henry Ford Hospital, both in Detroit.
In this analysis, the mean patient age was 60.8 years, 91.4% were female, 88.6% were Child-Pugh A, and 22.9% had portal hypertension, while the mean baseline liver stiffness by FibroScan was 19.9 kPa.
Baseline biochemical measures were mean ALP of 245.4 U/L, mean total bilirubin of 0.995 mg/dL, mean GGT of 216.1 U/L, and mean ALT of 36.6 U/L.
A total of 11 participants (65%) met the composite endpoint at 24 months, with ALP normalization in 4 patients (24%). The overall mean percent change from baseline in ALP was approximately −30% and in total bilirubin was around −14%. Other changes in biochemical markers included reductions from baseline in GGT and ALT of approximately −30% and −10%, respectively. No change was observed in AST.
While 80% of patients with cirrhosis “had an adverse event of some form,” there were no treatment-related serious adverse events.
“It’s interesting to see results in these patients who have advanced disease and are cirrhotic because it might stabilize disease or even provide improvement,” Dr. De Martin commented. “However, the numbers in the study are very small, so it’s hard to draw firm conclusions yet, but it is a first step in showing that this drug is safe.”
Seladelpar is an “important step forward in PBC because we’ve been stuck with ursodeoxycholic acid for so many years,” Dr. De Martin added. “We’ve seen in liver disease with other etiologies that sometimes just one drug can make a difference, and you can change the natural history of the disease.”
Dr. Frenette is an employee and stockholder of Gilead Sciences. Dr. Gordon declared grants and support from AbbVie, Arbutus, CymaBay, Cour Pharmaceuticals, GlaxoSmithKline (GSK), Ipsen, and Mirum Pharmaceuticals; and advisory board activity from CymaBay, GSK, and Ipsen Pharmaceuticals. Dr. De Martin had no disclosures of relevance to seladelpar but has received speaker fees from other companies, including GSK, Ipsen, and Astellas. Dr. Trivedi reports institutional funding support from National Institute for Health Research Birmingham (UK); lecture fees from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, and Dr. Falk Pharma; advisory board/consulting fees from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, Chemomab Therapeutics, CymaBay, Dr. Falk Pharma, Gilead Sciences, Perspectum, and Pliant Therapeutics; and grant support from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, Bristol-Myers Squibb, Core (Guts UK), EASL, Gilead Sciences, GSK, LifeArc, NIHR, Mirum Pharma, PSC Support, The Wellcome Trust, The Medical Research Foundation (UK), and Regeneron.
A version of this article first appeared on Medscape.com.
MILAN — according to two interim analyses of the ASSURE long-term extension study.
The first analysis of 337 patients with PBC, with and without cirrhosis, showed that treatment with seladelpar had a durable effect up to 2 years on cholestasis and markers of liver injury, as well as a sustained reduction in pruritus, Palak Trivedi, MD, associate professor at the National Institute for Health Research Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, England, reported in a poster presented at the European Association for the Study of the Liver (EASL) Congress 2024.
The 2-year analysis also showed that seladelpar, a first-in-class, orally active agent, was safe and well tolerated in this patient population, he added.
These “results are consistent with the pivotal phase 3 RESPONSE study,” Dr. Trivedi noted. The RESPONSE study showed that seladelpar significantly improved liver biomarkers of disease activity and symptoms of pruritus at 12 months in patients with PBC who had an inadequate response or intolerance to ursodeoxycholic acid (UDCA), the standard of care, and had no history of hepatic decompensation. Patients with cirrhosis were allowed to enroll.
A total of 158 patients from the RESPONSE trial, both from the placebo and from the active treatment arm, were rolled over into the ASSURE trial. Another subset of 179 patients were drawn from prior seladelpar placebo-controlled studies (referred to as “legacy studies”), including the ENHANCE study. All participants in the current analysis received 10 mg of seladelpar, once daily, for up to 155 weeks.
Of the participants from the legacy studies, 99 completed 24 months of treatment with seladelpar, and 164 completed 12 months of treatment. In the 24-month treatment group, 70% met the composite response endpoint, which included alkaline phosphatase (ALP) levels below 1.67 times the upper limit of normal, a decrease in ALP levels of at least 15%, and total bilirubin levels at or below the upper limit of normal, according to a press release of the study findings. In addition, 42% of these participants achieved ALP normalization at 24 months, a marker of liver disease progression. In the 12-month treatment group, 73% achieved the clinically meaningful composite response endpoint, with 42% experiencing ALP normalization.
For patients rolled over from RESPONSE, 102 received 18 months of treatment with seladelpar, and 29 received 24 months of treatment. A total of 62% of patients in the 18-month group achieved the composite endpoint, and 33% achieved ALP normalization, while 72% of the 24-month group reached the composite endpoint, and 17% had ALP normalization.
Of patients who had received a placebo in the RESPONSE trial and went on to receive treatment with seladelpar, 75% achieved the composite endpoint, 27% had ALP normalization at 6 months, and 94% achieved the composite endpoint and 50% reached ALP normalization at 12 months.
Key secondary endpoints included ALP normalization and changes in liver enzymes (ALP, total bilirubin, gamma-glutamyl transferase [GGT], alanine transaminase [ALT], and aspartate aminotransferase [AST]).
Pruritus Relief Important for Quality of Life
Among study participants who reported a four or more at baseline on the numerical rating scale (NRS) for pruritus, legacy patients at 12 months and 24 months of treatment reported a mean reduction of 3.8 and 3.1, respectively. Participants from RESPONSE also reported a mean reduction of 3.8.
This level of reduction in NRS is “considered clinically significant” and takes patients from a level of moderate to severe itching down to mild, said Carrie Frenette, MD, executive director, Global Medical Affairs, Liver Diseases, Gilead Sciences, Foster City, California, and a former hepatologist of 20 years with a special interest in liver transplantation.
This “is a huge benefit in quality of life for these patients,” Dr. Frenette said in an interview.
Dr. Frenette also noted that UDCA, the current first-line treatment for PBC, is inadequate in up to 40% of patients, and second-line treatments, notably obeticholic acid, can cause itching.
Eleonora De Martin, MD, transplant hepatologist at Centre Hépato-Biliaire, Paul Brousse Hospital, Paris, France, who comoderated the session, pointed out that PBC is a complex disease.
“We need both disease control and symptom control, and they’re not always compatible,” she said. “Sometimes you can control the disease but not the symptoms, and symptomatic control is so important,” especially with pruritus.
Patients With PBC and Cirrhosis
A separate analysis from ASSURE looked at a subset of 17 patients with PBC and cirrhosis who completed 24 months of treatment. The findings were presented by Stuart Gordon, MD, professor of medicine, Wayne State University School of Medicine, and hepatologist at Henry Ford Hospital, both in Detroit.
In this analysis, the mean patient age was 60.8 years, 91.4% were female, 88.6% were Child-Pugh A, and 22.9% had portal hypertension, while the mean baseline liver stiffness by FibroScan was 19.9 kPa.
Baseline biochemical measures were mean ALP of 245.4 U/L, mean total bilirubin of 0.995 mg/dL, mean GGT of 216.1 U/L, and mean ALT of 36.6 U/L.
A total of 11 participants (65%) met the composite endpoint at 24 months, with ALP normalization in 4 patients (24%). The overall mean percent change from baseline in ALP was approximately −30% and in total bilirubin was around −14%. Other changes in biochemical markers included reductions from baseline in GGT and ALT of approximately −30% and −10%, respectively. No change was observed in AST.
While 80% of patients with cirrhosis “had an adverse event of some form,” there were no treatment-related serious adverse events.
“It’s interesting to see results in these patients who have advanced disease and are cirrhotic because it might stabilize disease or even provide improvement,” Dr. De Martin commented. “However, the numbers in the study are very small, so it’s hard to draw firm conclusions yet, but it is a first step in showing that this drug is safe.”
Seladelpar is an “important step forward in PBC because we’ve been stuck with ursodeoxycholic acid for so many years,” Dr. De Martin added. “We’ve seen in liver disease with other etiologies that sometimes just one drug can make a difference, and you can change the natural history of the disease.”
