Patient & Survivor Care

SAN DIEGO — Combination therapy with osimertinib and savolitinib could become a novel first-line treatment option for patients with de novo MET-aberrant, EGFR-mutated advanced non–small cell lung cancer (NSCLC), according to results of the phase 2 FLOWERS study.

Compared with EGFR inhibitor osimertinib alone, the combination demonstrated a clinically meaningful improvement in the objective response rate — the study’s primary endpoint — with a positive trend in progression-free survival and a manageable safety profile.

About 30% patients with EGFR-mutated NSCLC fail to respond well to EGFR–tyrosine kinase inhibitors (TKIs), explained Jin-Ji Yang, MD, with Guangdong Lung Cancer Institute, Guangzhou, China, who reported the study results at the annual meeting of the World Conference on Lung Cancer.

Data suggested that de novo MET amplification occurs in up to 5% patients with treatment-naive, EGFR-mutated advanced NSCLC, and MET overexpression occurs in up to 15% these patients.

Coexistence of EGFR mutation and MET amplification/overexpression reduces sensitivity to EGFR-TKI therapy “and is likely the mechanism for mediating primary resistance to first-line EGFR-TKI monotherapy,” Dr. Yang explained in her presentation.

Osimertinib is a third-generation EGFR-TKI recommended as the first-line treatment for EGFR-mutant advanced NSCLC. Savolitinib is a highly selective MET-TKI which has demonstrated antitumor activity in various cancers with MET alterations.

The FLOWERS study is the first to test whether combining the two agents could improve efficacy and overcome MET-driven primary resistance in these patients.

The phase 2 study enrolled 44 treatment-naive patients with de novo MET-aberrant, EGFR-mutant, stage IIIB-IV NSCLC; 23 were randomly allocated to receive oral osimertinib (80 mg once daily) alone and 21 to receive oral osimertinib (80 mg once daily) plus savolitinib (300 mg twice daily).

At a median follow-up of 8.2 months, the objective response rate was 60.9% with osimertinib monotherapy vs 90.5% with combination therapy. The disease control rate was also better with the combination therapy than with monotherapy (95.2% vs 87%).

Median duration of response (not yet mature) was 8.4 months with monotherapy vs 18.6 months with combination therapy.

Preliminary progression-free survival data also showed a trend in favor of combination therapy over monotherapy (a median of 19.3 vs 9.3 months; hazard ratio, 0.59).

Most treatment-related adverse events were grade 1 or 2, and there were no fatal adverse events.

Treatment-related adverse events of grade 3 or higher were more common with combination therapy (57.1% vs 8.7%). The most common events with monotherapy were diarrhea (56.5%), rash (52.2%), and pruritus (43.5%) and with dual therapy were rash (52.4%), thrombocytopenia (52.4%), and peripheral edema (42.9%).

The results showed that the combination therapy has the potential to become a first-line treatment option for patients who do not respond well to EGFR-TKIs alone, Dr. Yang said in a press release.

Discussant for the study Paul Paik, MD, thoracic oncologist at Memorial Sloan Kettering Cancer Center in New York City, said this study “adds to data suggesting high MET expression might be a poor prognostic or predictive marker, the outcomes of which are improved with MET inhibition.”

He cautioned, however, that there appears to be “quality of life, side-effect trade-offs with dual MET plus EGFR TKI upfront.”

Dr. Paik said he looks forward to results from FLOWERS on serial circulating tumor DNA and formal androgen receptor testing, which “might aid in further assessing clonality and characterizing MET as a co-driver in this setting.”

The study was funded by AstraZeneca China. Dr. Yang had no disclosures. Dr. Paik disclosed relationships with EMD Serono, Bicara, Novartis, and Summit.

A version of this article first appeared on Medscape.com.

SAN DIEGO — Combination therapy with osimertinib and savolitinib could become a novel first-line treatment option for patients with de novo MET-aberrant, EGFR-mutated advanced non–small cell lung cancer (NSCLC), according to results of the phase 2 FLOWERS study.

Compared with EGFR inhibitor osimertinib alone, the combination demonstrated a clinically meaningful improvement in the objective response rate — the study’s primary endpoint — with a positive trend in progression-free survival and a manageable safety profile.

About 30% patients with EGFR-mutated NSCLC fail to respond well to EGFR–tyrosine kinase inhibitors (TKIs), explained Jin-Ji Yang, MD, with Guangdong Lung Cancer Institute, Guangzhou, China, who reported the study results at the annual meeting of the World Conference on Lung Cancer.

Data suggested that de novo MET amplification occurs in up to 5% patients with treatment-naive, EGFR-mutated advanced NSCLC, and MET overexpression occurs in up to 15% these patients.

Coexistence of EGFR mutation and MET amplification/overexpression reduces sensitivity to EGFR-TKI therapy “and is likely the mechanism for mediating primary resistance to first-line EGFR-TKI monotherapy,” Dr. Yang explained in her presentation.

Osimertinib is a third-generation EGFR-TKI recommended as the first-line treatment for EGFR-mutant advanced NSCLC. Savolitinib is a highly selective MET-TKI which has demonstrated antitumor activity in various cancers with MET alterations.

The FLOWERS study is the first to test whether combining the two agents could improve efficacy and overcome MET-driven primary resistance in these patients.

The phase 2 study enrolled 44 treatment-naive patients with de novo MET-aberrant, EGFR-mutant, stage IIIB-IV NSCLC; 23 were randomly allocated to receive oral osimertinib (80 mg once daily) alone and 21 to receive oral osimertinib (80 mg once daily) plus savolitinib (300 mg twice daily).

At a median follow-up of 8.2 months, the objective response rate was 60.9% with osimertinib monotherapy vs 90.5% with combination therapy. The disease control rate was also better with the combination therapy than with monotherapy (95.2% vs 87%).

Median duration of response (not yet mature) was 8.4 months with monotherapy vs 18.6 months with combination therapy.

Preliminary progression-free survival data also showed a trend in favor of combination therapy over monotherapy (a median of 19.3 vs 9.3 months; hazard ratio, 0.59).

Most treatment-related adverse events were grade 1 or 2, and there were no fatal adverse events.

Treatment-related adverse events of grade 3 or higher were more common with combination therapy (57.1% vs 8.7%). The most common events with monotherapy were diarrhea (56.5%), rash (52.2%), and pruritus (43.5%) and with dual therapy were rash (52.4%), thrombocytopenia (52.4%), and peripheral edema (42.9%).

The results showed that the combination therapy has the potential to become a first-line treatment option for patients who do not respond well to EGFR-TKIs alone, Dr. Yang said in a press release.

Discussant for the study Paul Paik, MD, thoracic oncologist at Memorial Sloan Kettering Cancer Center in New York City, said this study “adds to data suggesting high MET expression might be a poor prognostic or predictive marker, the outcomes of which are improved with MET inhibition.”

He cautioned, however, that there appears to be “quality of life, side-effect trade-offs with dual MET plus EGFR TKI upfront.”

Dr. Paik said he looks forward to results from FLOWERS on serial circulating tumor DNA and formal androgen receptor testing, which “might aid in further assessing clonality and characterizing MET as a co-driver in this setting.”

The study was funded by AstraZeneca China. Dr. Yang had no disclosures. Dr. Paik disclosed relationships with EMD Serono, Bicara, Novartis, and Summit.

A version of this article first appeared on Medscape.com.

SAN DIEGO — Combination therapy with osimertinib and savolitinib could become a novel first-line treatment option for patients with de novo MET-aberrant, EGFR-mutated advanced non–small cell lung cancer (NSCLC), according to results of the phase 2 FLOWERS study.

Compared with EGFR inhibitor osimertinib alone, the combination demonstrated a clinically meaningful improvement in the objective response rate — the study’s primary endpoint — with a positive trend in progression-free survival and a manageable safety profile.

About 30% patients with EGFR-mutated NSCLC fail to respond well to EGFR–tyrosine kinase inhibitors (TKIs), explained Jin-Ji Yang, MD, with Guangdong Lung Cancer Institute, Guangzhou, China, who reported the study results at the annual meeting of the World Conference on Lung Cancer.

Data suggested that de novo MET amplification occurs in up to 5% patients with treatment-naive, EGFR-mutated advanced NSCLC, and MET overexpression occurs in up to 15% these patients.

Coexistence of EGFR mutation and MET amplification/overexpression reduces sensitivity to EGFR-TKI therapy “and is likely the mechanism for mediating primary resistance to first-line EGFR-TKI monotherapy,” Dr. Yang explained in her presentation.

Osimertinib is a third-generation EGFR-TKI recommended as the first-line treatment for EGFR-mutant advanced NSCLC. Savolitinib is a highly selective MET-TKI which has demonstrated antitumor activity in various cancers with MET alterations.

The FLOWERS study is the first to test whether combining the two agents could improve efficacy and overcome MET-driven primary resistance in these patients.

The phase 2 study enrolled 44 treatment-naive patients with de novo MET-aberrant, EGFR-mutant, stage IIIB-IV NSCLC; 23 were randomly allocated to receive oral osimertinib (80 mg once daily) alone and 21 to receive oral osimertinib (80 mg once daily) plus savolitinib (300 mg twice daily).

At a median follow-up of 8.2 months, the objective response rate was 60.9% with osimertinib monotherapy vs 90.5% with combination therapy. The disease control rate was also better with the combination therapy than with monotherapy (95.2% vs 87%).

Median duration of response (not yet mature) was 8.4 months with monotherapy vs 18.6 months with combination therapy.

Preliminary progression-free survival data also showed a trend in favor of combination therapy over monotherapy (a median of 19.3 vs 9.3 months; hazard ratio, 0.59).

Most treatment-related adverse events were grade 1 or 2, and there were no fatal adverse events.

Treatment-related adverse events of grade 3 or higher were more common with combination therapy (57.1% vs 8.7%). The most common events with monotherapy were diarrhea (56.5%), rash (52.2%), and pruritus (43.5%) and with dual therapy were rash (52.4%), thrombocytopenia (52.4%), and peripheral edema (42.9%).

The results showed that the combination therapy has the potential to become a first-line treatment option for patients who do not respond well to EGFR-TKIs alone, Dr. Yang said in a press release.

Discussant for the study Paul Paik, MD, thoracic oncologist at Memorial Sloan Kettering Cancer Center in New York City, said this study “adds to data suggesting high MET expression might be a poor prognostic or predictive marker, the outcomes of which are improved with MET inhibition.”

He cautioned, however, that there appears to be “quality of life, side-effect trade-offs with dual MET plus EGFR TKI upfront.”

Dr. Paik said he looks forward to results from FLOWERS on serial circulating tumor DNA and formal androgen receptor testing, which “might aid in further assessing clonality and characterizing MET as a co-driver in this setting.”

The study was funded by AstraZeneca China. Dr. Yang had no disclosures. Dr. Paik disclosed relationships with EMD Serono, Bicara, Novartis, and Summit.

A version of this article first appeared on Medscape.com.

Research offers promising insights into the ideal frontline therapies for mantle cell lymphoma (MCL), but there are continued unmet needs in the relapsed/refractory setting, blood cancer specialists told colleagues. 

In the frontline setting, findings suggest that regimens should differ significantly on the basis of whether patients are older or younger, whereas more data are needed to understand whether treatment can overcome poor prognoses in patients with TP53 mutations, lymphoma specialist Nina Wagner-Johnston, MD, of Johns Hopkins University School of Medicine, Baltimore, said in a presentation at the annual meeting of the Society of Hematologic Oncology (SOHO) 2024 in Houston, Texas.

On the relapsed/refractory front, patients need better options after treatment with Bruton tyrosine kinase inhibitors or chimeric antigen receptor (CAR) T-cell therapy, Krish Patel, MD, a lymphoma specialist with Swedish Cancer Institute in Seattle, said in an adjoining presentation. Fortunately, he said, some treatments are showing early promise.

Here’s a closer look at the presentations by Dr. Wagner-Johnston and Dr. Patel.
 

Frontline MCL: Age Helps Determine Best Approach

“For older and less fit patients, the standard approach has typically been bendamustine (Bendeka, Treanda) and rituximab (Rituxan), and the median progression-free survival is about 4 years, with overall survival not reached at a median 5 years of follow-up,” Dr. Wagner-Johnston said. 

Low doses of the chemotherapy drug cytarabine have been added to the bendamustine-rituximab regimen, with encouraging results, she said. “Certainly there’s more toxicity associated even with lower doses, but those data look fairly promising.”

For younger and fit patients, “the standard of care approach has been to administer intensive chemoimmunotherapy that contains high-dose cytarabine, and then that’s typically followed with an autologous stem cell transplant,” she said. A 2016 study reported median progression-free survival of 8.5 years and median overall survival of 12.7 years.

Now, second-generation Bruton tyrosine kinase inhibitors “look very promising” in the frontline setting, Dr. Wagner-Johnston said.

The road has been rocky, however. The SHINE trial of more than 500 patients aged over 65 found that adding ibrutinib to bendamustine-rituximab improved progression-free survival. “However, progression-free survival did not [connect] to an overall survival benefit, and that’s likely due to the toxicity seen with ibrutinib,” she said. 

“It’s not surprising to many of you that ibrutinib has been removed from the FDA label for mantle cell lymphoma,” she said. However, “second-generation [Bruton tyrosine kinase inhibitors] are known to be associated with less toxicity and potentially increased potency.”

What about Bruton tyrosine kinase inhibitors in younger and fitter patients? The TRIANGLE trial demonstrated their benefit, Dr. Wagner-Johnston said, linking ibrutinib to improvement in progression-free survival. 

However, “it’s really too early to evaluate the statistical significance for overall survival.” And while the study looks at therapy without stem cell transplant, she believes it’s too early to know whether that’s a good option. 

