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Up-front pembro plus chemo boost survival in cervical cancer
This is based on final overall survival results from the phase 3, randomized KEYNOTE-826 study, which showed that adding immunotherapy resulted in a 40% reduction in risk of death, compared with chemotherapy alone, for women with advanced cervical cancers expressing programmed death–ligand 1 (PD-L1).
“At this protocol-specified final analysis of KEYNOTE-826, the addition of immune therapy to chemotherapy with or without the antiangiogenic bevacizumab showed substantial and clinically meaningful improvement in survival,” said lead author Bradley J. Monk, MD, from HonorHealth Research Institute, Phoenix.
He was speaking at a media briefing held prior to the annual meeting of the American Society of Clinical Oncology, where the results were presented.
“The results of this study solidify the addition of pembrolizumab to chemotherapy with or without bevacizumab in people with persistent, recurrent, or metastatic cervical cancer as the frontline standard of care for this disease. Survival significantly improved with this approach, regardless of PD-L1 expression, further supporting its use for all patients in this population,” commented ASCO expert Merry Jennifer Markham, MD, from the University of Florida, Gainesville.
At the briefing, Dr. Monk raised the possibility that adding immunotherapy to the standard of care could offer a chance for cure for some patients with advanced or recurrent cervical cancer.
“Is it possible to cure a widely metastatic cancer, a solid tumor? And I think it probably is,” he said. “There’s a tail to this [survival] curve, and I can’t believe that in my lifetime we as a group, as a team, have sort of figured out – and it’s not enough – that we can actually cure some patients, and if not maybe cure, have them at least live a long time, so it’s exciting.”
Briefing comoderater Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, agreed that the survival benefit “is exciting to see, and in my long career as a breast medical oncologist, I’m pretty sure we cure some metastatic breast cancer. We definitely had patients who lived out their normal life span and died of something else after decades.
“But the definition of cure, sadly, in these situations is that you die of something else without evidence of disease, so we certainly need to do better here and be better able to use the word ‘cure’ in the metastatic setting,” she added.
Promising start
Since 2014, the standard of care for treating patients with recurrent, persistent, or metastatic cervical cancer has been chemotherapy with a platinum compound, paclitaxel, and bevacizumab, based on the results of the GOG 240 study.
Immunotherapy with PD-1 inhibitors had previously shown efficacy as monotherapy in second- or later-line therapy for women with cervical cancer, but KEYNOTE 826 was the first study to show a benefit to promoting immunotherapy to the front ranks.
In the first interim analysis of the trial, reported at the 2021 annual meeting of the European Society for Medical Oncology, after a median follow-up of 22 months, the combination of pembrolizumab and chemotherapy demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy plus placebo in a biomarker-selected population, which consisted of patients with a combined positive score (CPS) for PD-L1 of 1 or greater.
Pembrolizumab had no apparent efficacy in patients whose tumors did not have detectable PD-L1, however.
Latest results
Now the investigators are reporting the final analysis, conducted after a median follow-up of 39.1 months. The results are those for all comers (308 randomly assigned to receive pembrolizumab plus chemotherapy, and 309 assigned to receive chemotherapy plus placebo), as well as for the biomarker-selected population (consisting of all patients with PD-L1 CPS of 1 or greater) and for the subpopulation of patients with PD-L1 CPS of 10 or greater.
In the all-comers population, the median OS was 26.4 months for patients who received pembrolizumab, compared with 16.8 months for those who received placebo. The 24-month OS rates were 52.1% and 38.7%, respectively. The difference translated into a hazard ratio for death with pembrolizumab of 0.63 (P < .0001).
In the biomarker-selected population (273 assigned to pembrolizumab and 275 assigned to placebo), the respective median OS was 28.6 months versus 16.6 months, with 24-month OS rates of 53.5% versus 39.4%, which translates into an HR for death with pembrolizumab of 0.60 (P < .0001).
Not surprisingly, the best responses to the addition of the PD-1 inhibitor were seen among patients with a PD-L1 CPS of 10 or greater (158 assigned to pembrolizumab and 159 assigned to placebo). In this subgroup, the median OS was 29.6 months with the immune checkpoint inhibitor added to chemotherapy versus 17.4 months for chemotherapy plus placebo. The respective 24-month OS rates were 54.4% and 42.5%, and the HR for overall survival favoring pembrolizumab was 0.58 (P < .0001).