Dr. Frenette is an employee and stockholder of Gilead Sciences. Dr. Gordon declared grants and support from AbbVie, Arbutus, CymaBay, Cour Pharmaceuticals, GlaxoSmithKline (GSK), Ipsen, and Mirum Pharmaceuticals; and advisory board activity from CymaBay, GSK, and Ipsen Pharmaceuticals. Dr. De Martin had no disclosures of relevance to seladelpar but has received speaker fees from other companies, including GSK, Ipsen, and Astellas. Dr. Trivedi reports institutional funding support from National Institute for Health Research Birmingham (UK); lecture fees from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, and Dr. Falk Pharma; advisory board/consulting fees from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, Chemomab Therapeutics, CymaBay, Dr. Falk Pharma, Gilead Sciences, Perspectum, and Pliant Therapeutics; and grant support from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, Bristol-Myers Squibb, Core (Guts UK), EASL, Gilead Sciences, GSK, LifeArc, NIHR, Mirum Pharma, PSC Support, The Wellcome Trust, The Medical Research Foundation (UK), and Regeneron.
A version of this article first appeared on Medscape.com.
MILAN — according to two interim analyses of the ASSURE long-term extension study.
The first analysis of 337 patients with PBC, with and without cirrhosis, showed that treatment with seladelpar had a durable effect up to 2 years on cholestasis and markers of liver injury, as well as a sustained reduction in pruritus, Palak Trivedi, MD, associate professor at the National Institute for Health Research Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, England, reported in a poster presented at the European Association for the Study of the Liver (EASL) Congress 2024.
The 2-year analysis also showed that seladelpar, a first-in-class, orally active agent, was safe and well tolerated in this patient population, he added.
These “results are consistent with the pivotal phase 3 RESPONSE study,” Dr. Trivedi noted. The RESPONSE study showed that seladelpar significantly improved liver biomarkers of disease activity and symptoms of pruritus at 12 months in patients with PBC who had an inadequate response or intolerance to ursodeoxycholic acid (UDCA), the standard of care, and had no history of hepatic decompensation. Patients with cirrhosis were allowed to enroll.
A total of 158 patients from the RESPONSE trial, both from the placebo and from the active treatment arm, were rolled over into the ASSURE trial. Another subset of 179 patients were drawn from prior seladelpar placebo-controlled studies (referred to as “legacy studies”), including the ENHANCE study. All participants in the current analysis received 10 mg of seladelpar, once daily, for up to 155 weeks.
Of the participants from the legacy studies, 99 completed 24 months of treatment with seladelpar, and 164 completed 12 months of treatment. In the 24-month treatment group, 70% met the composite response endpoint, which included alkaline phosphatase (ALP) levels below 1.67 times the upper limit of normal, a decrease in ALP levels of at least 15%, and total bilirubin levels at or below the upper limit of normal, according to a press release of the study findings. In addition, 42% of these participants achieved ALP normalization at 24 months, a marker of liver disease progression. In the 12-month treatment group, 73% achieved the clinically meaningful composite response endpoint, with 42% experiencing ALP normalization.
For patients rolled over from RESPONSE, 102 received 18 months of treatment with seladelpar, and 29 received 24 months of treatment. A total of 62% of patients in the 18-month group achieved the composite endpoint, and 33% achieved ALP normalization, while 72% of the 24-month group reached the composite endpoint, and 17% had ALP normalization.
Of patients who had received a placebo in the RESPONSE trial and went on to receive treatment with seladelpar, 75% achieved the composite endpoint, 27% had ALP normalization at 6 months, and 94% achieved the composite endpoint and 50% reached ALP normalization at 12 months.
Key secondary endpoints included ALP normalization and changes in liver enzymes (ALP, total bilirubin, gamma-glutamyl transferase [GGT], alanine transaminase [ALT], and aspartate aminotransferase [AST]).
Pruritus Relief Important for Quality of Life
Among study participants who reported a four or more at baseline on the numerical rating scale (NRS) for pruritus, legacy patients at 12 months and 24 months of treatment reported a mean reduction of 3.8 and 3.1, respectively. Participants from RESPONSE also reported a mean reduction of 3.8.
This level of reduction in NRS is “considered clinically significant” and takes patients from a level of moderate to severe itching down to mild, said Carrie Frenette, MD, executive director, Global Medical Affairs, Liver Diseases, Gilead Sciences, Foster City, California, and a former hepatologist of 20 years with a special interest in liver transplantation.
This “is a huge benefit in quality of life for these patients,” Dr. Frenette said in an interview.
Dr. Frenette also noted that UDCA, the current first-line treatment for PBC, is inadequate in up to 40% of patients, and second-line treatments, notably obeticholic acid, can cause itching.
Eleonora De Martin, MD, transplant hepatologist at Centre Hépato-Biliaire, Paul Brousse Hospital, Paris, France, who comoderated the session, pointed out that PBC is a complex disease.
“We need both disease control and symptom control, and they’re not always compatible,” she said. “Sometimes you can control the disease but not the symptoms, and symptomatic control is so important,” especially with pruritus.
Patients With PBC and Cirrhosis
A separate analysis from ASSURE looked at a subset of 17 patients with PBC and cirrhosis who completed 24 months of treatment. The findings were presented by Stuart Gordon, MD, professor of medicine, Wayne State University School of Medicine, and hepatologist at Henry Ford Hospital, both in Detroit.
In this analysis, the mean patient age was 60.8 years, 91.4% were female, 88.6% were Child-Pugh A, and 22.9% had portal hypertension, while the mean baseline liver stiffness by FibroScan was 19.9 kPa.
Baseline biochemical measures were mean ALP of 245.4 U/L, mean total bilirubin of 0.995 mg/dL, mean GGT of 216.1 U/L, and mean ALT of 36.6 U/L.
A total of 11 participants (65%) met the composite endpoint at 24 months, with ALP normalization in 4 patients (24%). The overall mean percent change from baseline in ALP was approximately −30% and in total bilirubin was around −14%. Other changes in biochemical markers included reductions from baseline in GGT and ALT of approximately −30% and −10%, respectively. No change was observed in AST.
While 80% of patients with cirrhosis “had an adverse event of some form,” there were no treatment-related serious adverse events.
“It’s interesting to see results in these patients who have advanced disease and are cirrhotic because it might stabilize disease or even provide improvement,” Dr. De Martin commented. “However, the numbers in the study are very small, so it’s hard to draw firm conclusions yet, but it is a first step in showing that this drug is safe.”
Seladelpar is an “important step forward in PBC because we’ve been stuck with ursodeoxycholic acid for so many years,” Dr. De Martin added. “We’ve seen in liver disease with other etiologies that sometimes just one drug can make a difference, and you can change the natural history of the disease.”
Dr. Frenette is an employee and stockholder of Gilead Sciences. Dr. Gordon declared grants and support from AbbVie, Arbutus, CymaBay, Cour Pharmaceuticals, GlaxoSmithKline (GSK), Ipsen, and Mirum Pharmaceuticals; and advisory board activity from CymaBay, GSK, and Ipsen Pharmaceuticals. Dr. De Martin had no disclosures of relevance to seladelpar but has received speaker fees from other companies, including GSK, Ipsen, and Astellas. Dr. Trivedi reports institutional funding support from National Institute for Health Research Birmingham (UK); lecture fees from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, and Dr. Falk Pharma; advisory board/consulting fees from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, Chemomab Therapeutics, CymaBay, Dr. Falk Pharma, Gilead Sciences, Perspectum, and Pliant Therapeutics; and grant support from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, Bristol-Myers Squibb, Core (Guts UK), EASL, Gilead Sciences, GSK, LifeArc, NIHR, Mirum Pharma, PSC Support, The Wellcome Trust, The Medical Research Foundation (UK), and Regeneron.
A version of this article first appeared on Medscape.com.
FROM EASL 2024
In Prostate Cancer, Most Roads Lead to VA Pathway
The newly updated US Department of Veterans Affairs (VA) prostate cancer clinical pathway looks like a set of guidelines, but it’s really something unique. As attendees learned at an Association of VA Hematology/Oncology (AVAHO) regional meeting in Detroit in June, the clinical pathways are designed to point the way toward a standard ideal treatment for the majority of cases, not just to suggest a number of possible options.
“Pathways will always offer one scenario. They try to get oncologists to practice in a similar fashion so things can be managed more uniformly,” Michael M. Goodman, MD, told Federal Practitioner prior to the AVAHO meeting that was focused on prostate cancer care. Goodman is an associate professor of medicine with Atrium Health Wake Forest Baptist Medical Center and helped develop the VA genitourinary oncology pathways.
“The overall goal is not just to standardize care as much as possible but also to synthesize the best and most cost-effective practices,” Goodman said. For example, “If you have 5 different therapies, and they all have about the same efficacy and safety, and 1 is less costly than the other 4, then it would make sense to choose that.”