Dr. Wagner-Johnston tackled another topic: Can Bruton tyrosine kinase inhibitors overcome the poor prognosis seen with MCL with TP53 mutation? For now, the limitations of research makes it “hard to know,” she said, although early results of the BOVen trial are promising. 
 

Relapsed/Refractory MCL: Better Options Are Still Needed

In his presentation, Dr. Patel spoke about therapy in patients with MCL and relapsed/refractory disease. “We know that outcomes for patients who progress on covalent [Bruton tyrosine kinase inhibitors] is really dismal,” he said. “This has been shown by multiple groups now across the globe.”

Noncovalent Bruton tyrosine kinase inhibitors are now an option, he noted. “We do understand that they work for some patients, and it can be quite useful, but even noncovalent [Bruton tyrosine kinase inhibitors] themselves are susceptible to resistance mutations. We’ve seen that in the [chronic lymphocytic leukemia] world.”

Dr. Patel asked the audience, “Why not just give everybody CAR T-cells, post-[Bruton tyrosine kinase inhibitors]? You get a CAR T-cell! You get a CAR T-cell! Everybody gets one.”

However, he noted, “Unfortunately, mantle cell lymphoma patients experience the worst high-grade toxicity when receiving CD19[-targeted] CAR T-cells.” 

Are there better options? At the moment, “really, really early data” suggest benefits from molecular glues and degraders, novel inhibitors, antibody-drug conjugates, novel CAR T-cells, and bispecific antibodies, Dr. Patel said.

“All of these tools are in clinical trials, and hopefully some of them will help,” he said.

Disclosures were not provided. Dr. Wagner-Johnston recently disclosed advisory committee/board of directors’ relationships with ADC Therapeutics, Regeneron, Calibr, and Verastem. Dr. Patel recently disclosed ties with a long list of pharmaceutical companies, including AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Genentech, Janssen, Merck, and others.
 

A version of this article first appeared on Medscape.com.

Research offers promising insights into the ideal frontline therapies for mantle cell lymphoma (MCL), but there are continued unmet needs in the relapsed/refractory setting, blood cancer specialists told colleagues. 

In the frontline setting, findings suggest that regimens should differ significantly on the basis of whether patients are older or younger, whereas more data are needed to understand whether treatment can overcome poor prognoses in patients with TP53 mutations, lymphoma specialist Nina Wagner-Johnston, MD, of Johns Hopkins University School of Medicine, Baltimore, said in a presentation at the annual meeting of the Society of Hematologic Oncology (SOHO) 2024 in Houston, Texas.

On the relapsed/refractory front, patients need better options after treatment with Bruton tyrosine kinase inhibitors or chimeric antigen receptor (CAR) T-cell therapy, Krish Patel, MD, a lymphoma specialist with Swedish Cancer Institute in Seattle, said in an adjoining presentation. Fortunately, he said, some treatments are showing early promise.

Here’s a closer look at the presentations by Dr. Wagner-Johnston and Dr. Patel.
 

Frontline MCL: Age Helps Determine Best Approach

“For older and less fit patients, the standard approach has typically been bendamustine (Bendeka, Treanda) and rituximab (Rituxan), and the median progression-free survival is about 4 years, with overall survival not reached at a median 5 years of follow-up,” Dr. Wagner-Johnston said. 

Low doses of the chemotherapy drug cytarabine have been added to the bendamustine-rituximab regimen, with encouraging results, she said. “Certainly there’s more toxicity associated even with lower doses, but those data look fairly promising.”

For younger and fit patients, “the standard of care approach has been to administer intensive chemoimmunotherapy that contains high-dose cytarabine, and then that’s typically followed with an autologous stem cell transplant,” she said. A 2016 study reported median progression-free survival of 8.5 years and median overall survival of 12.7 years.

Now, second-generation Bruton tyrosine kinase inhibitors “look very promising” in the frontline setting, Dr. Wagner-Johnston said.

The road has been rocky, however. The SHINE trial of more than 500 patients aged over 65 found that adding ibrutinib to bendamustine-rituximab improved progression-free survival. “However, progression-free survival did not [connect] to an overall survival benefit, and that’s likely due to the toxicity seen with ibrutinib,” she said. 

“It’s not surprising to many of you that ibrutinib has been removed from the FDA label for mantle cell lymphoma,” she said. However, “second-generation [Bruton tyrosine kinase inhibitors] are known to be associated with less toxicity and potentially increased potency.”

What about Bruton tyrosine kinase inhibitors in younger and fitter patients? The TRIANGLE trial demonstrated their benefit, Dr. Wagner-Johnston said, linking ibrutinib to improvement in progression-free survival. 

However, “it’s really too early to evaluate the statistical significance for overall survival.” And while the study looks at therapy without stem cell transplant, she believes it’s too early to know whether that’s a good option. 

Dr. Wagner-Johnston tackled another topic: Can Bruton tyrosine kinase inhibitors overcome the poor prognosis seen with MCL with TP53 mutation? For now, the limitations of research makes it “hard to know,” she said, although early results of the BOVen trial are promising. 
 

Relapsed/Refractory MCL: Better Options Are Still Needed

In his presentation, Dr. Patel spoke about therapy in patients with MCL and relapsed/refractory disease. “We know that outcomes for patients who progress on covalent [Bruton tyrosine kinase inhibitors] is really dismal,” he said. “This has been shown by multiple groups now across the globe.”

Noncovalent Bruton tyrosine kinase inhibitors are now an option, he noted. “We do understand that they work for some patients, and it can be quite useful, but even noncovalent [Bruton tyrosine kinase inhibitors] themselves are susceptible to resistance mutations. We’ve seen that in the [chronic lymphocytic leukemia] world.”

Dr. Patel asked the audience, “Why not just give everybody CAR T-cells, post-[Bruton tyrosine kinase inhibitors]? You get a CAR T-cell! You get a CAR T-cell! Everybody gets one.”

However, he noted, “Unfortunately, mantle cell lymphoma patients experience the worst high-grade toxicity when receiving CD19[-targeted] CAR T-cells.” 

Are there better options? At the moment, “really, really early data” suggest benefits from molecular glues and degraders, novel inhibitors, antibody-drug conjugates, novel CAR T-cells, and bispecific antibodies, Dr. Patel said.

“All of these tools are in clinical trials, and hopefully some of them will help,” he said.

Disclosures were not provided. Dr. Wagner-Johnston recently disclosed advisory committee/board of directors’ relationships with ADC Therapeutics, Regeneron, Calibr, and Verastem. Dr. Patel recently disclosed ties with a long list of pharmaceutical companies, including AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Genentech, Janssen, Merck, and others.
 

A version of this article first appeared on Medscape.com.

Research offers promising insights into the ideal frontline therapies for mantle cell lymphoma (MCL), but there are continued unmet needs in the relapsed/refractory setting, blood cancer specialists told colleagues. 

In the frontline setting, findings suggest that regimens should differ significantly on the basis of whether patients are older or younger, whereas more data are needed to understand whether treatment can overcome poor prognoses in patients with TP53 mutations, lymphoma specialist Nina Wagner-Johnston, MD, of Johns Hopkins University School of Medicine, Baltimore, said in a presentation at the annual meeting of the Society of Hematologic Oncology (SOHO) 2024 in Houston, Texas.

On the relapsed/refractory front, patients need better options after treatment with Bruton tyrosine kinase inhibitors or chimeric antigen receptor (CAR) T-cell therapy, Krish Patel, MD, a lymphoma specialist with Swedish Cancer Institute in Seattle, said in an adjoining presentation. Fortunately, he said, some treatments are showing early promise.

Here’s a closer look at the presentations by Dr. Wagner-Johnston and Dr. Patel.
 

Frontline MCL: Age Helps Determine Best Approach

“For older and less fit patients, the standard approach has typically been bendamustine (Bendeka, Treanda) and rituximab (Rituxan), and the median progression-free survival is about 4 years, with overall survival not reached at a median 5 years of follow-up,” Dr. Wagner-Johnston said. 

Low doses of the chemotherapy drug cytarabine have been added to the bendamustine-rituximab regimen, with encouraging results, she said. “Certainly there’s more toxicity associated even with lower doses, but those data look fairly promising.”

For younger and fit patients, “the standard of care approach has been to administer intensive chemoimmunotherapy that contains high-dose cytarabine, and then that’s typically followed with an autologous stem cell transplant,” she said. A 2016 study reported median progression-free survival of 8.5 years and median overall survival of 12.7 years.

Now, second-generation Bruton tyrosine kinase inhibitors “look very promising” in the frontline setting, Dr. Wagner-Johnston said.

The road has been rocky, however. The SHINE trial of more than 500 patients aged over 65 found that adding ibrutinib to bendamustine-rituximab improved progression-free survival. “However, progression-free survival did not [connect] to an overall survival benefit, and that’s likely due to the toxicity seen with ibrutinib,” she said. 

“It’s not surprising to many of you that ibrutinib has been removed from the FDA label for mantle cell lymphoma,” she said. However, “second-generation [Bruton tyrosine kinase inhibitors] are known to be associated with less toxicity and potentially increased potency.”

What about Bruton tyrosine kinase inhibitors in younger and fitter patients? The TRIANGLE trial demonstrated their benefit, Dr. Wagner-Johnston said, linking ibrutinib to improvement in progression-free survival. 

However, “it’s really too early to evaluate the statistical significance for overall survival.” And while the study looks at therapy without stem cell transplant, she believes it’s too early to know whether that’s a good option. 

Dr. Wagner-Johnston tackled another topic: Can Bruton tyrosine kinase inhibitors overcome the poor prognosis seen with MCL with TP53 mutation? For now, the limitations of research makes it “hard to know,” she said, although early results of the BOVen trial are promising. 
 

Relapsed/Refractory MCL: Better Options Are Still Needed

In his presentation, Dr. Patel spoke about therapy in patients with MCL and relapsed/refractory disease. “We know that outcomes for patients who progress on covalent [Bruton tyrosine kinase inhibitors] is really dismal,” he said. “This has been shown by multiple groups now across the globe.”

Noncovalent Bruton tyrosine kinase inhibitors are now an option, he noted. “We do understand that they work for some patients, and it can be quite useful, but even noncovalent [Bruton tyrosine kinase inhibitors] themselves are susceptible to resistance mutations. We’ve seen that in the [chronic lymphocytic leukemia] world.”

Dr. Patel asked the audience, “Why not just give everybody CAR T-cells, post-[Bruton tyrosine kinase inhibitors]? You get a CAR T-cell! You get a CAR T-cell! Everybody gets one.”

However, he noted, “Unfortunately, mantle cell lymphoma patients experience the worst high-grade toxicity when receiving CD19[-targeted] CAR T-cells.” 

Are there better options? At the moment, “really, really early data” suggest benefits from molecular glues and degraders, novel inhibitors, antibody-drug conjugates, novel CAR T-cells, and bispecific antibodies, Dr. Patel said.

“All of these tools are in clinical trials, and hopefully some of them will help,” he said.

Disclosures were not provided. Dr. Wagner-Johnston recently disclosed advisory committee/board of directors’ relationships with ADC Therapeutics, Regeneron, Calibr, and Verastem. Dr. Patel recently disclosed ties with a long list of pharmaceutical companies, including AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Genentech, Janssen, Merck, and others.
 

A version of this article first appeared on Medscape.com.

TOPLINE:

MADRID — Elevated interleukin (IL) 6 levels are associated with an increased risk for obesity-related cancers in patients newly diagnosed with type 2 diabetes (T2D), potentially enabling the identification of higher-risk individuals through a simple blood test.

METHODOLOGY:

• T2D is associated with an increased risk for obesity-related cancers, including breast, renal, uterine, thyroid, ovarian, and gastrointestinal cancers, as well as multiple myeloma, possibly because of chronic low-grade inflammation.
• Researchers explored whether the markers of inflammation IL-6, tumor necrosis factor alpha (TNF-alpha), and high-sensitivity C-reactive protein (hsCRP) can serve as predictive biomarkers for obesity-related cancers in patients recently diagnosed with T2D.
• They identified patients with recent-onset T2D and no prior history of cancer participating in the ongoing Danish Centre for Strategic Research in Type 2 Diabetes cohort study.
• At study initiation, plasma levels of IL-6 and TNF-alpha were measured using Meso Scale Discovery assays, and serum levels of hsCRP were measured using immunofluorometric assays.

TAKEAWAY:

• Among 6,466 eligible patients (40.5% women; median age, 60.9 years), 327 developed obesity-related cancers over a median follow-up of 8.8 years.
• Each SD increase in log-transformed IL-6 levels increased the risk for obesity-related cancers by 19%.
• The researchers did not find a strong association between TNF-alpha or hsCRP and obesity-related cancers.
• The addition of baseline IL-6 levels to other well-known risk factors for obesity-related cancers improved the performance of a cancer prediction model from 0.685 to 0.693, translating to a small but important increase in the ability to predict whether an individual would develop one of these cancers.

IN PRACTICE:

“In future, a simple blood test could identify those at higher risk of the cancers,” said the study’s lead author in an accompanying press release.

SOURCE:

The study was led by Mathilde D. Bennetsen, Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark, and published online on August 27 as an early release from the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting.

LIMITATIONS:

No limitations were discussed in this abstract. However, the reliance on registry data may have introduced potential biases related to data accuracy and completeness.

DISCLOSURES:

The Danish Centre for Strategic Research in Type 2 Diabetes was supported by grants from the Danish Agency for Science and the Novo Nordisk Foundation. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

MADRID — Elevated interleukin (IL) 6 levels are associated with an increased risk for obesity-related cancers in patients newly diagnosed with type 2 diabetes (T2D), potentially enabling the identification of higher-risk individuals through a simple blood test.