Median PFS 12-month PFS rates also favored pembrolizumab in both the total patient population and the biomarker-selected groups, with median PFS of approximately 10.4 months with pembrolizumab versus approximately 8.2 months with placebo.
The safety profile was manageable, with adverse events as expected from the safety profiles of the individual drugs in the combined regimen. No new safety signals have been seen since the interim analysis, Dr. Monk said.
Regimen details
Patients were randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy, with bevacizumab added at the investigator’s discretion. Approximately two-thirds of patients in each study arm received bevacizumab.
The dual primary endpoints of PFS and OS were each tested sequentially in patients with a PD-L1 CPS of 1 or greater in both the intention-to-treat or “all-comers” population and in patients with a PD-L1 CPS of 10 or greater.
Patient characteristics were generally well balanced between the treatment groups, except that a slightly higher proportion of patients in the pembrolizumab had tumors of squamous cell histology, compared with the placebo group (76.3% vs. 68.3%).
KEYNOTE-826 was funded by Merck. Dr. Monk has received honoraria and has participated in consulting/advising and speaker’s bureau activity with Merck and other companies. Dr. Gralow has had a consulting or advisory role with Genentech and Roche. Dr. Markham has had a consulting/advisory role for GlaxoSmithKline and has received institutional research funding from Merck and other companies.
A version of this article first appeared on Medscape.com.
This is based on final overall survival results from the phase 3, randomized KEYNOTE-826 study, which showed that adding immunotherapy resulted in a 40% reduction in risk of death, compared with chemotherapy alone, for women with advanced cervical cancers expressing programmed death–ligand 1 (PD-L1).
“At this protocol-specified final analysis of KEYNOTE-826, the addition of immune therapy to chemotherapy with or without the antiangiogenic bevacizumab showed substantial and clinically meaningful improvement in survival,” said lead author Bradley J. Monk, MD, from HonorHealth Research Institute, Phoenix.
He was speaking at a media briefing held prior to the annual meeting of the American Society of Clinical Oncology, where the results were presented.
“The results of this study solidify the addition of pembrolizumab to chemotherapy with or without bevacizumab in people with persistent, recurrent, or metastatic cervical cancer as the frontline standard of care for this disease. Survival significantly improved with this approach, regardless of PD-L1 expression, further supporting its use for all patients in this population,” commented ASCO expert Merry Jennifer Markham, MD, from the University of Florida, Gainesville.
At the briefing, Dr. Monk raised the possibility that adding immunotherapy to the standard of care could offer a chance for cure for some patients with advanced or recurrent cervical cancer.
“Is it possible to cure a widely metastatic cancer, a solid tumor? And I think it probably is,” he said. “There’s a tail to this [survival] curve, and I can’t believe that in my lifetime we as a group, as a team, have sort of figured out – and it’s not enough – that we can actually cure some patients, and if not maybe cure, have them at least live a long time, so it’s exciting.”
Briefing comoderater Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, agreed that the survival benefit “is exciting to see, and in my long career as a breast medical oncologist, I’m pretty sure we cure some metastatic breast cancer. We definitely had patients who lived out their normal life span and died of something else after decades.
“But the definition of cure, sadly, in these situations is that you die of something else without evidence of disease, so we certainly need to do better here and be better able to use the word ‘cure’ in the metastatic setting,” she added.
Promising start
Since 2014, the standard of care for treating patients with recurrent, persistent, or metastatic cervical cancer has been chemotherapy with a platinum compound, paclitaxel, and bevacizumab, based on the results of the GOG 240 study.
Immunotherapy with PD-1 inhibitors had previously shown efficacy as monotherapy in second- or later-line therapy for women with cervical cancer, but KEYNOTE 826 was the first study to show a benefit to promoting immunotherapy to the front ranks.
In the first interim analysis of the trial, reported at the 2021 annual meeting of the European Society for Medical Oncology, after a median follow-up of 22 months, the combination of pembrolizumab and chemotherapy demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy plus placebo in a biomarker-selected population, which consisted of patients with a combined positive score (CPS) for PD-L1 of 1 or greater.
Pembrolizumab had no apparent efficacy in patients whose tumors did not have detectable PD-L1, however.
