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‘Huge step forward’ in advanced ovarian cancer
The results come from the DUO-O trial, in which the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza) and immunotherapy with the anti–PD-L1 antibody durvalumab (Imfinzi) were added on to standard of care with paclitaxel/carboplatin chemotherapy and bevacizumab (Avastin) in patients with newly diagnosed,non–BRCA-mutated advanced ovarian cancer.
A preplanned interim analysis revealed that the addition of durvalumab and olaparib was associated with a 37% improvement of PFS, compared with the standard of care of chemotherapy plus bevacizumab alone.
This improvement increased to 51% in patients who had tumors positive for homologous recombination deficiency (HRD), which indicates the inability to effectively repair double-stranded DNA breaks, a defect that is present in approximately 70% of ovarian cancers.
Coprincipal investigator Carol Aghajanian, MD, chief of the gynecologic medical oncology service at Memorial Sloan Kettering Cancer Center, New York, described the benefit seen with the novel combination therapy as both “statistically significant and clinically meaningful.”
She was speaking at a press briefing held ahead of the annual meeting of the American Society of Clinical Oncology, where the results were presented.
Commenting for ASCO, Merry Jennifer Markham, MD, professor of medicine and chief of the division of hematology and oncology at University of Florida Health, Gainesville, said the results represents a “huge step forward.”
She added the rate of progress it represents may not be “quick enough for our patients with advanced ovarian cancer but every little integral improvement that we can find in studies that are important, like this one, really means so much to that individual patient in that exam room.”
Dr. Markham underlined that around 80% of women with epithelial ovarian cancer are diagnosed at an advanced stage. “They know what they are facing,” she said. “The vast majority” of them will have a recurrence “at some point.”
“So while progression-free survival may not necessarily mean their overall survival, there will be hope it does. And I’m very excited to see where this study heads in that direction.” Dr. Markham added that PFS is “very important to our patients,” and the study does represent progress. “We are chipping away at improving outcomes for advanced ovarian cancer.”
Moreover, “women are often disappointed when their tumor doesn’t have a BRCA mutation because they know that that may limit some of their treatment options,” and so the current study suggests that there are “options for all-comers” and “there is still hope.”
Access to treatment and testing
When asked whether there could be any access issues for patients clinically eligible for the novel combination, Dr. Aghajanian said that all of the drugs have been approved by the Food and Drug Administration for indications that cover this usage.
They are also covered by medical insurance and, for those patients with financial toxicity, “there is access to co-pay assistance programs and the like.”
She said that patients can then “be counseled on their expected benefit,” based on their BRCA and HRD testing.
Dr. Markham, on the other hand, said she is “a little less optimistic” about access, explaining that she practices in the southern United States, and “our populations [and] insurance coverages are a bit different.”
She noted that, at her institution, a “fair number of patients are underinsured,” and they “ran into a lot of issues with people not being able to afford their copays,” which can be “prohibitive.”
“A large portion of my counseling has been and will continue to be around the benefit, but also the financial toxicity, that that individual patient may experience and the need for copay assistance programs or other support mechanisms,” Markham said.
Dr. Aghajanian added that “financial toxicity and the access issue comes even prior to the treatment, in getting those BRCA1/2 tests and the HRD testing done, so patients have the information they need to make informed decisions.”
“We do have disparities with genetic testing and genomic testing that need to be solved,” she said.
Study details
Previous studies, including SOLO1 and PAOLA-1, have shown that maintenance therapy with olaparib and bevacizumab improves outcomes in the first-line treatment of advanced ovarian cancer.
“However, there still remains unmet need, especially in some patient subgroups without a BRCA mutation,” Dr. Aghajanian said.
While the addition of immunotherapy to standard of care has yet to show a clinical benefit in this setting in phase 3 trials, the phase 2 MEDIOLA study indicated that the combination of durvalumab, bevacizumab, and olaparib was active in nongermline, BRCA-mutated, platinum-sensitive relapsed cancer.
The phase 3 DUO-O study therefore set out to determine whether this combination would be beneficial as a maintenance therapy in 1130 patients with newly diagnosed stage III or IV high-grade ovarian cancer without a tumor BRCA1/2 mutation.
Patients were required to have had no prior systemic therapy for ovarian cancer, and be naive to both PARP inhibition and immunotherapy. They also had to have completed up-front primary debulking surgery, or be scheduled to undergo the procedure.
After an initial cycle of paclitaxel/carboplatin chemotherapy, the patients were randomly assigned to one of three regimens:
- Standard of care treatment, comprising chemotherapy plus bevacizumab and durvalumab-placebo, followed by maintenance therapy with bevacizumab, durvalumab-placebo, and olaparib-placebo (arm 1)
- Chemotherapy plus bevacizumab and durvalumab, followed by maintenance therapy with bevacizumab, durvalumab, and olaparib-placebo (arm 2)
- Chemotherapy plus bevacizumab and durvalumab, followed by maintenance therapy with bevacizumab, durvalumab, and olaparib (arm 3)
In the maintenance phase, bevacizumab was to be given for a total of 15 months, while durvalumab and olaparib, or their equivalent placebos, were prescribed for 24 months. Treatment was continued until disease progression, study completion, or another discontinuation criteria was met.
Dr. Aghajanian presented results from a preplanned interim analysis, with a date cutoff of Dec. 5, 2022.
Among HRD-positive patients, those in arm 3 had a significantly longer PFS than those in arm 1, at a median of 37.3 months versus 23 months, or a hazard ratio of 0.49 (P < .0001).
In the intention-to-treat analysis, arm 3 was also associated with a significant improvement in median PFS over arm 1, at 24.2 months versus 19.3 months, or an HR of 0.63 (P < .0001), indicating that the trial met both of its primary endpoints.
While there was a numerical difference in median PFS between arm 2 and arm 1, at a median of 20.6 months versus 19.3 months, this was not significant. This means that relative contribution of adding durvalumab alone is not clear, Dr. Aghajanian commented, and said that this comparison “will be reassessed at the time of the final PFS analysis.”
She added that a “PFS effect was observed across all subgroups for the arm 3 versus arm 1 comparison,” including in the HRD-negative subgroup, at a median of 20.9 months versus 17.4 months, or an HR of 0.68.
The safety and tolerability of the regimens were generally consistent with what is known for the individual agents, she commented.
Serious adverse events were reported in 34%, 43%, and 39% of patients in arms 1, 2, and 3, respectively.
The most common grade 3 or higher adverse events were neutropenia (in 26% of arm 1 patients, 28% of those in arm 2, and 31% of those in arm 3) followed by anemia (in 8%, 8%, and 24%, respectively).
Dose modifications were required in 72% of arm 1 patients, 80% of those in arm 2, and 85% of arm 3 patients. Treatment discontinuation was recorded in 20%, 26%, and 35%, respectively.
Tackling underserved patient populations
Discussing the results, Christina Fotopoulou, MD, PhD, professor of gynecological cancer surgery in the department of surgery and cancer, Imperial College London, said that, while the regimen may seem new, the treatments involved are “veterans,” and that they are nevertheless tackling previously underserved patient populations.
Dr. Fotopoulou, who was not involved in the study, noted that the results were highly anticipated, and the study has delivered a “breakthrough in ovarian cancer.” She nevertheless questioned the choice of the control arm, and pointed out that the hazard ratio in favor of the combination therapy is “relatively modest” considering that it involves three drugs.
Dr. Fotopoulou highlighted, however, that one of the most important results was in the HRD-negative patients, which she characterized as the equivalent of the clinicians going to “the dark side of the moon.” She said that “for the first time, we have a positive study in this patient population,” although she underlined that the results are from an interim analysis.
The key question that remains, Dr. Fotopoulou asked, is “why? What is making the difference?” She noted that, unfortunately, the trial design does not allow the identification of the relative contribution of olaparib and durvalumab.
The study was sponsored by AstraZeneca, and conducted in collaboration with the European Network of Gynaecological Oncological Trial Groups, GOG Foundation, and Myriad Genetic Laboratories. Dr. Aghajanian declared relationships with AstraZeneca, Merck, Eisai, Repare Therapeutics, AbbVie, Clovis Oncology, and Genentech/Roche. Dr. Markham declared relationships with Pfizer, GlaxoSmithKline, Aduro Biotech, Lilly, Tesaro, Novartis, VBL Therapeutics, AstraZeneca, and Merck.
A version of this article first appeared on Medscape.com.
The results come from the DUO-O trial, in which the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza) and immunotherapy with the anti–PD-L1 antibody durvalumab (Imfinzi) were added on to standard of care with paclitaxel/carboplatin chemotherapy and bevacizumab (Avastin) in patients with newly diagnosed,non–BRCA-mutated advanced ovarian cancer.
A preplanned interim analysis revealed that the addition of durvalumab and olaparib was associated with a 37% improvement of PFS, compared with the standard of care of chemotherapy plus bevacizumab alone.
This improvement increased to 51% in patients who had tumors positive for homologous recombination deficiency (HRD), which indicates the inability to effectively repair double-stranded DNA breaks, a defect that is present in approximately 70% of ovarian cancers.
Coprincipal investigator Carol Aghajanian, MD, chief of the gynecologic medical oncology service at Memorial Sloan Kettering Cancer Center, New York, described the benefit seen with the novel combination therapy as both “statistically significant and clinically meaningful.”
She was speaking at a press briefing held ahead of the annual meeting of the American Society of Clinical Oncology, where the results were presented.
Commenting for ASCO, Merry Jennifer Markham, MD, professor of medicine and chief of the division of hematology and oncology at University of Florida Health, Gainesville, said the results represents a “huge step forward.”
She added the rate of progress it represents may not be “quick enough for our patients with advanced ovarian cancer but every little integral improvement that we can find in studies that are important, like this one, really means so much to that individual patient in that exam room.”
Dr. Markham underlined that around 80% of women with epithelial ovarian cancer are diagnosed at an advanced stage. “They know what they are facing,” she said. “The vast majority” of them will have a recurrence “at some point.”
“So while progression-free survival may not necessarily mean their overall survival, there will be hope it does. And I’m very excited to see where this study heads in that direction.” Dr. Markham added that PFS is “very important to our patients,” and the study does represent progress. “We are chipping away at improving outcomes for advanced ovarian cancer.”
Moreover, “women are often disappointed when their tumor doesn’t have a BRCA mutation because they know that that may limit some of their treatment options,” and so the current study suggests that there are “options for all-comers” and “there is still hope.”
Access to treatment and testing
When asked whether there could be any access issues for patients clinically eligible for the novel combination, Dr. Aghajanian said that all of the drugs have been approved by the Food and Drug Administration for indications that cover this usage.
They are also covered by medical insurance and, for those patients with financial toxicity, “there is access to co-pay assistance programs and the like.”
She said that patients can then “be counseled on their expected benefit,” based on their BRCA and HRD testing.
Dr. Markham, on the other hand, said she is “a little less optimistic” about access, explaining that she practices in the southern United States, and “our populations [and] insurance coverages are a bit different.”
She noted that, at her institution, a “fair number of patients are underinsured,” and they “ran into a lot of issues with people not being able to afford their copays,” which can be “prohibitive.”
“A large portion of my counseling has been and will continue to be around the benefit, but also the financial toxicity, that that individual patient may experience and the need for copay assistance programs or other support mechanisms,” Markham said.
Dr. Aghajanian added that “financial toxicity and the access issue comes even prior to the treatment, in getting those BRCA1/2 tests and the HRD testing done, so patients have the information they need to make informed decisions.”
“We do have disparities with genetic testing and genomic testing that need to be solved,” she said.
Study details
Previous studies, including SOLO1 and PAOLA-1, have shown that maintenance therapy with olaparib and bevacizumab improves outcomes in the first-line treatment of advanced ovarian cancer.
“However, there still remains unmet need, especially in some patient subgroups without a BRCA mutation,” Dr. Aghajanian said.
While the addition of immunotherapy to standard of care has yet to show a clinical benefit in this setting in phase 3 trials, the phase 2 MEDIOLA study indicated that the combination of durvalumab, bevacizumab, and olaparib was active in nongermline, BRCA-mutated, platinum-sensitive relapsed cancer.
The phase 3 DUO-O study therefore set out to determine whether this combination would be beneficial as a maintenance therapy in 1130 patients with newly diagnosed stage III or IV high-grade ovarian cancer without a tumor BRCA1/2 mutation.
Patients were required to have had no prior systemic therapy for ovarian cancer, and be naive to both PARP inhibition and immunotherapy. They also had to have completed up-front primary debulking surgery, or be scheduled to undergo the procedure.
After an initial cycle of paclitaxel/carboplatin chemotherapy, the patients were randomly assigned to one of three regimens:
- Standard of care treatment, comprising chemotherapy plus bevacizumab and durvalumab-placebo, followed by maintenance therapy with bevacizumab, durvalumab-placebo, and olaparib-placebo (arm 1)
- Chemotherapy plus bevacizumab and durvalumab, followed by maintenance therapy with bevacizumab, durvalumab, and olaparib-placebo (arm 2)
- Chemotherapy plus bevacizumab and durvalumab, followed by maintenance therapy with bevacizumab, durvalumab, and olaparib (arm 3)
In the maintenance phase, bevacizumab was to be given for a total of 15 months, while durvalumab and olaparib, or their equivalent placebos, were prescribed for 24 months. Treatment was continued until disease progression, study completion, or another discontinuation criteria was met.
Dr. Aghajanian presented results from a preplanned interim analysis, with a date cutoff of Dec. 5, 2022.
Among HRD-positive patients, those in arm 3 had a significantly longer PFS than those in arm 1, at a median of 37.3 months versus 23 months, or a hazard ratio of 0.49 (P < .0001).
In the intention-to-treat analysis, arm 3 was also associated with a significant improvement in median PFS over arm 1, at 24.2 months versus 19.3 months, or an HR of 0.63 (P < .0001), indicating that the trial met both of its primary endpoints.
While there was a numerical difference in median PFS between arm 2 and arm 1, at a median of 20.6 months versus 19.3 months, this was not significant. This means that relative contribution of adding durvalumab alone is not clear, Dr. Aghajanian commented, and said that this comparison “will be reassessed at the time of the final PFS analysis.”
She added that a “PFS effect was observed across all subgroups for the arm 3 versus arm 1 comparison,” including in the HRD-negative subgroup, at a median of 20.9 months versus 17.4 months, or an HR of 0.68.
The safety and tolerability of the regimens were generally consistent with what is known for the individual agents, she commented.
Serious adverse events were reported in 34%, 43%, and 39% of patients in arms 1, 2, and 3, respectively.
The most common grade 3 or higher adverse events were neutropenia (in 26% of arm 1 patients, 28% of those in arm 2, and 31% of those in arm 3) followed by anemia (in 8%, 8%, and 24%, respectively).
Dose modifications were required in 72% of arm 1 patients, 80% of those in arm 2, and 85% of arm 3 patients. Treatment discontinuation was recorded in 20%, 26%, and 35%, respectively.
Tackling underserved patient populations
Discussing the results, Christina Fotopoulou, MD, PhD, professor of gynecological cancer surgery in the department of surgery and cancer, Imperial College London, said that, while the regimen may seem new, the treatments involved are “veterans,” and that they are nevertheless tackling previously underserved patient populations.
Dr. Fotopoulou, who was not involved in the study, noted that the results were highly anticipated, and the study has delivered a “breakthrough in ovarian cancer.” She nevertheless questioned the choice of the control arm, and pointed out that the hazard ratio in favor of the combination therapy is “relatively modest” considering that it involves three drugs.
Dr. Fotopoulou highlighted, however, that one of the most important results was in the HRD-negative patients, which she characterized as the equivalent of the clinicians going to “the dark side of the moon.” She said that “for the first time, we have a positive study in this patient population,” although she underlined that the results are from an interim analysis.
The key question that remains, Dr. Fotopoulou asked, is “why? What is making the difference?” She noted that, unfortunately, the trial design does not allow the identification of the relative contribution of olaparib and durvalumab.
The study was sponsored by AstraZeneca, and conducted in collaboration with the European Network of Gynaecological Oncological Trial Groups, GOG Foundation, and Myriad Genetic Laboratories. Dr. Aghajanian declared relationships with AstraZeneca, Merck, Eisai, Repare Therapeutics, AbbVie, Clovis Oncology, and Genentech/Roche. Dr. Markham declared relationships with Pfizer, GlaxoSmithKline, Aduro Biotech, Lilly, Tesaro, Novartis, VBL Therapeutics, AstraZeneca, and Merck.
A version of this article first appeared on Medscape.com.
The results come from the DUO-O trial, in which the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza) and immunotherapy with the anti–PD-L1 antibody durvalumab (Imfinzi) were added on to standard of care with paclitaxel/carboplatin chemotherapy and bevacizumab (Avastin) in patients with newly diagnosed,non–BRCA-mutated advanced ovarian cancer.
A preplanned interim analysis revealed that the addition of durvalumab and olaparib was associated with a 37% improvement of PFS, compared with the standard of care of chemotherapy plus bevacizumab alone.