METHODOLOGY:

• T2D is associated with an increased risk for obesity-related cancers, including breast, renal, uterine, thyroid, ovarian, and gastrointestinal cancers, as well as multiple myeloma, possibly because of chronic low-grade inflammation.
• Researchers explored whether the markers of inflammation IL-6, tumor necrosis factor alpha (TNF-alpha), and high-sensitivity C-reactive protein (hsCRP) can serve as predictive biomarkers for obesity-related cancers in patients recently diagnosed with T2D.
• They identified patients with recent-onset T2D and no prior history of cancer participating in the ongoing Danish Centre for Strategic Research in Type 2 Diabetes cohort study.
• At study initiation, plasma levels of IL-6 and TNF-alpha were measured using Meso Scale Discovery assays, and serum levels of hsCRP were measured using immunofluorometric assays.

TAKEAWAY:

• Among 6,466 eligible patients (40.5% women; median age, 60.9 years), 327 developed obesity-related cancers over a median follow-up of 8.8 years.
• Each SD increase in log-transformed IL-6 levels increased the risk for obesity-related cancers by 19%.
• The researchers did not find a strong association between TNF-alpha or hsCRP and obesity-related cancers.
• The addition of baseline IL-6 levels to other well-known risk factors for obesity-related cancers improved the performance of a cancer prediction model from 0.685 to 0.693, translating to a small but important increase in the ability to predict whether an individual would develop one of these cancers.

IN PRACTICE:

“In future, a simple blood test could identify those at higher risk of the cancers,” said the study’s lead author in an accompanying press release.

SOURCE:

The study was led by Mathilde D. Bennetsen, Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark, and published online on August 27 as an early release from the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting.

LIMITATIONS:

No limitations were discussed in this abstract. However, the reliance on registry data may have introduced potential biases related to data accuracy and completeness.

DISCLOSURES:

The Danish Centre for Strategic Research in Type 2 Diabetes was supported by grants from the Danish Agency for Science and the Novo Nordisk Foundation. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

MADRID — Elevated interleukin (IL) 6 levels are associated with an increased risk for obesity-related cancers in patients newly diagnosed with type 2 diabetes (T2D), potentially enabling the identification of higher-risk individuals through a simple blood test.

METHODOLOGY:

• T2D is associated with an increased risk for obesity-related cancers, including breast, renal, uterine, thyroid, ovarian, and gastrointestinal cancers, as well as multiple myeloma, possibly because of chronic low-grade inflammation.
• Researchers explored whether the markers of inflammation IL-6, tumor necrosis factor alpha (TNF-alpha), and high-sensitivity C-reactive protein (hsCRP) can serve as predictive biomarkers for obesity-related cancers in patients recently diagnosed with T2D.
• They identified patients with recent-onset T2D and no prior history of cancer participating in the ongoing Danish Centre for Strategic Research in Type 2 Diabetes cohort study.
• At study initiation, plasma levels of IL-6 and TNF-alpha were measured using Meso Scale Discovery assays, and serum levels of hsCRP were measured using immunofluorometric assays.

TAKEAWAY:

• Among 6,466 eligible patients (40.5% women; median age, 60.9 years), 327 developed obesity-related cancers over a median follow-up of 8.8 years.
• Each SD increase in log-transformed IL-6 levels increased the risk for obesity-related cancers by 19%.
• The researchers did not find a strong association between TNF-alpha or hsCRP and obesity-related cancers.
• The addition of baseline IL-6 levels to other well-known risk factors for obesity-related cancers improved the performance of a cancer prediction model from 0.685 to 0.693, translating to a small but important increase in the ability to predict whether an individual would develop one of these cancers.

IN PRACTICE:

“In future, a simple blood test could identify those at higher risk of the cancers,” said the study’s lead author in an accompanying press release.

SOURCE:

The study was led by Mathilde D. Bennetsen, Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark, and published online on August 27 as an early release from the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting.

LIMITATIONS:

No limitations were discussed in this abstract. However, the reliance on registry data may have introduced potential biases related to data accuracy and completeness.

DISCLOSURES:

The Danish Centre for Strategic Research in Type 2 Diabetes was supported by grants from the Danish Agency for Science and the Novo Nordisk Foundation. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Bruton’s tyrosine kinase inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib have revolutionized the treatment of chronic lymphocytic leukemia (CLL). But should patients take a break from them?

At the annual meeting of the Society of Hematologic Oncology, two hematologist-oncologists — Inhye Ahn, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, and Kerry A. Rogers, MD, of Ohio State University in Columbus — faced off in a debate. Ahn said the drugs can indeed be discontinued, while Rogers argued against stopping the medications.

“When I talk to my own patient about standard of care options in CLL, I use the analogy of a marathon and a sprint,” Dr. Ahn said. A marathon refers to continuous treatment with Bruton’s kinase inhibitors given daily for years, while the sprint refers to the combination of venetoclax with an anti-CD20 monoclonal antibody given over 12 cycles for the frontline regimen and 2 years for refractory CLL.

“I tell them these are both considered very efficacious regimens and well tolerated, one is by IV [the venetoclax regimen] and the other isn’t [Bruton’s kinase inhibitors], and they have different toxicity profile. I ask them what would you do? The most common question that I get from my patient is, ‘why would anyone do a marathon?’ ”

It’s not solely the length of treatment that’s important, Dr. Ahn said, as toxicities from the long-term use of Bruton’s kinase inhibitors build up over time and can lead to hypertension, arrhythmia, and sudden cardiac death.

In addition, she said, infections can occur, as well as hampered vaccine response, an important risk in the era of the COVID-19 pandemic. The cost of the drugs is high and adds up over time, and continuous use can boost resistance.

Is there a way to turn the marathon of Bruton’s kinase inhibitor use into a sprint without hurting patients? The answer is yes, through temporary discontinuation, Dr. Ahn said, although she cautioned that early cessation could lead to disease flare. “We dipped into our own database of 84 CLL patients treated with ibrutinib, and our conclusion was that temporary dose interruption or dose reduction did not impact progression-free survival”

Moving forward, she said, “more research is needed to define the optimal regimen that would lead to treatment cessation, the optimal patient population, who would benefit most from the cessation strategy, treatment duration, and how we define success.” For her part, Dr. Rogers argued that the continuous use of Bruton’s kinase inhibitors is “really the most effective treatment we have in CLL.”

It’s clear that “responses deepen with continued treatment,” Dr. Rogers said, noting that remission times grow over years of treatment. She highlighted a 2022 study of patients with CLL who took ibrutinib that found complete remission or complete remission with incomplete hematologic recovery was 7% at 12 months and 34% at 7 years. When patients quit taking the drugs, “you don’t get to maximize your patient’s response to this treatment.”

Dr. Rogers also noted that the RESONATE-2 trial found that ibrutinib is linked to the longest median progression-free survival of any CLL treatment at 8.9 years. “That really struck me a very effective initial therapy.”

Indeed, “when you’re offering someone initial therapy with a Bruton’s kinase inhibitor as a continuous treatment strategy, you can tell people that they can expect a normal lifespan with this approach. That’s extremely important when you’re talking to patients about whether they might want to alter their leukemia treatment.”

Finally, she noted that discontinuation of ibrutinib was linked to shorter survival in early research. “This was the first suggestion that discontinuation is not good.”

Dr. Rogers said that discontinuing the drugs is sometimes necessary because of adverse events, but patients can “certainly switch to a more tolerable Bruton’s kinase inhibitor. With the options available today, that should be a strategy that’s considered.”

Audience members at the debate were invited to respond to a live online survey about whether Bruton’s kinase inhibitors can be discontinued. Among 49 respondents, most (52.3%) said no, 42.8% said yes, and the rest were undecided/other.

Disclosures for the speakers were not provided. Dr. Ahn disclosed consulting for BeiGene and AstraZeneca. Dr. Rogers disclosed receiving research funding from Genentech, AbbVie, Janssen, and Novartis; consulting for AstraZeneca, BeiGene, Janssen, Pharmacyclics, AbbVie, Genentech, and LOXO@Lilly; and receiving travel funding from AstraZeneca.

A version of this article appeared on Medscape.com.

Bruton’s tyrosine kinase inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib have revolutionized the treatment of chronic lymphocytic leukemia (CLL). But should patients take a break from them?

At the annual meeting of the Society of Hematologic Oncology, two hematologist-oncologists — Inhye Ahn, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, and Kerry A. Rogers, MD, of Ohio State University in Columbus — faced off in a debate. Ahn said the drugs can indeed be discontinued, while Rogers argued against stopping the medications.

“When I talk to my own patient about standard of care options in CLL, I use the analogy of a marathon and a sprint,” Dr. Ahn said. A marathon refers to continuous treatment with Bruton’s kinase inhibitors given daily for years, while the sprint refers to the combination of venetoclax with an anti-CD20 monoclonal antibody given over 12 cycles for the frontline regimen and 2 years for refractory CLL.

“I tell them these are both considered very efficacious regimens and well tolerated, one is by IV [the venetoclax regimen] and the other isn’t [Bruton’s kinase inhibitors], and they have different toxicity profile. I ask them what would you do? The most common question that I get from my patient is, ‘why would anyone do a marathon?’ ”

It’s not solely the length of treatment that’s important, Dr. Ahn said, as toxicities from the long-term use of Bruton’s kinase inhibitors build up over time and can lead to hypertension, arrhythmia, and sudden cardiac death.

In addition, she said, infections can occur, as well as hampered vaccine response, an important risk in the era of the COVID-19 pandemic. The cost of the drugs is high and adds up over time, and continuous use can boost resistance.

Is there a way to turn the marathon of Bruton’s kinase inhibitor use into a sprint without hurting patients? The answer is yes, through temporary discontinuation, Dr. Ahn said, although she cautioned that early cessation could lead to disease flare. “We dipped into our own database of 84 CLL patients treated with ibrutinib, and our conclusion was that temporary dose interruption or dose reduction did not impact progression-free survival”

Moving forward, she said, “more research is needed to define the optimal regimen that would lead to treatment cessation, the optimal patient population, who would benefit most from the cessation strategy, treatment duration, and how we define success.” For her part, Dr. Rogers argued that the continuous use of Bruton’s kinase inhibitors is “really the most effective treatment we have in CLL.”

It’s clear that “responses deepen with continued treatment,” Dr. Rogers said, noting that remission times grow over years of treatment. She highlighted a 2022 study of patients with CLL who took ibrutinib that found complete remission or complete remission with incomplete hematologic recovery was 7% at 12 months and 34% at 7 years. When patients quit taking the drugs, “you don’t get to maximize your patient’s response to this treatment.”

Dr. Rogers also noted that the RESONATE-2 trial found that ibrutinib is linked to the longest median progression-free survival of any CLL treatment at 8.9 years. “That really struck me a very effective initial therapy.”

Indeed, “when you’re offering someone initial therapy with a Bruton’s kinase inhibitor as a continuous treatment strategy, you can tell people that they can expect a normal lifespan with this approach. That’s extremely important when you’re talking to patients about whether they might want to alter their leukemia treatment.”

Finally, she noted that discontinuation of ibrutinib was linked to shorter survival in early research. “This was the first suggestion that discontinuation is not good.”

Dr. Rogers said that discontinuing the drugs is sometimes necessary because of adverse events, but patients can “certainly switch to a more tolerable Bruton’s kinase inhibitor. With the options available today, that should be a strategy that’s considered.”

Audience members at the debate were invited to respond to a live online survey about whether Bruton’s kinase inhibitors can be discontinued. Among 49 respondents, most (52.3%) said no, 42.8% said yes, and the rest were undecided/other.

Disclosures for the speakers were not provided. Dr. Ahn disclosed consulting for BeiGene and AstraZeneca. Dr. Rogers disclosed receiving research funding from Genentech, AbbVie, Janssen, and Novartis; consulting for AstraZeneca, BeiGene, Janssen, Pharmacyclics, AbbVie, Genentech, and LOXO@Lilly; and receiving travel funding from AstraZeneca.

A version of this article appeared on Medscape.com.

Bruton’s tyrosine kinase inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib have revolutionized the treatment of chronic lymphocytic leukemia (CLL). But should patients take a break from them?

At the annual meeting of the Society of Hematologic Oncology, two hematologist-oncologists — Inhye Ahn, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, and Kerry A. Rogers, MD, of Ohio State University in Columbus — faced off in a debate. Ahn said the drugs can indeed be discontinued, while Rogers argued against stopping the medications.

“When I talk to my own patient about standard of care options in CLL, I use the analogy of a marathon and a sprint,” Dr. Ahn said. A marathon refers to continuous treatment with Bruton’s kinase inhibitors given daily for years, while the sprint refers to the combination of venetoclax with an anti-CD20 monoclonal antibody given over 12 cycles for the frontline regimen and 2 years for refractory CLL.

“I tell them these are both considered very efficacious regimens and well tolerated, one is by IV [the venetoclax regimen] and the other isn’t [Bruton’s kinase inhibitors], and they have different toxicity profile. I ask them what would you do? The most common question that I get from my patient is, ‘why would anyone do a marathon?’ ”

It’s not solely the length of treatment that’s important, Dr. Ahn said, as toxicities from the long-term use of Bruton’s kinase inhibitors build up over time and can lead to hypertension, arrhythmia, and sudden cardiac death.

In addition, she said, infections can occur, as well as hampered vaccine response, an important risk in the era of the COVID-19 pandemic. The cost of the drugs is high and adds up over time, and continuous use can boost resistance.

Is there a way to turn the marathon of Bruton’s kinase inhibitor use into a sprint without hurting patients? The answer is yes, through temporary discontinuation, Dr. Ahn said, although she cautioned that early cessation could lead to disease flare. “We dipped into our own database of 84 CLL patients treated with ibrutinib, and our conclusion was that temporary dose interruption or dose reduction did not impact progression-free survival”

Moving forward, she said, “more research is needed to define the optimal regimen that would lead to treatment cessation, the optimal patient population, who would benefit most from the cessation strategy, treatment duration, and how we define success.” For her part, Dr. Rogers argued that the continuous use of Bruton’s kinase inhibitors is “really the most effective treatment we have in CLL.”