The VA has offered pathways for multiple types of cancer since 2021, and the pathway for prostate cancer is among the most comprehensive. The VA system updated the pathway in March 2024, is available online both via SharePoint and externally.
“It goes through the entire gamut from screening, diagnosis, and management to end of life,” Goodman explained. Multiple disciplines, from primary care and surgery to genetics and imaging, can rely on the pathway to assist decision-making.
In terms of screening, the pathway offers a flow map guiding the screening choices. In patients aged ≤ 54 years, only certain high-risk groups, such as African Americans and those with a family history of prostate cancer, should be screened. From ages 54 to 69 years, patients should be consulted as part of a shared decision making process, while screening is not recommended for patients aged ≥ 70 years.
Pathway flow maps also provide information about diagnostic standards, evaluation of the newly diagnosed, risk stratification, molecular testing, and end-of-life care.
Goodman says the pathway is now integrated into the VA electronic health record system via a template so clinicians can easily document pathway use. This allows the VA to track the use of the pathways locally, regionally, and nationally track the use of the pathways.
Clinicians are not mandated to follow every step in the pathway, but Goodman said the goal is > 80% adherence. If clinicians follow the standards, he said, “you’re considering efficacy, safety, and cost for that veteran.”
Prospective data suggests that adherence to the pathway eliminates certain disparities. African American veterans, for example, are as well-represented or even better represented than White veterans in prostate cancer care when pathways are followed.
Why might clinicians veer from the pathway? “If you’re seeing a patient who was treated in the community with drug X, but drug Y is chosen by the pathway, you can carry on with the previous care.” Alternatively, in some cases, patients may not tolerate the pathway standard, Goodman noted.
Goodman reports that he consults the pathway every day. “It’s helped standardize the care I provide to ensure there’s no gaps in how I’m treating patients.”
The newly updated US Department of Veterans Affairs (VA) prostate cancer clinical pathway looks like a set of guidelines, but it’s really something unique. As attendees learned at an Association of VA Hematology/Oncology (AVAHO) regional meeting in Detroit in June, the clinical pathways are designed to point the way toward a standard ideal treatment for the majority of cases, not just to suggest a number of possible options.
“Pathways will always offer one scenario. They try to get oncologists to practice in a similar fashion so things can be managed more uniformly,” Michael M. Goodman, MD, told Federal Practitioner prior to the AVAHO meeting that was focused on prostate cancer care. Goodman is an associate professor of medicine with Atrium Health Wake Forest Baptist Medical Center and helped develop the VA genitourinary oncology pathways.
“The overall goal is not just to standardize care as much as possible but also to synthesize the best and most cost-effective practices,” Goodman said. For example, “If you have 5 different therapies, and they all have about the same efficacy and safety, and 1 is less costly than the other 4, then it would make sense to choose that.”
The VA has offered pathways for multiple types of cancer since 2021, and the pathway for prostate cancer is among the most comprehensive. The VA system updated the pathway in March 2024, is available online both via SharePoint and externally.
“It goes through the entire gamut from screening, diagnosis, and management to end of life,” Goodman explained. Multiple disciplines, from primary care and surgery to genetics and imaging, can rely on the pathway to assist decision-making.
In terms of screening, the pathway offers a flow map guiding the screening choices. In patients aged ≤ 54 years, only certain high-risk groups, such as African Americans and those with a family history of prostate cancer, should be screened. From ages 54 to 69 years, patients should be consulted as part of a shared decision making process, while screening is not recommended for patients aged ≥ 70 years.
Pathway flow maps also provide information about diagnostic standards, evaluation of the newly diagnosed, risk stratification, molecular testing, and end-of-life care.
Goodman says the pathway is now integrated into the VA electronic health record system via a template so clinicians can easily document pathway use. This allows the VA to track the use of the pathways locally, regionally, and nationally track the use of the pathways.
Clinicians are not mandated to follow every step in the pathway, but Goodman said the goal is > 80% adherence. If clinicians follow the standards, he said, “you’re considering efficacy, safety, and cost for that veteran.”
Prospective data suggests that adherence to the pathway eliminates certain disparities. African American veterans, for example, are as well-represented or even better represented than White veterans in prostate cancer care when pathways are followed.
Why might clinicians veer from the pathway? “If you’re seeing a patient who was treated in the community with drug X, but drug Y is chosen by the pathway, you can carry on with the previous care.” Alternatively, in some cases, patients may not tolerate the pathway standard, Goodman noted.
Goodman reports that he consults the pathway every day. “It’s helped standardize the care I provide to ensure there’s no gaps in how I’m treating patients.”
The newly updated US Department of Veterans Affairs (VA) prostate cancer clinical pathway looks like a set of guidelines, but it’s really something unique. As attendees learned at an Association of VA Hematology/Oncology (AVAHO) regional meeting in Detroit in June, the clinical pathways are designed to point the way toward a standard ideal treatment for the majority of cases, not just to suggest a number of possible options.
“Pathways will always offer one scenario. They try to get oncologists to practice in a similar fashion so things can be managed more uniformly,” Michael M. Goodman, MD, told Federal Practitioner prior to the AVAHO meeting that was focused on prostate cancer care. Goodman is an associate professor of medicine with Atrium Health Wake Forest Baptist Medical Center and helped develop the VA genitourinary oncology pathways.
“The overall goal is not just to standardize care as much as possible but also to synthesize the best and most cost-effective practices,” Goodman said. For example, “If you have 5 different therapies, and they all have about the same efficacy and safety, and 1 is less costly than the other 4, then it would make sense to choose that.”
The VA has offered pathways for multiple types of cancer since 2021, and the pathway for prostate cancer is among the most comprehensive. The VA system updated the pathway in March 2024, is available online both via SharePoint and externally.
“It goes through the entire gamut from screening, diagnosis, and management to end of life,” Goodman explained. Multiple disciplines, from primary care and surgery to genetics and imaging, can rely on the pathway to assist decision-making.
In terms of screening, the pathway offers a flow map guiding the screening choices. In patients aged ≤ 54 years, only certain high-risk groups, such as African Americans and those with a family history of prostate cancer, should be screened. From ages 54 to 69 years, patients should be consulted as part of a shared decision making process, while screening is not recommended for patients aged ≥ 70 years.
Pathway flow maps also provide information about diagnostic standards, evaluation of the newly diagnosed, risk stratification, molecular testing, and end-of-life care.
Goodman says the pathway is now integrated into the VA electronic health record system via a template so clinicians can easily document pathway use. This allows the VA to track the use of the pathways locally, regionally, and nationally track the use of the pathways.
Clinicians are not mandated to follow every step in the pathway, but Goodman said the goal is > 80% adherence. If clinicians follow the standards, he said, “you’re considering efficacy, safety, and cost for that veteran.”
Prospective data suggests that adherence to the pathway eliminates certain disparities. African American veterans, for example, are as well-represented or even better represented than White veterans in prostate cancer care when pathways are followed.
Why might clinicians veer from the pathway? “If you’re seeing a patient who was treated in the community with drug X, but drug Y is chosen by the pathway, you can carry on with the previous care.” Alternatively, in some cases, patients may not tolerate the pathway standard, Goodman noted.
Goodman reports that he consults the pathway every day. “It’s helped standardize the care I provide to ensure there’s no gaps in how I’m treating patients.”
Tirzepatide Shows Improvements in MASH Resolution, Fibrosis
MILAN — , according to the results of the phase 2 SYNERGY-NASH trial.
Specifically, 44%-62% of participants with MASH and moderate or severe fibrosis treated with 5-15 mg of tirzepatide achieved MASH resolution without worsening of fibrosis compared with 10% on placebo; 51%-55% of those on tirzepatide achieved at least one stage of fibrosis improvement without worsening of MASH compared with 30% on placebo. Tirzepatide also led to weight loss.
The study (Abstract LBO-001) was presented at the European Association for the Study of the Liver (EASL) Congress 2024 by Rohit Loomba, MD, professor of medicine, NAFLD Research Center, University of California at San Diego in La Jolla, and published simultaneously in The New England Journal of Medicine.
“The results are clinically meaningful,” Dr. Loomba said in an interview.
Both of the endpoints — improvements in MASH resolution and fibrosis — are considered approvable endpoints for MASH therapeutic development, and therefore, increase the likelihood of success of using such a strategy in a phase 3 setting, Dr. Loomba said.