This improvement increased to 51% in patients who had tumors positive for homologous recombination deficiency (HRD), which indicates the inability to effectively repair double-stranded DNA breaks, a defect that is present in approximately 70% of ovarian cancers.
Coprincipal investigator Carol Aghajanian, MD, chief of the gynecologic medical oncology service at Memorial Sloan Kettering Cancer Center, New York, described the benefit seen with the novel combination therapy as both “statistically significant and clinically meaningful.”
She was speaking at a press briefing held ahead of the annual meeting of the American Society of Clinical Oncology, where the results were presented.
Commenting for ASCO, Merry Jennifer Markham, MD, professor of medicine and chief of the division of hematology and oncology at University of Florida Health, Gainesville, said the results represents a “huge step forward.”
She added the rate of progress it represents may not be “quick enough for our patients with advanced ovarian cancer but every little integral improvement that we can find in studies that are important, like this one, really means so much to that individual patient in that exam room.”
Dr. Markham underlined that around 80% of women with epithelial ovarian cancer are diagnosed at an advanced stage. “They know what they are facing,” she said. “The vast majority” of them will have a recurrence “at some point.”
“So while progression-free survival may not necessarily mean their overall survival, there will be hope it does. And I’m very excited to see where this study heads in that direction.” Dr. Markham added that PFS is “very important to our patients,” and the study does represent progress. “We are chipping away at improving outcomes for advanced ovarian cancer.”
Moreover, “women are often disappointed when their tumor doesn’t have a BRCA mutation because they know that that may limit some of their treatment options,” and so the current study suggests that there are “options for all-comers” and “there is still hope.”
Access to treatment and testing
When asked whether there could be any access issues for patients clinically eligible for the novel combination, Dr. Aghajanian said that all of the drugs have been approved by the Food and Drug Administration for indications that cover this usage.
They are also covered by medical insurance and, for those patients with financial toxicity, “there is access to co-pay assistance programs and the like.”
She said that patients can then “be counseled on their expected benefit,” based on their BRCA and HRD testing.
Dr. Markham, on the other hand, said she is “a little less optimistic” about access, explaining that she practices in the southern United States, and “our populations [and] insurance coverages are a bit different.”
She noted that, at her institution, a “fair number of patients are underinsured,” and they “ran into a lot of issues with people not being able to afford their copays,” which can be “prohibitive.”
“A large portion of my counseling has been and will continue to be around the benefit, but also the financial toxicity, that that individual patient may experience and the need for copay assistance programs or other support mechanisms,” Markham said.
Dr. Aghajanian added that “financial toxicity and the access issue comes even prior to the treatment, in getting those BRCA1/2 tests and the HRD testing done, so patients have the information they need to make informed decisions.”
“We do have disparities with genetic testing and genomic testing that need to be solved,” she said.
Study details
Previous studies, including SOLO1 and PAOLA-1, have shown that maintenance therapy with olaparib and bevacizumab improves outcomes in the first-line treatment of advanced ovarian cancer.
“However, there still remains unmet need, especially in some patient subgroups without a BRCA mutation,” Dr. Aghajanian said.
While the addition of immunotherapy to standard of care has yet to show a clinical benefit in this setting in phase 3 trials, the phase 2 MEDIOLA study indicated that the combination of durvalumab, bevacizumab, and olaparib was active in nongermline, BRCA-mutated, platinum-sensitive relapsed cancer.
The phase 3 DUO-O study therefore set out to determine whether this combination would be beneficial as a maintenance therapy in 1130 patients with newly diagnosed stage III or IV high-grade ovarian cancer without a tumor BRCA1/2 mutation.
Patients were required to have had no prior systemic therapy for ovarian cancer, and be naive to both PARP inhibition and immunotherapy. They also had to have completed up-front primary debulking surgery, or be scheduled to undergo the procedure.
After an initial cycle of paclitaxel/carboplatin chemotherapy, the patients were randomly assigned to one of three regimens:
- Standard of care treatment, comprising chemotherapy plus bevacizumab and durvalumab-placebo, followed by maintenance therapy with bevacizumab, durvalumab-placebo, and olaparib-placebo (arm 1)
- Chemotherapy plus bevacizumab and durvalumab, followed by maintenance therapy with bevacizumab, durvalumab, and olaparib-placebo (arm 2)
- Chemotherapy plus bevacizumab and durvalumab, followed by maintenance therapy with bevacizumab, durvalumab, and olaparib (arm 3)
In the maintenance phase, bevacizumab was to be given for a total of 15 months, while durvalumab and olaparib, or their equivalent placebos, were prescribed for 24 months. Treatment was continued until disease progression, study completion, or another discontinuation criteria was met.
Dr. Aghajanian presented results from a preplanned interim analysis, with a date cutoff of Dec. 5, 2022.
Among HRD-positive patients, those in arm 3 had a significantly longer PFS than those in arm 1, at a median of 37.3 months versus 23 months, or a hazard ratio of 0.49 (P < .0001).
In the intention-to-treat analysis, arm 3 was also associated with a significant improvement in median PFS over arm 1, at 24.2 months versus 19.3 months, or an HR of 0.63 (P < .0001), indicating that the trial met both of its primary endpoints.
While there was a numerical difference in median PFS between arm 2 and arm 1, at a median of 20.6 months versus 19.3 months, this was not significant. This means that relative contribution of adding durvalumab alone is not clear, Dr. Aghajanian commented, and said that this comparison “will be reassessed at the time of the final PFS analysis.”
She added that a “PFS effect was observed across all subgroups for the arm 3 versus arm 1 comparison,” including in the HRD-negative subgroup, at a median of 20.9 months versus 17.4 months, or an HR of 0.68.
The safety and tolerability of the regimens were generally consistent with what is known for the individual agents, she commented.
Serious adverse events were reported in 34%, 43%, and 39% of patients in arms 1, 2, and 3, respectively.
The most common grade 3 or higher adverse events were neutropenia (in 26% of arm 1 patients, 28% of those in arm 2, and 31% of those in arm 3) followed by anemia (in 8%, 8%, and 24%, respectively).
Dose modifications were required in 72% of arm 1 patients, 80% of those in arm 2, and 85% of arm 3 patients. Treatment discontinuation was recorded in 20%, 26%, and 35%, respectively.
Tackling underserved patient populations
Discussing the results, Christina Fotopoulou, MD, PhD, professor of gynecological cancer surgery in the department of surgery and cancer, Imperial College London, said that, while the regimen may seem new, the treatments involved are “veterans,” and that they are nevertheless tackling previously underserved patient populations.
Dr. Fotopoulou, who was not involved in the study, noted that the results were highly anticipated, and the study has delivered a “breakthrough in ovarian cancer.” She nevertheless questioned the choice of the control arm, and pointed out that the hazard ratio in favor of the combination therapy is “relatively modest” considering that it involves three drugs.
Dr. Fotopoulou highlighted, however, that one of the most important results was in the HRD-negative patients, which she characterized as the equivalent of the clinicians going to “the dark side of the moon.” She said that “for the first time, we have a positive study in this patient population,” although she underlined that the results are from an interim analysis.
The key question that remains, Dr. Fotopoulou asked, is “why? What is making the difference?” She noted that, unfortunately, the trial design does not allow the identification of the relative contribution of olaparib and durvalumab.
The study was sponsored by AstraZeneca, and conducted in collaboration with the European Network of Gynaecological Oncological Trial Groups, GOG Foundation, and Myriad Genetic Laboratories. Dr. Aghajanian declared relationships with AstraZeneca, Merck, Eisai, Repare Therapeutics, AbbVie, Clovis Oncology, and Genentech/Roche. Dr. Markham declared relationships with Pfizer, GlaxoSmithKline, Aduro Biotech, Lilly, Tesaro, Novartis, VBL Therapeutics, AstraZeneca, and Merck.
A version of this article first appeared on Medscape.com.
AT ASCO 2023
SCLC: Bispecific antibody shows phase 1 promise
CHICAGO –
The antibody promotes the destruction of tumor cells by T cells by acting as a bridge between T cells and tumors.
SCLC has largely resisted efforts to identify unique surface markers. DLL3 is an exception: It is rarely expressed in normal cells, and it seems to be important to tumor biology, according to Martin Wermke, MD, who presented the study at the annual meeting of the American Society of Clinical Oncology.
A rare SCLC biomarker
“The problem, I think, is that small cell [lung cancer] with its high mutational burden is a bunch of many different subentities and you will probably not find a single driver mutation as you do in non–small cell lung cancer. So in that [way] it’s different in its biology,” said Dr. Wermke, professor of experimental tumor therapy at the National Center for Tumor Diseases in Dresden, Germany.
Nevertheless, DLL3 is a sensitive biomarker, with over 90% of SCLC tumors positive for the surface marker, according to Dr. Wermke. “It’s one of the first which proved to be a reliable [SCLC] biomarker for therapeutic approaches,” said Dr. Wermke.
This isn’t the first clinical experience with DLL3. An anti-DLL3 antibody was used as part of an antibody-drug conjugate called Rova-T, which failed a phase 3 trial in SCLC in 2021 and was subsequently canceled by AbbVie, but Dr. Wermke believes that the issue was with the drug and linker (a chemical tag that links the cytotoxic drug to the antibody, which is designed to release the drug in an appropriate environment such as the interior of a tumor cell after an antibody-drug conjugate has been internalized by the tumor cell), not DLL3. DLL3 is also being investigated as a component of chimeric antigen receptor T-cell therapy, though no clinical results have been reported, Dr. Wermke said.
Study methods and results
The study included 107 patients. The median age was 60.0 years, and 57% were male. To be included, patients had to have advanced SCLC, large cell neuroendocrine carcinoma, or extrapulmonary neuroendocrine carcinoma, as well as test positive for DLL3 expression.
The drug was well tolerated: 86% of patients experienced at least one treatment-related adverse event: 59% with a grade 1-2 TRAE and 27% with a grade 3-5 TRAE. Cytokine release syndrome (CRS) occurred in 59% of patients, but just 2% were grade 3-5. TRAEs led to discontinuation in 4% of patients. Physicians were able to manage CRS with supportive care, steroids, and anti–interleukin-6 receptor antibodies.
The treatment showed signs of efficacy, with partial responses occurring in 18% of patients, stable disease in 23%, progressive disease in 45%, while 13% were not evaluable.
At doses of 90 mg/kg or above, partial response occurred in 25% of patients, stable disease in 27%, and progressive disease in 31%, while 13% were not evaluable. Similar patterns were seen across three tumor types.
Of 18 responders, 14 continued to be responders at the time of the presentation. The longest response lengths were 13.1 months, 10.7 months, and 9.4 months.
Dr. Wermke said that the responses were encouraging, particularly the duration of some responses.
“Having a small cell [lung cancer] patient responding to something for more than a year is extraordinary. It comes with side effects, which are usually seen during the first [doses]. After that, the drug is pretty well tolerable, and that is also something which distinguishes it from alternative second-line approaches,” he said.
Well tolerated, but take efficacy data with a grain of salt
The study was encouraging but should be treated with caution, according to Vamsidhar Velcheti, MD, who moderated the session where the research was presented.
“The toxicity profile is actually very promising and it’s still very early, but there’s certainly a lot of interest in DLL3-targeted [therapies]. We’ve seen some very exciting data with other assets in this category as well,” said Dr. Velcheti, director of thoracic oncology at NYU Langone Health, New York.
Phase 1 efficacy data can be tantalizing but often fails to hold up to further testing, according to Dr. Velcheti. “We’ve seen signals in phase 1 data before, and we’ve been burned. We saw really promising data with Rova-T, and the confirmatory trials were negative, – so we want to be cautiously optimistic,” said Dr. Velcheti.
He also pointed out that patient selection will be important for such studies, considering that SCLC patients often have a lot of comorbidities and the therapy’s potential for causing CRS.
Both Dr. Wermke and Dr. Velcheti have received funding from numerous pharmaceutical companies. Dr. Wermke has consulted with or advised with Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, ImCheck Therapeutics, Immatics, ISA Pharmaceuticals, Lilly, and Novartis.
CHICAGO –
The antibody promotes the destruction of tumor cells by T cells by acting as a bridge between T cells and tumors.
SCLC has largely resisted efforts to identify unique surface markers. DLL3 is an exception: It is rarely expressed in normal cells, and it seems to be important to tumor biology, according to Martin Wermke, MD, who presented the study at the annual meeting of the American Society of Clinical Oncology.
A rare SCLC biomarker
“The problem, I think, is that small cell [lung cancer] with its high mutational burden is a bunch of many different subentities and you will probably not find a single driver mutation as you do in non–small cell lung cancer. So in that [way] it’s different in its biology,” said Dr. Wermke, professor of experimental tumor therapy at the National Center for Tumor Diseases in Dresden, Germany.
Nevertheless, DLL3 is a sensitive biomarker, with over 90% of SCLC tumors positive for the surface marker, according to Dr. Wermke. “It’s one of the first which proved to be a reliable [SCLC] biomarker for therapeutic approaches,” said Dr. Wermke.
This isn’t the first clinical experience with DLL3. An anti-DLL3 antibody was used as part of an antibody-drug conjugate called Rova-T, which failed a phase 3 trial in SCLC in 2021 and was subsequently canceled by AbbVie, but Dr. Wermke believes that the issue was with the drug and linker (a chemical tag that links the cytotoxic drug to the antibody, which is designed to release the drug in an appropriate environment such as the interior of a tumor cell after an antibody-drug conjugate has been internalized by the tumor cell), not DLL3. DLL3 is also being investigated as a component of chimeric antigen receptor T-cell therapy, though no clinical results have been reported, Dr. Wermke said.
Study methods and results
The study included 107 patients. The median age was 60.0 years, and 57% were male. To be included, patients had to have advanced SCLC, large cell neuroendocrine carcinoma, or extrapulmonary neuroendocrine carcinoma, as well as test positive for DLL3 expression.
The drug was well tolerated: 86% of patients experienced at least one treatment-related adverse event: 59% with a grade 1-2 TRAE and 27% with a grade 3-5 TRAE. Cytokine release syndrome (CRS) occurred in 59% of patients, but just 2% were grade 3-5. TRAEs led to discontinuation in 4% of patients. Physicians were able to manage CRS with supportive care, steroids, and anti–interleukin-6 receptor antibodies.
The treatment showed signs of efficacy, with partial responses occurring in 18% of patients, stable disease in 23%, progressive disease in 45%, while 13% were not evaluable.
At doses of 90 mg/kg or above, partial response occurred in 25% of patients, stable disease in 27%, and progressive disease in 31%, while 13% were not evaluable. Similar patterns were seen across three tumor types.
Of 18 responders, 14 continued to be responders at the time of the presentation. The longest response lengths were 13.1 months, 10.7 months, and 9.4 months.
Dr. Wermke said that the responses were encouraging, particularly the duration of some responses.
“Having a small cell [lung cancer] patient responding to something for more than a year is extraordinary. It comes with side effects, which are usually seen during the first [doses]. After that, the drug is pretty well tolerable, and that is also something which distinguishes it from alternative second-line approaches,” he said.
Well tolerated, but take efficacy data with a grain of salt
The study was encouraging but should be treated with caution, according to Vamsidhar Velcheti, MD, who moderated the session where the research was presented.
“The toxicity profile is actually very promising and it’s still very early, but there’s certainly a lot of interest in DLL3-targeted [therapies]. We’ve seen some very exciting data with other assets in this category as well,” said Dr. Velcheti, director of thoracic oncology at NYU Langone Health, New York.
Phase 1 efficacy data can be tantalizing but often fails to hold up to further testing, according to Dr. Velcheti. “We’ve seen signals in phase 1 data before, and we’ve been burned. We saw really promising data with Rova-T, and the confirmatory trials were negative, – so we want to be cautiously optimistic,” said Dr. Velcheti.
He also pointed out that patient selection will be important for such studies, considering that SCLC patients often have a lot of comorbidities and the therapy’s potential for causing CRS.
Both Dr. Wermke and Dr. Velcheti have received funding from numerous pharmaceutical companies. Dr. Wermke has consulted with or advised with Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, ImCheck Therapeutics, Immatics, ISA Pharmaceuticals, Lilly, and Novartis.
CHICAGO –
The antibody promotes the destruction of tumor cells by T cells by acting as a bridge between T cells and tumors.
SCLC has largely resisted efforts to identify unique surface markers. DLL3 is an exception: It is rarely expressed in normal cells, and it seems to be important to tumor biology, according to Martin Wermke, MD, who presented the study at the annual meeting of the American Society of Clinical Oncology.
A rare SCLC biomarker
“The problem, I think, is that small cell [lung cancer] with its high mutational burden is a bunch of many different subentities and you will probably not find a single driver mutation as you do in non–small cell lung cancer. So in that [way] it’s different in its biology,” said Dr. Wermke, professor of experimental tumor therapy at the National Center for Tumor Diseases in Dresden, Germany.
Nevertheless, DLL3 is a sensitive biomarker, with over 90% of SCLC tumors positive for the surface marker, according to Dr. Wermke. “It’s one of the first which proved to be a reliable [SCLC] biomarker for therapeutic approaches,” said Dr. Wermke.