It’s clear that “responses deepen with continued treatment,” Dr. Rogers said, noting that remission times grow over years of treatment. She highlighted a 2022 study of patients with CLL who took ibrutinib that found complete remission or complete remission with incomplete hematologic recovery was 7% at 12 months and 34% at 7 years. When patients quit taking the drugs, “you don’t get to maximize your patient’s response to this treatment.”

Dr. Rogers also noted that the RESONATE-2 trial found that ibrutinib is linked to the longest median progression-free survival of any CLL treatment at 8.9 years. “That really struck me a very effective initial therapy.”

Indeed, “when you’re offering someone initial therapy with a Bruton’s kinase inhibitor as a continuous treatment strategy, you can tell people that they can expect a normal lifespan with this approach. That’s extremely important when you’re talking to patients about whether they might want to alter their leukemia treatment.”

Finally, she noted that discontinuation of ibrutinib was linked to shorter survival in early research. “This was the first suggestion that discontinuation is not good.”

Dr. Rogers said that discontinuing the drugs is sometimes necessary because of adverse events, but patients can “certainly switch to a more tolerable Bruton’s kinase inhibitor. With the options available today, that should be a strategy that’s considered.”

Audience members at the debate were invited to respond to a live online survey about whether Bruton’s kinase inhibitors can be discontinued. Among 49 respondents, most (52.3%) said no, 42.8% said yes, and the rest were undecided/other.

Disclosures for the speakers were not provided. Dr. Ahn disclosed consulting for BeiGene and AstraZeneca. Dr. Rogers disclosed receiving research funding from Genentech, AbbVie, Janssen, and Novartis; consulting for AstraZeneca, BeiGene, Janssen, Pharmacyclics, AbbVie, Genentech, and LOXO@Lilly; and receiving travel funding from AstraZeneca.

A version of this article appeared on Medscape.com.

Pancreatic cancer remains one of the deadliest cancers. 

When the disease is caught earlier, the 5-year survival rates hover around 44%, but once the cancer metastasizes, only about 3% of patients live that long.

Finding effective treatments for the disease continues to be a challenge. 

No significant new therapies in pancreatic cancer have emerged in the past 20 years, explained John Marshall, MD, a gastrointestinal medical oncologist at Georgetown University in Washington, DC.

Oncology researchers have long eyed a potential holy grail target: the KRAS oncogene. Present in about 90% of patients with pancreatic cancer, KRAS mutations are considered a key driver of the disease. But for decades, KRAS was considered “undruggable.” 

Until recently. 

In the past 2 years, the US Food and Drug Administration has approved two KRAS inhibitors — sotorasib and adagrasib — to treat certain colorectal and lung cancers. 

A pipeline of KRAS inhibitors targeting pancreatic cancer has now emerged, leaving some oncologists feeling optimistic about the future of treating the disease.

“I think KRAS inhibitors — [maybe not alone] but as a foundational agent for combinations — are really poised to transform how we care for patients,” said Andrew Aguirre, MD, PhD, a gastrointestinal medical oncologist at the Dana-Farber Cancer Institute, Boston, who heads a lab focused on RAS signaling and pancreatic cancer. These agents won’t necessarily cure pancreatic cancer but will be “part of the solution” to improve outcomes, Dr. Aguirre said.
 

A Challenging Cancer

Pharmaceutical companies currently have at least eight agents in development and are conducting dozens of KRAS/RAS studies that focus on or include pancreatic cancer.

But it’s still early days on the evidence front.

The investigational drugs are only in phase 1/2 testing, and the reported outcomes have been limited so far. 

The current mainstay frontline options in pancreatic cancer largely center on chemotherapy combinations. These include FOLFIRINOX (irinotecan, fluorouracil, leucovorin, and oxaliplatin), gemcitabine, nab-paclitaxel, and capecitabine. The four-drug chemotherapy combination NALIRIFOX — a slight tweak on FOLFIRINOX — was also recently approved in the first-line setting.

Patient outcomes on these chemotherapy combinations have been modest, with median overall survival in the metastatic setting ranging from 6.7 months to 11.1 months.

And although two KRAS inhibitors, sotorasib and adagrasib, are currently on the US market, neither is approved for pancreatic cancer, and use of these agents to treat pancreatic cancer would be limited. Only about 1%-2% of tumors have the specific KRAS G12C mutation that these drugs target. These KRAS inhibitors have shown limited efficacy in pancreatic cancer.

For instance, a small study evaluating sotorasib in pancreatic cancer found that only 21% of 38 patients with metastatic disease who carried the G12C mutation achieved an objective response, and no patients had a complete response. In the overall population, median progression-free survival was 4 months and median overall survival was 6.9 months, with 19.6% of patients alive at 12 months.

In pancreatic cancer, better targets for KRAS inhibitors include the G12D mutation, carried by about 44% of tumors; G12V, present in 29% of tumors; G12R, present in 20%; and pan-RAS inhibitors, which cover all mutations. 

At this year’s American Society of Clinical Oncology meeting, Dr. Aguirre discussed the pipeline of investigational KRAS agents targeting some of these more relevant mutations.

Results from a recent phase 1 study, evaluating the investigational pan-RAS inhibitor RMC-6236 from Revolution Medicines, showed initial promise. The study revealed an objective response rate at 14 weeks of 20% in 76 patients with metastatic pancreatic ductal adenocarcinoma treated in the second line. The disease control rate reached almost 90% at 14 weeks. 

Median progression-free survival was 8.1 months, an improvement over the 2-3.5 months expected with additional chemotherapy. Overall survival was not reached but started at 8.5 months. The rate of grade 3 or higher adverse events — most commonly rash, diarrhea, and thrombocytopenia — was 22%. 

Revolution Medicines is now planning a phase 3 trial.

Other investigational KRAS inhibitors, outside of KRAS G12C agents, are entering or are in early trials, but without results reported yet.

While there’s “room for improvement,” such studies only offer “proof of concept” that KRAS inhibition has potential, Dr. Aguirre said. 

Oncologists may ultimately see better outcomes by expanding when and how patients receive these drugs. The research to date has been limited to monotherapy in previously treated patients with metastatic disease, which leaves the door open to explore the inhibitors in earlier lines of treatment; in patients with resectable disease; and in combination with chemotherapy, immunotherapy, or other targeted approaches, Dr. Aguirre explained. 

In his own lab, Dr. Aguirre and colleagues have data suggesting that combining KRAS inhibitors and chemotherapy may bring more benefit than either treatment alone.

Pancreatic tumors generally comprise a mix of both basal-like and classical cell subtypes, and basal-like cells have shown more resistance to chemotherapy. Dr. Aguirre’s team has found that basal-like cells may be more sensitive to KRAS inhibitors, which suggests that combining these inhibitors with chemotherapy could improve patient outcomes. 

Alan Venook, MD, said he “remains to be convinced” about the benefit of KRAS inhibition because he’s seen many other promising approaches, such as pegylated hyaluronidase, show initial potential but then fall flat in phase 3 testing. 

“We tend to get excited about preliminary data,” said Dr. Venook, a gastrointestinal medical oncologist at the University of California, San Francisco. “At the moment, there’s no data that suggests [KRAS inhibition] is going to be a game changer.” 

Mutation testing in patients with pancreatic cancer will be critical to identify who might benefit from different KRAS agents, and a subset of patients may do very well.

But with many patients presenting with advanced disease, “I just don’t see how turning off the disease [process] can happen adequately enough to stop it from progressing,” Dr. Venook said. And “is it a big advance to keep disease from progressing over 3 or 6 months?” 

Dr. Aguirre said he respects the caution. Much work remains to be done, including how to improve response rates and durability and to overcome the resistance that sets in with monotherapy. 

Still, “I think there’s tremendous reason for optimism right now,” Dr. Aguirre said.

Although the benefits of these agents may be limited, any improvement in pancreatic cancer treatment would still be a “game changer,” Dr. Marshall said. And that’s because “we need a new game.”

Dr. Aguirre is an advisor and/or disclosed research funding from companies developing KRAS/RAS inhibitors, including Revolution Medicines, Boehringer Ingelheim, Novartis, and Mirati. Dr. Venook did not have any disclosures. Dr. Marshall has ties to numerous companies, including Caris Life Sciences, Bayer, Merck, and Pfizer. He is also a Medscape Oncology editorial advisor.

A version of this article first appeared on Medscape.com.

Pancreatic cancer remains one of the deadliest cancers. 

When the disease is caught earlier, the 5-year survival rates hover around 44%, but once the cancer metastasizes, only about 3% of patients live that long.

Finding effective treatments for the disease continues to be a challenge. 

No significant new therapies in pancreatic cancer have emerged in the past 20 years, explained John Marshall, MD, a gastrointestinal medical oncologist at Georgetown University in Washington, DC.

Oncology researchers have long eyed a potential holy grail target: the KRAS oncogene. Present in about 90% of patients with pancreatic cancer, KRAS mutations are considered a key driver of the disease. But for decades, KRAS was considered “undruggable.” 

Until recently. 

In the past 2 years, the US Food and Drug Administration has approved two KRAS inhibitors — sotorasib and adagrasib — to treat certain colorectal and lung cancers. 

A pipeline of KRAS inhibitors targeting pancreatic cancer has now emerged, leaving some oncologists feeling optimistic about the future of treating the disease.

“I think KRAS inhibitors — [maybe not alone] but as a foundational agent for combinations — are really poised to transform how we care for patients,” said Andrew Aguirre, MD, PhD, a gastrointestinal medical oncologist at the Dana-Farber Cancer Institute, Boston, who heads a lab focused on RAS signaling and pancreatic cancer. These agents won’t necessarily cure pancreatic cancer but will be “part of the solution” to improve outcomes, Dr. Aguirre said.
 

A Challenging Cancer

Pharmaceutical companies currently have at least eight agents in development and are conducting dozens of KRAS/RAS studies that focus on or include pancreatic cancer.

But it’s still early days on the evidence front.

The investigational drugs are only in phase 1/2 testing, and the reported outcomes have been limited so far. 

The current mainstay frontline options in pancreatic cancer largely center on chemotherapy combinations. These include FOLFIRINOX (irinotecan, fluorouracil, leucovorin, and oxaliplatin), gemcitabine, nab-paclitaxel, and capecitabine. The four-drug chemotherapy combination NALIRIFOX — a slight tweak on FOLFIRINOX — was also recently approved in the first-line setting.

Patient outcomes on these chemotherapy combinations have been modest, with median overall survival in the metastatic setting ranging from 6.7 months to 11.1 months.

And although two KRAS inhibitors, sotorasib and adagrasib, are currently on the US market, neither is approved for pancreatic cancer, and use of these agents to treat pancreatic cancer would be limited. Only about 1%-2% of tumors have the specific KRAS G12C mutation that these drugs target. These KRAS inhibitors have shown limited efficacy in pancreatic cancer.

For instance, a small study evaluating sotorasib in pancreatic cancer found that only 21% of 38 patients with metastatic disease who carried the G12C mutation achieved an objective response, and no patients had a complete response. In the overall population, median progression-free survival was 4 months and median overall survival was 6.9 months, with 19.6% of patients alive at 12 months.

In pancreatic cancer, better targets for KRAS inhibitors include the G12D mutation, carried by about 44% of tumors; G12V, present in 29% of tumors; G12R, present in 20%; and pan-RAS inhibitors, which cover all mutations. 

At this year’s American Society of Clinical Oncology meeting, Dr. Aguirre discussed the pipeline of investigational KRAS agents targeting some of these more relevant mutations.

Results from a recent phase 1 study, evaluating the investigational pan-RAS inhibitor RMC-6236 from Revolution Medicines, showed initial promise. The study revealed an objective response rate at 14 weeks of 20% in 76 patients with metastatic pancreatic ductal adenocarcinoma treated in the second line. The disease control rate reached almost 90% at 14 weeks. 

Median progression-free survival was 8.1 months, an improvement over the 2-3.5 months expected with additional chemotherapy. Overall survival was not reached but started at 8.5 months. The rate of grade 3 or higher adverse events — most commonly rash, diarrhea, and thrombocytopenia — was 22%. 

Revolution Medicines is now planning a phase 3 trial.

Other investigational KRAS inhibitors, outside of KRAS G12C agents, are entering or are in early trials, but without results reported yet.

While there’s “room for improvement,” such studies only offer “proof of concept” that KRAS inhibition has potential, Dr. Aguirre said. 

Oncologists may ultimately see better outcomes by expanding when and how patients receive these drugs. The research to date has been limited to monotherapy in previously treated patients with metastatic disease, which leaves the door open to explore the inhibitors in earlier lines of treatment; in patients with resectable disease; and in combination with chemotherapy, immunotherapy, or other targeted approaches, Dr. Aguirre explained. 

In his own lab, Dr. Aguirre and colleagues have data suggesting that combining KRAS inhibitors and chemotherapy may bring more benefit than either treatment alone.

Pancreatic tumors generally comprise a mix of both basal-like and classical cell subtypes, and basal-like cells have shown more resistance to chemotherapy. Dr. Aguirre’s team has found that basal-like cells may be more sensitive to KRAS inhibitors, which suggests that combining these inhibitors with chemotherapy could improve patient outcomes. 

Alan Venook, MD, said he “remains to be convinced” about the benefit of KRAS inhibition because he’s seen many other promising approaches, such as pegylated hyaluronidase, show initial potential but then fall flat in phase 3 testing. 

“We tend to get excited about preliminary data,” said Dr. Venook, a gastrointestinal medical oncologist at the University of California, San Francisco. “At the moment, there’s no data that suggests [KRAS inhibition] is going to be a game changer.” 

Mutation testing in patients with pancreatic cancer will be critical to identify who might benefit from different KRAS agents, and a subset of patients may do very well.