MASH Resolution, No Worsening of Fibrosis
The dose-finding, multicenter, double-blind, placebo-controlled trial randomly assigned a total of 190 participants to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. Participants had biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis.
Overall, approximately 42% of participants had F2 fibrosis and over 57% had F3 fibrosis. The proportion of F3 fibrosis was numerically higher in the placebo (64.6%) and 5-mg tirzepatide (63.8%) groups.
The mean age of the study cohort was 54 years; 57% were female, 86% were White, and 36% were Hispanic; the mean body mass index was 36; 58% had type 2 diabetes; and A1c was 6.5. NAFLD activity score (NAS) was 5.3. Baseline noninvasive test results were consistent with the study population of MASH with F2/F3 fibrosis and NAS ≥ 4.
The primary endpoint was resolution of MASH without worsening of fibrosis at 52 weeks, and the key secondary endpoint was an improvement (decrease) of at least one fibrosis stage without worsening of MASH. Other secondary endpoints included a ≥ 2-point decrease in NAS with ≤ 1-point decrease in two or more NAS components.
A total of 157 participants (83%) underwent liver biopsies at week 52, providing results for the current analysis.
Among tirzepatide-treated patients, 43.6% in the 5-mg group, 55.5% in the 10-mg group, and 62.4% in the 15-mg group met the criteria for resolution of MASH without worsening of fibrosis compared with 10% in the placebo group (P < .001 for all three comparisons).
Fibrosis improved by at least one stage without worsening of MASH in 54.9% of participants in the 5-mg tirzepatide group, 51.3% in the 10-mg tirzepatide group, and 51.0% in the 15-mg tirzepatide group compared with 29.7% in the placebo group (P < .001 for all risk differences with placebo).
Changes in NAS and subscores for the individual components of NAS, including steatosis, lobular inflammation, and hepatocellular ballooning, were also seen in participants on tirzepatide.
The researchers used a composite endpoint of a ≥ 2-point decrease in NAS with a ≥ 1-point decrease in at least two NAS components. Of the tirzepatide-treated groups, 71.7%,78.3%, and 76.6% in the 5-mg, 10-mg, and 15-mg groups, respectively, met this endpoint compared with 36.7% in placebo.
Imaging of liver fat with MRI-based proton density fat fraction (MRI-PDFF) showed reductions from baseline of -45.7, -41.3, -57.0 in participants on 5-mg, 10-mg, and 15-mg tirzepatide, respectively. Differences from placebo were all statistically significant.
Percentage of body weight change from baseline was -10.7%, -13.3%, and -15.6% in the 5-mg, 10-mg, and 15-mg tirzepatide groups, respectively, compared with weight loss of -0.8% in the placebo group.
“Tirzepatide led to significant weight loss in both patients with diabetes and those without diabetes,” reported Dr. Loomba.
There were more adverse events in patients on tirzepatide (92.3%) compared with patients on placebo (83.3%).
“The most common adverse events were gastrointestinal in nature, with 96% of them mild to moderate in severity,” said Dr. Loomba. “Discontinuations occurred in 4.2% of participants, which was similar between patients on tirzepatide and those on placebo.”
He pointed out that the safety profile of tirzepatide in a MASH population “was generally similar to that observed in the phase 3 trials of type 2 diabetes and obesity.”
Incidence of serious adverse events was also similar at 6.3% for participants on tirzepatide vs 6.2% for those on placebo; 2.8% on tirzepatide and 4.2% on placebo progressed to cirrhosis. There was no evidence of drug-induced liver injury.
‘Convincing Results’
Commenting on the study, co-moderator Sven Francque, MD, hepatologist and head of department at the University Hospital of Antwerp, Belgium, said that the study was in a relatively “severe” patient population, which was one of its strengths.
“These are convincing results in terms of MASH resolution, showing a strong response and dose-dependence,” he said.
“In terms of fibrosis, the results look numerically strong but are somewhat more puzzling to interpret, as there was no dose-response relationship and no data on NITs [noninvasive tests] that could support the results,” he added.
“Patients with no-end-of-treatment biopsies were handled differently than in previous trials, which makes it difficult to appreciate antifibrotic potency,” he said. But “such a strong effect on MASH should translate into a reduction in fibrosis even in the absence of direct antifibrotic effects.”
Given that “about one third of patients in the active treatment arms” did not have end-of-treatment biopsy, these “are rather small numbers precluding firm conclusions,” he added.
However, Dr. Francque said that he believes the findings are compelling enough for the drug to go into phase 3 trials.
Dr. Francque has no disclosures of relevance to this study. Dr. Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse Bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals and Viking Therapeutics. In addition, his institutions received research grants from Arrowhead Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Merck, Pfizer, Sonic Incytes, and Terns Pharmaceuticals. Dr. Loomba is a co-founder of LipoNexus.
A version of this article first appeared on Medscape.com.
MILAN — , according to the results of the phase 2 SYNERGY-NASH trial.
Specifically, 44%-62% of participants with MASH and moderate or severe fibrosis treated with 5-15 mg of tirzepatide achieved MASH resolution without worsening of fibrosis compared with 10% on placebo; 51%-55% of those on tirzepatide achieved at least one stage of fibrosis improvement without worsening of MASH compared with 30% on placebo. Tirzepatide also led to weight loss.
The study (Abstract LBO-001) was presented at the European Association for the Study of the Liver (EASL) Congress 2024 by Rohit Loomba, MD, professor of medicine, NAFLD Research Center, University of California at San Diego in La Jolla, and published simultaneously in The New England Journal of Medicine.
“The results are clinically meaningful,” Dr. Loomba said in an interview.
Both of the endpoints — improvements in MASH resolution and fibrosis — are considered approvable endpoints for MASH therapeutic development, and therefore, increase the likelihood of success of using such a strategy in a phase 3 setting, Dr. Loomba said.
MASH Resolution, No Worsening of Fibrosis
The dose-finding, multicenter, double-blind, placebo-controlled trial randomly assigned a total of 190 participants to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. Participants had biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis.
Overall, approximately 42% of participants had F2 fibrosis and over 57% had F3 fibrosis. The proportion of F3 fibrosis was numerically higher in the placebo (64.6%) and 5-mg tirzepatide (63.8%) groups.
The mean age of the study cohort was 54 years; 57% were female, 86% were White, and 36% were Hispanic; the mean body mass index was 36; 58% had type 2 diabetes; and A1c was 6.5. NAFLD activity score (NAS) was 5.3. Baseline noninvasive test results were consistent with the study population of MASH with F2/F3 fibrosis and NAS ≥ 4.
The primary endpoint was resolution of MASH without worsening of fibrosis at 52 weeks, and the key secondary endpoint was an improvement (decrease) of at least one fibrosis stage without worsening of MASH. Other secondary endpoints included a ≥ 2-point decrease in NAS with ≤ 1-point decrease in two or more NAS components.
A total of 157 participants (83%) underwent liver biopsies at week 52, providing results for the current analysis.
Among tirzepatide-treated patients, 43.6% in the 5-mg group, 55.5% in the 10-mg group, and 62.4% in the 15-mg group met the criteria for resolution of MASH without worsening of fibrosis compared with 10% in the placebo group (P < .001 for all three comparisons).
Fibrosis improved by at least one stage without worsening of MASH in 54.9% of participants in the 5-mg tirzepatide group, 51.3% in the 10-mg tirzepatide group, and 51.0% in the 15-mg tirzepatide group compared with 29.7% in the placebo group (P < .001 for all risk differences with placebo).
Changes in NAS and subscores for the individual components of NAS, including steatosis, lobular inflammation, and hepatocellular ballooning, were also seen in participants on tirzepatide.
The researchers used a composite endpoint of a ≥ 2-point decrease in NAS with a ≥ 1-point decrease in at least two NAS components. Of the tirzepatide-treated groups, 71.7%,78.3%, and 76.6% in the 5-mg, 10-mg, and 15-mg groups, respectively, met this endpoint compared with 36.7% in placebo.
Imaging of liver fat with MRI-based proton density fat fraction (MRI-PDFF) showed reductions from baseline of -45.7, -41.3, -57.0 in participants on 5-mg, 10-mg, and 15-mg tirzepatide, respectively. Differences from placebo were all statistically significant.
Percentage of body weight change from baseline was -10.7%, -13.3%, and -15.6% in the 5-mg, 10-mg, and 15-mg tirzepatide groups, respectively, compared with weight loss of -0.8% in the placebo group.