This isn’t the first clinical experience with DLL3. An anti-DLL3 antibody was used as part of an antibody-drug conjugate called Rova-T, which failed a phase 3 trial in SCLC in 2021 and was subsequently canceled by AbbVie, but Dr. Wermke believes that the issue was with the drug and linker (a chemical tag that links the cytotoxic drug to the antibody, which is designed to release the drug in an appropriate environment such as the interior of a tumor cell after an antibody-drug conjugate has been internalized by the tumor cell), not DLL3. DLL3 is also being investigated as a component of chimeric antigen receptor T-cell therapy, though no clinical results have been reported, Dr. Wermke said.
Study methods and results
The study included 107 patients. The median age was 60.0 years, and 57% were male. To be included, patients had to have advanced SCLC, large cell neuroendocrine carcinoma, or extrapulmonary neuroendocrine carcinoma, as well as test positive for DLL3 expression.
The drug was well tolerated: 86% of patients experienced at least one treatment-related adverse event: 59% with a grade 1-2 TRAE and 27% with a grade 3-5 TRAE. Cytokine release syndrome (CRS) occurred in 59% of patients, but just 2% were grade 3-5. TRAEs led to discontinuation in 4% of patients. Physicians were able to manage CRS with supportive care, steroids, and anti–interleukin-6 receptor antibodies.
The treatment showed signs of efficacy, with partial responses occurring in 18% of patients, stable disease in 23%, progressive disease in 45%, while 13% were not evaluable.
At doses of 90 mg/kg or above, partial response occurred in 25% of patients, stable disease in 27%, and progressive disease in 31%, while 13% were not evaluable. Similar patterns were seen across three tumor types.
Of 18 responders, 14 continued to be responders at the time of the presentation. The longest response lengths were 13.1 months, 10.7 months, and 9.4 months.
Dr. Wermke said that the responses were encouraging, particularly the duration of some responses.
“Having a small cell [lung cancer] patient responding to something for more than a year is extraordinary. It comes with side effects, which are usually seen during the first [doses]. After that, the drug is pretty well tolerable, and that is also something which distinguishes it from alternative second-line approaches,” he said.
Well tolerated, but take efficacy data with a grain of salt
The study was encouraging but should be treated with caution, according to Vamsidhar Velcheti, MD, who moderated the session where the research was presented.
“The toxicity profile is actually very promising and it’s still very early, but there’s certainly a lot of interest in DLL3-targeted [therapies]. We’ve seen some very exciting data with other assets in this category as well,” said Dr. Velcheti, director of thoracic oncology at NYU Langone Health, New York.
Phase 1 efficacy data can be tantalizing but often fails to hold up to further testing, according to Dr. Velcheti. “We’ve seen signals in phase 1 data before, and we’ve been burned. We saw really promising data with Rova-T, and the confirmatory trials were negative, – so we want to be cautiously optimistic,” said Dr. Velcheti.
He also pointed out that patient selection will be important for such studies, considering that SCLC patients often have a lot of comorbidities and the therapy’s potential for causing CRS.
Both Dr. Wermke and Dr. Velcheti have received funding from numerous pharmaceutical companies. Dr. Wermke has consulted with or advised with Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, ImCheck Therapeutics, Immatics, ISA Pharmaceuticals, Lilly, and Novartis.
AT ASCO 2023
‘Exciting’ results for cancer vaccine plus pembro in melanoma
according to the latest data from the KEYNOTE-942 trial.
This recurrence-free survival benefit corresponded to a 44% reduced risk of recurrence or death in patients who received the personalized vaccine plus pembrolizumab compared with the immunotherapy alone.
The randomized phase 2b trial is the first to show a positive result for a cancer vaccine in a randomized trial. The results, if confirmed in further studies, hold promise for treating other solid tumors with sensitivity to the programmed death-1 (PD-1) protein, investigators said.
“KEYNOTE-942 is the first randomized study to demonstrate improvement in recurrence-free survival in melanoma, or in any cancer in my view, with an individualized neoantigen vaccine approach,” trial investigator Jeffrey S. Weber, MD, PhD, of NYU Langone Perlmutter Cancer Center in New York, said during an oral abstract session at the annual meeting of the American Association for Cancer Research.
“I have every confidence that this strategy will be expanded to other histologies that are PD-1 sensitive, such as non–small cell lung cancer, renal cell cancer, hepatocellular cancer, gastroesophageal cancer, et cetera,” Dr. Weber said.
Invited discussant Margaret Callahan, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, called the results “exciting,” especially in light of previous results in cancer vaccine trials. “Despite hundreds of formulations and dozens of studies, cancer vaccines have been disappointing so far, and have largely failed to have a meaningful impact in oncology,” she said.
A promising personalized vaccine
The mRNA vaccine is individually tailored and encodes up to 34 patient-specific tumor neoantigens. The vaccine also acts as an adjuvant to strengthen the immune response.
Dr. Weber said that the “mRNA 4157 is what one would call an individualized neoantigen therapy. It will target an individual patient’s unique tumor mutations, and the revelation over the last 5-10 years, is that, for better or worse, virtually all the neoantigens are unique to an individual patient. There are very, very few true universal neoantigens, or at least universal neoantigens that could have clinical utility.”
The vaccines are developed from tumor biopsy tissues that then undergo whole exome and RNA sequencing to identify single nucleotide variants that are present in the tumor but not in normal tissue.
The findings are then fed into a computer algorithm that identifies potential neoepitope peptides that would bind well to the patient’s human leukocyte antigen (HLA) type and could evoke strong T-cell responses.
“Once they’re chosen, you concatenate the sequences together into a single-strand mRNA vaccine, it’s packaged with nanoparticles to encapsulate it, and there you have your mRNA vaccine,” Dr. Weber explained.
In the KEYNOTE-942 trial, the investigators randomly assigned patients with completely resected high-risk cutaneous melanoma on a 2:1 basis to receive mRNA-4157 via intramuscular injection every 3 weeks for a total of nine doses, plus intravenous pembrolizumab every 3 weeks for 18 cycles (107 patients) or pembrolizumab alone (50 patients). Median follow-up was 101 weeks in the combination group and 105 weeks in the pembrolizumab group.
Overall, the 18-month recurrence-free survival rates were 78.6% in the combination arm and 62.2% in the pembrolizumab arm. The recurrence-free survival rates corresponded to a 44% reduced risk of recurrence or death in patients who received the personalized vaccine plus pembrolizumab compared with those who received only pembrolizumab (hazard ratio [HR] for recurrence, 0.561; P =.0266).
Grade 3 or greater adverse events occurred in 25% of patients in the combination group and 18% of patients in the pembrolizumab group. The most common grade 3 event associated with the vaccine was fatigue. No grade 4 adverse events or deaths were associated with the vaccine, and the addition of the vaccine to pembrolizumab did not appear to increase risk for immune-mediated adverse events.
In a subanalysis, Dr. Weber and colleagues explored the relationship between tumor mutational burden and recurrence-free survival. Higher tumor mutational burden may mean more neoepitopes to target, which is helpful when developing personalized neoantigen vaccines, explained coinvestigator Ryan Sullivan, MD, associate director of the melanoma program at Mass General Cancer Center, Boston, who presented the subanalysis results.
The investigators performed whole exome and whole transcriptome sequencing of baseline tumor biopsy samples to determine the mutational burden of tumors and defined a high mutational burden as 10 or more mutations per megabase.
Overall, in the combination group, patients with a higher tumor mutational burden at baseline showed improved outcomes (HR, 0.652; 95% confidence interval [CI], 0.284-1.494), as did patients with a lower tumor mutational burden (HR, 0.586; 95% CI, 0.243-1.415).
The authors found the same was true for patients with high vs. low tumor inflammation scores (high: HR, 0.576; 95% CI, 0.209-1.591 vs. low: HR, 0.528; 95% CI, 0.253-1.101) and higher PD-L1 expression (PD-L1 positive: HR, 0.485; 95% CI, 0.226-1.039 vs. PD-L1 negative: HR, 0.162; 95% CI, 0.038-0.685).
The hazard ratios crossed 1, which suggest that the combination was similarly effective in all patient subsets, said Dr. Sullivan.
Dr. Callahan also highlighted that the P value was based on a one-side log-rank test, “a relatively low bar to jump over” and that there were slight imbalances in both PD-1 expression status and tumor mutational burden – both of which favored the vaccine group and may be associated with better recurrence-free survival.
The 16% difference in recurrence-free survival seen with the combination vs. pembrolizumab alone, if confirmed in further studies, “is clinically meaningful for high-risk patients,” said Dr. Callahan. “The authors are to be congratulated for presenting the first randomized study of a neoantigen vaccine with a clinical efficacy primary endpoint, and this is a trial that incorporates many of the lessons we’ve learned along the years.”
Dr. Sullivan also commented on the promising results. “The field of cancer vaccines is a wasteland of failed clinical trials after some initial promising data, so to have something like this where it does appear that this vaccine strategy works is good not only for patients with melanoma but for those people who have dedicated their lives to trying to develop cancer vaccines,” he said in an interview.
KEYNOTE-942 was funded by Moderna with collaboration from Merck. Dr. Weber has financial relationships with Merck, Moderna, and other companies. Dr. Sullivan has served as a paid consultant for Merck and has received research funding from the company. Dr. Callahan disclosed a consulting/advisory role with Moderna, Merck, and others.
A version of this article first appeared on Medscape.com.
according to the latest data from the KEYNOTE-942 trial.
This recurrence-free survival benefit corresponded to a 44% reduced risk of recurrence or death in patients who received the personalized vaccine plus pembrolizumab compared with the immunotherapy alone.
The randomized phase 2b trial is the first to show a positive result for a cancer vaccine in a randomized trial. The results, if confirmed in further studies, hold promise for treating other solid tumors with sensitivity to the programmed death-1 (PD-1) protein, investigators said.
“KEYNOTE-942 is the first randomized study to demonstrate improvement in recurrence-free survival in melanoma, or in any cancer in my view, with an individualized neoantigen vaccine approach,” trial investigator Jeffrey S. Weber, MD, PhD, of NYU Langone Perlmutter Cancer Center in New York, said during an oral abstract session at the annual meeting of the American Association for Cancer Research.
“I have every confidence that this strategy will be expanded to other histologies that are PD-1 sensitive, such as non–small cell lung cancer, renal cell cancer, hepatocellular cancer, gastroesophageal cancer, et cetera,” Dr. Weber said.
Invited discussant Margaret Callahan, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, called the results “exciting,” especially in light of previous results in cancer vaccine trials. “Despite hundreds of formulations and dozens of studies, cancer vaccines have been disappointing so far, and have largely failed to have a meaningful impact in oncology,” she said.
A promising personalized vaccine
The mRNA vaccine is individually tailored and encodes up to 34 patient-specific tumor neoantigens. The vaccine also acts as an adjuvant to strengthen the immune response.
Dr. Weber said that the “mRNA 4157 is what one would call an individualized neoantigen therapy. It will target an individual patient’s unique tumor mutations, and the revelation over the last 5-10 years, is that, for better or worse, virtually all the neoantigens are unique to an individual patient. There are very, very few true universal neoantigens, or at least universal neoantigens that could have clinical utility.”
The vaccines are developed from tumor biopsy tissues that then undergo whole exome and RNA sequencing to identify single nucleotide variants that are present in the tumor but not in normal tissue.
The findings are then fed into a computer algorithm that identifies potential neoepitope peptides that would bind well to the patient’s human leukocyte antigen (HLA) type and could evoke strong T-cell responses.
“Once they’re chosen, you concatenate the sequences together into a single-strand mRNA vaccine, it’s packaged with nanoparticles to encapsulate it, and there you have your mRNA vaccine,” Dr. Weber explained.
In the KEYNOTE-942 trial, the investigators randomly assigned patients with completely resected high-risk cutaneous melanoma on a 2:1 basis to receive mRNA-4157 via intramuscular injection every 3 weeks for a total of nine doses, plus intravenous pembrolizumab every 3 weeks for 18 cycles (107 patients) or pembrolizumab alone (50 patients). Median follow-up was 101 weeks in the combination group and 105 weeks in the pembrolizumab group.
Overall, the 18-month recurrence-free survival rates were 78.6% in the combination arm and 62.2% in the pembrolizumab arm. The recurrence-free survival rates corresponded to a 44% reduced risk of recurrence or death in patients who received the personalized vaccine plus pembrolizumab compared with those who received only pembrolizumab (hazard ratio [HR] for recurrence, 0.561; P =.0266).
Grade 3 or greater adverse events occurred in 25% of patients in the combination group and 18% of patients in the pembrolizumab group. The most common grade 3 event associated with the vaccine was fatigue. No grade 4 adverse events or deaths were associated with the vaccine, and the addition of the vaccine to pembrolizumab did not appear to increase risk for immune-mediated adverse events.
In a subanalysis, Dr. Weber and colleagues explored the relationship between tumor mutational burden and recurrence-free survival. Higher tumor mutational burden may mean more neoepitopes to target, which is helpful when developing personalized neoantigen vaccines, explained coinvestigator Ryan Sullivan, MD, associate director of the melanoma program at Mass General Cancer Center, Boston, who presented the subanalysis results.
The investigators performed whole exome and whole transcriptome sequencing of baseline tumor biopsy samples to determine the mutational burden of tumors and defined a high mutational burden as 10 or more mutations per megabase.
Overall, in the combination group, patients with a higher tumor mutational burden at baseline showed improved outcomes (HR, 0.652; 95% confidence interval [CI], 0.284-1.494), as did patients with a lower tumor mutational burden (HR, 0.586; 95% CI, 0.243-1.415).
The authors found the same was true for patients with high vs. low tumor inflammation scores (high: HR, 0.576; 95% CI, 0.209-1.591 vs. low: HR, 0.528; 95% CI, 0.253-1.101) and higher PD-L1 expression (PD-L1 positive: HR, 0.485; 95% CI, 0.226-1.039 vs. PD-L1 negative: HR, 0.162; 95% CI, 0.038-0.685).
The hazard ratios crossed 1, which suggest that the combination was similarly effective in all patient subsets, said Dr. Sullivan.
Dr. Callahan also highlighted that the P value was based on a one-side log-rank test, “a relatively low bar to jump over” and that there were slight imbalances in both PD-1 expression status and tumor mutational burden – both of which favored the vaccine group and may be associated with better recurrence-free survival.
The 16% difference in recurrence-free survival seen with the combination vs. pembrolizumab alone, if confirmed in further studies, “is clinically meaningful for high-risk patients,” said Dr. Callahan. “The authors are to be congratulated for presenting the first randomized study of a neoantigen vaccine with a clinical efficacy primary endpoint, and this is a trial that incorporates many of the lessons we’ve learned along the years.”
Dr. Sullivan also commented on the promising results. “The field of cancer vaccines is a wasteland of failed clinical trials after some initial promising data, so to have something like this where it does appear that this vaccine strategy works is good not only for patients with melanoma but for those people who have dedicated their lives to trying to develop cancer vaccines,” he said in an interview.
KEYNOTE-942 was funded by Moderna with collaboration from Merck. Dr. Weber has financial relationships with Merck, Moderna, and other companies. Dr. Sullivan has served as a paid consultant for Merck and has received research funding from the company. Dr. Callahan disclosed a consulting/advisory role with Moderna, Merck, and others.
A version of this article first appeared on Medscape.com.
according to the latest data from the KEYNOTE-942 trial.
This recurrence-free survival benefit corresponded to a 44% reduced risk of recurrence or death in patients who received the personalized vaccine plus pembrolizumab compared with the immunotherapy alone.
The randomized phase 2b trial is the first to show a positive result for a cancer vaccine in a randomized trial. The results, if confirmed in further studies, hold promise for treating other solid tumors with sensitivity to the programmed death-1 (PD-1) protein, investigators said.
“KEYNOTE-942 is the first randomized study to demonstrate improvement in recurrence-free survival in melanoma, or in any cancer in my view, with an individualized neoantigen vaccine approach,” trial investigator Jeffrey S. Weber, MD, PhD, of NYU Langone Perlmutter Cancer Center in New York, said during an oral abstract session at the annual meeting of the American Association for Cancer Research.
“I have every confidence that this strategy will be expanded to other histologies that are PD-1 sensitive, such as non–small cell lung cancer, renal cell cancer, hepatocellular cancer, gastroesophageal cancer, et cetera,” Dr. Weber said.
Invited discussant Margaret Callahan, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, called the results “exciting,” especially in light of previous results in cancer vaccine trials. “Despite hundreds of formulations and dozens of studies, cancer vaccines have been disappointing so far, and have largely failed to have a meaningful impact in oncology,” she said.
A promising personalized vaccine
The mRNA vaccine is individually tailored and encodes up to 34 patient-specific tumor neoantigens. The vaccine also acts as an adjuvant to strengthen the immune response.