But with many patients presenting with advanced disease, “I just don’t see how turning off the disease [process] can happen adequately enough to stop it from progressing,” Dr. Venook said. And “is it a big advance to keep disease from progressing over 3 or 6 months?” 

Dr. Aguirre said he respects the caution. Much work remains to be done, including how to improve response rates and durability and to overcome the resistance that sets in with monotherapy. 

Still, “I think there’s tremendous reason for optimism right now,” Dr. Aguirre said.

Although the benefits of these agents may be limited, any improvement in pancreatic cancer treatment would still be a “game changer,” Dr. Marshall said. And that’s because “we need a new game.”

Dr. Aguirre is an advisor and/or disclosed research funding from companies developing KRAS/RAS inhibitors, including Revolution Medicines, Boehringer Ingelheim, Novartis, and Mirati. Dr. Venook did not have any disclosures. Dr. Marshall has ties to numerous companies, including Caris Life Sciences, Bayer, Merck, and Pfizer. He is also a Medscape Oncology editorial advisor.

A version of this article first appeared on Medscape.com.

Pancreatic cancer remains one of the deadliest cancers. 

When the disease is caught earlier, the 5-year survival rates hover around 44%, but once the cancer metastasizes, only about 3% of patients live that long.

Finding effective treatments for the disease continues to be a challenge. 

No significant new therapies in pancreatic cancer have emerged in the past 20 years, explained John Marshall, MD, a gastrointestinal medical oncologist at Georgetown University in Washington, DC.

Oncology researchers have long eyed a potential holy grail target: the KRAS oncogene. Present in about 90% of patients with pancreatic cancer, KRAS mutations are considered a key driver of the disease. But for decades, KRAS was considered “undruggable.” 

Until recently. 

In the past 2 years, the US Food and Drug Administration has approved two KRAS inhibitors — sotorasib and adagrasib — to treat certain colorectal and lung cancers. 

A pipeline of KRAS inhibitors targeting pancreatic cancer has now emerged, leaving some oncologists feeling optimistic about the future of treating the disease.

“I think KRAS inhibitors — [maybe not alone] but as a foundational agent for combinations — are really poised to transform how we care for patients,” said Andrew Aguirre, MD, PhD, a gastrointestinal medical oncologist at the Dana-Farber Cancer Institute, Boston, who heads a lab focused on RAS signaling and pancreatic cancer. These agents won’t necessarily cure pancreatic cancer but will be “part of the solution” to improve outcomes, Dr. Aguirre said.
 

A Challenging Cancer

Pharmaceutical companies currently have at least eight agents in development and are conducting dozens of KRAS/RAS studies that focus on or include pancreatic cancer.

But it’s still early days on the evidence front.

The investigational drugs are only in phase 1/2 testing, and the reported outcomes have been limited so far. 

The current mainstay frontline options in pancreatic cancer largely center on chemotherapy combinations. These include FOLFIRINOX (irinotecan, fluorouracil, leucovorin, and oxaliplatin), gemcitabine, nab-paclitaxel, and capecitabine. The four-drug chemotherapy combination NALIRIFOX — a slight tweak on FOLFIRINOX — was also recently approved in the first-line setting.

Patient outcomes on these chemotherapy combinations have been modest, with median overall survival in the metastatic setting ranging from 6.7 months to 11.1 months.

And although two KRAS inhibitors, sotorasib and adagrasib, are currently on the US market, neither is approved for pancreatic cancer, and use of these agents to treat pancreatic cancer would be limited. Only about 1%-2% of tumors have the specific KRAS G12C mutation that these drugs target. These KRAS inhibitors have shown limited efficacy in pancreatic cancer.

For instance, a small study evaluating sotorasib in pancreatic cancer found that only 21% of 38 patients with metastatic disease who carried the G12C mutation achieved an objective response, and no patients had a complete response. In the overall population, median progression-free survival was 4 months and median overall survival was 6.9 months, with 19.6% of patients alive at 12 months.

In pancreatic cancer, better targets for KRAS inhibitors include the G12D mutation, carried by about 44% of tumors; G12V, present in 29% of tumors; G12R, present in 20%; and pan-RAS inhibitors, which cover all mutations. 

At this year’s American Society of Clinical Oncology meeting, Dr. Aguirre discussed the pipeline of investigational KRAS agents targeting some of these more relevant mutations.

Results from a recent phase 1 study, evaluating the investigational pan-RAS inhibitor RMC-6236 from Revolution Medicines, showed initial promise. The study revealed an objective response rate at 14 weeks of 20% in 76 patients with metastatic pancreatic ductal adenocarcinoma treated in the second line. The disease control rate reached almost 90% at 14 weeks. 

Median progression-free survival was 8.1 months, an improvement over the 2-3.5 months expected with additional chemotherapy. Overall survival was not reached but started at 8.5 months. The rate of grade 3 or higher adverse events — most commonly rash, diarrhea, and thrombocytopenia — was 22%. 

Revolution Medicines is now planning a phase 3 trial.

Other investigational KRAS inhibitors, outside of KRAS G12C agents, are entering or are in early trials, but without results reported yet.

While there’s “room for improvement,” such studies only offer “proof of concept” that KRAS inhibition has potential, Dr. Aguirre said. 

Oncologists may ultimately see better outcomes by expanding when and how patients receive these drugs. The research to date has been limited to monotherapy in previously treated patients with metastatic disease, which leaves the door open to explore the inhibitors in earlier lines of treatment; in patients with resectable disease; and in combination with chemotherapy, immunotherapy, or other targeted approaches, Dr. Aguirre explained. 

In his own lab, Dr. Aguirre and colleagues have data suggesting that combining KRAS inhibitors and chemotherapy may bring more benefit than either treatment alone.

Pancreatic tumors generally comprise a mix of both basal-like and classical cell subtypes, and basal-like cells have shown more resistance to chemotherapy. Dr. Aguirre’s team has found that basal-like cells may be more sensitive to KRAS inhibitors, which suggests that combining these inhibitors with chemotherapy could improve patient outcomes. 

Alan Venook, MD, said he “remains to be convinced” about the benefit of KRAS inhibition because he’s seen many other promising approaches, such as pegylated hyaluronidase, show initial potential but then fall flat in phase 3 testing. 

“We tend to get excited about preliminary data,” said Dr. Venook, a gastrointestinal medical oncologist at the University of California, San Francisco. “At the moment, there’s no data that suggests [KRAS inhibition] is going to be a game changer.” 

Mutation testing in patients with pancreatic cancer will be critical to identify who might benefit from different KRAS agents, and a subset of patients may do very well.

But with many patients presenting with advanced disease, “I just don’t see how turning off the disease [process] can happen adequately enough to stop it from progressing,” Dr. Venook said. And “is it a big advance to keep disease from progressing over 3 or 6 months?” 

Dr. Aguirre said he respects the caution. Much work remains to be done, including how to improve response rates and durability and to overcome the resistance that sets in with monotherapy. 

Still, “I think there’s tremendous reason for optimism right now,” Dr. Aguirre said.

Although the benefits of these agents may be limited, any improvement in pancreatic cancer treatment would still be a “game changer,” Dr. Marshall said. And that’s because “we need a new game.”

Dr. Aguirre is an advisor and/or disclosed research funding from companies developing KRAS/RAS inhibitors, including Revolution Medicines, Boehringer Ingelheim, Novartis, and Mirati. Dr. Venook did not have any disclosures. Dr. Marshall has ties to numerous companies, including Caris Life Sciences, Bayer, Merck, and Pfizer. He is also a Medscape Oncology editorial advisor.

A version of this article first appeared on Medscape.com.

First-line treatment with ivonescimab led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS), compared with pembrolizumab (Keytruda), in patients with programmed death ligand 1 (PD-L1)–positive advanced non–small cell lung cancer (NSCLC), according to recent findings from the HARMONi-2 trial. 

“This is the first randomized, phase 3 study to demonstrate a clinically significant improvement in efficacy with a novel drug compared to pembrolizumab in advanced NSCLC,” said study investigator Caicun Zhou, MD, PhD, with Shanghai Pulmonary Hospital in China, 

The results highlight ivonescimab’s potential to become a “new standard of care” in advanced PD-L1–positive advanced NSCLC, said Dr. Zhou, who presented the analysis at the annual International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer in San Diego. Dr. Zhou is president-elect of the IASLC. 

Ivonescimab (AK112) is a novel, potentially first-in-class investigational bispecific antibody that targets PD-1 and vascular endothelial growth factor (VEGF) developed by Akeso Biopharma, which funded the HARMONi-2 trial. 

Conducted at 55 centers in China, HARMONi-2 enrolled 398 patients with untreated locally advanced or metastatic NSCLC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, PD-L1 positive (with at least 1% of tumor cells expressing PD-L1), and no EGFR mutations or ALK rearrangements.

Patients were randomly allocated (1:1) to receive ivonescimab (20 mg/kg) or pembrolizumab (200 mg) every 3 weeks. The two groups were well balanced, and randomization was stratified by histology (squamous vs nonsquamous), clinical stage (IIIB/IIIC vs IV) and PD-L1 expression (PD-L1 of 1%-49% vs 50% or greater). 

Dr. Zhou reported that patients who received ivonescimab were progression free for nearly twice as long as those on pembrolizumab — a median of 11.1 vs 5.8 months, indicating a 49% lower risk for progression or death (stratified hazard ratio [HR], 0.51; P < .0001). 

The meaningful improvement in PFS with ivonescimab, compared with pembrolizumab, was “broadly consistent” in all prespecified subgroups, Dr. Zhou noted. That included patients with squamous NSCLC (HR, 0.48) and nonsquamous NSCLC (HR, 0.54), those with PD-L1 expression of 1%-49% (HR, 0.54) and 50% or higher (HR, 0.46), as well as those with liver metastases (HR, 0.47) and brain metastases (HR, 0.55). 

The PFS benefit seen with ivonescimab in HARMONi-2 is “striking,” and the results “highlight the potential benefits of combined VEGF and PD-1 blockade together,” said John Heymach, MD, with the University of Texas MD Anderson Cancer Center in Houston, who served as discussant for the study. 

Ivonescimab also led to a higher objective response rate (50% vs 38.5%) and disease control rate (89.9% vs 70.5%). 

Grade 3 or higher treatment-related adverse events occurred in more patients receiving ivonescimab — 29.4% vs 15.6% on pembrolizumab. The difference largely stemmed from higher rates of proteinuria, hypertension, and lab abnormalities.

The rates of serious treatment-related adverse events were similar between the groups —20.8% in the ivonescimab group and 16.1% in the pembrolizumab group. Rates of grade 3 or higher immune-related adverse events were also similar, occurring in 7% of patients treated with ivonescimab and 8% of those receiving pembrolizumab. 

In patients with squamous cell carcinoma, in particular, ivonescimab demonstrated a “very manageable” safety profile, Dr. Zhou noted. In this group, grade 3 or higher treatment-related adverse events occurred in 22.2% of patients (vs 18.7% receiving pembrolizumab).

Ivonescimab was associated with comparable but “numerically better” time to deterioration of global health status, based on the EORTC Core Quality of Life questionnaire, Dr. Zhou said. 

Although the “really impressive and clinically meaningful” PFS benefits extended across different subgroups, “we await the overall survival results and additional studies done outside of China to confirm the benefit seen,” Dr. Heymach noted.

He also cautioned that, for patients with low to intermediate PD-L1 expression (1%-49%), pembrolizumab monotherapy “would not be the relevant comparator in the US and the rest of the world, and different study designs are going to be required for those populations.”

Based on the results of HARMONi-2, Akeso’s partner, Summit Therapeutics, plans to initiate HARMONi-7 in early 2025. 

HARMONi-7 is currently planned as a multiregional, phase 3 clinical trial that will compare ivonescimab monotherapy to pembrolizumab monotherapy in patients with metastatic NSCLC whose tumors have high PD-L1 expression (50% or more). 

Dr. Zhou has received consulting fees from Qilu Pharmaceutical, Hengrui, and TopAlliance Biosciences and honoraria from Eli Lilly China, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Qilu, Hengrui, Innovent Biologics, Alice, C-Stone, Luye Pharma, TopAlliance Biosciences, Amoy Diagnostics, and AnHeart Therapeutics. Dr. Heymach is a consultant for AbbVie, AnHeart Therapeutics, ArriVent Biopharma, AstraZeneca, BioCurity Pharmaceuticals, BioNTech, Blueprint Medicines, Boehringer Ingelheim, BMS, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Mirati Therapeutics, Novartis Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, Spectrum Pharmaceuticals, and Takeda.

A version of this article first appeared on Medscape.com.

First-line treatment with ivonescimab led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS), compared with pembrolizumab (Keytruda), in patients with programmed death ligand 1 (PD-L1)–positive advanced non–small cell lung cancer (NSCLC), according to recent findings from the HARMONi-2 trial. 

“This is the first randomized, phase 3 study to demonstrate a clinically significant improvement in efficacy with a novel drug compared to pembrolizumab in advanced NSCLC,” said study investigator Caicun Zhou, MD, PhD, with Shanghai Pulmonary Hospital in China, 

The results highlight ivonescimab’s potential to become a “new standard of care” in advanced PD-L1–positive advanced NSCLC, said Dr. Zhou, who presented the analysis at the annual International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer in San Diego. Dr. Zhou is president-elect of the IASLC. 

Ivonescimab (AK112) is a novel, potentially first-in-class investigational bispecific antibody that targets PD-1 and vascular endothelial growth factor (VEGF) developed by Akeso Biopharma, which funded the HARMONi-2 trial. 

Conducted at 55 centers in China, HARMONi-2 enrolled 398 patients with untreated locally advanced or metastatic NSCLC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, PD-L1 positive (with at least 1% of tumor cells expressing PD-L1), and no EGFR mutations or ALK rearrangements.