“Tirzepatide led to significant weight loss in both patients with diabetes and those without diabetes,” reported Dr. Loomba.
There were more adverse events in patients on tirzepatide (92.3%) compared with patients on placebo (83.3%).
“The most common adverse events were gastrointestinal in nature, with 96% of them mild to moderate in severity,” said Dr. Loomba. “Discontinuations occurred in 4.2% of participants, which was similar between patients on tirzepatide and those on placebo.”
He pointed out that the safety profile of tirzepatide in a MASH population “was generally similar to that observed in the phase 3 trials of type 2 diabetes and obesity.”
Incidence of serious adverse events was also similar at 6.3% for participants on tirzepatide vs 6.2% for those on placebo; 2.8% on tirzepatide and 4.2% on placebo progressed to cirrhosis. There was no evidence of drug-induced liver injury.
‘Convincing Results’
Commenting on the study, co-moderator Sven Francque, MD, hepatologist and head of department at the University Hospital of Antwerp, Belgium, said that the study was in a relatively “severe” patient population, which was one of its strengths.
“These are convincing results in terms of MASH resolution, showing a strong response and dose-dependence,” he said.
“In terms of fibrosis, the results look numerically strong but are somewhat more puzzling to interpret, as there was no dose-response relationship and no data on NITs [noninvasive tests] that could support the results,” he added.
“Patients with no-end-of-treatment biopsies were handled differently than in previous trials, which makes it difficult to appreciate antifibrotic potency,” he said. But “such a strong effect on MASH should translate into a reduction in fibrosis even in the absence of direct antifibrotic effects.”
Given that “about one third of patients in the active treatment arms” did not have end-of-treatment biopsy, these “are rather small numbers precluding firm conclusions,” he added.
However, Dr. Francque said that he believes the findings are compelling enough for the drug to go into phase 3 trials.
Dr. Francque has no disclosures of relevance to this study. Dr. Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse Bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals and Viking Therapeutics. In addition, his institutions received research grants from Arrowhead Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Merck, Pfizer, Sonic Incytes, and Terns Pharmaceuticals. Dr. Loomba is a co-founder of LipoNexus.
A version of this article first appeared on Medscape.com.
MILAN — , according to the results of the phase 2 SYNERGY-NASH trial.
Specifically, 44%-62% of participants with MASH and moderate or severe fibrosis treated with 5-15 mg of tirzepatide achieved MASH resolution without worsening of fibrosis compared with 10% on placebo; 51%-55% of those on tirzepatide achieved at least one stage of fibrosis improvement without worsening of MASH compared with 30% on placebo. Tirzepatide also led to weight loss.
The study (Abstract LBO-001) was presented at the European Association for the Study of the Liver (EASL) Congress 2024 by Rohit Loomba, MD, professor of medicine, NAFLD Research Center, University of California at San Diego in La Jolla, and published simultaneously in The New England Journal of Medicine.
“The results are clinically meaningful,” Dr. Loomba said in an interview.
Both of the endpoints — improvements in MASH resolution and fibrosis — are considered approvable endpoints for MASH therapeutic development, and therefore, increase the likelihood of success of using such a strategy in a phase 3 setting, Dr. Loomba said.
MASH Resolution, No Worsening of Fibrosis
The dose-finding, multicenter, double-blind, placebo-controlled trial randomly assigned a total of 190 participants to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. Participants had biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis.
Overall, approximately 42% of participants had F2 fibrosis and over 57% had F3 fibrosis. The proportion of F3 fibrosis was numerically higher in the placebo (64.6%) and 5-mg tirzepatide (63.8%) groups.
The mean age of the study cohort was 54 years; 57% were female, 86% were White, and 36% were Hispanic; the mean body mass index was 36; 58% had type 2 diabetes; and A1c was 6.5. NAFLD activity score (NAS) was 5.3. Baseline noninvasive test results were consistent with the study population of MASH with F2/F3 fibrosis and NAS ≥ 4.
The primary endpoint was resolution of MASH without worsening of fibrosis at 52 weeks, and the key secondary endpoint was an improvement (decrease) of at least one fibrosis stage without worsening of MASH. Other secondary endpoints included a ≥ 2-point decrease in NAS with ≤ 1-point decrease in two or more NAS components.
A total of 157 participants (83%) underwent liver biopsies at week 52, providing results for the current analysis.
Among tirzepatide-treated patients, 43.6% in the 5-mg group, 55.5% in the 10-mg group, and 62.4% in the 15-mg group met the criteria for resolution of MASH without worsening of fibrosis compared with 10% in the placebo group (P < .001 for all three comparisons).
Fibrosis improved by at least one stage without worsening of MASH in 54.9% of participants in the 5-mg tirzepatide group, 51.3% in the 10-mg tirzepatide group, and 51.0% in the 15-mg tirzepatide group compared with 29.7% in the placebo group (P < .001 for all risk differences with placebo).
Changes in NAS and subscores for the individual components of NAS, including steatosis, lobular inflammation, and hepatocellular ballooning, were also seen in participants on tirzepatide.
The researchers used a composite endpoint of a ≥ 2-point decrease in NAS with a ≥ 1-point decrease in at least two NAS components. Of the tirzepatide-treated groups, 71.7%,78.3%, and 76.6% in the 5-mg, 10-mg, and 15-mg groups, respectively, met this endpoint compared with 36.7% in placebo.
Imaging of liver fat with MRI-based proton density fat fraction (MRI-PDFF) showed reductions from baseline of -45.7, -41.3, -57.0 in participants on 5-mg, 10-mg, and 15-mg tirzepatide, respectively. Differences from placebo were all statistically significant.
Percentage of body weight change from baseline was -10.7%, -13.3%, and -15.6% in the 5-mg, 10-mg, and 15-mg tirzepatide groups, respectively, compared with weight loss of -0.8% in the placebo group.
“Tirzepatide led to significant weight loss in both patients with diabetes and those without diabetes,” reported Dr. Loomba.
There were more adverse events in patients on tirzepatide (92.3%) compared with patients on placebo (83.3%).
“The most common adverse events were gastrointestinal in nature, with 96% of them mild to moderate in severity,” said Dr. Loomba. “Discontinuations occurred in 4.2% of participants, which was similar between patients on tirzepatide and those on placebo.”
He pointed out that the safety profile of tirzepatide in a MASH population “was generally similar to that observed in the phase 3 trials of type 2 diabetes and obesity.”
Incidence of serious adverse events was also similar at 6.3% for participants on tirzepatide vs 6.2% for those on placebo; 2.8% on tirzepatide and 4.2% on placebo progressed to cirrhosis. There was no evidence of drug-induced liver injury.
‘Convincing Results’
Commenting on the study, co-moderator Sven Francque, MD, hepatologist and head of department at the University Hospital of Antwerp, Belgium, said that the study was in a relatively “severe” patient population, which was one of its strengths.
“These are convincing results in terms of MASH resolution, showing a strong response and dose-dependence,” he said.
“In terms of fibrosis, the results look numerically strong but are somewhat more puzzling to interpret, as there was no dose-response relationship and no data on NITs [noninvasive tests] that could support the results,” he added.
“Patients with no-end-of-treatment biopsies were handled differently than in previous trials, which makes it difficult to appreciate antifibrotic potency,” he said. But “such a strong effect on MASH should translate into a reduction in fibrosis even in the absence of direct antifibrotic effects.”
Given that “about one third of patients in the active treatment arms” did not have end-of-treatment biopsy, these “are rather small numbers precluding firm conclusions,” he added.
However, Dr. Francque said that he believes the findings are compelling enough for the drug to go into phase 3 trials.
Dr. Francque has no disclosures of relevance to this study. Dr. Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse Bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals and Viking Therapeutics. In addition, his institutions received research grants from Arrowhead Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Merck, Pfizer, Sonic Incytes, and Terns Pharmaceuticals. Dr. Loomba is a co-founder of LipoNexus.
A version of this article first appeared on Medscape.com.
FROM EASL 2024
New ADC results mixed in metastatic breast cancer
CHICAGO — Indications are expanding, new agents are emerging, combinations with other drug classes are being tested, and many patients with this disease are now receiving more than one ADC.