Dr. Weber said that the “mRNA 4157 is what one would call an individualized neoantigen therapy. It will target an individual patient’s unique tumor mutations, and the revelation over the last 5-10 years, is that, for better or worse, virtually all the neoantigens are unique to an individual patient. There are very, very few true universal neoantigens, or at least universal neoantigens that could have clinical utility.”
The vaccines are developed from tumor biopsy tissues that then undergo whole exome and RNA sequencing to identify single nucleotide variants that are present in the tumor but not in normal tissue.
The findings are then fed into a computer algorithm that identifies potential neoepitope peptides that would bind well to the patient’s human leukocyte antigen (HLA) type and could evoke strong T-cell responses.
“Once they’re chosen, you concatenate the sequences together into a single-strand mRNA vaccine, it’s packaged with nanoparticles to encapsulate it, and there you have your mRNA vaccine,” Dr. Weber explained.
In the KEYNOTE-942 trial, the investigators randomly assigned patients with completely resected high-risk cutaneous melanoma on a 2:1 basis to receive mRNA-4157 via intramuscular injection every 3 weeks for a total of nine doses, plus intravenous pembrolizumab every 3 weeks for 18 cycles (107 patients) or pembrolizumab alone (50 patients). Median follow-up was 101 weeks in the combination group and 105 weeks in the pembrolizumab group.
Overall, the 18-month recurrence-free survival rates were 78.6% in the combination arm and 62.2% in the pembrolizumab arm. The recurrence-free survival rates corresponded to a 44% reduced risk of recurrence or death in patients who received the personalized vaccine plus pembrolizumab compared with those who received only pembrolizumab (hazard ratio [HR] for recurrence, 0.561; P =.0266).
Grade 3 or greater adverse events occurred in 25% of patients in the combination group and 18% of patients in the pembrolizumab group. The most common grade 3 event associated with the vaccine was fatigue. No grade 4 adverse events or deaths were associated with the vaccine, and the addition of the vaccine to pembrolizumab did not appear to increase risk for immune-mediated adverse events.
In a subanalysis, Dr. Weber and colleagues explored the relationship between tumor mutational burden and recurrence-free survival. Higher tumor mutational burden may mean more neoepitopes to target, which is helpful when developing personalized neoantigen vaccines, explained coinvestigator Ryan Sullivan, MD, associate director of the melanoma program at Mass General Cancer Center, Boston, who presented the subanalysis results.
The investigators performed whole exome and whole transcriptome sequencing of baseline tumor biopsy samples to determine the mutational burden of tumors and defined a high mutational burden as 10 or more mutations per megabase.
Overall, in the combination group, patients with a higher tumor mutational burden at baseline showed improved outcomes (HR, 0.652; 95% confidence interval [CI], 0.284-1.494), as did patients with a lower tumor mutational burden (HR, 0.586; 95% CI, 0.243-1.415).
The authors found the same was true for patients with high vs. low tumor inflammation scores (high: HR, 0.576; 95% CI, 0.209-1.591 vs. low: HR, 0.528; 95% CI, 0.253-1.101) and higher PD-L1 expression (PD-L1 positive: HR, 0.485; 95% CI, 0.226-1.039 vs. PD-L1 negative: HR, 0.162; 95% CI, 0.038-0.685).
The hazard ratios crossed 1, which suggest that the combination was similarly effective in all patient subsets, said Dr. Sullivan.
Dr. Callahan also highlighted that the P value was based on a one-side log-rank test, “a relatively low bar to jump over” and that there were slight imbalances in both PD-1 expression status and tumor mutational burden – both of which favored the vaccine group and may be associated with better recurrence-free survival.
The 16% difference in recurrence-free survival seen with the combination vs. pembrolizumab alone, if confirmed in further studies, “is clinically meaningful for high-risk patients,” said Dr. Callahan. “The authors are to be congratulated for presenting the first randomized study of a neoantigen vaccine with a clinical efficacy primary endpoint, and this is a trial that incorporates many of the lessons we’ve learned along the years.”
Dr. Sullivan also commented on the promising results. “The field of cancer vaccines is a wasteland of failed clinical trials after some initial promising data, so to have something like this where it does appear that this vaccine strategy works is good not only for patients with melanoma but for those people who have dedicated their lives to trying to develop cancer vaccines,” he said in an interview.
KEYNOTE-942 was funded by Moderna with collaboration from Merck. Dr. Weber has financial relationships with Merck, Moderna, and other companies. Dr. Sullivan has served as a paid consultant for Merck and has received research funding from the company. Dr. Callahan disclosed a consulting/advisory role with Moderna, Merck, and others.
A version of this article first appeared on Medscape.com.
FROM AACR 2023
AFib risk with cancer drugs underestimated
Atrial fibrillation (AFib) is a known and serious side effect of some cancer treatments, but it is underreported in cancer drug trials, French investigators said in a new report.
As a result, oncologists likely underestimate the risk of atrial fibrillation when new cancer drugs come to market, they said.
The team came to these conclusions after conducting a meta-analysis of 191 phase 2 or 3 clinical trials that included 26,604 patients. The trials investigated 15 anticancer drugs used as monotherapy.
The meta-analysis showed that the annualized incidence rate of AFib ranged from 0.26 cases per 100 person-years – about the same as placebo – to 4.92 cases, a nearly 20 times’ higher risk.
Rates were the highest for ibrutinib, clofarabine, and ponatinib.
The study was published in JACC: CardioOncology, a journal of the American College of Cardiology.
Actual rates of AFib are probably higher than what they found in this meta-analysis, the authors suspect, because most oncology trials only identify and report severe cases of AFib that require immediate medical attention. Less severe cases can also lead to serious complications, including strokes, but they go unreported, said the investigators, led by Joachim Alexandre, MD, PhD, a member of the cardio-oncology program at the University of Caen Normandie Hospital Center, France.
“These findings suggest a global and systemic underreporting and/or underidentification of cardiotoxicity among cancer clinical trial participants,” and AFib reporting is “particularly affected,” they said.
Call for routine monitoring
The root of the problem is the lack of routine rhythm monitoring in cancer trials. This in turn “leads to a significant underestimation of AFib incidence” and rates “markedly lower than those observed among real-life” patients, the authors pointed out.
To address the issue, Dr. Alexandre and his team called for routine cardiac monitoring in trials to capture the true incidence of AFib and to “clearly define which anticancer drugs are significantly associated” with the condition.
Approached for comment, Michael G. Fradley, MD, medical director of cardio-oncology at the University of Pennsylvania, Philadelphia, agreed.
“It’s incredibly important” to “identify the drugs most likely to cause arrhythmias and determine the best prevention and treatment strategies. Unfortunately, systematic evaluation of arrhythmias in cancer clinical trials has often been lacking,” Dr. Fradley told this news organization.
The investigators said the issue is particularly pressing for drugs known to be associated with AFib. For Bruton’s tyrosine kinase inhibitors such as ibrutinib, for instance, they call for standardize AFib detection in trials “not only on 12-lead ECGs” for symptomatic AFib but also with “longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AFib.”
Dr. Fradley said there might also be a role for newer wearable technologies that can detect arrhythmias through a skin patch or by other means.
Details of the meta-analysis
The investigators pulled the 191 studies they used in their meta-analysis from the ClinicalTrials.gov database.
The trials covered anticancer drugs used as monotherapy up to Sept. 18, 2020. Almost half were randomized trials, but only seven had placebo arms. Trials involving hematologic cancers outnumbered those involving solid tumors.
The 15 drugs examined were dacarbazine, abiraterone, clofarabine, azacitidine, ibrutinib, nilotinib, ponatinib, midostaurin, ipilimumab, aldesleukin, lenalidomide, pomalidomide, rituximab, bortezomib, and docetaxel.
The annualized incidence AFib rates per 100 person-years were 4.92 cases for ibrutinib, 2.38 cases for clofarabine, and 2.35 cases for ponatinib.
The lowest AFib rates were for ipilimumab (0.26 cases), rituximab (0.27), and nilotinib (0.29).
For placebo, the annualized rate was 0.25 cases per 100 person-years.
The team said caution is warranted regarding their estimations for clofarabine and midostaurin (0.65 cases) because no trials were registered after September 2009, when adverse event reporting became mandatory. As a result, estimates may be artificially low.
One of the limits of the study is that it focused on monotherapy in an age when combination treatment is generally the rule for cancer, the authors noted.
No external funding was reported for the study. Dr. Alexandre has received honoraria for presentations and consulting fees from Bayer, BMS, Pfizer, Amgen, and Bioserenity.
A version of this article first appeared on Medscape.com.
Atrial fibrillation (AFib) is a known and serious side effect of some cancer treatments, but it is underreported in cancer drug trials, French investigators said in a new report.
As a result, oncologists likely underestimate the risk of atrial fibrillation when new cancer drugs come to market, they said.
The team came to these conclusions after conducting a meta-analysis of 191 phase 2 or 3 clinical trials that included 26,604 patients. The trials investigated 15 anticancer drugs used as monotherapy.
The meta-analysis showed that the annualized incidence rate of AFib ranged from 0.26 cases per 100 person-years – about the same as placebo – to 4.92 cases, a nearly 20 times’ higher risk.
Rates were the highest for ibrutinib, clofarabine, and ponatinib.
The study was published in JACC: CardioOncology, a journal of the American College of Cardiology.
Actual rates of AFib are probably higher than what they found in this meta-analysis, the authors suspect, because most oncology trials only identify and report severe cases of AFib that require immediate medical attention. Less severe cases can also lead to serious complications, including strokes, but they go unreported, said the investigators, led by Joachim Alexandre, MD, PhD, a member of the cardio-oncology program at the University of Caen Normandie Hospital Center, France.
“These findings suggest a global and systemic underreporting and/or underidentification of cardiotoxicity among cancer clinical trial participants,” and AFib reporting is “particularly affected,” they said.
Call for routine monitoring
The root of the problem is the lack of routine rhythm monitoring in cancer trials. This in turn “leads to a significant underestimation of AFib incidence” and rates “markedly lower than those observed among real-life” patients, the authors pointed out.
To address the issue, Dr. Alexandre and his team called for routine cardiac monitoring in trials to capture the true incidence of AFib and to “clearly define which anticancer drugs are significantly associated” with the condition.
Approached for comment, Michael G. Fradley, MD, medical director of cardio-oncology at the University of Pennsylvania, Philadelphia, agreed.
“It’s incredibly important” to “identify the drugs most likely to cause arrhythmias and determine the best prevention and treatment strategies. Unfortunately, systematic evaluation of arrhythmias in cancer clinical trials has often been lacking,” Dr. Fradley told this news organization.
The investigators said the issue is particularly pressing for drugs known to be associated with AFib. For Bruton’s tyrosine kinase inhibitors such as ibrutinib, for instance, they call for standardize AFib detection in trials “not only on 12-lead ECGs” for symptomatic AFib but also with “longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AFib.”
Dr. Fradley said there might also be a role for newer wearable technologies that can detect arrhythmias through a skin patch or by other means.
Details of the meta-analysis
The investigators pulled the 191 studies they used in their meta-analysis from the ClinicalTrials.gov database.
The trials covered anticancer drugs used as monotherapy up to Sept. 18, 2020. Almost half were randomized trials, but only seven had placebo arms. Trials involving hematologic cancers outnumbered those involving solid tumors.
The 15 drugs examined were dacarbazine, abiraterone, clofarabine, azacitidine, ibrutinib, nilotinib, ponatinib, midostaurin, ipilimumab, aldesleukin, lenalidomide, pomalidomide, rituximab, bortezomib, and docetaxel.
The annualized incidence AFib rates per 100 person-years were 4.92 cases for ibrutinib, 2.38 cases for clofarabine, and 2.35 cases for ponatinib.
The lowest AFib rates were for ipilimumab (0.26 cases), rituximab (0.27), and nilotinib (0.29).
For placebo, the annualized rate was 0.25 cases per 100 person-years.
The team said caution is warranted regarding their estimations for clofarabine and midostaurin (0.65 cases) because no trials were registered after September 2009, when adverse event reporting became mandatory. As a result, estimates may be artificially low.
One of the limits of the study is that it focused on monotherapy in an age when combination treatment is generally the rule for cancer, the authors noted.
No external funding was reported for the study. Dr. Alexandre has received honoraria for presentations and consulting fees from Bayer, BMS, Pfizer, Amgen, and Bioserenity.
A version of this article first appeared on Medscape.com.
Atrial fibrillation (AFib) is a known and serious side effect of some cancer treatments, but it is underreported in cancer drug trials, French investigators said in a new report.
As a result, oncologists likely underestimate the risk of atrial fibrillation when new cancer drugs come to market, they said.
The team came to these conclusions after conducting a meta-analysis of 191 phase 2 or 3 clinical trials that included 26,604 patients. The trials investigated 15 anticancer drugs used as monotherapy.
The meta-analysis showed that the annualized incidence rate of AFib ranged from 0.26 cases per 100 person-years – about the same as placebo – to 4.92 cases, a nearly 20 times’ higher risk.
Rates were the highest for ibrutinib, clofarabine, and ponatinib.
The study was published in JACC: CardioOncology, a journal of the American College of Cardiology.
Actual rates of AFib are probably higher than what they found in this meta-analysis, the authors suspect, because most oncology trials only identify and report severe cases of AFib that require immediate medical attention. Less severe cases can also lead to serious complications, including strokes, but they go unreported, said the investigators, led by Joachim Alexandre, MD, PhD, a member of the cardio-oncology program at the University of Caen Normandie Hospital Center, France.
“These findings suggest a global and systemic underreporting and/or underidentification of cardiotoxicity among cancer clinical trial participants,” and AFib reporting is “particularly affected,” they said.
Call for routine monitoring
The root of the problem is the lack of routine rhythm monitoring in cancer trials. This in turn “leads to a significant underestimation of AFib incidence” and rates “markedly lower than those observed among real-life” patients, the authors pointed out.
To address the issue, Dr. Alexandre and his team called for routine cardiac monitoring in trials to capture the true incidence of AFib and to “clearly define which anticancer drugs are significantly associated” with the condition.
Approached for comment, Michael G. Fradley, MD, medical director of cardio-oncology at the University of Pennsylvania, Philadelphia, agreed.
“It’s incredibly important” to “identify the drugs most likely to cause arrhythmias and determine the best prevention and treatment strategies. Unfortunately, systematic evaluation of arrhythmias in cancer clinical trials has often been lacking,” Dr. Fradley told this news organization.
The investigators said the issue is particularly pressing for drugs known to be associated with AFib. For Bruton’s tyrosine kinase inhibitors such as ibrutinib, for instance, they call for standardize AFib detection in trials “not only on 12-lead ECGs” for symptomatic AFib but also with “longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AFib.”
Dr. Fradley said there might also be a role for newer wearable technologies that can detect arrhythmias through a skin patch or by other means.
Details of the meta-analysis
The investigators pulled the 191 studies they used in their meta-analysis from the ClinicalTrials.gov database.
The trials covered anticancer drugs used as monotherapy up to Sept. 18, 2020. Almost half were randomized trials, but only seven had placebo arms. Trials involving hematologic cancers outnumbered those involving solid tumors.
The 15 drugs examined were dacarbazine, abiraterone, clofarabine, azacitidine, ibrutinib, nilotinib, ponatinib, midostaurin, ipilimumab, aldesleukin, lenalidomide, pomalidomide, rituximab, bortezomib, and docetaxel.
The annualized incidence AFib rates per 100 person-years were 4.92 cases for ibrutinib, 2.38 cases for clofarabine, and 2.35 cases for ponatinib.
The lowest AFib rates were for ipilimumab (0.26 cases), rituximab (0.27), and nilotinib (0.29).
For placebo, the annualized rate was 0.25 cases per 100 person-years.
The team said caution is warranted regarding their estimations for clofarabine and midostaurin (0.65 cases) because no trials were registered after September 2009, when adverse event reporting became mandatory. As a result, estimates may be artificially low.
One of the limits of the study is that it focused on monotherapy in an age when combination treatment is generally the rule for cancer, the authors noted.
No external funding was reported for the study. Dr. Alexandre has received honoraria for presentations and consulting fees from Bayer, BMS, Pfizer, Amgen, and Bioserenity.
A version of this article first appeared on Medscape.com.
Study gives new insight into timing of combo treatment in metastatic NSCLC
However, patients still fared poorly on average since overall survival remained low and didn’t change significantly.
While not conclusive, the new research – released at European Lung Cancer Congress 2023 – offers early insight into the best timing for the experimental combination treatment, study coauthor Yanyan Lou, MD, PhD, an oncologist at Mayo Clinic in Jacksonville, Fla., said in an interview.
The wide availability of radiation therapy could also allow the therapy to be administered even in regions with poor access to sophisticated medical care, she said. “Radiation is a very feasible approach that pretty much everybody in your community can get.”
Radiotherapy is typically not added to immunotherapy in patients with non–small cell lung cancer. But “there has been recent interest in the combination: Would tumor necrosis from radiation enhance the immunogenicity of the tumor and thus enhance the effect of immunotherapy?” oncologist Toby Campbell, MD, of University of Wisconsin–Madison, said in an interview.