Patients were randomly allocated (1:1) to receive ivonescimab (20 mg/kg) or pembrolizumab (200 mg) every 3 weeks. The two groups were well balanced, and randomization was stratified by histology (squamous vs nonsquamous), clinical stage (IIIB/IIIC vs IV) and PD-L1 expression (PD-L1 of 1%-49% vs 50% or greater). 

Dr. Zhou reported that patients who received ivonescimab were progression free for nearly twice as long as those on pembrolizumab — a median of 11.1 vs 5.8 months, indicating a 49% lower risk for progression or death (stratified hazard ratio [HR], 0.51; P < .0001). 

The meaningful improvement in PFS with ivonescimab, compared with pembrolizumab, was “broadly consistent” in all prespecified subgroups, Dr. Zhou noted. That included patients with squamous NSCLC (HR, 0.48) and nonsquamous NSCLC (HR, 0.54), those with PD-L1 expression of 1%-49% (HR, 0.54) and 50% or higher (HR, 0.46), as well as those with liver metastases (HR, 0.47) and brain metastases (HR, 0.55). 

The PFS benefit seen with ivonescimab in HARMONi-2 is “striking,” and the results “highlight the potential benefits of combined VEGF and PD-1 blockade together,” said John Heymach, MD, with the University of Texas MD Anderson Cancer Center in Houston, who served as discussant for the study. 

Ivonescimab also led to a higher objective response rate (50% vs 38.5%) and disease control rate (89.9% vs 70.5%). 

Grade 3 or higher treatment-related adverse events occurred in more patients receiving ivonescimab — 29.4% vs 15.6% on pembrolizumab. The difference largely stemmed from higher rates of proteinuria, hypertension, and lab abnormalities.

The rates of serious treatment-related adverse events were similar between the groups —20.8% in the ivonescimab group and 16.1% in the pembrolizumab group. Rates of grade 3 or higher immune-related adverse events were also similar, occurring in 7% of patients treated with ivonescimab and 8% of those receiving pembrolizumab. 

In patients with squamous cell carcinoma, in particular, ivonescimab demonstrated a “very manageable” safety profile, Dr. Zhou noted. In this group, grade 3 or higher treatment-related adverse events occurred in 22.2% of patients (vs 18.7% receiving pembrolizumab).

Ivonescimab was associated with comparable but “numerically better” time to deterioration of global health status, based on the EORTC Core Quality of Life questionnaire, Dr. Zhou said. 

Although the “really impressive and clinically meaningful” PFS benefits extended across different subgroups, “we await the overall survival results and additional studies done outside of China to confirm the benefit seen,” Dr. Heymach noted.

He also cautioned that, for patients with low to intermediate PD-L1 expression (1%-49%), pembrolizumab monotherapy “would not be the relevant comparator in the US and the rest of the world, and different study designs are going to be required for those populations.”

Based on the results of HARMONi-2, Akeso’s partner, Summit Therapeutics, plans to initiate HARMONi-7 in early 2025. 

HARMONi-7 is currently planned as a multiregional, phase 3 clinical trial that will compare ivonescimab monotherapy to pembrolizumab monotherapy in patients with metastatic NSCLC whose tumors have high PD-L1 expression (50% or more). 

Dr. Zhou has received consulting fees from Qilu Pharmaceutical, Hengrui, and TopAlliance Biosciences and honoraria from Eli Lilly China, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Qilu, Hengrui, Innovent Biologics, Alice, C-Stone, Luye Pharma, TopAlliance Biosciences, Amoy Diagnostics, and AnHeart Therapeutics. Dr. Heymach is a consultant for AbbVie, AnHeart Therapeutics, ArriVent Biopharma, AstraZeneca, BioCurity Pharmaceuticals, BioNTech, Blueprint Medicines, Boehringer Ingelheim, BMS, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Mirati Therapeutics, Novartis Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, Spectrum Pharmaceuticals, and Takeda.

A version of this article first appeared on Medscape.com.

First-line treatment with ivonescimab led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS), compared with pembrolizumab (Keytruda), in patients with programmed death ligand 1 (PD-L1)–positive advanced non–small cell lung cancer (NSCLC), according to recent findings from the HARMONi-2 trial. 

“This is the first randomized, phase 3 study to demonstrate a clinically significant improvement in efficacy with a novel drug compared to pembrolizumab in advanced NSCLC,” said study investigator Caicun Zhou, MD, PhD, with Shanghai Pulmonary Hospital in China, 

The results highlight ivonescimab’s potential to become a “new standard of care” in advanced PD-L1–positive advanced NSCLC, said Dr. Zhou, who presented the analysis at the annual International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer in San Diego. Dr. Zhou is president-elect of the IASLC. 

Ivonescimab (AK112) is a novel, potentially first-in-class investigational bispecific antibody that targets PD-1 and vascular endothelial growth factor (VEGF) developed by Akeso Biopharma, which funded the HARMONi-2 trial. 

Conducted at 55 centers in China, HARMONi-2 enrolled 398 patients with untreated locally advanced or metastatic NSCLC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, PD-L1 positive (with at least 1% of tumor cells expressing PD-L1), and no EGFR mutations or ALK rearrangements.

Patients were randomly allocated (1:1) to receive ivonescimab (20 mg/kg) or pembrolizumab (200 mg) every 3 weeks. The two groups were well balanced, and randomization was stratified by histology (squamous vs nonsquamous), clinical stage (IIIB/IIIC vs IV) and PD-L1 expression (PD-L1 of 1%-49% vs 50% or greater). 

Dr. Zhou reported that patients who received ivonescimab were progression free for nearly twice as long as those on pembrolizumab — a median of 11.1 vs 5.8 months, indicating a 49% lower risk for progression or death (stratified hazard ratio [HR], 0.51; P < .0001). 

The meaningful improvement in PFS with ivonescimab, compared with pembrolizumab, was “broadly consistent” in all prespecified subgroups, Dr. Zhou noted. That included patients with squamous NSCLC (HR, 0.48) and nonsquamous NSCLC (HR, 0.54), those with PD-L1 expression of 1%-49% (HR, 0.54) and 50% or higher (HR, 0.46), as well as those with liver metastases (HR, 0.47) and brain metastases (HR, 0.55). 

The PFS benefit seen with ivonescimab in HARMONi-2 is “striking,” and the results “highlight the potential benefits of combined VEGF and PD-1 blockade together,” said John Heymach, MD, with the University of Texas MD Anderson Cancer Center in Houston, who served as discussant for the study. 

Ivonescimab also led to a higher objective response rate (50% vs 38.5%) and disease control rate (89.9% vs 70.5%). 

Grade 3 or higher treatment-related adverse events occurred in more patients receiving ivonescimab — 29.4% vs 15.6% on pembrolizumab. The difference largely stemmed from higher rates of proteinuria, hypertension, and lab abnormalities.

The rates of serious treatment-related adverse events were similar between the groups —20.8% in the ivonescimab group and 16.1% in the pembrolizumab group. Rates of grade 3 or higher immune-related adverse events were also similar, occurring in 7% of patients treated with ivonescimab and 8% of those receiving pembrolizumab. 

In patients with squamous cell carcinoma, in particular, ivonescimab demonstrated a “very manageable” safety profile, Dr. Zhou noted. In this group, grade 3 or higher treatment-related adverse events occurred in 22.2% of patients (vs 18.7% receiving pembrolizumab).

Ivonescimab was associated with comparable but “numerically better” time to deterioration of global health status, based on the EORTC Core Quality of Life questionnaire, Dr. Zhou said. 

Although the “really impressive and clinically meaningful” PFS benefits extended across different subgroups, “we await the overall survival results and additional studies done outside of China to confirm the benefit seen,” Dr. Heymach noted.

He also cautioned that, for patients with low to intermediate PD-L1 expression (1%-49%), pembrolizumab monotherapy “would not be the relevant comparator in the US and the rest of the world, and different study designs are going to be required for those populations.”

Based on the results of HARMONi-2, Akeso’s partner, Summit Therapeutics, plans to initiate HARMONi-7 in early 2025. 

HARMONi-7 is currently planned as a multiregional, phase 3 clinical trial that will compare ivonescimab monotherapy to pembrolizumab monotherapy in patients with metastatic NSCLC whose tumors have high PD-L1 expression (50% or more). 

Dr. Zhou has received consulting fees from Qilu Pharmaceutical, Hengrui, and TopAlliance Biosciences and honoraria from Eli Lilly China, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Qilu, Hengrui, Innovent Biologics, Alice, C-Stone, Luye Pharma, TopAlliance Biosciences, Amoy Diagnostics, and AnHeart Therapeutics. Dr. Heymach is a consultant for AbbVie, AnHeart Therapeutics, ArriVent Biopharma, AstraZeneca, BioCurity Pharmaceuticals, BioNTech, Blueprint Medicines, Boehringer Ingelheim, BMS, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Mirati Therapeutics, Novartis Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, Spectrum Pharmaceuticals, and Takeda.

A version of this article first appeared on Medscape.com.

Adjuvant radiotherapy reduces the risk for short-term recurrence in patients with early breast cancer, but it may have no impact on long-term recurrence or overall survival, based on a 30-year follow-up of the Scottish Breast Conservation Trial.

These findings suggest that patients with biology predicting late relapse may receive little benefit from adjuvant radiotherapy, lead author Linda J. Williams, PhD, of the University of Edinburgh in Scotland, and colleagues, reported.

“During the past 30 years, several randomized controlled trials have investigated the role of postoperative radiotherapy after breast-conserving surgery for early breast cancer,” the investigators wrote in The Lancet Oncology. “These trials showed that radiotherapy reduces the risk of local recurrence but were underpowered individually to detect a difference in overall survival.”
 

How Did the Present Study Increase Our Understanding of the Benefits of Adjuvant Radiotherapy in Early Breast Cancer?

The present analysis included data from a trial that began in 1985, when 589 patients with early breast cancer (tumors ≤ 4 cm [T1 or T2 and N0 or N1]) were randomized to receive either high-dose or no radiotherapy, with final cohorts including 291 patients and 294 patients, respectively. The radiotherapy was given 50 Gy in 20-25 fractions, either locally or locoregionally.

Estrogen receptor (ER)–positive patients (≥ 20 fmol/mg protein) received 5 years of daily oral tamoxifen. ER-poor patients (< 20 fmol/mg protein) received a chemotherapy combination of cyclophosphamide, methotrexate, and fluorouracil on a 21-day cycle for eight cycles.

Considering all data across a median follow-up of 17.5 years, adjuvant radiotherapy appeared to offer benefit, as it was associated with significantly lower ipsilateral breast tumor recurrence (16% vs 36%; hazard ratio [HR], 0.39; P < .0001).

But that tells only part of the story.

The positive impact of radiotherapy persisted for 1 decade (HR, 0.24; P < .0001), but risk beyond this point was no different between groups (HR, 0.98; P = .95).

“[The] benefit of radiotherapy was time dependent,” the investigators noted.

What’s more, median overall survival was no different between those who received radiotherapy and those who did not (18.7 vs 19.2 years; HR, 1.08; log-rank P = .43), and “reassuringly,” omitting radiotherapy did not increase the rate of distant metastasis.
 

How Might These Findings Influence Treatment Planning for Patients With Early Breast Cancer?

“The results can help clinicians to advise patients better about their choice to have radiotherapy or not if they better understand what benefits it does and does not bring,” the investigators wrote. “These results might provide clues perhaps to the biology of radiotherapy benefit, given that it does not prevent late recurrences, suggesting that patients whose biology predicts a late relapse only might not gain a benefit from radiotherapy.”

Gary M. Freedman, MD, chief of Women’s Health Service, Radiation Oncology, at Penn Medicine, Philadelphia, offered a different perspective.

“The study lumps together a local recurrence of breast cancer — that is relapse of the cancer years after treatment with lumpectomy and radiation — with the development of an entirely new breast cancer in the same breast,” Dr. Freedman said in a written comment. “When something comes back between years 0-5 and 0-8, we usually think of it as a true local recurrence arbitrarily, but beyond that they are new cancers.”

He went on to emphasize the clinical importance of reducing local recurrence within the first decade, noting that “this leads to much less morbidity and better quality of life for the patients.”

Dr. Freedman also shared his perspective on the survival data.

“Radiation did reduce breast cancer mortality very significantly — death from breast cancers went down from 46% to 37%,” he wrote (P = .054). “This is on the same level as chemo or hormone therapy. The study was not powered to detect significant differences in survival by radiation, but that has been shown with other meta-analyses.”
 

Are Findings From a Trial Started 30 Years Ago Still Relevant Today?

“Clearly the treatment of early breast cancer has advanced since the 1980s when the Scottish Conservation trial was launched,” study coauthor Ian Kunkler, MB, FRCR, of the University of Edinburgh, said in a written comment. “There is more breast screening, attention to clearing surgical margins of residual disease, more effective and longer periods of adjuvant hormonal therapy, reduced radiotherapy toxicity from more precise delivery. However, most anticancer treatments lose their effectiveness over time.”

He suggested that more trials are needed to confirm the present findings and reiterated that the lack of long-term recurrence benefit is most relevant for patients with disease features that predict late relapse, who “seem to gain little from adjuvant radiotherapy given as part of primary treatment.”

Dr. Kunkler noted that the observed benefit in the first decade supports the continued use of radiotherapy alongside anticancer drug treatment.

When asked the same question, Freedman emphasized the differences in treatment today vs the 1980s.

“The results of modern multidisciplinary cancer care are much, much better than these 30-year results,” Dr. Freedman said. “The risk for local recurrence in the breast after radiation is now about 2%-3% at 10 years in most studies.”

He also noted that modern radiotherapy techniques have “significantly lowered dose and risks to heart and lung,” compared with techniques used 30 years ago.

“A take-home point for the study is after breast conservation, whether or not you have radiation, you have to continue long-term screening mammograms for new breast cancers that may occur even decades later,” Dr. Freedman concluded.
 

How Might These Findings Impact Future Research Design and Funding?