Latest results
Now the investigators are reporting the final analysis, conducted after a median follow-up of 39.1 months. The results are those for all comers (308 randomly assigned to receive pembrolizumab plus chemotherapy, and 309 assigned to receive chemotherapy plus placebo), as well as for the biomarker-selected population (consisting of all patients with PD-L1 CPS of 1 or greater) and for the subpopulation of patients with PD-L1 CPS of 10 or greater.
In the all-comers population, the median OS was 26.4 months for patients who received pembrolizumab, compared with 16.8 months for those who received placebo. The 24-month OS rates were 52.1% and 38.7%, respectively. The difference translated into a hazard ratio for death with pembrolizumab of 0.63 (P < .0001).
In the biomarker-selected population (273 assigned to pembrolizumab and 275 assigned to placebo), the respective median OS was 28.6 months versus 16.6 months, with 24-month OS rates of 53.5% versus 39.4%, which translates into an HR for death with pembrolizumab of 0.60 (P < .0001).
Not surprisingly, the best responses to the addition of the PD-1 inhibitor were seen among patients with a PD-L1 CPS of 10 or greater (158 assigned to pembrolizumab and 159 assigned to placebo). In this subgroup, the median OS was 29.6 months with the immune checkpoint inhibitor added to chemotherapy versus 17.4 months for chemotherapy plus placebo. The respective 24-month OS rates were 54.4% and 42.5%, and the HR for overall survival favoring pembrolizumab was 0.58 (P < .0001).
Median PFS 12-month PFS rates also favored pembrolizumab in both the total patient population and the biomarker-selected groups, with median PFS of approximately 10.4 months with pembrolizumab versus approximately 8.2 months with placebo.
The safety profile was manageable, with adverse events as expected from the safety profiles of the individual drugs in the combined regimen. No new safety signals have been seen since the interim analysis, Dr. Monk said.
Regimen details
Patients were randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy, with bevacizumab added at the investigator’s discretion. Approximately two-thirds of patients in each study arm received bevacizumab.
The dual primary endpoints of PFS and OS were each tested sequentially in patients with a PD-L1 CPS of 1 or greater in both the intention-to-treat or “all-comers” population and in patients with a PD-L1 CPS of 10 or greater.
Patient characteristics were generally well balanced between the treatment groups, except that a slightly higher proportion of patients in the pembrolizumab had tumors of squamous cell histology, compared with the placebo group (76.3% vs. 68.3%).
KEYNOTE-826 was funded by Merck. Dr. Monk has received honoraria and has participated in consulting/advising and speaker’s bureau activity with Merck and other companies. Dr. Gralow has had a consulting or advisory role with Genentech and Roche. Dr. Markham has had a consulting/advisory role for GlaxoSmithKline and has received institutional research funding from Merck and other companies.
A version of this article first appeared on Medscape.com.
This is based on final overall survival results from the phase 3, randomized KEYNOTE-826 study, which showed that adding immunotherapy resulted in a 40% reduction in risk of death, compared with chemotherapy alone, for women with advanced cervical cancers expressing programmed death–ligand 1 (PD-L1).
“At this protocol-specified final analysis of KEYNOTE-826, the addition of immune therapy to chemotherapy with or without the antiangiogenic bevacizumab showed substantial and clinically meaningful improvement in survival,” said lead author Bradley J. Monk, MD, from HonorHealth Research Institute, Phoenix.
He was speaking at a media briefing held prior to the annual meeting of the American Society of Clinical Oncology, where the results were presented.
“The results of this study solidify the addition of pembrolizumab to chemotherapy with or without bevacizumab in people with persistent, recurrent, or metastatic cervical cancer as the frontline standard of care for this disease. Survival significantly improved with this approach, regardless of PD-L1 expression, further supporting its use for all patients in this population,” commented ASCO expert Merry Jennifer Markham, MD, from the University of Florida, Gainesville.
At the briefing, Dr. Monk raised the possibility that adding immunotherapy to the standard of care could offer a chance for cure for some patients with advanced or recurrent cervical cancer.
“Is it possible to cure a widely metastatic cancer, a solid tumor? And I think it probably is,” he said. “There’s a tail to this [survival] curve, and I can’t believe that in my lifetime we as a group, as a team, have sort of figured out – and it’s not enough – that we can actually cure some patients, and if not maybe cure, have them at least live a long time, so it’s exciting.”
Briefing comoderater Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, agreed that the survival benefit “is exciting to see, and in my long career as a breast medical oncologist, I’m pretty sure we cure some metastatic breast cancer. We definitely had patients who lived out their normal life span and died of something else after decades.