ADCs use antibodies to bind to the surface proteins of cancer cells to deliver a potent payload of cytotoxic chemotherapy. Three are approved for use in pretreated patients with metastatic breast cancer: sacituzumab govitecan, or SG, for patients with triple-negative disease; trastuzumab deruxtecan, or T-DXd, for patients with HER2-positive and HER2-low disease; and trastuzumab emtansine, or T-DM1, for patients with HER2-positive disease. A fourth agent, datopotamab deruxtecan, or Dato-DXd, is being assessed by the US Food and Drug Administration (FDA) for use in pretreated HR-positive, HER2-negative patients, and others, including sacituzumab tirumotecan, are being tested in clinical trials.At the annual meeting of the American Society of Clinical Oncology, T-DXd (Enhertu, AstraZeneca) showed better progression free survival than chemotherapy in people with HR-positive, HER 2-low metastatic breast cancers. These findings, from the DESTINY Breast-06 trial, were among the most talked-about at ASCO, and are likely to change clinical practice (J Clin Oncol. 2024;42[suppl 17; abstr LBA1000]).
But other ADC results presented at ASCO showed that there is still much to be worked out about the timing and sequencing of these agents, as well as their synergy with other drug classes, in metastatic breast cancer.
An ADC gets its first test, and falls short
Antonio Giordano, MD, PhD, of the Dana-Farber Cancer Institute in Boston, presented findings from an open-label phase 2 study of the ADC enfortumab vedotin (EV), an agent currently approved for use in advanced or metastatic urothelial cancer, at ASCO. This study included two cohorts of previously treated metastatic breast cancer patients: one with triple-negative disease (n = 42) and the other with HR-positive HER2-negative (n = 45).
Dr. Giordano and his colleagues’ study is the first to look at this ADC in breast cancer. EV’s antibody targets the cell adhesion molecule Nectin-4.
The researchers found that though EV demonstrated anti-tumor activity in both cohorts — with 19% of the triple-negative patients and 15.6% of the HR-positive/HER2-negative patients responding — the results did not meet the prespecified response thresholds for either cohort. (J Clin Oncol. 2024;42[suppl 16; abstr 1005]).
In an interview, Dr. Giordano said that studies in urothelial cancer had shown better response to EV associated with more expression of Nectin-4, but this study did not see such clear associations between expression and response. While there is no question that Nectin-4 is highly expressed in breast cancer and therefore a viable target, he said, “it may need to be looked at a little more deeply.”
It could also be the case, Dr. Giordano said, that the effect of EV’s payload may have been less robust in participants who had been previously treated with taxane chemotherapy, as nearly all patients in the two cohorts were.
“Taxanes are microtubule disruptors. And with this drug we had a payload with pretty much the same mechanism of action,” Dr. Giordano said. Ideally, he said, he would like to test the agent in a first-line setting, possibly in combination with an immunotherapy agent.
The timing of ADCs is as important as their targets and their payloads — and something that investigators are still struggling to figure out, he said.
A third of the patients in the triple-negative cohort of his study had been previously treated with SG, and a handful of individuals with T-Dxd, he noted.
“We’re in the middle of an ADC revolution,” he said. “It’s really key to figure out the best sequencing for a patient and if it’s actually worth it to do it. Very often we see patients respond best to the first ADC. But sometimes we see patients that do not respond to the first ADC and then they respond to the second one. It’s not very frequent, but it happens.”
Hint of Benefit from Adding Immunotherapy to SG
In a separate presentation at ASCO, Ana C. Garrido-Castro, MD, also of the Dana-Farber Cancer Institute, presented results from the SACI-IO HR+ trial, a randomized phase 2 study of SG (Trodelvy, Gilead) with and without pembrolizumab (Keytruda, Merck) in 104 patients with metastatic HR-positive/HER2-negative breast cancer who received prior endocrine therapy and up to one chemotherapy regimen for advanced disease. SACI-IO HR+ is the first randomized trial to report the efficacy of a topoisomerase I-inhibitor ADC with an immune checkpoint inhibitor for the treatment of breast cancer.
The addition of the immune checkpoint inhibitor did not result in a significant improvement in median progression-free survival in the overall population, Dr. Garrido-Castro reported. Median PFS was 8.1 vs 6.2 months with the combination of SG plus pembrolizumab or sacituzumab govitecan alone, respectively. At a median follow-up of 12.5 months, there was also no significant difference seen in median overall survival (OS): 18.5 vs 18.0 months.
About 40% of participants were found to have PD-L1-positive tumors and, among this subgroup, there was a 4.4-month increase in median PFS and 6.0-month increase in median OS with the addition of pembrolizumab to SG, although this did not reach statistical significance. (J Clin Oncol. 2024;42[suppl 17; abstr LBA1004]).
“While the study did not demonstrate a statistically significant benefit with the addition of the immune checkpoint inhibitor to the ADC, there is an interesting signal for potential synergistic activity between the two agents, particularly in those patients with PD-L1 positive tumors,” Dr. Garrido-Castro said in an interview. She noted that the sample sizes for the PD-L1 subgroup were relatively small, and overall survival data are not yet mature.
A separate phase 3 study is looking at the experimental ADC called sacituzumab tirumotecan with and without pembrolizumab compared with chemotherapy in patients with metastatic HR-positive, HER2-negative breast cancer who have received prior endocrine therapy and no prior chemotherapy for metastatic disease, she said.
Similar to SG, sacituzumab tirumotecan is a TROP2-directed ADC with a topoisomerase I-inhibitor payload. With an estimated enrollment of 1,200 patients, this trial may help shed light on whether adding the immune checkpoint inhibitor to the topoisomerase I-inhibitor TROP2-directed ADC improves outcomes in the subgroup of patients with PD-L1 positive tumors, Dr. Garrido-Castro said.
Unlocking the Order and Timing of ADCs
Dr. Garrido-Castro is also leading a study that will evaluate the sequential use of ADCs in metastatic breast cancer. That trial, to be called TRADE-DXd, will enroll patients with HER2-low metastatic breast cancer who have received up to one prior line of chemotherapy and no previous topoisomerase I-inhibitors. Participants will receive either T-DXd or Dato-DXd as the first ADC, and then switch to the other ADC (Dato-DXd or T-DXd, respectively) at the time of progression, thus switching the target of the ADC from HER2 to TROP2 or vice versa.
“In real-world practice now, there are patients who receive sequential ADCs, because they are candidates for both,” Dr. Garrido-Castro explained. However, more robust data are needed to refine the selection of the initial antibody drug conjugate and to determine who is more likely to benefit from a second — or maybe even third — ADC.
“One potential mechanism of resistance to antibody drug conjugates is the downregulation of the target of the antibody drug conjugate,” Dr. Garrido-Castro said. “Thus, an important question is, if you modify the target of the ADC, is it possible to overcome that mechanism of resistance?” Another possible mechanism of resistance is to the chemotherapy payload of the ADCs, she said.
Dr. Garrido-Castro’s study will collect tumor samples and blood samples for the purposes of planned correlative analyses to try to better understand the mechanisms that drive response and resistance to these agents.
Dr. Giordano commented that Dr. Garrido-Castro’s study was likely to result in a much better understanding of ADCs and how to use them strategically.
At Dana-Farber, “we collect a lot of samples of patients receiving ADCs. And we are trying to do all kinds of work on circulating tumor DNA, immunohistochemistry expression, and protein expression,” he said. “We are trying to figure out how ADCs really work, and why they stop working.”
Dr. Giordano and colleagues’ study was funded by Astellas Pharma and by Seagen, which was bought by Pfizer in 2023. Dr. Giordano disclosed receiving consulting fees from Pfizer, and several of his coauthors reported relationships with this and other companies. Two were Astellas employees.
Dr. Garrido-Castro and colleagues’ study was funded by Merck and Gilead Sciences. Dr. Garrido-Castro disclosed receiving research support from Gilead Sciences, AstraZeneca, Daiichi Sankyo, Merck, Zenith Epigenetics, Bristol-Myers Squibb, Novartis, Biovica, Foundation Medicine, 4D Path, Precede Biosciences; scientific advisory board/consulting fees from AstraZeneca, Novartis, Daiichi Sankyo; speaker honoraria from AstraZeneca, Daiichi Sankyo; and other support from Roche/Genentech, Gilead Sciences, AstraZeneca, Daiichi Sankyo, Novartis, and Merck, while her coauthors reported similar relationships.
CHICAGO — Indications are expanding, new agents are emerging, combinations with other drug classes are being tested, and many patients with this disease are now receiving more than one ADC.