“The findings should encourage trial funders to consider funding long-term follow-up beyond 10 years to assess benefits and risks of anticancer therapies,” Dr. Kunkler said. “The importance of long-term follow-up cannot be understated.”

This study was funded by Breast Cancer Institute (part of Edinburgh and Lothians Health Foundation), PFS Genomics (now part of Exact Sciences), the University of Edinburgh, and NHS Lothian. The investigators reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

Adjuvant radiotherapy reduces the risk for short-term recurrence in patients with early breast cancer, but it may have no impact on long-term recurrence or overall survival, based on a 30-year follow-up of the Scottish Breast Conservation Trial.

These findings suggest that patients with biology predicting late relapse may receive little benefit from adjuvant radiotherapy, lead author Linda J. Williams, PhD, of the University of Edinburgh in Scotland, and colleagues, reported.

“During the past 30 years, several randomized controlled trials have investigated the role of postoperative radiotherapy after breast-conserving surgery for early breast cancer,” the investigators wrote in The Lancet Oncology. “These trials showed that radiotherapy reduces the risk of local recurrence but were underpowered individually to detect a difference in overall survival.”
 

How Did the Present Study Increase Our Understanding of the Benefits of Adjuvant Radiotherapy in Early Breast Cancer?

The present analysis included data from a trial that began in 1985, when 589 patients with early breast cancer (tumors ≤ 4 cm [T1 or T2 and N0 or N1]) were randomized to receive either high-dose or no radiotherapy, with final cohorts including 291 patients and 294 patients, respectively. The radiotherapy was given 50 Gy in 20-25 fractions, either locally or locoregionally.

Estrogen receptor (ER)–positive patients (≥ 20 fmol/mg protein) received 5 years of daily oral tamoxifen. ER-poor patients (< 20 fmol/mg protein) received a chemotherapy combination of cyclophosphamide, methotrexate, and fluorouracil on a 21-day cycle for eight cycles.

Considering all data across a median follow-up of 17.5 years, adjuvant radiotherapy appeared to offer benefit, as it was associated with significantly lower ipsilateral breast tumor recurrence (16% vs 36%; hazard ratio [HR], 0.39; P < .0001).

But that tells only part of the story.

The positive impact of radiotherapy persisted for 1 decade (HR, 0.24; P < .0001), but risk beyond this point was no different between groups (HR, 0.98; P = .95).

“[The] benefit of radiotherapy was time dependent,” the investigators noted.

What’s more, median overall survival was no different between those who received radiotherapy and those who did not (18.7 vs 19.2 years; HR, 1.08; log-rank P = .43), and “reassuringly,” omitting radiotherapy did not increase the rate of distant metastasis.
 

How Might These Findings Influence Treatment Planning for Patients With Early Breast Cancer?

“The results can help clinicians to advise patients better about their choice to have radiotherapy or not if they better understand what benefits it does and does not bring,” the investigators wrote. “These results might provide clues perhaps to the biology of radiotherapy benefit, given that it does not prevent late recurrences, suggesting that patients whose biology predicts a late relapse only might not gain a benefit from radiotherapy.”

Gary M. Freedman, MD, chief of Women’s Health Service, Radiation Oncology, at Penn Medicine, Philadelphia, offered a different perspective.

“The study lumps together a local recurrence of breast cancer — that is relapse of the cancer years after treatment with lumpectomy and radiation — with the development of an entirely new breast cancer in the same breast,” Dr. Freedman said in a written comment. “When something comes back between years 0-5 and 0-8, we usually think of it as a true local recurrence arbitrarily, but beyond that they are new cancers.”

He went on to emphasize the clinical importance of reducing local recurrence within the first decade, noting that “this leads to much less morbidity and better quality of life for the patients.”

Dr. Freedman also shared his perspective on the survival data.

“Radiation did reduce breast cancer mortality very significantly — death from breast cancers went down from 46% to 37%,” he wrote (P = .054). “This is on the same level as chemo or hormone therapy. The study was not powered to detect significant differences in survival by radiation, but that has been shown with other meta-analyses.”
 

Are Findings From a Trial Started 30 Years Ago Still Relevant Today?

“Clearly the treatment of early breast cancer has advanced since the 1980s when the Scottish Conservation trial was launched,” study coauthor Ian Kunkler, MB, FRCR, of the University of Edinburgh, said in a written comment. “There is more breast screening, attention to clearing surgical margins of residual disease, more effective and longer periods of adjuvant hormonal therapy, reduced radiotherapy toxicity from more precise delivery. However, most anticancer treatments lose their effectiveness over time.”

He suggested that more trials are needed to confirm the present findings and reiterated that the lack of long-term recurrence benefit is most relevant for patients with disease features that predict late relapse, who “seem to gain little from adjuvant radiotherapy given as part of primary treatment.”

Dr. Kunkler noted that the observed benefit in the first decade supports the continued use of radiotherapy alongside anticancer drug treatment.

When asked the same question, Freedman emphasized the differences in treatment today vs the 1980s.

“The results of modern multidisciplinary cancer care are much, much better than these 30-year results,” Dr. Freedman said. “The risk for local recurrence in the breast after radiation is now about 2%-3% at 10 years in most studies.”

He also noted that modern radiotherapy techniques have “significantly lowered dose and risks to heart and lung,” compared with techniques used 30 years ago.

“A take-home point for the study is after breast conservation, whether or not you have radiation, you have to continue long-term screening mammograms for new breast cancers that may occur even decades later,” Dr. Freedman concluded.
 

How Might These Findings Impact Future Research Design and Funding?

“The findings should encourage trial funders to consider funding long-term follow-up beyond 10 years to assess benefits and risks of anticancer therapies,” Dr. Kunkler said. “The importance of long-term follow-up cannot be understated.”

This study was funded by Breast Cancer Institute (part of Edinburgh and Lothians Health Foundation), PFS Genomics (now part of Exact Sciences), the University of Edinburgh, and NHS Lothian. The investigators reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

Adjuvant radiotherapy reduces the risk for short-term recurrence in patients with early breast cancer, but it may have no impact on long-term recurrence or overall survival, based on a 30-year follow-up of the Scottish Breast Conservation Trial.

These findings suggest that patients with biology predicting late relapse may receive little benefit from adjuvant radiotherapy, lead author Linda J. Williams, PhD, of the University of Edinburgh in Scotland, and colleagues, reported.

“During the past 30 years, several randomized controlled trials have investigated the role of postoperative radiotherapy after breast-conserving surgery for early breast cancer,” the investigators wrote in The Lancet Oncology. “These trials showed that radiotherapy reduces the risk of local recurrence but were underpowered individually to detect a difference in overall survival.”
 

How Did the Present Study Increase Our Understanding of the Benefits of Adjuvant Radiotherapy in Early Breast Cancer?

The present analysis included data from a trial that began in 1985, when 589 patients with early breast cancer (tumors ≤ 4 cm [T1 or T2 and N0 or N1]) were randomized to receive either high-dose or no radiotherapy, with final cohorts including 291 patients and 294 patients, respectively. The radiotherapy was given 50 Gy in 20-25 fractions, either locally or locoregionally.

Estrogen receptor (ER)–positive patients (≥ 20 fmol/mg protein) received 5 years of daily oral tamoxifen. ER-poor patients (< 20 fmol/mg protein) received a chemotherapy combination of cyclophosphamide, methotrexate, and fluorouracil on a 21-day cycle for eight cycles.

Considering all data across a median follow-up of 17.5 years, adjuvant radiotherapy appeared to offer benefit, as it was associated with significantly lower ipsilateral breast tumor recurrence (16% vs 36%; hazard ratio [HR], 0.39; P < .0001).

But that tells only part of the story.

The positive impact of radiotherapy persisted for 1 decade (HR, 0.24; P < .0001), but risk beyond this point was no different between groups (HR, 0.98; P = .95).

“[The] benefit of radiotherapy was time dependent,” the investigators noted.

What’s more, median overall survival was no different between those who received radiotherapy and those who did not (18.7 vs 19.2 years; HR, 1.08; log-rank P = .43), and “reassuringly,” omitting radiotherapy did not increase the rate of distant metastasis.
 

How Might These Findings Influence Treatment Planning for Patients With Early Breast Cancer?

“The results can help clinicians to advise patients better about their choice to have radiotherapy or not if they better understand what benefits it does and does not bring,” the investigators wrote. “These results might provide clues perhaps to the biology of radiotherapy benefit, given that it does not prevent late recurrences, suggesting that patients whose biology predicts a late relapse only might not gain a benefit from radiotherapy.”

Gary M. Freedman, MD, chief of Women’s Health Service, Radiation Oncology, at Penn Medicine, Philadelphia, offered a different perspective.

“The study lumps together a local recurrence of breast cancer — that is relapse of the cancer years after treatment with lumpectomy and radiation — with the development of an entirely new breast cancer in the same breast,” Dr. Freedman said in a written comment. “When something comes back between years 0-5 and 0-8, we usually think of it as a true local recurrence arbitrarily, but beyond that they are new cancers.”

He went on to emphasize the clinical importance of reducing local recurrence within the first decade, noting that “this leads to much less morbidity and better quality of life for the patients.”

Dr. Freedman also shared his perspective on the survival data.

“Radiation did reduce breast cancer mortality very significantly — death from breast cancers went down from 46% to 37%,” he wrote (P = .054). “This is on the same level as chemo or hormone therapy. The study was not powered to detect significant differences in survival by radiation, but that has been shown with other meta-analyses.”
 

Are Findings From a Trial Started 30 Years Ago Still Relevant Today?

“Clearly the treatment of early breast cancer has advanced since the 1980s when the Scottish Conservation trial was launched,” study coauthor Ian Kunkler, MB, FRCR, of the University of Edinburgh, said in a written comment. “There is more breast screening, attention to clearing surgical margins of residual disease, more effective and longer periods of adjuvant hormonal therapy, reduced radiotherapy toxicity from more precise delivery. However, most anticancer treatments lose their effectiveness over time.”

He suggested that more trials are needed to confirm the present findings and reiterated that the lack of long-term recurrence benefit is most relevant for patients with disease features that predict late relapse, who “seem to gain little from adjuvant radiotherapy given as part of primary treatment.”

Dr. Kunkler noted that the observed benefit in the first decade supports the continued use of radiotherapy alongside anticancer drug treatment.

When asked the same question, Freedman emphasized the differences in treatment today vs the 1980s.

“The results of modern multidisciplinary cancer care are much, much better than these 30-year results,” Dr. Freedman said. “The risk for local recurrence in the breast after radiation is now about 2%-3% at 10 years in most studies.”

He also noted that modern radiotherapy techniques have “significantly lowered dose and risks to heart and lung,” compared with techniques used 30 years ago.

“A take-home point for the study is after breast conservation, whether or not you have radiation, you have to continue long-term screening mammograms for new breast cancers that may occur even decades later,” Dr. Freedman concluded.
 

How Might These Findings Impact Future Research Design and Funding?

“The findings should encourage trial funders to consider funding long-term follow-up beyond 10 years to assess benefits and risks of anticancer therapies,” Dr. Kunkler said. “The importance of long-term follow-up cannot be understated.”

This study was funded by Breast Cancer Institute (part of Edinburgh and Lothians Health Foundation), PFS Genomics (now part of Exact Sciences), the University of Edinburgh, and NHS Lothian. The investigators reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

The use of menopausal hormone therapy (MHT) increases breast cancer risk in women with a strong family history of breast cancer. These women have a striking cumulative risk of developing breast cancer (age, 50-80 years) of 22.4%, according to a new modelling study of UK women.

METHODOLOGY:

This was a modeling study integrating two data-sets of UK women: the BOADICEA dataset of age-specific breast cancer risk with family history and the Collaborative Group on Hormonal Factors in Breast Cancer, which covers relative risk for breast cancer with different types and durations of MHT.

Four different breast cancer family history profiles were:

• “Average” family history of breast cancer has unknown affected family members;
• “Modest” family history comprises a single first-degree relative with breast cancer at the age of 60 years.
• “Intermediate” family history comprises a single first-degree relative who developed breast cancer at the age of 40 years.
• “Strong” family history comprises two first-degree relatives who developed breast cancer at the age of 50 years.

TAKEAWAY:

• The lowest risk category: “Average” family history with no MHT use has a cumulative breast cancer risk (age, 50-80 years) of 9.8% and a risk of dying from breast cancer of 1.7%. These risks rise with 5 years’ exposure to MHT (age, 50-55 years) to 11.0% and 1.8%, respectively.
• The highest risk category: “Strong” family history with no MHT use has a cumulative breast cancer risk (age, 50-80 years) of 19.6% and a risk of dying from breast cancer of 3.2%. These risks rise with 5 years’ exposure to MHT (age, 50-55 years) to 22.4% and 3.5%, respectively.

IN PRACTICE:

The authors concluded that, “These integrated data will enable more accurate estimates of absolute and attributable risk associated with MHT exposure for women with a family history of breast cancer, informing shared decision-making.”

SOURCE:

The lead author is Catherine Huntley of the Institute of Cancer Research, London, England. The study appeared in the British Journal of General Practice.

LIMITATIONS:

Limitations included modeling study that did not directly measure individuals with combined risks.

DISCLOSURES:

The study was funded by several sources including Cancer Research UK. The authors reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

The use of menopausal hormone therapy (MHT) increases breast cancer risk in women with a strong family history of breast cancer. These women have a striking cumulative risk of developing breast cancer (age, 50-80 years) of 22.4%, according to a new modelling study of UK women.

METHODOLOGY:

This was a modeling study integrating two data-sets of UK women: the BOADICEA dataset of age-specific breast cancer risk with family history and the Collaborative Group on Hormonal Factors in Breast Cancer, which covers relative risk for breast cancer with different types and durations of MHT.