“But the definition of cure, sadly, in these situations is that you die of something else without evidence of disease, so we certainly need to do better here and be better able to use the word ‘cure’ in the metastatic setting,” she added.
Promising start
Since 2014, the standard of care for treating patients with recurrent, persistent, or metastatic cervical cancer has been chemotherapy with a platinum compound, paclitaxel, and bevacizumab, based on the results of the GOG 240 study.
Immunotherapy with PD-1 inhibitors had previously shown efficacy as monotherapy in second- or later-line therapy for women with cervical cancer, but KEYNOTE 826 was the first study to show a benefit to promoting immunotherapy to the front ranks.
In the first interim analysis of the trial, reported at the 2021 annual meeting of the European Society for Medical Oncology, after a median follow-up of 22 months, the combination of pembrolizumab and chemotherapy demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy plus placebo in a biomarker-selected population, which consisted of patients with a combined positive score (CPS) for PD-L1 of 1 or greater.
Pembrolizumab had no apparent efficacy in patients whose tumors did not have detectable PD-L1, however.
Latest results
Now the investigators are reporting the final analysis, conducted after a median follow-up of 39.1 months. The results are those for all comers (308 randomly assigned to receive pembrolizumab plus chemotherapy, and 309 assigned to receive chemotherapy plus placebo), as well as for the biomarker-selected population (consisting of all patients with PD-L1 CPS of 1 or greater) and for the subpopulation of patients with PD-L1 CPS of 10 or greater.
In the all-comers population, the median OS was 26.4 months for patients who received pembrolizumab, compared with 16.8 months for those who received placebo. The 24-month OS rates were 52.1% and 38.7%, respectively. The difference translated into a hazard ratio for death with pembrolizumab of 0.63 (P < .0001).
In the biomarker-selected population (273 assigned to pembrolizumab and 275 assigned to placebo), the respective median OS was 28.6 months versus 16.6 months, with 24-month OS rates of 53.5% versus 39.4%, which translates into an HR for death with pembrolizumab of 0.60 (P < .0001).
Not surprisingly, the best responses to the addition of the PD-1 inhibitor were seen among patients with a PD-L1 CPS of 10 or greater (158 assigned to pembrolizumab and 159 assigned to placebo). In this subgroup, the median OS was 29.6 months with the immune checkpoint inhibitor added to chemotherapy versus 17.4 months for chemotherapy plus placebo. The respective 24-month OS rates were 54.4% and 42.5%, and the HR for overall survival favoring pembrolizumab was 0.58 (P < .0001).
Median PFS 12-month PFS rates also favored pembrolizumab in both the total patient population and the biomarker-selected groups, with median PFS of approximately 10.4 months with pembrolizumab versus approximately 8.2 months with placebo.
The safety profile was manageable, with adverse events as expected from the safety profiles of the individual drugs in the combined regimen. No new safety signals have been seen since the interim analysis, Dr. Monk said.
Regimen details
Patients were randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy, with bevacizumab added at the investigator’s discretion. Approximately two-thirds of patients in each study arm received bevacizumab.
The dual primary endpoints of PFS and OS were each tested sequentially in patients with a PD-L1 CPS of 1 or greater in both the intention-to-treat or “all-comers” population and in patients with a PD-L1 CPS of 10 or greater.
Patient characteristics were generally well balanced between the treatment groups, except that a slightly higher proportion of patients in the pembrolizumab had tumors of squamous cell histology, compared with the placebo group (76.3% vs. 68.3%).
KEYNOTE-826 was funded by Merck. Dr. Monk has received honoraria and has participated in consulting/advising and speaker’s bureau activity with Merck and other companies. Dr. Gralow has had a consulting or advisory role with Genentech and Roche. Dr. Markham has had a consulting/advisory role for GlaxoSmithKline and has received institutional research funding from Merck and other companies.
A version of this article first appeared on Medscape.com.
FROM ASCO 2023
‘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
Durvalumab pre, post surgery in NSCLC: Practice changing?
FROM AACR 2023
(NSCLC), primarily out of concern that neoadjuvant therapy could delay surgery or render patients ineligible for resection.
That may change, however, in light of new data from the phase 3 AEGEAN trial.