ADCs use antibodies to bind to the surface proteins of cancer cells to deliver a potent payload of cytotoxic chemotherapy. Three are approved for use in pretreated patients with metastatic breast cancer: sacituzumab govitecan, or SG, for patients with triple-negative disease; trastuzumab deruxtecan, or T-DXd, for patients with HER2-positive and HER2-low disease; and trastuzumab emtansine, or T-DM1, for patients with HER2-positive disease. A fourth agent, datopotamab deruxtecan, or Dato-DXd, is being assessed by the US Food and Drug Administration (FDA) for use in pretreated HR-positive, HER2-negative patients, and others, including sacituzumab tirumotecan, are being tested in clinical trials.At the annual meeting of the American Society of Clinical Oncology, T-DXd (Enhertu, AstraZeneca) showed better progression free survival than chemotherapy in people with HR-positive, HER 2-low metastatic breast cancers. These findings, from the DESTINY Breast-06 trial, were among the most talked-about at ASCO, and are likely to change clinical practice (J Clin Oncol. 2024;42[suppl 17; abstr LBA1000]).
But other ADC results presented at ASCO showed that there is still much to be worked out about the timing and sequencing of these agents, as well as their synergy with other drug classes, in metastatic breast cancer.
An ADC gets its first test, and falls short
Antonio Giordano, MD, PhD, of the Dana-Farber Cancer Institute in Boston, presented findings from an open-label phase 2 study of the ADC enfortumab vedotin (EV), an agent currently approved for use in advanced or metastatic urothelial cancer, at ASCO. This study included two cohorts of previously treated metastatic breast cancer patients: one with triple-negative disease (n = 42) and the other with HR-positive HER2-negative (n = 45).
Dr. Giordano and his colleagues’ study is the first to look at this ADC in breast cancer. EV’s antibody targets the cell adhesion molecule Nectin-4.
The researchers found that though EV demonstrated anti-tumor activity in both cohorts — with 19% of the triple-negative patients and 15.6% of the HR-positive/HER2-negative patients responding — the results did not meet the prespecified response thresholds for either cohort. (J Clin Oncol. 2024;42[suppl 16; abstr 1005]).
In an interview, Dr. Giordano said that studies in urothelial cancer had shown better response to EV associated with more expression of Nectin-4, but this study did not see such clear associations between expression and response. While there is no question that Nectin-4 is highly expressed in breast cancer and therefore a viable target, he said, “it may need to be looked at a little more deeply.”
It could also be the case, Dr. Giordano said, that the effect of EV’s payload may have been less robust in participants who had been previously treated with taxane chemotherapy, as nearly all patients in the two cohorts were.
“Taxanes are microtubule disruptors. And with this drug we had a payload with pretty much the same mechanism of action,” Dr. Giordano said. Ideally, he said, he would like to test the agent in a first-line setting, possibly in combination with an immunotherapy agent.
The timing of ADCs is as important as their targets and their payloads — and something that investigators are still struggling to figure out, he said.
A third of the patients in the triple-negative cohort of his study had been previously treated with SG, and a handful of individuals with T-Dxd, he noted.
“We’re in the middle of an ADC revolution,” he said. “It’s really key to figure out the best sequencing for a patient and if it’s actually worth it to do it. Very often we see patients respond best to the first ADC. But sometimes we see patients that do not respond to the first ADC and then they respond to the second one. It’s not very frequent, but it happens.”
Hint of Benefit from Adding Immunotherapy to SG
In a separate presentation at ASCO, Ana C. Garrido-Castro, MD, also of the Dana-Farber Cancer Institute, presented results from the SACI-IO HR+ trial, a randomized phase 2 study of SG (Trodelvy, Gilead) with and without pembrolizumab (Keytruda, Merck) in 104 patients with metastatic HR-positive/HER2-negative breast cancer who received prior endocrine therapy and up to one chemotherapy regimen for advanced disease. SACI-IO HR+ is the first randomized trial to report the efficacy of a topoisomerase I-inhibitor ADC with an immune checkpoint inhibitor for the treatment of breast cancer.
The addition of the immune checkpoint inhibitor did not result in a significant improvement in median progression-free survival in the overall population, Dr. Garrido-Castro reported. Median PFS was 8.1 vs 6.2 months with the combination of SG plus pembrolizumab or sacituzumab govitecan alone, respectively. At a median follow-up of 12.5 months, there was also no significant difference seen in median overall survival (OS): 18.5 vs 18.0 months.
About 40% of participants were found to have PD-L1-positive tumors and, among this subgroup, there was a 4.4-month increase in median PFS and 6.0-month increase in median OS with the addition of pembrolizumab to SG, although this did not reach statistical significance. (J Clin Oncol. 2024;42[suppl 17; abstr LBA1004]).
“While the study did not demonstrate a statistically significant benefit with the addition of the immune checkpoint inhibitor to the ADC, there is an interesting signal for potential synergistic activity between the two agents, particularly in those patients with PD-L1 positive tumors,” Dr. Garrido-Castro said in an interview. She noted that the sample sizes for the PD-L1 subgroup were relatively small, and overall survival data are not yet mature.
A separate phase 3 study is looking at the experimental ADC called sacituzumab tirumotecan with and without pembrolizumab compared with chemotherapy in patients with metastatic HR-positive, HER2-negative breast cancer who have received prior endocrine therapy and no prior chemotherapy for metastatic disease, she said.
Similar to SG, sacituzumab tirumotecan is a TROP2-directed ADC with a topoisomerase I-inhibitor payload. With an estimated enrollment of 1,200 patients, this trial may help shed light on whether adding the immune checkpoint inhibitor to the topoisomerase I-inhibitor TROP2-directed ADC improves outcomes in the subgroup of patients with PD-L1 positive tumors, Dr. Garrido-Castro said.
Unlocking the Order and Timing of ADCs
Dr. Garrido-Castro is also leading a study that will evaluate the sequential use of ADCs in metastatic breast cancer. That trial, to be called TRADE-DXd, will enroll patients with HER2-low metastatic breast cancer who have received up to one prior line of chemotherapy and no previous topoisomerase I-inhibitors. Participants will receive either T-DXd or Dato-DXd as the first ADC, and then switch to the other ADC (Dato-DXd or T-DXd, respectively) at the time of progression, thus switching the target of the ADC from HER2 to TROP2 or vice versa.
“In real-world practice now, there are patients who receive sequential ADCs, because they are candidates for both,” Dr. Garrido-Castro explained. However, more robust data are needed to refine the selection of the initial antibody drug conjugate and to determine who is more likely to benefit from a second — or maybe even third — ADC.
“One potential mechanism of resistance to antibody drug conjugates is the downregulation of the target of the antibody drug conjugate,” Dr. Garrido-Castro said. “Thus, an important question is, if you modify the target of the ADC, is it possible to overcome that mechanism of resistance?” Another possible mechanism of resistance is to the chemotherapy payload of the ADCs, she said.
Dr. Garrido-Castro’s study will collect tumor samples and blood samples for the purposes of planned correlative analyses to try to better understand the mechanisms that drive response and resistance to these agents.
Dr. Giordano commented that Dr. Garrido-Castro’s study was likely to result in a much better understanding of ADCs and how to use them strategically.
At Dana-Farber, “we collect a lot of samples of patients receiving ADCs. And we are trying to do all kinds of work on circulating tumor DNA, immunohistochemistry expression, and protein expression,” he said. “We are trying to figure out how ADCs really work, and why they stop working.”
Dr. Giordano and colleagues’ study was funded by Astellas Pharma and by Seagen, which was bought by Pfizer in 2023. Dr. Giordano disclosed receiving consulting fees from Pfizer, and several of his coauthors reported relationships with this and other companies. Two were Astellas employees.
Dr. Garrido-Castro and colleagues’ study was funded by Merck and Gilead Sciences. Dr. Garrido-Castro disclosed receiving research support from Gilead Sciences, AstraZeneca, Daiichi Sankyo, Merck, Zenith Epigenetics, Bristol-Myers Squibb, Novartis, Biovica, Foundation Medicine, 4D Path, Precede Biosciences; scientific advisory board/consulting fees from AstraZeneca, Novartis, Daiichi Sankyo; speaker honoraria from AstraZeneca, Daiichi Sankyo; and other support from Roche/Genentech, Gilead Sciences, AstraZeneca, Daiichi Sankyo, Novartis, and Merck, while her coauthors reported similar relationships.
CHICAGO — Indications are expanding, new agents are emerging, combinations with other drug classes are being tested, and many patients with this disease are now receiving more than one ADC.