Four different breast cancer family history profiles were:

• “Average” family history of breast cancer has unknown affected family members;
• “Modest” family history comprises a single first-degree relative with breast cancer at the age of 60 years.
• “Intermediate” family history comprises a single first-degree relative who developed breast cancer at the age of 40 years.
• “Strong” family history comprises two first-degree relatives who developed breast cancer at the age of 50 years.

TAKEAWAY:

• The lowest risk category: “Average” family history with no MHT use has a cumulative breast cancer risk (age, 50-80 years) of 9.8% and a risk of dying from breast cancer of 1.7%. These risks rise with 5 years’ exposure to MHT (age, 50-55 years) to 11.0% and 1.8%, respectively.
• The highest risk category: “Strong” family history with no MHT use has a cumulative breast cancer risk (age, 50-80 years) of 19.6% and a risk of dying from breast cancer of 3.2%. These risks rise with 5 years’ exposure to MHT (age, 50-55 years) to 22.4% and 3.5%, respectively.

IN PRACTICE:

The authors concluded that, “These integrated data will enable more accurate estimates of absolute and attributable risk associated with MHT exposure for women with a family history of breast cancer, informing shared decision-making.”

SOURCE:

The lead author is Catherine Huntley of the Institute of Cancer Research, London, England. The study appeared in the British Journal of General Practice.

LIMITATIONS:

Limitations included modeling study that did not directly measure individuals with combined risks.

DISCLOSURES:

The study was funded by several sources including Cancer Research UK. The authors reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

The use of menopausal hormone therapy (MHT) increases breast cancer risk in women with a strong family history of breast cancer. These women have a striking cumulative risk of developing breast cancer (age, 50-80 years) of 22.4%, according to a new modelling study of UK women.

METHODOLOGY:

This was a modeling study integrating two data-sets of UK women: the BOADICEA dataset of age-specific breast cancer risk with family history and the Collaborative Group on Hormonal Factors in Breast Cancer, which covers relative risk for breast cancer with different types and durations of MHT.

Four different breast cancer family history profiles were:

• “Average” family history of breast cancer has unknown affected family members;
• “Modest” family history comprises a single first-degree relative with breast cancer at the age of 60 years.
• “Intermediate” family history comprises a single first-degree relative who developed breast cancer at the age of 40 years.
• “Strong” family history comprises two first-degree relatives who developed breast cancer at the age of 50 years.

TAKEAWAY:

• The lowest risk category: “Average” family history with no MHT use has a cumulative breast cancer risk (age, 50-80 years) of 9.8% and a risk of dying from breast cancer of 1.7%. These risks rise with 5 years’ exposure to MHT (age, 50-55 years) to 11.0% and 1.8%, respectively.
• The highest risk category: “Strong” family history with no MHT use has a cumulative breast cancer risk (age, 50-80 years) of 19.6% and a risk of dying from breast cancer of 3.2%. These risks rise with 5 years’ exposure to MHT (age, 50-55 years) to 22.4% and 3.5%, respectively.

IN PRACTICE:

The authors concluded that, “These integrated data will enable more accurate estimates of absolute and attributable risk associated with MHT exposure for women with a family history of breast cancer, informing shared decision-making.”

SOURCE:

The lead author is Catherine Huntley of the Institute of Cancer Research, London, England. The study appeared in the British Journal of General Practice.

LIMITATIONS:

Limitations included modeling study that did not directly measure individuals with combined risks.

DISCLOSURES:

The study was funded by several sources including Cancer Research UK. The authors reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

Hormone-modulating therapy for breast cancer may protect older women from Alzheimer’s disease and related dementias, although the protective effect varies by age and race, with the greatest benefit seen in younger Black women.

METHODOLOGY:

• Hormone-modulating therapy is widely used to treat hormone receptor–positive breast cancer, but the cognitive effects of the treatment, including a potential link to dementia, remain unclear.
• To investigate, researchers used the SEER-Medicare linked database to identify women aged 65 years or older with breast cancer who did and did not receive hormone-modulating therapy within 3 years following their diagnosis.
• The researchers excluded women with preexisting Alzheimer’s disease/dementia diagnoses or those who had received hormone-modulating therapy before their breast cancer diagnosis.
• Analyses were adjusted for demographic, sociocultural, and clinical variables, and subgroup analyses evaluated the impact of age, race, and type of hormone-modulating therapy on Alzheimer’s disease/dementia risk.

TAKEAWAY:

• Among the 18,808 women included in the analysis, 66% received hormone-modulating therapy and 34% did not. During the mean follow-up of 12 years, 24% of hormone-modulating therapy users and 28% of nonusers developed Alzheimer’s disease/dementia.
• Overall, hormone-modulating therapy use (vs nonuse) was associated with a significant 7% lower risk for Alzheimer’s disease/dementia (hazard ratio [HR], 0.93; P = .005), with notable age and racial differences.
• Hormone-modulating therapy use was associated with a 24% lower risk for Alzheimer’s disease/dementia in Black women aged 65-74 years (HR, 0.76), but that protective effect decreased to 19% in Black women aged 75 years or older (HR, 0.81). White women aged 65-74 years who received hormone-modulating therapy (vs those who did not) had an 11% lower risk for Alzheimer’s disease/dementia (HR, 0.89), but the association disappeared among those aged 75 years or older (HR, 0.96; 95% CI, 0.90-1.02). Other races demonstrated no significant association between hormone-modulating therapy use and Alzheimer’s disease/dementia.
• Overall, the use of an aromatase inhibitor or a selective estrogen receptor modulator was associated with a significantly lower risk for Alzheimer’s disease/dementia (HR, 0.93 and HR, 0.89, respectively).

IN PRACTICE:

Overall, the retrospective study found that “hormone therapy was associated with protection against [Alzheimer’s/dementia] in women aged 65 years or older with newly diagnosed breast cancer,” with the decrease in risk relatively greater for Black women and women younger than 75 years, the authors concluded.

“The results highlight the critical need for personalized breast cancer treatment plans that are tailored to the individual characteristics of each patient, particularly given the significantly higher likelihood (two to three times more) of Black women developing [Alzheimer’s/dementia], compared with their White counterparts,” the researchers added.
 

SOURCE:

The study, with first author Chao Cai, PhD, Department of Clinical Pharmacy and Outcomes Sciences, University of South Carolina, Columbia, was published online on July 16 in JAMA Network Open.

LIMITATIONS:

The study included only women aged 65 years or older, limiting generalizability to younger women. The dataset lacked genetic information and laboratory data related to dementia. The duration of hormone-modulating therapy use beyond 3 years and specific formulations were not assessed. Potential confounders such as variations in chemotherapy, radiation, and surgery were not fully addressed.

DISCLOSURES:

Support for the study was provided by the National Institutes of Health; Carolina Center on Alzheimer’s Disease and Minority Research pilot project; and the Dean’s Faculty Advancement Fund, University of Pittsburgh, Pennsylvania. The authors reported no relevant disclosures.

A version of this article first appeared on Medscape.com.

TOPLINE:

Hormone-modulating therapy for breast cancer may protect older women from Alzheimer’s disease and related dementias, although the protective effect varies by age and race, with the greatest benefit seen in younger Black women.

METHODOLOGY:

• Hormone-modulating therapy is widely used to treat hormone receptor–positive breast cancer, but the cognitive effects of the treatment, including a potential link to dementia, remain unclear.
• To investigate, researchers used the SEER-Medicare linked database to identify women aged 65 years or older with breast cancer who did and did not receive hormone-modulating therapy within 3 years following their diagnosis.
• The researchers excluded women with preexisting Alzheimer’s disease/dementia diagnoses or those who had received hormone-modulating therapy before their breast cancer diagnosis.
• Analyses were adjusted for demographic, sociocultural, and clinical variables, and subgroup analyses evaluated the impact of age, race, and type of hormone-modulating therapy on Alzheimer’s disease/dementia risk.

TAKEAWAY:

• Among the 18,808 women included in the analysis, 66% received hormone-modulating therapy and 34% did not. During the mean follow-up of 12 years, 24% of hormone-modulating therapy users and 28% of nonusers developed Alzheimer’s disease/dementia.
• Overall, hormone-modulating therapy use (vs nonuse) was associated with a significant 7% lower risk for Alzheimer’s disease/dementia (hazard ratio [HR], 0.93; P = .005), with notable age and racial differences.
• Hormone-modulating therapy use was associated with a 24% lower risk for Alzheimer’s disease/dementia in Black women aged 65-74 years (HR, 0.76), but that protective effect decreased to 19% in Black women aged 75 years or older (HR, 0.81). White women aged 65-74 years who received hormone-modulating therapy (vs those who did not) had an 11% lower risk for Alzheimer’s disease/dementia (HR, 0.89), but the association disappeared among those aged 75 years or older (HR, 0.96; 95% CI, 0.90-1.02). Other races demonstrated no significant association between hormone-modulating therapy use and Alzheimer’s disease/dementia.
• Overall, the use of an aromatase inhibitor or a selective estrogen receptor modulator was associated with a significantly lower risk for Alzheimer’s disease/dementia (HR, 0.93 and HR, 0.89, respectively).

IN PRACTICE:

Overall, the retrospective study found that “hormone therapy was associated with protection against [Alzheimer’s/dementia] in women aged 65 years or older with newly diagnosed breast cancer,” with the decrease in risk relatively greater for Black women and women younger than 75 years, the authors concluded.

“The results highlight the critical need for personalized breast cancer treatment plans that are tailored to the individual characteristics of each patient, particularly given the significantly higher likelihood (two to three times more) of Black women developing [Alzheimer’s/dementia], compared with their White counterparts,” the researchers added.
 

SOURCE:

The study, with first author Chao Cai, PhD, Department of Clinical Pharmacy and Outcomes Sciences, University of South Carolina, Columbia, was published online on July 16 in JAMA Network Open.

LIMITATIONS:

The study included only women aged 65 years or older, limiting generalizability to younger women. The dataset lacked genetic information and laboratory data related to dementia. The duration of hormone-modulating therapy use beyond 3 years and specific formulations were not assessed. Potential confounders such as variations in chemotherapy, radiation, and surgery were not fully addressed.

DISCLOSURES:

Support for the study was provided by the National Institutes of Health; Carolina Center on Alzheimer’s Disease and Minority Research pilot project; and the Dean’s Faculty Advancement Fund, University of Pittsburgh, Pennsylvania. The authors reported no relevant disclosures.

A version of this article first appeared on Medscape.com.

TOPLINE:

Hormone-modulating therapy for breast cancer may protect older women from Alzheimer’s disease and related dementias, although the protective effect varies by age and race, with the greatest benefit seen in younger Black women.

METHODOLOGY:

• Hormone-modulating therapy is widely used to treat hormone receptor–positive breast cancer, but the cognitive effects of the treatment, including a potential link to dementia, remain unclear.
• To investigate, researchers used the SEER-Medicare linked database to identify women aged 65 years or older with breast cancer who did and did not receive hormone-modulating therapy within 3 years following their diagnosis.
• The researchers excluded women with preexisting Alzheimer’s disease/dementia diagnoses or those who had received hormone-modulating therapy before their breast cancer diagnosis.
• Analyses were adjusted for demographic, sociocultural, and clinical variables, and subgroup analyses evaluated the impact of age, race, and type of hormone-modulating therapy on Alzheimer’s disease/dementia risk.

TAKEAWAY:

• Among the 18,808 women included in the analysis, 66% received hormone-modulating therapy and 34% did not. During the mean follow-up of 12 years, 24% of hormone-modulating therapy users and 28% of nonusers developed Alzheimer’s disease/dementia.
• Overall, hormone-modulating therapy use (vs nonuse) was associated with a significant 7% lower risk for Alzheimer’s disease/dementia (hazard ratio [HR], 0.93; P = .005), with notable age and racial differences.
• Hormone-modulating therapy use was associated with a 24% lower risk for Alzheimer’s disease/dementia in Black women aged 65-74 years (HR, 0.76), but that protective effect decreased to 19% in Black women aged 75 years or older (HR, 0.81). White women aged 65-74 years who received hormone-modulating therapy (vs those who did not) had an 11% lower risk for Alzheimer’s disease/dementia (HR, 0.89), but the association disappeared among those aged 75 years or older (HR, 0.96; 95% CI, 0.90-1.02). Other races demonstrated no significant association between hormone-modulating therapy use and Alzheimer’s disease/dementia.
• Overall, the use of an aromatase inhibitor or a selective estrogen receptor modulator was associated with a significantly lower risk for Alzheimer’s disease/dementia (HR, 0.93 and HR, 0.89, respectively).

IN PRACTICE:

Overall, the retrospective study found that “hormone therapy was associated with protection against [Alzheimer’s/dementia] in women aged 65 years or older with newly diagnosed breast cancer,” with the decrease in risk relatively greater for Black women and women younger than 75 years, the authors concluded.

“The results highlight the critical need for personalized breast cancer treatment plans that are tailored to the individual characteristics of each patient, particularly given the significantly higher likelihood (two to three times more) of Black women developing [Alzheimer’s/dementia], compared with their White counterparts,” the researchers added.
 

SOURCE:

The study, with first author Chao Cai, PhD, Department of Clinical Pharmacy and Outcomes Sciences, University of South Carolina, Columbia, was published online on July 16 in JAMA Network Open.

LIMITATIONS:

The study included only women aged 65 years or older, limiting generalizability to younger women. The dataset lacked genetic information and laboratory data related to dementia. The duration of hormone-modulating therapy use beyond 3 years and specific formulations were not assessed. Potential confounders such as variations in chemotherapy, radiation, and surgery were not fully addressed.

DISCLOSURES:

Support for the study was provided by the National Institutes of Health; Carolina Center on Alzheimer’s Disease and Minority Research pilot project; and the Dean’s Faculty Advancement Fund, University of Pittsburgh, Pennsylvania. The authors reported no relevant disclosures.

A version of this article first appeared on Medscape.com.