AEGEAN showed that neoadjuvant immunotherapy with durvalumab (Imfinzi) and chemotherapy followed by adjuvant durvalumab was associated with significant improvements in pathologic complete response rates and event-free survival, compared with neoadjuvant placebo plus chemotherapy followed by adjuvant placebo, and it did not affect patients’ ability to undergo surgery.
The event-free survival benefit among patients who received durvalumab translated to a 32% reduction in the risk of recurrence, recurrence precluding definitive surgery, or death, John V. Heymach, MD, reported in an oral abstract session at the annual meeting of the American Association for Cancer Research.
“Perioperative durvalumab plus neoadjuvant chemotherapy is a potential new treatment for patients with resectable non–small cell lung cancer,” said Dr. Heymach, chair of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center in Houston.
The AEGEAN findings confirm the benefits of neoadjuvant immunotherapy that were first seen on a large scale in the Checkmate 816 study, which was reported at last year’s AACR annual meeting.
In Checkmate 816, adding the immune checkpoint inhibitor nivolumab to chemotherapy in the neoadjuvant setting resulted in significantly longer event-free survival and a 14-fold greater likelihood of a pathologic complete response compared with chemotherapy alone.
“I’m impressed by the fact that we now have a second study that shows the benefits of immunotherapy in the neoadjuvant setting, along with several adjuvant studies,” the invited discussant, Roy S. Herbst, MD, PhD, deputy director of the Yale Cancer Center, New Haven, Conn., said in an interview. “There’s no doubt that in early lung cancer, resectable disease, immunotherapy is part of the equation.”
For the current study, Dr. Heymach and colleagues recruited 802 patients from 222 sites in North and South America, Europe, and Asia. The patients had NSCLC and were treatment-naive, regardless of programmed cell death–ligand-1 (PD-L1) expression.
After excluding patients with targetable EGFR/ALK alterations, the team randomly allocated 740 patients who had good performance status (ECOG 0 or 1) to receive either neoadjuvant chemoimmunotherapy plus adjuvant immunotherapy or neoadjuvant chemotherapy alone. Overall, 77.6% of patients in the treatment arm and 76.7% of patients in the placebo arm underwent surgery following neoadjuvant therapy.
At the trial’s first planned interim analysis, for patients assigned to preoperative durvalumab plus platinum-based chemotherapy and postoperative durvalumab, the 12-month event-free survival rate was 73.4%, compared with 64.5% for patients who received chemotherapy alone before and placebo after surgery (stratified P = .003902).
The other endpoint, pathologic complete response, was observed in 17.2% of patients in the durvalumab arm, vs. 4.3% in the control arm – a 13% difference (P = .000036). Major pathologic responses, a secondary efficacy endpoint, were seen in 33.3% and 12.3% of patients, respectively.
The benefits of durvalumab were consistent across all subgroups, including those based on age at randomization, sex, performance status, race, smoking, histology (squamous vs. nonsquamous), disease stage, baseline PD-L1 expression, and planned neoadjuvant agent.
The safety profile of durvalumab plus chemotherapy was manageable, and the addition of durvalumab did not affect patients’ ability to complete four cycles of neoadjuvant chemotherapy, Dr. Heymach said.
Are these data practice changing?
Dr. Herbst gave a “resounding ‘Yes.’ “
But while the AEGEAN protocol represents a new standard of care, it can’t yet be labeled the standard of care, Dr. Herbst explained.
Dr. Herbst emphasized that, because this regimen was not compared against the current standard of care, it’s “impossible to determine” whether this is indeed the new standard.
“The data are early, and additional maturity is needed to better understand the benefit of the extra adjuvant therapy, and we’ll await the survival results,” he said.
It will also be important to analyze why some patients have only minor responses with the addition of durvalumab and whether there are resistance mechanisms at play for these patients. That would be a great setting “to start to test new therapies in a personalized way,” Dr. Herbst said.
Dr. Heymach and Dr. Herbst disclosed ties to AstraZeneca, which funded the study.
A version of this article first appeared on Medscape.com.
FROM AACR 2023
(NSCLC), primarily out of concern that neoadjuvant therapy could delay surgery or render patients ineligible for resection.
That may change, however, in light of new data from the phase 3 AEGEAN trial.
AEGEAN showed that neoadjuvant immunotherapy with durvalumab (Imfinzi) and chemotherapy followed by adjuvant durvalumab was associated with significant improvements in pathologic complete response rates and event-free survival, compared with neoadjuvant placebo plus chemotherapy followed by adjuvant placebo, and it did not affect patients’ ability to undergo surgery.