ADCs use antibodies to bind to the surface proteins of cancer cells to deliver a potent payload of cytotoxic chemotherapy. Three are approved for use in pretreated patients with metastatic breast cancer: sacituzumab govitecan, or SG, for patients with triple-negative disease; trastuzumab deruxtecan, or T-DXd, for patients with HER2-positive and HER2-low disease; and trastuzumab emtansine, or T-DM1, for patients with HER2-positive disease. A fourth agent, datopotamab deruxtecan, or Dato-DXd, is being assessed by the US Food and Drug Administration (FDA) for use in pretreated HR-positive, HER2-negative patients, and others, including sacituzumab tirumotecan, are being tested in clinical trials.At the annual meeting of the American Society of Clinical Oncology, T-DXd (Enhertu, AstraZeneca) showed better progression free survival than chemotherapy in people with HR-positive, HER 2-low metastatic breast cancers. These findings, from the DESTINY Breast-06 trial, were among the most talked-about at ASCO, and are likely to change clinical practice (J Clin Oncol. 2024;42[suppl 17; abstr LBA1000]).
But other ADC results presented at ASCO showed that there is still much to be worked out about the timing and sequencing of these agents, as well as their synergy with other drug classes, in metastatic breast cancer.
An ADC gets its first test, and falls short
Antonio Giordano, MD, PhD, of the Dana-Farber Cancer Institute in Boston, presented findings from an open-label phase 2 study of the ADC enfortumab vedotin (EV), an agent currently approved for use in advanced or metastatic urothelial cancer, at ASCO. This study included two cohorts of previously treated metastatic breast cancer patients: one with triple-negative disease (n = 42) and the other with HR-positive HER2-negative (n = 45).
Dr. Giordano and his colleagues’ study is the first to look at this ADC in breast cancer. EV’s antibody targets the cell adhesion molecule Nectin-4.
The researchers found that though EV demonstrated anti-tumor activity in both cohorts — with 19% of the triple-negative patients and 15.6% of the HR-positive/HER2-negative patients responding — the results did not meet the prespecified response thresholds for either cohort. (J Clin Oncol. 2024;42[suppl 16; abstr 1005]).
In an interview, Dr. Giordano said that studies in urothelial cancer had shown better response to EV associated with more expression of Nectin-4, but this study did not see such clear associations between expression and response. While there is no question that Nectin-4 is highly expressed in breast cancer and therefore a viable target, he said, “it may need to be looked at a little more deeply.”
It could also be the case, Dr. Giordano said, that the effect of EV’s payload may have been less robust in participants who had been previously treated with taxane chemotherapy, as nearly all patients in the two cohorts were.
“Taxanes are microtubule disruptors. And with this drug we had a payload with pretty much the same mechanism of action,” Dr. Giordano said. Ideally, he said, he would like to test the agent in a first-line setting, possibly in combination with an immunotherapy agent.
The timing of ADCs is as important as their targets and their payloads — and something that investigators are still struggling to figure out, he said.
A third of the patients in the triple-negative cohort of his study had been previously treated with SG, and a handful of individuals with T-Dxd, he noted.
“We’re in the middle of an ADC revolution,” he said. “It’s really key to figure out the best sequencing for a patient and if it’s actually worth it to do it. Very often we see patients respond best to the first ADC. But sometimes we see patients that do not respond to the first ADC and then they respond to the second one. It’s not very frequent, but it happens.”
Hint of Benefit from Adding Immunotherapy to SG
In a separate presentation at ASCO, Ana C. Garrido-Castro, MD, also of the Dana-Farber Cancer Institute, presented results from the SACI-IO HR+ trial, a randomized phase 2 study of SG (Trodelvy, Gilead) with and without pembrolizumab (Keytruda, Merck) in 104 patients with metastatic HR-positive/HER2-negative breast cancer who received prior endocrine therapy and up to one chemotherapy regimen for advanced disease. SACI-IO HR+ is the first randomized trial to report the efficacy of a topoisomerase I-inhibitor ADC with an immune checkpoint inhibitor for the treatment of breast cancer.
The addition of the immune checkpoint inhibitor did not result in a significant improvement in median progression-free survival in the overall population, Dr. Garrido-Castro reported. Median PFS was 8.1 vs 6.2 months with the combination of SG plus pembrolizumab or sacituzumab govitecan alone, respectively. At a median follow-up of 12.5 months, there was also no significant difference seen in median overall survival (OS): 18.5 vs 18.0 months.
About 40% of participants were found to have PD-L1-positive tumors and, among this subgroup, there was a 4.4-month increase in median PFS and 6.0-month increase in median OS with the addition of pembrolizumab to SG, although this did not reach statistical significance. (J Clin Oncol. 2024;42[suppl 17; abstr LBA1004]).
“While the study did not demonstrate a statistically significant benefit with the addition of the immune checkpoint inhibitor to the ADC, there is an interesting signal for potential synergistic activity between the two agents, particularly in those patients with PD-L1 positive tumors,” Dr. Garrido-Castro said in an interview. She noted that the sample sizes for the PD-L1 subgroup were relatively small, and overall survival data are not yet mature.
A separate phase 3 study is looking at the experimental ADC called sacituzumab tirumotecan with and without pembrolizumab compared with chemotherapy in patients with metastatic HR-positive, HER2-negative breast cancer who have received prior endocrine therapy and no prior chemotherapy for metastatic disease, she said.
Similar to SG, sacituzumab tirumotecan is a TROP2-directed ADC with a topoisomerase I-inhibitor payload. With an estimated enrollment of 1,200 patients, this trial may help shed light on whether adding the immune checkpoint inhibitor to the topoisomerase I-inhibitor TROP2-directed ADC improves outcomes in the subgroup of patients with PD-L1 positive tumors, Dr. Garrido-Castro said.
Unlocking the Order and Timing of ADCs
Dr. Garrido-Castro is also leading a study that will evaluate the sequential use of ADCs in metastatic breast cancer. That trial, to be called TRADE-DXd, will enroll patients with HER2-low metastatic breast cancer who have received up to one prior line of chemotherapy and no previous topoisomerase I-inhibitors. Participants will receive either T-DXd or Dato-DXd as the first ADC, and then switch to the other ADC (Dato-DXd or T-DXd, respectively) at the time of progression, thus switching the target of the ADC from HER2 to TROP2 or vice versa.
“In real-world practice now, there are patients who receive sequential ADCs, because they are candidates for both,” Dr. Garrido-Castro explained. However, more robust data are needed to refine the selection of the initial antibody drug conjugate and to determine who is more likely to benefit from a second — or maybe even third — ADC.
“One potential mechanism of resistance to antibody drug conjugates is the downregulation of the target of the antibody drug conjugate,” Dr. Garrido-Castro said. “Thus, an important question is, if you modify the target of the ADC, is it possible to overcome that mechanism of resistance?” Another possible mechanism of resistance is to the chemotherapy payload of the ADCs, she said.
Dr. Garrido-Castro’s study will collect tumor samples and blood samples for the purposes of planned correlative analyses to try to better understand the mechanisms that drive response and resistance to these agents.
Dr. Giordano commented that Dr. Garrido-Castro’s study was likely to result in a much better understanding of ADCs and how to use them strategically.
At Dana-Farber, “we collect a lot of samples of patients receiving ADCs. And we are trying to do all kinds of work on circulating tumor DNA, immunohistochemistry expression, and protein expression,” he said. “We are trying to figure out how ADCs really work, and why they stop working.”
Dr. Giordano and colleagues’ study was funded by Astellas Pharma and by Seagen, which was bought by Pfizer in 2023. Dr. Giordano disclosed receiving consulting fees from Pfizer, and several of his coauthors reported relationships with this and other companies. Two were Astellas employees.
Dr. Garrido-Castro and colleagues’ study was funded by Merck and Gilead Sciences. Dr. Garrido-Castro disclosed receiving research support from Gilead Sciences, AstraZeneca, Daiichi Sankyo, Merck, Zenith Epigenetics, Bristol-Myers Squibb, Novartis, Biovica, Foundation Medicine, 4D Path, Precede Biosciences; scientific advisory board/consulting fees from AstraZeneca, Novartis, Daiichi Sankyo; speaker honoraria from AstraZeneca, Daiichi Sankyo; and other support from Roche/Genentech, Gilead Sciences, AstraZeneca, Daiichi Sankyo, Novartis, and Merck, while her coauthors reported similar relationships.
FROM ASCO 2024