Research has indeed suggested that the treatments may have a synergistic effect, he said, and it’s clear that “strategies to try and increase immunogenicity are an important area to investigate.”
But he cautioned that “we have a long way to go to understanding how immunogenicity works and how the gut microbiome, tumor, immunotherapy, and the immune system interact with one another.”
For the new study, researchers retrospectively analyzed cases of 225 patients with metastatic non–small cell lung cancer (male = 56%, median age = 68, 79% adenocarcinoma) who were treated with immunotherapy at Mayo Clinic–Jacksonville from 2011 to 2022. The study excluded those who received targeted therapy or prior concurrent chemoradiotherapy and durvalumab.
The most common metastases were bone and central nervous system types (41% and 25%, respectively). Fifty-six percent of patients received radiotherapy before or during immunotherapy. Another 27% never received radiotherapy, and 17% received it after immunotherapy was discontinued.
Common types of immunotherapy included pembrolizumab (78%), nivolumab (14%), and atezolizumab (12%).
Overall, the researchers found no statistically significant differences in various outcomes between patients who received radiotherapy before or during immunotherapy compared with those who didn’t get radiotherapy (progression-free survival: 5.9 vs. 5.5 months, P = .66; overall survival: 16.9 vs. 13.1 months, P = .84; immune-related adverse events: 26.2% vs. 34.4%, P = .24).
However, the researchers found that progression-free survival was significantly higher in one group: Those who received radiotherapy 1-12 months before immunotherapy vs. those who received it less than 1 month before (12.6 vs. 4.2 months, hazard ratio [HR], 0.46, 95% confidence interval [CI], 0.26-0.83, P = .005,) and those who never received radiotherapy (12.6 vs. 5.5 months, HR, 0.56, 95% CI, 0.36-0.89, P = .0197).
There wasn’t a statistically significant difference in overall survival.
The small number of subjects and the variation in treatment protocols may have prevented the study from revealing a survival benefit, Dr. Lou said.
As for adverse effects, she said a preliminary analysis didn’t turn up any.
It’s not clear why a 1- to 12-month gap between radiotherapy and immunotherapy may be most effective, she said. Moving forward, “we need validate this in a large cohort,” she noted.
In regard to cost, immunotherapy is notoriously expensive. Pembrolizumab, for example, has a list price of $10,897 per 200-mg dose given every 3 weeks, and patients may take the drug for a year or two.
Dr. Campbell, who didn’t take part in the new study, said it suggests that research into radiation-immunotherapy combination treatment may be worthwhile.
No funding was reported. The study authors and Dr. Campbell reported no disclosures.
However, patients still fared poorly on average since overall survival remained low and didn’t change significantly.
While not conclusive, the new research – released at European Lung Cancer Congress 2023 – offers early insight into the best timing for the experimental combination treatment, study coauthor Yanyan Lou, MD, PhD, an oncologist at Mayo Clinic in Jacksonville, Fla., said in an interview.
The wide availability of radiation therapy could also allow the therapy to be administered even in regions with poor access to sophisticated medical care, she said. “Radiation is a very feasible approach that pretty much everybody in your community can get.”
Radiotherapy is typically not added to immunotherapy in patients with non–small cell lung cancer. But “there has been recent interest in the combination: Would tumor necrosis from radiation enhance the immunogenicity of the tumor and thus enhance the effect of immunotherapy?” oncologist Toby Campbell, MD, of University of Wisconsin–Madison, said in an interview.
Research has indeed suggested that the treatments may have a synergistic effect, he said, and it’s clear that “strategies to try and increase immunogenicity are an important area to investigate.”
But he cautioned that “we have a long way to go to understanding how immunogenicity works and how the gut microbiome, tumor, immunotherapy, and the immune system interact with one another.”
For the new study, researchers retrospectively analyzed cases of 225 patients with metastatic non–small cell lung cancer (male = 56%, median age = 68, 79% adenocarcinoma) who were treated with immunotherapy at Mayo Clinic–Jacksonville from 2011 to 2022. The study excluded those who received targeted therapy or prior concurrent chemoradiotherapy and durvalumab.
The most common metastases were bone and central nervous system types (41% and 25%, respectively). Fifty-six percent of patients received radiotherapy before or during immunotherapy. Another 27% never received radiotherapy, and 17% received it after immunotherapy was discontinued.
Common types of immunotherapy included pembrolizumab (78%), nivolumab (14%), and atezolizumab (12%).
Overall, the researchers found no statistically significant differences in various outcomes between patients who received radiotherapy before or during immunotherapy compared with those who didn’t get radiotherapy (progression-free survival: 5.9 vs. 5.5 months, P = .66; overall survival: 16.9 vs. 13.1 months, P = .84; immune-related adverse events: 26.2% vs. 34.4%, P = .24).
However, the researchers found that progression-free survival was significantly higher in one group: Those who received radiotherapy 1-12 months before immunotherapy vs. those who received it less than 1 month before (12.6 vs. 4.2 months, hazard ratio [HR], 0.46, 95% confidence interval [CI], 0.26-0.83, P = .005,) and those who never received radiotherapy (12.6 vs. 5.5 months, HR, 0.56, 95% CI, 0.36-0.89, P = .0197).
There wasn’t a statistically significant difference in overall survival.
The small number of subjects and the variation in treatment protocols may have prevented the study from revealing a survival benefit, Dr. Lou said.
As for adverse effects, she said a preliminary analysis didn’t turn up any.
It’s not clear why a 1- to 12-month gap between radiotherapy and immunotherapy may be most effective, she said. Moving forward, “we need validate this in a large cohort,” she noted.
In regard to cost, immunotherapy is notoriously expensive. Pembrolizumab, for example, has a list price of $10,897 per 200-mg dose given every 3 weeks, and patients may take the drug for a year or two.
Dr. Campbell, who didn’t take part in the new study, said it suggests that research into radiation-immunotherapy combination treatment may be worthwhile.
No funding was reported. The study authors and Dr. Campbell reported no disclosures.
However, patients still fared poorly on average since overall survival remained low and didn’t change significantly.
While not conclusive, the new research – released at European Lung Cancer Congress 2023 – offers early insight into the best timing for the experimental combination treatment, study coauthor Yanyan Lou, MD, PhD, an oncologist at Mayo Clinic in Jacksonville, Fla., said in an interview.
The wide availability of radiation therapy could also allow the therapy to be administered even in regions with poor access to sophisticated medical care, she said. “Radiation is a very feasible approach that pretty much everybody in your community can get.”
Radiotherapy is typically not added to immunotherapy in patients with non–small cell lung cancer. But “there has been recent interest in the combination: Would tumor necrosis from radiation enhance the immunogenicity of the tumor and thus enhance the effect of immunotherapy?” oncologist Toby Campbell, MD, of University of Wisconsin–Madison, said in an interview.
Research has indeed suggested that the treatments may have a synergistic effect, he said, and it’s clear that “strategies to try and increase immunogenicity are an important area to investigate.”
But he cautioned that “we have a long way to go to understanding how immunogenicity works and how the gut microbiome, tumor, immunotherapy, and the immune system interact with one another.”
For the new study, researchers retrospectively analyzed cases of 225 patients with metastatic non–small cell lung cancer (male = 56%, median age = 68, 79% adenocarcinoma) who were treated with immunotherapy at Mayo Clinic–Jacksonville from 2011 to 2022. The study excluded those who received targeted therapy or prior concurrent chemoradiotherapy and durvalumab.
The most common metastases were bone and central nervous system types (41% and 25%, respectively). Fifty-six percent of patients received radiotherapy before or during immunotherapy. Another 27% never received radiotherapy, and 17% received it after immunotherapy was discontinued.
Common types of immunotherapy included pembrolizumab (78%), nivolumab (14%), and atezolizumab (12%).
Overall, the researchers found no statistically significant differences in various outcomes between patients who received radiotherapy before or during immunotherapy compared with those who didn’t get radiotherapy (progression-free survival: 5.9 vs. 5.5 months, P = .66; overall survival: 16.9 vs. 13.1 months, P = .84; immune-related adverse events: 26.2% vs. 34.4%, P = .24).
However, the researchers found that progression-free survival was significantly higher in one group: Those who received radiotherapy 1-12 months before immunotherapy vs. those who received it less than 1 month before (12.6 vs. 4.2 months, hazard ratio [HR], 0.46, 95% confidence interval [CI], 0.26-0.83, P = .005,) and those who never received radiotherapy (12.6 vs. 5.5 months, HR, 0.56, 95% CI, 0.36-0.89, P = .0197).
There wasn’t a statistically significant difference in overall survival.
The small number of subjects and the variation in treatment protocols may have prevented the study from revealing a survival benefit, Dr. Lou said.
As for adverse effects, she said a preliminary analysis didn’t turn up any.
It’s not clear why a 1- to 12-month gap between radiotherapy and immunotherapy may be most effective, she said. Moving forward, “we need validate this in a large cohort,” she noted.
In regard to cost, immunotherapy is notoriously expensive. Pembrolizumab, for example, has a list price of $10,897 per 200-mg dose given every 3 weeks, and patients may take the drug for a year or two.
Dr. Campbell, who didn’t take part in the new study, said it suggests that research into radiation-immunotherapy combination treatment may be worthwhile.
No funding was reported. The study authors and Dr. Campbell reported no disclosures.
FROM ELCC 2023
Thoracic cancer approvals differ at FDA, EMA
The findings of this new study suggest that patients in Europe may face delayed access to new therapies, the authors wrote in a poster presentation at the European Lung Cancer Congress 2023.
They also noted that some FDA approvals occurred before pivotal trial data became available, which can leave doubt about efficacy.
“Effective cancer management relies on availability of therapies which improve patient outcomes, such as immunotherapy. The two largest regulators involved in approving immunotherapies are the FDA and the EMA and therefore we aimed to compare the approval timings between both to see if a difference in approval timings was present,” coauthor Aakash Desai, MD, said in an interview.
Previously, the researchers conducted a study of cancer approval patterns at the FDA and EMA between 2010 and 2019, and found U.S. patients gain access to new cancer therapeutics more quickly than do European patients. Of 89 new therapies approved in that time span, the FDA approval occurred first in 85 cases (95%), though just 72% were submitted to FDA first. The median increased time it took for EMA approval compared with the FDA was 241 days. Thirty-nine percent of U.S. approvals came before the publication of the pivotal clinical trial, versus 9% of EMA approvals.
The new study focuses on thoracic oncology, where lung cancer is the leading cause of death. “As such, prompt approval timings for immunotherapies are crucial for effective treatment. Furthermore, lung cancer immunotherapies target certain biomarkers, of which, PD1 and PD-L1 are key,” said Dr. Desai, a fellow at Mayo Clinic, Rochester, Minn.
Still, Dr. Desai sounded a note of caution. “Just because a therapy is approved more quickly does not necessarily mean it is efficacious, as the clinical trials involving these drugs may not have been completed or fully reported at the time of authorization. [Drug developers] need to have a more global and coordinated approach to evaluating evidence and approval of drugs so the care received by a particular patient is not a factor of where they live,” he said.
The researchers surveyed approvals of seven immune checkpoint inhibitors (ICIs) approved by both the FDA and the EMA for thoracic malignancies, including non–small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and mesothelioma. The FDA approved 22 indications for the novel ICIs in thoracic malignancies, compared with 16 indications at the EMA. The difference in median approval times was larger for SCLC (179 versus 308 days) and mesothelioma (39 versus 280 days) than for NSCLC (242 versus 272 days).
“There are two discrepancies in biomarker requirements between the FDA and EMA, whereby the FDA has a broader requirement, despite these being ranked fairly consistently in terms of evidence of benefit by [European Society for Medical Oncology Magnitude of Clinical Benefit Scale and National Comprehensive Cancer Network] frameworks,” said Dr. Desai. In the case of atezolizumab for adjuvant NSCLC, the FDA required PDL1 levels of 1% or higher, while the EMA required 50% or higher. For durvalumab in unresectable NSCLC, the FDA had no PDL1 requirement, while the EMA required 1% or higher.
Dr. Desai suggested a need for further investigation into the differences between the two agencies. Asked why the two agencies might have different views on the biomarkers, Dr. Desai responded: “That is the million-dollar question. My guess is [the] EMA weighs subgroup data more than [the] FDA.”
Dr. Desai has no relevant financial disclosures.
The findings of this new study suggest that patients in Europe may face delayed access to new therapies, the authors wrote in a poster presentation at the European Lung Cancer Congress 2023.
They also noted that some FDA approvals occurred before pivotal trial data became available, which can leave doubt about efficacy.
“Effective cancer management relies on availability of therapies which improve patient outcomes, such as immunotherapy. The two largest regulators involved in approving immunotherapies are the FDA and the EMA and therefore we aimed to compare the approval timings between both to see if a difference in approval timings was present,” coauthor Aakash Desai, MD, said in an interview.
Previously, the researchers conducted a study of cancer approval patterns at the FDA and EMA between 2010 and 2019, and found U.S. patients gain access to new cancer therapeutics more quickly than do European patients. Of 89 new therapies approved in that time span, the FDA approval occurred first in 85 cases (95%), though just 72% were submitted to FDA first. The median increased time it took for EMA approval compared with the FDA was 241 days. Thirty-nine percent of U.S. approvals came before the publication of the pivotal clinical trial, versus 9% of EMA approvals.
The new study focuses on thoracic oncology, where lung cancer is the leading cause of death. “As such, prompt approval timings for immunotherapies are crucial for effective treatment. Furthermore, lung cancer immunotherapies target certain biomarkers, of which, PD1 and PD-L1 are key,” said Dr. Desai, a fellow at Mayo Clinic, Rochester, Minn.
Still, Dr. Desai sounded a note of caution. “Just because a therapy is approved more quickly does not necessarily mean it is efficacious, as the clinical trials involving these drugs may not have been completed or fully reported at the time of authorization. [Drug developers] need to have a more global and coordinated approach to evaluating evidence and approval of drugs so the care received by a particular patient is not a factor of where they live,” he said.
The researchers surveyed approvals of seven immune checkpoint inhibitors (ICIs) approved by both the FDA and the EMA for thoracic malignancies, including non–small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and mesothelioma. The FDA approved 22 indications for the novel ICIs in thoracic malignancies, compared with 16 indications at the EMA. The difference in median approval times was larger for SCLC (179 versus 308 days) and mesothelioma (39 versus 280 days) than for NSCLC (242 versus 272 days).
“There are two discrepancies in biomarker requirements between the FDA and EMA, whereby the FDA has a broader requirement, despite these being ranked fairly consistently in terms of evidence of benefit by [European Society for Medical Oncology Magnitude of Clinical Benefit Scale and National Comprehensive Cancer Network] frameworks,” said Dr. Desai. In the case of atezolizumab for adjuvant NSCLC, the FDA required PDL1 levels of 1% or higher, while the EMA required 50% or higher. For durvalumab in unresectable NSCLC, the FDA had no PDL1 requirement, while the EMA required 1% or higher.
Dr. Desai suggested a need for further investigation into the differences between the two agencies. Asked why the two agencies might have different views on the biomarkers, Dr. Desai responded: “That is the million-dollar question. My guess is [the] EMA weighs subgroup data more than [the] FDA.”
Dr. Desai has no relevant financial disclosures.
The findings of this new study suggest that patients in Europe may face delayed access to new therapies, the authors wrote in a poster presentation at the European Lung Cancer Congress 2023.
They also noted that some FDA approvals occurred before pivotal trial data became available, which can leave doubt about efficacy.
“Effective cancer management relies on availability of therapies which improve patient outcomes, such as immunotherapy. The two largest regulators involved in approving immunotherapies are the FDA and the EMA and therefore we aimed to compare the approval timings between both to see if a difference in approval timings was present,” coauthor Aakash Desai, MD, said in an interview.
Previously, the researchers conducted a study of cancer approval patterns at the FDA and EMA between 2010 and 2019, and found U.S. patients gain access to new cancer therapeutics more quickly than do European patients. Of 89 new therapies approved in that time span, the FDA approval occurred first in 85 cases (95%), though just 72% were submitted to FDA first. The median increased time it took for EMA approval compared with the FDA was 241 days. Thirty-nine percent of U.S. approvals came before the publication of the pivotal clinical trial, versus 9% of EMA approvals.
The new study focuses on thoracic oncology, where lung cancer is the leading cause of death. “As such, prompt approval timings for immunotherapies are crucial for effective treatment. Furthermore, lung cancer immunotherapies target certain biomarkers, of which, PD1 and PD-L1 are key,” said Dr. Desai, a fellow at Mayo Clinic, Rochester, Minn.
Still, Dr. Desai sounded a note of caution. “Just because a therapy is approved more quickly does not necessarily mean it is efficacious, as the clinical trials involving these drugs may not have been completed or fully reported at the time of authorization. [Drug developers] need to have a more global and coordinated approach to evaluating evidence and approval of drugs so the care received by a particular patient is not a factor of where they live,” he said.
The researchers surveyed approvals of seven immune checkpoint inhibitors (ICIs) approved by both the FDA and the EMA for thoracic malignancies, including non–small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and mesothelioma. The FDA approved 22 indications for the novel ICIs in thoracic malignancies, compared with 16 indications at the EMA. The difference in median approval times was larger for SCLC (179 versus 308 days) and mesothelioma (39 versus 280 days) than for NSCLC (242 versus 272 days).
“There are two discrepancies in biomarker requirements between the FDA and EMA, whereby the FDA has a broader requirement, despite these being ranked fairly consistently in terms of evidence of benefit by [European Society for Medical Oncology Magnitude of Clinical Benefit Scale and National Comprehensive Cancer Network] frameworks,” said Dr. Desai. In the case of atezolizumab for adjuvant NSCLC, the FDA required PDL1 levels of 1% or higher, while the EMA required 50% or higher. For durvalumab in unresectable NSCLC, the FDA had no PDL1 requirement, while the EMA required 1% or higher.
Dr. Desai suggested a need for further investigation into the differences between the two agencies. Asked why the two agencies might have different views on the biomarkers, Dr. Desai responded: “That is the million-dollar question. My guess is [the] EMA weighs subgroup data more than [the] FDA.”
Dr. Desai has no relevant financial disclosures.
FROM ELCC 2023
Adverse events linked to better survival with ICIs in melanoma
Among Survival is further improved if the immunotherapy is continued after the adverse event develops, a new study confirms.
“In the largest clinical cohort to date, our data support a positive association with overall survival for patients who develop clinically significant immune-related adverse events while receiving combination immune checkpoint blockade, in keeping with other reported series,” the authors wrote.
The study was published online in JAMA Network Open.
Immune-related adverse events are common with these drugs. Severe events of grade 3 or higher occur in 59% of trial patients who receive combination ICI therapy.
The adverse events have increasingly been positively associated with survival. However, the effects for patients with metastatic melanoma, in particular, are less clear. There is little research on the effects in relation to combination therapy with ipilimumab and nivolumab, which is the standard of care for many patients with metastatic melanoma.
To investigate, Alexander S. Watson, MD, and colleagues evaluated data on 492 patients with metastatic melanoma who had been treated with one or more doses of an anti–programmed death 1 agent as single or combination immune checkpoint blockade in the multicenter Alberta Immunotherapy Database from August 2013 to May 2020.
Of these 492 patients, 198 patients (40%) developed immune-related adverse events. The mean age of the patients who developed adverse events was 61.8 years; of those who did not develop adverse events, the mean age was 65.5 years. Men made up 69.2% and 62.2%, respectively.
A total of 288 patients received pembrolizumab as their first ICI therapy, 80 received nivolumab, and 124 received combination blockade with ipilimumab-nivolumab.
Overall, with a median follow-up of 36.6 months, among patients who experienced clinically significant immune-related adverse events, defined as requiring systemic corticosteroids and/or a treatment delay, median overall survival was significantly improved, at 56.3 months, compared with 18.5 months among those who did not experience immune-related adverse events (P < .001).
In addition, among those who received combination ICI treatment, the median overall survival was 56.2 months for those who experienced adverse events versus 19.0 months for those who did not (P < .001).
There were no significant differences in overall survival between those who were and those who were not hospitalized for their immune-related adverse events (P = .53).
For patients who resumed their ICI therapy following the adverse events, overall survival was longer, compared with those who did not resume the therapy (median, 56.3 months vs. 31.5 months; P = .009).
The improvements in overall survival seen with immune-related adverse events remained consistent after adjustment in a multivariable analysis (hazard ratio for death, 0.382; P < .001).
There were no significant differences in the median number of cycles of ICIs between those with and those without the adverse events.
The risk of recurrence of immune-related adverse events following the reintroduction of therapy after initial events was a concern, so the improved overall survival among those patients is encouraging, although further investigation is needed, commented lead author Dr. Watson, from the department of oncology, University of Calgary (Alta.).
“It may be, for certain patients with immune-related adverse events, that continued immune-priming is safe and optimizes anticancer response,” he told this news organization. “However, in a retrospective analysis such as ours, selection bias can have an impact.”
“Confirming this finding and better identifying patients who may benefit from resumption will be an area for future investigation,” he said.
Patients who developed immune-related adverse events were more likely to be younger than 50 years (21.8% vs. 13.9%), have normal albumin levels (86.4% vs. 74.8%), and have a more robust Eastern Cooperative Oncology Group status, which is consistent with other studies that have shown survival benefits among those who experience adverse events.
“We, and others, speculate this could be due to such groups having immune systems more ready to respond strongly to immunotherapy,” Dr. Watson explained.
After controlling for age and performance status in the multivariable analysis, however, “immune-related adverse events remained strongly associated with survival, potentially [indicating] that robust responses to immunotherapy lead to both cancer control and immune-related adverse events,” he said.
Overall, “we feel these findings will help clinicians in discussions with patients and in clinical decision-making after adverse events develop,” Dr. Watson said.
Dr. Watson has received personal fees from Apobiologix Canada.
A version of this article first appeared on Medscape.com.
Among Survival is further improved if the immunotherapy is continued after the adverse event develops, a new study confirms.
“In the largest clinical cohort to date, our data support a positive association with overall survival for patients who develop clinically significant immune-related adverse events while receiving combination immune checkpoint blockade, in keeping with other reported series,” the authors wrote.
The study was published online in JAMA Network Open.
Immune-related adverse events are common with these drugs. Severe events of grade 3 or higher occur in 59% of trial patients who receive combination ICI therapy.
The adverse events have increasingly been positively associated with survival. However, the effects for patients with metastatic melanoma, in particular, are less clear. There is little research on the effects in relation to combination therapy with ipilimumab and nivolumab, which is the standard of care for many patients with metastatic melanoma.
To investigate, Alexander S. Watson, MD, and colleagues evaluated data on 492 patients with metastatic melanoma who had been treated with one or more doses of an anti–programmed death 1 agent as single or combination immune checkpoint blockade in the multicenter Alberta Immunotherapy Database from August 2013 to May 2020.
Of these 492 patients, 198 patients (40%) developed immune-related adverse events. The mean age of the patients who developed adverse events was 61.8 years; of those who did not develop adverse events, the mean age was 65.5 years. Men made up 69.2% and 62.2%, respectively.
A total of 288 patients received pembrolizumab as their first ICI therapy, 80 received nivolumab, and 124 received combination blockade with ipilimumab-nivolumab.
Overall, with a median follow-up of 36.6 months, among patients who experienced clinically significant immune-related adverse events, defined as requiring systemic corticosteroids and/or a treatment delay, median overall survival was significantly improved, at 56.3 months, compared with 18.5 months among those who did not experience immune-related adverse events (P < .001).
In addition, among those who received combination ICI treatment, the median overall survival was 56.2 months for those who experienced adverse events versus 19.0 months for those who did not (P < .001).
There were no significant differences in overall survival between those who were and those who were not hospitalized for their immune-related adverse events (P = .53).
For patients who resumed their ICI therapy following the adverse events, overall survival was longer, compared with those who did not resume the therapy (median, 56.3 months vs. 31.5 months; P = .009).
The improvements in overall survival seen with immune-related adverse events remained consistent after adjustment in a multivariable analysis (hazard ratio for death, 0.382; P < .001).
There were no significant differences in the median number of cycles of ICIs between those with and those without the adverse events.
The risk of recurrence of immune-related adverse events following the reintroduction of therapy after initial events was a concern, so the improved overall survival among those patients is encouraging, although further investigation is needed, commented lead author Dr. Watson, from the department of oncology, University of Calgary (Alta.).
“It may be, for certain patients with immune-related adverse events, that continued immune-priming is safe and optimizes anticancer response,” he told this news organization. “However, in a retrospective analysis such as ours, selection bias can have an impact.”
“Confirming this finding and better identifying patients who may benefit from resumption will be an area for future investigation,” he said.
Patients who developed immune-related adverse events were more likely to be younger than 50 years (21.8% vs. 13.9%), have normal albumin levels (86.4% vs. 74.8%), and have a more robust Eastern Cooperative Oncology Group status, which is consistent with other studies that have shown survival benefits among those who experience adverse events.
“We, and others, speculate this could be due to such groups having immune systems more ready to respond strongly to immunotherapy,” Dr. Watson explained.
After controlling for age and performance status in the multivariable analysis, however, “immune-related adverse events remained strongly associated with survival, potentially [indicating] that robust responses to immunotherapy lead to both cancer control and immune-related adverse events,” he said.
Overall, “we feel these findings will help clinicians in discussions with patients and in clinical decision-making after adverse events develop,” Dr. Watson said.
Dr. Watson has received personal fees from Apobiologix Canada.
A version of this article first appeared on Medscape.com.
Among Survival is further improved if the immunotherapy is continued after the adverse event develops, a new study confirms.
“In the largest clinical cohort to date, our data support a positive association with overall survival for patients who develop clinically significant immune-related adverse events while receiving combination immune checkpoint blockade, in keeping with other reported series,” the authors wrote.
The study was published online in JAMA Network Open.
Immune-related adverse events are common with these drugs. Severe events of grade 3 or higher occur in 59% of trial patients who receive combination ICI therapy.
The adverse events have increasingly been positively associated with survival. However, the effects for patients with metastatic melanoma, in particular, are less clear. There is little research on the effects in relation to combination therapy with ipilimumab and nivolumab, which is the standard of care for many patients with metastatic melanoma.
To investigate, Alexander S. Watson, MD, and colleagues evaluated data on 492 patients with metastatic melanoma who had been treated with one or more doses of an anti–programmed death 1 agent as single or combination immune checkpoint blockade in the multicenter Alberta Immunotherapy Database from August 2013 to May 2020.
Of these 492 patients, 198 patients (40%) developed immune-related adverse events. The mean age of the patients who developed adverse events was 61.8 years; of those who did not develop adverse events, the mean age was 65.5 years. Men made up 69.2% and 62.2%, respectively.
A total of 288 patients received pembrolizumab as their first ICI therapy, 80 received nivolumab, and 124 received combination blockade with ipilimumab-nivolumab.
Overall, with a median follow-up of 36.6 months, among patients who experienced clinically significant immune-related adverse events, defined as requiring systemic corticosteroids and/or a treatment delay, median overall survival was significantly improved, at 56.3 months, compared with 18.5 months among those who did not experience immune-related adverse events (P < .001).
In addition, among those who received combination ICI treatment, the median overall survival was 56.2 months for those who experienced adverse events versus 19.0 months for those who did not (P < .001).
There were no significant differences in overall survival between those who were and those who were not hospitalized for their immune-related adverse events (P = .53).
For patients who resumed their ICI therapy following the adverse events, overall survival was longer, compared with those who did not resume the therapy (median, 56.3 months vs. 31.5 months; P = .009).
The improvements in overall survival seen with immune-related adverse events remained consistent after adjustment in a multivariable analysis (hazard ratio for death, 0.382; P < .001).
There were no significant differences in the median number of cycles of ICIs between those with and those without the adverse events.
The risk of recurrence of immune-related adverse events following the reintroduction of therapy after initial events was a concern, so the improved overall survival among those patients is encouraging, although further investigation is needed, commented lead author Dr. Watson, from the department of oncology, University of Calgary (Alta.).
“It may be, for certain patients with immune-related adverse events, that continued immune-priming is safe and optimizes anticancer response,” he told this news organization. “However, in a retrospective analysis such as ours, selection bias can have an impact.”
“Confirming this finding and better identifying patients who may benefit from resumption will be an area for future investigation,” he said.
Patients who developed immune-related adverse events were more likely to be younger than 50 years (21.8% vs. 13.9%), have normal albumin levels (86.4% vs. 74.8%), and have a more robust Eastern Cooperative Oncology Group status, which is consistent with other studies that have shown survival benefits among those who experience adverse events.
“We, and others, speculate this could be due to such groups having immune systems more ready to respond strongly to immunotherapy,” Dr. Watson explained.
After controlling for age and performance status in the multivariable analysis, however, “immune-related adverse events remained strongly associated with survival, potentially [indicating] that robust responses to immunotherapy lead to both cancer control and immune-related adverse events,” he said.
Overall, “we feel these findings will help clinicians in discussions with patients and in clinical decision-making after adverse events develop,” Dr. Watson said.
Dr. Watson has received personal fees from Apobiologix Canada.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Discontinuing immunotherapy: Is the infusion bag half empty or half full?
It’s a “champagne problem” many of us have encountered over the past few years in the clinic.
A patient with advanced non–small cell lung cancer (NSCLC) is fortunate enough to continue to do well for 2 years on ongoing pembrolizumab or perhaps pemetrexed and pembrolizumab as maintenance therapy. The latest CT shows a residual but far smaller primary tumor than what she started with.
In this instance, you may be considering stopping treatment but are concerned about doing so with evidence of disease still present.
Clinical trials of immunotherapy or chemoimmunotherapy have generally terminated treatment in nonprogressing patients after 2 years. We also know that some patients in early trials of immunotherapy stopped treatment after a fixed period of 1 or 2 years and continued to show no evidence of progression many years later.
The reason some patients experience this kind of success: Unlike the mechanism of action of conventional chemotherapy or targeted therapies, where ongoing treatment would be important to continue to exert an inhibitory effect, the active substrate of immunotherapy is the patient’s immune system, which can potentially have a self-sustaining efficacy beyond the stimulatory effect of the checkpoint inhibitor.
One trial directly addressed this question of stopping vs. continuing treatment in patients on immunotherapy. The CheckMate 153 trial, published in 2020, randomly assigned 252 previously treated patients who hadn’t demonstrated progression after 1 year on nivolumab to either discontinue nivolumab or continue nivolumab on an ongoing basis. The results were strongly in favor of ongoing therapy. Both progression-free survival (PFS) and overall survival (OS) were significantly longer in patients who continued therapy: PFS of 24.7 months vs. 9.4 months and OS not reached vs. 32.5 months.
This finding is important, but there’s an important caveat. The study population included many heavily pretreated patients, but, in practice, immunotherapy has generally moved into the first-line setting, where we see dramatic responses in a significant subset of patients.
Even more recent data are emerging that may help us evaluate who will do well off therapy and who should continue treatment.
We now have a growing collection of long-term data on patients who are more likely to have good outcomes with immunotherapy, specifically those with high tumor programmed death-ligand 1 (PD-L1) expression (≥ 50%), from the KEYNOTE-024 trial. In this study, 39 of 151 (25.8%) patients assigned to pembrolizumab completed the planned maximum of 2 years of treatment, among whom 82.1% achieved an objective response; but, only 10% (4 patients) achieved a complete response. The proportion of patients without progression and remaining off therapy wasn’t reported, but the OS rate 3 years after completing treatment was 81.4%.
In addition, restarting immunotherapy after discontinuing appears to be a moderately effective strategy. In the KEYNOTE-024 trial, 12 patients received a second course of pembrolizumab because of disease progression a median of 15.2 months after discontinuing pembrolizumab. In this small cohort, eight of these patients (66.7%) were alive at the data cutoff, and six (50%) achieved stable disease.
Recently, we received additional insight in the follow-up from two chemoimmunotherapy trials that have most shaped my practice for patients with advanced NSCLC and any level of PD-L1 expression. These are the KEYNOTE-189 trial of platinum-pemetrexed with pembrolizumab vs. placebo in those with nonsquamous NSCLC, and the KEYNOTE-407 trial of carboplatin-taxane with pembrolizumab vs. placebo in patients with advanced squamous NSCLC. The National Comprehensive Cancer Network has designated each as a “preferred regimen” for patients with advanced NSCLC.
Both regimens have demonstrated sustained efficacy benefits with prolonged follow-up, including significantly superior objective response rate, PFS, and OS with the addition of pembrolizumab. These findings merely cemented the role of these regimens in our practice, but the trials also reported on the cohort of patients who completed 35 cycles of treatment over 2 years then discontinued therapy. In both, the majority of patients showed an objective response (86% in KEYNOTE-189 and 90% in KEYNOTE-407), with most patients alive at 3 years after 2 years of treatment (71.9% in KEYNOTE-189 and 69.5% in KEYNOTE-407). In addition, the proportion of patients alive without disease progression or subsequent therapy was notable – 40.4% in KEYNOTE-189 and 43.6% KEYNOTE-407.
How should we interpret these data for the patient who is in the exam room with us?
The short answer is that we don’t know. I see this as a half-empty, half-full conundrum.
I’m disappointed that more patients who responded for 2 years will experience disease progression in the 1-3 years that follow. This signals that their immune systems have not perpetuated their initial response over the long-term. But these patients may have demonstrated disease progression even if they had continued therapy.
We also know that some patients can be rechallenged and will respond again. Some of these patients will show stable disease, whereas others will progress with repeat treatment. I would love to be able to better predict which patients are destined to do well without treatment vs. those who benefit from treatment beyond 2 years.
Might the level of PD-L1 expression tell us? Can PET imaging discriminate those with residual hypermetabolism who may need continued treatment from those with no residual uptake who could be spared it? Would serial measurement of circulating tumor DNA (ctDNA) in responding patients identify when they have achieved a point of diminishing returns, potentially indicating that some can safely discontinue treatment after 2 years, whereas others need to continue to suppress on prolonged maintenance therapy?
These questions have yet to be studied systematically. In the meantime, I take an individualized approach with my patients facing this decision. Some have experienced escalating arthralgias and myalgias, cost concerns, or other issues related to immunotherapy that may dissuade us from continuing treatment. But several others have been grateful to continue with their treatment, hesitant to do anything that could change the path of their disease.
In my patients who tolerate therapy well, I’m more worried about potential undertreatment than overtreatment. I tend to favor having my patients continue therapy in the absence of problematic toxicity or practical challenges. There is certainly room for debate here while we await data to better guide these decisions. How do you approach these patients?
Dr. West is Clinical Associate Professor, Department of Medical Oncology, City of Hope Comprehensive Cancer Care, Duarte, Calif. He reported conflicts of interest with Ariad/Takeda, Bristol-Myers Squibb, Boehringer Ingelheim, Spectrum, AstraZeneca, Celgene, Genentech/Roche, Pfizer, Merck, and Eli Lilly.
A version of this article first appeared on Medscape.com.
It’s a “champagne problem” many of us have encountered over the past few years in the clinic.
A patient with advanced non–small cell lung cancer (NSCLC) is fortunate enough to continue to do well for 2 years on ongoing pembrolizumab or perhaps pemetrexed and pembrolizumab as maintenance therapy. The latest CT shows a residual but far smaller primary tumor than what she started with.
In this instance, you may be considering stopping treatment but are concerned about doing so with evidence of disease still present.
Clinical trials of immunotherapy or chemoimmunotherapy have generally terminated treatment in nonprogressing patients after 2 years. We also know that some patients in early trials of immunotherapy stopped treatment after a fixed period of 1 or 2 years and continued to show no evidence of progression many years later.
The reason some patients experience this kind of success: Unlike the mechanism of action of conventional chemotherapy or targeted therapies, where ongoing treatment would be important to continue to exert an inhibitory effect, the active substrate of immunotherapy is the patient’s immune system, which can potentially have a self-sustaining efficacy beyond the stimulatory effect of the checkpoint inhibitor.
One trial directly addressed this question of stopping vs. continuing treatment in patients on immunotherapy. The CheckMate 153 trial, published in 2020, randomly assigned 252 previously treated patients who hadn’t demonstrated progression after 1 year on nivolumab to either discontinue nivolumab or continue nivolumab on an ongoing basis. The results were strongly in favor of ongoing therapy. Both progression-free survival (PFS) and overall survival (OS) were significantly longer in patients who continued therapy: PFS of 24.7 months vs. 9.4 months and OS not reached vs. 32.5 months.
This finding is important, but there’s an important caveat. The study population included many heavily pretreated patients, but, in practice, immunotherapy has generally moved into the first-line setting, where we see dramatic responses in a significant subset of patients.
Even more recent data are emerging that may help us evaluate who will do well off therapy and who should continue treatment.
We now have a growing collection of long-term data on patients who are more likely to have good outcomes with immunotherapy, specifically those with high tumor programmed death-ligand 1 (PD-L1) expression (≥ 50%), from the KEYNOTE-024 trial. In this study, 39 of 151 (25.8%) patients assigned to pembrolizumab completed the planned maximum of 2 years of treatment, among whom 82.1% achieved an objective response; but, only 10% (4 patients) achieved a complete response. The proportion of patients without progression and remaining off therapy wasn’t reported, but the OS rate 3 years after completing treatment was 81.4%.
In addition, restarting immunotherapy after discontinuing appears to be a moderately effective strategy. In the KEYNOTE-024 trial, 12 patients received a second course of pembrolizumab because of disease progression a median of 15.2 months after discontinuing pembrolizumab. In this small cohort, eight of these patients (66.7%) were alive at the data cutoff, and six (50%) achieved stable disease.
Recently, we received additional insight in the follow-up from two chemoimmunotherapy trials that have most shaped my practice for patients with advanced NSCLC and any level of PD-L1 expression. These are the KEYNOTE-189 trial of platinum-pemetrexed with pembrolizumab vs. placebo in those with nonsquamous NSCLC, and the KEYNOTE-407 trial of carboplatin-taxane with pembrolizumab vs. placebo in patients with advanced squamous NSCLC. The National Comprehensive Cancer Network has designated each as a “preferred regimen” for patients with advanced NSCLC.
Both regimens have demonstrated sustained efficacy benefits with prolonged follow-up, including significantly superior objective response rate, PFS, and OS with the addition of pembrolizumab. These findings merely cemented the role of these regimens in our practice, but the trials also reported on the cohort of patients who completed 35 cycles of treatment over 2 years then discontinued therapy. In both, the majority of patients showed an objective response (86% in KEYNOTE-189 and 90% in KEYNOTE-407), with most patients alive at 3 years after 2 years of treatment (71.9% in KEYNOTE-189 and 69.5% in KEYNOTE-407). In addition, the proportion of patients alive without disease progression or subsequent therapy was notable – 40.4% in KEYNOTE-189 and 43.6% KEYNOTE-407.
How should we interpret these data for the patient who is in the exam room with us?
The short answer is that we don’t know. I see this as a half-empty, half-full conundrum.
I’m disappointed that more patients who responded for 2 years will experience disease progression in the 1-3 years that follow. This signals that their immune systems have not perpetuated their initial response over the long-term. But these patients may have demonstrated disease progression even if they had continued therapy.
We also know that some patients can be rechallenged and will respond again. Some of these patients will show stable disease, whereas others will progress with repeat treatment. I would love to be able to better predict which patients are destined to do well without treatment vs. those who benefit from treatment beyond 2 years.
Might the level of PD-L1 expression tell us? Can PET imaging discriminate those with residual hypermetabolism who may need continued treatment from those with no residual uptake who could be spared it? Would serial measurement of circulating tumor DNA (ctDNA) in responding patients identify when they have achieved a point of diminishing returns, potentially indicating that some can safely discontinue treatment after 2 years, whereas others need to continue to suppress on prolonged maintenance therapy?
These questions have yet to be studied systematically. In the meantime, I take an individualized approach with my patients facing this decision. Some have experienced escalating arthralgias and myalgias, cost concerns, or other issues related to immunotherapy that may dissuade us from continuing treatment. But several others have been grateful to continue with their treatment, hesitant to do anything that could change the path of their disease.
In my patients who tolerate therapy well, I’m more worried about potential undertreatment than overtreatment. I tend to favor having my patients continue therapy in the absence of problematic toxicity or practical challenges. There is certainly room for debate here while we await data to better guide these decisions. How do you approach these patients?
Dr. West is Clinical Associate Professor, Department of Medical Oncology, City of Hope Comprehensive Cancer Care, Duarte, Calif. He reported conflicts of interest with Ariad/Takeda, Bristol-Myers Squibb, Boehringer Ingelheim, Spectrum, AstraZeneca, Celgene, Genentech/Roche, Pfizer, Merck, and Eli Lilly.
A version of this article first appeared on Medscape.com.
It’s a “champagne problem” many of us have encountered over the past few years in the clinic.
A patient with advanced non–small cell lung cancer (NSCLC) is fortunate enough to continue to do well for 2 years on ongoing pembrolizumab or perhaps pemetrexed and pembrolizumab as maintenance therapy. The latest CT shows a residual but far smaller primary tumor than what she started with.
In this instance, you may be considering stopping treatment but are concerned about doing so with evidence of disease still present.
Clinical trials of immunotherapy or chemoimmunotherapy have generally terminated treatment in nonprogressing patients after 2 years. We also know that some patients in early trials of immunotherapy stopped treatment after a fixed period of 1 or 2 years and continued to show no evidence of progression many years later.
The reason some patients experience this kind of success: Unlike the mechanism of action of conventional chemotherapy or targeted therapies, where ongoing treatment would be important to continue to exert an inhibitory effect, the active substrate of immunotherapy is the patient’s immune system, which can potentially have a self-sustaining efficacy beyond the stimulatory effect of the checkpoint inhibitor.
One trial directly addressed this question of stopping vs. continuing treatment in patients on immunotherapy. The CheckMate 153 trial, published in 2020, randomly assigned 252 previously treated patients who hadn’t demonstrated progression after 1 year on nivolumab to either discontinue nivolumab or continue nivolumab on an ongoing basis. The results were strongly in favor of ongoing therapy. Both progression-free survival (PFS) and overall survival (OS) were significantly longer in patients who continued therapy: PFS of 24.7 months vs. 9.4 months and OS not reached vs. 32.5 months.
This finding is important, but there’s an important caveat. The study population included many heavily pretreated patients, but, in practice, immunotherapy has generally moved into the first-line setting, where we see dramatic responses in a significant subset of patients.
Even more recent data are emerging that may help us evaluate who will do well off therapy and who should continue treatment.
We now have a growing collection of long-term data on patients who are more likely to have good outcomes with immunotherapy, specifically those with high tumor programmed death-ligand 1 (PD-L1) expression (≥ 50%), from the KEYNOTE-024 trial. In this study, 39 of 151 (25.8%) patients assigned to pembrolizumab completed the planned maximum of 2 years of treatment, among whom 82.1% achieved an objective response; but, only 10% (4 patients) achieved a complete response. The proportion of patients without progression and remaining off therapy wasn’t reported, but the OS rate 3 years after completing treatment was 81.4%.
In addition, restarting immunotherapy after discontinuing appears to be a moderately effective strategy. In the KEYNOTE-024 trial, 12 patients received a second course of pembrolizumab because of disease progression a median of 15.2 months after discontinuing pembrolizumab. In this small cohort, eight of these patients (66.7%) were alive at the data cutoff, and six (50%) achieved stable disease.
Recently, we received additional insight in the follow-up from two chemoimmunotherapy trials that have most shaped my practice for patients with advanced NSCLC and any level of PD-L1 expression. These are the KEYNOTE-189 trial of platinum-pemetrexed with pembrolizumab vs. placebo in those with nonsquamous NSCLC, and the KEYNOTE-407 trial of carboplatin-taxane with pembrolizumab vs. placebo in patients with advanced squamous NSCLC. The National Comprehensive Cancer Network has designated each as a “preferred regimen” for patients with advanced NSCLC.
Both regimens have demonstrated sustained efficacy benefits with prolonged follow-up, including significantly superior objective response rate, PFS, and OS with the addition of pembrolizumab. These findings merely cemented the role of these regimens in our practice, but the trials also reported on the cohort of patients who completed 35 cycles of treatment over 2 years then discontinued therapy. In both, the majority of patients showed an objective response (86% in KEYNOTE-189 and 90% in KEYNOTE-407), with most patients alive at 3 years after 2 years of treatment (71.9% in KEYNOTE-189 and 69.5% in KEYNOTE-407). In addition, the proportion of patients alive without disease progression or subsequent therapy was notable – 40.4% in KEYNOTE-189 and 43.6% KEYNOTE-407.
How should we interpret these data for the patient who is in the exam room with us?
The short answer is that we don’t know. I see this as a half-empty, half-full conundrum.
I’m disappointed that more patients who responded for 2 years will experience disease progression in the 1-3 years that follow. This signals that their immune systems have not perpetuated their initial response over the long-term. But these patients may have demonstrated disease progression even if they had continued therapy.
We also know that some patients can be rechallenged and will respond again. Some of these patients will show stable disease, whereas others will progress with repeat treatment. I would love to be able to better predict which patients are destined to do well without treatment vs. those who benefit from treatment beyond 2 years.
Might the level of PD-L1 expression tell us? Can PET imaging discriminate those with residual hypermetabolism who may need continued treatment from those with no residual uptake who could be spared it? Would serial measurement of circulating tumor DNA (ctDNA) in responding patients identify when they have achieved a point of diminishing returns, potentially indicating that some can safely discontinue treatment after 2 years, whereas others need to continue to suppress on prolonged maintenance therapy?
These questions have yet to be studied systematically. In the meantime, I take an individualized approach with my patients facing this decision. Some have experienced escalating arthralgias and myalgias, cost concerns, or other issues related to immunotherapy that may dissuade us from continuing treatment. But several others have been grateful to continue with their treatment, hesitant to do anything that could change the path of their disease.
In my patients who tolerate therapy well, I’m more worried about potential undertreatment than overtreatment. I tend to favor having my patients continue therapy in the absence of problematic toxicity or practical challenges. There is certainly room for debate here while we await data to better guide these decisions. How do you approach these patients?
Dr. West is Clinical Associate Professor, Department of Medical Oncology, City of Hope Comprehensive Cancer Care, Duarte, Calif. He reported conflicts of interest with Ariad/Takeda, Bristol-Myers Squibb, Boehringer Ingelheim, Spectrum, AstraZeneca, Celgene, Genentech/Roche, Pfizer, Merck, and Eli Lilly.
A version of this article first appeared on Medscape.com.
Close to Me: CBOC Infusion Program
Background
Currently, within the Veterans Affairs Healthcare System, anticancer therapy infusions and injections are primarily offered at VA medical centers (VAMCs) in urban areas. The time and out-of-pocket expenses related to travel present a barrier to care, often leading veterans to seek cancer care in the community. The Minneapolis VA developed a “Remote Infusion” program that deploys a chemotherapy certified RN to administer anticancer and supportive therapies at surrounding Community Based Outpatient Clinics (CBOCs). The program expanded in October 2021, and since, they have provided 259 infusions and injections to 145 veterans at 16 CBOCs. These efforts have saved at least 20,000 miles of travel for veterans in the Minneapolis/ St. Cloud catchment area. Building off the success of this program, the National Oncology Program Integrated Project Team has developed the “Close to Me” CBOC Infusion Program.
Methods
The “Close to Me” CBOC Infusion Program utilizes VAMCs to compound treatments. Then a chemotherapy certified RN is deployed to the surrounding CBOCs to administer treatments. Veterans eligible for this program must have received and tolerated their first dose of treatment at a VAMC. Medications included in this program have low risk of reaction, short infusion time, and at least 8 hours of drug stability. Treatments include immune check point inhibitors, leuprolide, octreotide, IV fluids, and iron infusions. Additional treatments continue to be evaluated and added. Telehealth modalities are utilized for patient visits with their oncology provider for treatment clearance. An implementation toolkit, including a library of standard operating procedures, note templates, and staffing models, has been developed for VAMCs interested in replicating this program.
Results
The Pittsburgh VAMC launched the first “Close to Me” CBOC Infusion Program June 8, 2022.
Conclusions
The “Close to Me” CBOC infusion program optimizes current VA infrastructure and processes to expand access to the world class oncology care VA provides by reducing travel burden for the veterans. Additional areas of novel solutions under development to provide expanded access points to anticancer therapies include mobile infusion units, mobile compounding units, and home administration.
Background
Currently, within the Veterans Affairs Healthcare System, anticancer therapy infusions and injections are primarily offered at VA medical centers (VAMCs) in urban areas. The time and out-of-pocket expenses related to travel present a barrier to care, often leading veterans to seek cancer care in the community. The Minneapolis VA developed a “Remote Infusion” program that deploys a chemotherapy certified RN to administer anticancer and supportive therapies at surrounding Community Based Outpatient Clinics (CBOCs). The program expanded in October 2021, and since, they have provided 259 infusions and injections to 145 veterans at 16 CBOCs. These efforts have saved at least 20,000 miles of travel for veterans in the Minneapolis/ St. Cloud catchment area. Building off the success of this program, the National Oncology Program Integrated Project Team has developed the “Close to Me” CBOC Infusion Program.
Methods
The “Close to Me” CBOC Infusion Program utilizes VAMCs to compound treatments. Then a chemotherapy certified RN is deployed to the surrounding CBOCs to administer treatments. Veterans eligible for this program must have received and tolerated their first dose of treatment at a VAMC. Medications included in this program have low risk of reaction, short infusion time, and at least 8 hours of drug stability. Treatments include immune check point inhibitors, leuprolide, octreotide, IV fluids, and iron infusions. Additional treatments continue to be evaluated and added. Telehealth modalities are utilized for patient visits with their oncology provider for treatment clearance. An implementation toolkit, including a library of standard operating procedures, note templates, and staffing models, has been developed for VAMCs interested in replicating this program.
Results
The Pittsburgh VAMC launched the first “Close to Me” CBOC Infusion Program June 8, 2022.
Conclusions
The “Close to Me” CBOC infusion program optimizes current VA infrastructure and processes to expand access to the world class oncology care VA provides by reducing travel burden for the veterans. Additional areas of novel solutions under development to provide expanded access points to anticancer therapies include mobile infusion units, mobile compounding units, and home administration.
Background
Currently, within the Veterans Affairs Healthcare System, anticancer therapy infusions and injections are primarily offered at VA medical centers (VAMCs) in urban areas. The time and out-of-pocket expenses related to travel present a barrier to care, often leading veterans to seek cancer care in the community. The Minneapolis VA developed a “Remote Infusion” program that deploys a chemotherapy certified RN to administer anticancer and supportive therapies at surrounding Community Based Outpatient Clinics (CBOCs). The program expanded in October 2021, and since, they have provided 259 infusions and injections to 145 veterans at 16 CBOCs. These efforts have saved at least 20,000 miles of travel for veterans in the Minneapolis/ St. Cloud catchment area. Building off the success of this program, the National Oncology Program Integrated Project Team has developed the “Close to Me” CBOC Infusion Program.
Methods
The “Close to Me” CBOC Infusion Program utilizes VAMCs to compound treatments. Then a chemotherapy certified RN is deployed to the surrounding CBOCs to administer treatments. Veterans eligible for this program must have received and tolerated their first dose of treatment at a VAMC. Medications included in this program have low risk of reaction, short infusion time, and at least 8 hours of drug stability. Treatments include immune check point inhibitors, leuprolide, octreotide, IV fluids, and iron infusions. Additional treatments continue to be evaluated and added. Telehealth modalities are utilized for patient visits with their oncology provider for treatment clearance. An implementation toolkit, including a library of standard operating procedures, note templates, and staffing models, has been developed for VAMCs interested in replicating this program.
Results
The Pittsburgh VAMC launched the first “Close to Me” CBOC Infusion Program June 8, 2022.
Conclusions
The “Close to Me” CBOC infusion program optimizes current VA infrastructure and processes to expand access to the world class oncology care VA provides by reducing travel burden for the veterans. Additional areas of novel solutions under development to provide expanded access points to anticancer therapies include mobile infusion units, mobile compounding units, and home administration.
Acetaminophen linked to diminished response to immunotherapy in cancer
The team found a strong association between the use of acetaminophen and a decreased response to immune checkpoint inhibitors in a study of three clinical cohorts involving more than 600 patients with advanced cancer.
Patients who took acetaminophen at the start of immunotherapy – with acetaminophen exposure confirmed by plasma testing – were found to have worse overall survival and progression-free survival than patients who did not take the analgesic. Multivariate analysis confirmed the association independent of other prognostic factors. “It is unlikely that our data are the result of bias or unmeasured confounding,” the authors comment.
The findings “present a compelling case for caution” in using acetaminophen in patients with cancer who are receiving immune checkpoint blockers, senior investigator Antoine Italiano, MD, PhD, a medical oncologist at the University of Bordeaux (France), and colleagues concluded.
The study was presented at the annual meeting of the American Society of Clinical Oncology and published simultaneously in Annals of Oncology.
“Patients with advanced cancer taking [acetaminophen] during immunotherapy experience worse clinical outcomes, which suggests that [acetaminophen] decreases T cell–mediated antitumor immunity,” the authors comment.
They also report bench research and blood studies in four healthy volunteers, which showed an up-regulation of immunosuppressive regulatory T cells (Tregs) with acetaminophen, and other findings that together suggest that acetaminophen undermines the antitumor immune processes by which checkpoint inhibitors work.
Reconsider acetaminophen pretreatment
After hearing Dr. Italiano present the results at the meeting, a Polish oncologist in the audience said he was concerned that his clinic premedicates with acetaminophen before immune checkpoint blockade and wanted to know if they should stop doing it.
“I don’t think inducing Tregs ... in cancer patients is a good approach. I do a lot of clinical trials,” and “I do not understand why in several cases sponsors required mandatory premedication with acetaminophen. I think ... we should reconsider this approach,” Dr. Italiano said.
There’s precedence for the findings. Acetaminophen – also known as paracetamol – has been shown in some studies to limit immune cell proliferation, T-cell–dependent antibody response, and viral clearance, among other things. After a randomized trial showing blunted responses to vaccines in individuals who were taking acetaminophen, the World Health Organization recommended in 2015 against concurrent use of acetaminophen with vaccines.
Steroids, antibiotics, and proton pump inhibitors have also recently been shown to worsen outcomes with pembrolizumab, noted invited discussant, Margaret Gatti-Mays, MD, a medical oncologist at Ohio State University, Columbus.
“We are starting to understand that ... commonly used medications may have a larger impact on the efficacy and toxicity of immune checkpoint blockade than historically seen with chemotherapy,” she said.
However, she expressed some uncertainty over the French findings, as she was concerned that even the multivariate analysis didn’t completely rule out that acetaminophen users had worse disease to begin with and so would be expected to have worse outcomes.
She was also unsure of how much acetaminophen is too much.
Acetaminophen has a half-life of around 3 hours or less, where the immune checkpoint inhibitors have a half-life of around 20 days or more.
Given that, Dr. Gatti-Mays wondered whether “a single dose of acetaminophen [is] enough to derail the benefit of checkpoint inhibition? Does exposure need to be continuous?”
She allowed that acetaminophen use may turn out to be one more of the many patient-level factors emerging lately – such as chronic stress, diet, body flora, and physiological age, among others – that might help explain why checkpoint inhibition works in only about 20% of eligible patients with cancer.
Study details
Dr. Italiano and his team analyzed plasma samples from 297 participants in the CheckMate 025 trial of nivolumab for renal cancer; 34 participants in the BIP study into actionable molecular alterations in cancer; and 297 participants in the PREMIS immune-related adverse events study. The patients in these last two studies had a variety of cancers and were taking various agents.
All 628 patients were on checkpoint inhibitors. The investigators divided them according to who had acetaminophen or its metabolite acetaminophen glucuronide in their plasma when they started checkpoint inhibition and those who did not.
In CheckMate 025, overall survival was significantly worse among participants who had detectable acetaminophen or its metabolite in plasma (hazard ratio, 0.67; P = .004).
None of the acetaminophen-positive participants in the BIP study responded to checkpoint blockade, compared with almost 30% of those who were negative. Acetaminophen-positive participants also trended toward worse progression-free survival (median, 1.87 vs. 4.72 months) and overall survival (median, 7.87 vs. 16.56 months).
In PREMIS, progression-free survival was a median of 2.63 months in the acetaminophen group versus 5.03 months in negative participants (P = .009); median overall survival was 8.43 months versus 14.93 months, respectively (P < .0001).
A multivariate analysis was performed in PREMIS. Acetaminophen exposure was associated with both progression-free survival (hazard ratio, 1.43; P =.015) and overall survival (HR, 1.78; P =.006) independently of performance status, liver metastases, bone metastases, number of metastases sites, tumor type, number of previous lines of treatment, steroid/antibiotic use, lactate dehydrogenase levels, and other factors.
There was no funding for the work. Dr. Italiano is a consultant for AstraZeneca, Bayer, Chugai, Deciphera, Merck, Parthenon, Roche, and Springworks, He also has grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck, MSD, Novartis, Pharmamar, and Roche. Two authors work for Explicyte and one works for Amgen. Dr. Gatti-Mays is a consultant for Seattle Genetics.
A version of this article first appeared on Medscape.com.
The team found a strong association between the use of acetaminophen and a decreased response to immune checkpoint inhibitors in a study of three clinical cohorts involving more than 600 patients with advanced cancer.
Patients who took acetaminophen at the start of immunotherapy – with acetaminophen exposure confirmed by plasma testing – were found to have worse overall survival and progression-free survival than patients who did not take the analgesic. Multivariate analysis confirmed the association independent of other prognostic factors. “It is unlikely that our data are the result of bias or unmeasured confounding,” the authors comment.
The findings “present a compelling case for caution” in using acetaminophen in patients with cancer who are receiving immune checkpoint blockers, senior investigator Antoine Italiano, MD, PhD, a medical oncologist at the University of Bordeaux (France), and colleagues concluded.
The study was presented at the annual meeting of the American Society of Clinical Oncology and published simultaneously in Annals of Oncology.
“Patients with advanced cancer taking [acetaminophen] during immunotherapy experience worse clinical outcomes, which suggests that [acetaminophen] decreases T cell–mediated antitumor immunity,” the authors comment.
They also report bench research and blood studies in four healthy volunteers, which showed an up-regulation of immunosuppressive regulatory T cells (Tregs) with acetaminophen, and other findings that together suggest that acetaminophen undermines the antitumor immune processes by which checkpoint inhibitors work.
Reconsider acetaminophen pretreatment
After hearing Dr. Italiano present the results at the meeting, a Polish oncologist in the audience said he was concerned that his clinic premedicates with acetaminophen before immune checkpoint blockade and wanted to know if they should stop doing it.
“I don’t think inducing Tregs ... in cancer patients is a good approach. I do a lot of clinical trials,” and “I do not understand why in several cases sponsors required mandatory premedication with acetaminophen. I think ... we should reconsider this approach,” Dr. Italiano said.
There’s precedence for the findings. Acetaminophen – also known as paracetamol – has been shown in some studies to limit immune cell proliferation, T-cell–dependent antibody response, and viral clearance, among other things. After a randomized trial showing blunted responses to vaccines in individuals who were taking acetaminophen, the World Health Organization recommended in 2015 against concurrent use of acetaminophen with vaccines.
Steroids, antibiotics, and proton pump inhibitors have also recently been shown to worsen outcomes with pembrolizumab, noted invited discussant, Margaret Gatti-Mays, MD, a medical oncologist at Ohio State University, Columbus.
“We are starting to understand that ... commonly used medications may have a larger impact on the efficacy and toxicity of immune checkpoint blockade than historically seen with chemotherapy,” she said.
However, she expressed some uncertainty over the French findings, as she was concerned that even the multivariate analysis didn’t completely rule out that acetaminophen users had worse disease to begin with and so would be expected to have worse outcomes.
She was also unsure of how much acetaminophen is too much.
Acetaminophen has a half-life of around 3 hours or less, where the immune checkpoint inhibitors have a half-life of around 20 days or more.
Given that, Dr. Gatti-Mays wondered whether “a single dose of acetaminophen [is] enough to derail the benefit of checkpoint inhibition? Does exposure need to be continuous?”
She allowed that acetaminophen use may turn out to be one more of the many patient-level factors emerging lately – such as chronic stress, diet, body flora, and physiological age, among others – that might help explain why checkpoint inhibition works in only about 20% of eligible patients with cancer.
Study details
Dr. Italiano and his team analyzed plasma samples from 297 participants in the CheckMate 025 trial of nivolumab for renal cancer; 34 participants in the BIP study into actionable molecular alterations in cancer; and 297 participants in the PREMIS immune-related adverse events study. The patients in these last two studies had a variety of cancers and were taking various agents.
All 628 patients were on checkpoint inhibitors. The investigators divided them according to who had acetaminophen or its metabolite acetaminophen glucuronide in their plasma when they started checkpoint inhibition and those who did not.
In CheckMate 025, overall survival was significantly worse among participants who had detectable acetaminophen or its metabolite in plasma (hazard ratio, 0.67; P = .004).
None of the acetaminophen-positive participants in the BIP study responded to checkpoint blockade, compared with almost 30% of those who were negative. Acetaminophen-positive participants also trended toward worse progression-free survival (median, 1.87 vs. 4.72 months) and overall survival (median, 7.87 vs. 16.56 months).
In PREMIS, progression-free survival was a median of 2.63 months in the acetaminophen group versus 5.03 months in negative participants (P = .009); median overall survival was 8.43 months versus 14.93 months, respectively (P < .0001).
A multivariate analysis was performed in PREMIS. Acetaminophen exposure was associated with both progression-free survival (hazard ratio, 1.43; P =.015) and overall survival (HR, 1.78; P =.006) independently of performance status, liver metastases, bone metastases, number of metastases sites, tumor type, number of previous lines of treatment, steroid/antibiotic use, lactate dehydrogenase levels, and other factors.
There was no funding for the work. Dr. Italiano is a consultant for AstraZeneca, Bayer, Chugai, Deciphera, Merck, Parthenon, Roche, and Springworks, He also has grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck, MSD, Novartis, Pharmamar, and Roche. Two authors work for Explicyte and one works for Amgen. Dr. Gatti-Mays is a consultant for Seattle Genetics.
A version of this article first appeared on Medscape.com.
The team found a strong association between the use of acetaminophen and a decreased response to immune checkpoint inhibitors in a study of three clinical cohorts involving more than 600 patients with advanced cancer.
Patients who took acetaminophen at the start of immunotherapy – with acetaminophen exposure confirmed by plasma testing – were found to have worse overall survival and progression-free survival than patients who did not take the analgesic. Multivariate analysis confirmed the association independent of other prognostic factors. “It is unlikely that our data are the result of bias or unmeasured confounding,” the authors comment.
The findings “present a compelling case for caution” in using acetaminophen in patients with cancer who are receiving immune checkpoint blockers, senior investigator Antoine Italiano, MD, PhD, a medical oncologist at the University of Bordeaux (France), and colleagues concluded.
The study was presented at the annual meeting of the American Society of Clinical Oncology and published simultaneously in Annals of Oncology.
“Patients with advanced cancer taking [acetaminophen] during immunotherapy experience worse clinical outcomes, which suggests that [acetaminophen] decreases T cell–mediated antitumor immunity,” the authors comment.
They also report bench research and blood studies in four healthy volunteers, which showed an up-regulation of immunosuppressive regulatory T cells (Tregs) with acetaminophen, and other findings that together suggest that acetaminophen undermines the antitumor immune processes by which checkpoint inhibitors work.
Reconsider acetaminophen pretreatment
After hearing Dr. Italiano present the results at the meeting, a Polish oncologist in the audience said he was concerned that his clinic premedicates with acetaminophen before immune checkpoint blockade and wanted to know if they should stop doing it.
“I don’t think inducing Tregs ... in cancer patients is a good approach. I do a lot of clinical trials,” and “I do not understand why in several cases sponsors required mandatory premedication with acetaminophen. I think ... we should reconsider this approach,” Dr. Italiano said.
There’s precedence for the findings. Acetaminophen – also known as paracetamol – has been shown in some studies to limit immune cell proliferation, T-cell–dependent antibody response, and viral clearance, among other things. After a randomized trial showing blunted responses to vaccines in individuals who were taking acetaminophen, the World Health Organization recommended in 2015 against concurrent use of acetaminophen with vaccines.
Steroids, antibiotics, and proton pump inhibitors have also recently been shown to worsen outcomes with pembrolizumab, noted invited discussant, Margaret Gatti-Mays, MD, a medical oncologist at Ohio State University, Columbus.
“We are starting to understand that ... commonly used medications may have a larger impact on the efficacy and toxicity of immune checkpoint blockade than historically seen with chemotherapy,” she said.
However, she expressed some uncertainty over the French findings, as she was concerned that even the multivariate analysis didn’t completely rule out that acetaminophen users had worse disease to begin with and so would be expected to have worse outcomes.
She was also unsure of how much acetaminophen is too much.
Acetaminophen has a half-life of around 3 hours or less, where the immune checkpoint inhibitors have a half-life of around 20 days or more.
Given that, Dr. Gatti-Mays wondered whether “a single dose of acetaminophen [is] enough to derail the benefit of checkpoint inhibition? Does exposure need to be continuous?”
She allowed that acetaminophen use may turn out to be one more of the many patient-level factors emerging lately – such as chronic stress, diet, body flora, and physiological age, among others – that might help explain why checkpoint inhibition works in only about 20% of eligible patients with cancer.
Study details
Dr. Italiano and his team analyzed plasma samples from 297 participants in the CheckMate 025 trial of nivolumab for renal cancer; 34 participants in the BIP study into actionable molecular alterations in cancer; and 297 participants in the PREMIS immune-related adverse events study. The patients in these last two studies had a variety of cancers and were taking various agents.
All 628 patients were on checkpoint inhibitors. The investigators divided them according to who had acetaminophen or its metabolite acetaminophen glucuronide in their plasma when they started checkpoint inhibition and those who did not.
In CheckMate 025, overall survival was significantly worse among participants who had detectable acetaminophen or its metabolite in plasma (hazard ratio, 0.67; P = .004).
None of the acetaminophen-positive participants in the BIP study responded to checkpoint blockade, compared with almost 30% of those who were negative. Acetaminophen-positive participants also trended toward worse progression-free survival (median, 1.87 vs. 4.72 months) and overall survival (median, 7.87 vs. 16.56 months).
In PREMIS, progression-free survival was a median of 2.63 months in the acetaminophen group versus 5.03 months in negative participants (P = .009); median overall survival was 8.43 months versus 14.93 months, respectively (P < .0001).
A multivariate analysis was performed in PREMIS. Acetaminophen exposure was associated with both progression-free survival (hazard ratio, 1.43; P =.015) and overall survival (HR, 1.78; P =.006) independently of performance status, liver metastases, bone metastases, number of metastases sites, tumor type, number of previous lines of treatment, steroid/antibiotic use, lactate dehydrogenase levels, and other factors.
There was no funding for the work. Dr. Italiano is a consultant for AstraZeneca, Bayer, Chugai, Deciphera, Merck, Parthenon, Roche, and Springworks, He also has grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck, MSD, Novartis, Pharmamar, and Roche. Two authors work for Explicyte and one works for Amgen. Dr. Gatti-Mays is a consultant for Seattle Genetics.
A version of this article first appeared on Medscape.com.
FROM ASCO 2022