The event-free survival benefit among patients who received durvalumab translated to a 32% reduction in the risk of recurrence, recurrence precluding definitive surgery, or death, John V. Heymach, MD, reported in an oral abstract session at the annual meeting of the American Association for Cancer Research.
“Perioperative durvalumab plus neoadjuvant chemotherapy is a potential new treatment for patients with resectable non–small cell lung cancer,” said Dr. Heymach, chair of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center in Houston.
The AEGEAN findings confirm the benefits of neoadjuvant immunotherapy that were first seen on a large scale in the Checkmate 816 study, which was reported at last year’s AACR annual meeting.
In Checkmate 816, adding the immune checkpoint inhibitor nivolumab to chemotherapy in the neoadjuvant setting resulted in significantly longer event-free survival and a 14-fold greater likelihood of a pathologic complete response compared with chemotherapy alone.
“I’m impressed by the fact that we now have a second study that shows the benefits of immunotherapy in the neoadjuvant setting, along with several adjuvant studies,” the invited discussant, Roy S. Herbst, MD, PhD, deputy director of the Yale Cancer Center, New Haven, Conn., said in an interview. “There’s no doubt that in early lung cancer, resectable disease, immunotherapy is part of the equation.”
For the current study, Dr. Heymach and colleagues recruited 802 patients from 222 sites in North and South America, Europe, and Asia. The patients had NSCLC and were treatment-naive, regardless of programmed cell death–ligand-1 (PD-L1) expression.
After excluding patients with targetable EGFR/ALK alterations, the team randomly allocated 740 patients who had good performance status (ECOG 0 or 1) to receive either neoadjuvant chemoimmunotherapy plus adjuvant immunotherapy or neoadjuvant chemotherapy alone. Overall, 77.6% of patients in the treatment arm and 76.7% of patients in the placebo arm underwent surgery following neoadjuvant therapy.
At the trial’s first planned interim analysis, for patients assigned to preoperative durvalumab plus platinum-based chemotherapy and postoperative durvalumab, the 12-month event-free survival rate was 73.4%, compared with 64.5% for patients who received chemotherapy alone before and placebo after surgery (stratified P = .003902).
The other endpoint, pathologic complete response, was observed in 17.2% of patients in the durvalumab arm, vs. 4.3% in the control arm – a 13% difference (P = .000036). Major pathologic responses, a secondary efficacy endpoint, were seen in 33.3% and 12.3% of patients, respectively.
The benefits of durvalumab were consistent across all subgroups, including those based on age at randomization, sex, performance status, race, smoking, histology (squamous vs. nonsquamous), disease stage, baseline PD-L1 expression, and planned neoadjuvant agent.
The safety profile of durvalumab plus chemotherapy was manageable, and the addition of durvalumab did not affect patients’ ability to complete four cycles of neoadjuvant chemotherapy, Dr. Heymach said.
Are these data practice changing?
Dr. Herbst gave a “resounding ‘Yes.’ “
But while the AEGEAN protocol represents a new standard of care, it can’t yet be labeled the standard of care, Dr. Herbst explained.
Dr. Herbst emphasized that, because this regimen was not compared against the current standard of care, it’s “impossible to determine” whether this is indeed the new standard.
“The data are early, and additional maturity is needed to better understand the benefit of the extra adjuvant therapy, and we’ll await the survival results,” he said.
It will also be important to analyze why some patients have only minor responses with the addition of durvalumab and whether there are resistance mechanisms at play for these patients. That would be a great setting “to start to test new therapies in a personalized way,” Dr. Herbst said.
Dr. Heymach and Dr. Herbst disclosed ties to AstraZeneca, which funded the study.
A version of this article first appeared on Medscape.com.
FROM AACR 2023
(NSCLC), primarily out of concern that neoadjuvant therapy could delay surgery or render patients ineligible for resection.
That may change, however, in light of new data from the phase 3 AEGEAN trial.
AEGEAN showed that neoadjuvant immunotherapy with durvalumab (Imfinzi) and chemotherapy followed by adjuvant durvalumab was associated with significant improvements in pathologic complete response rates and event-free survival, compared with neoadjuvant placebo plus chemotherapy followed by adjuvant placebo, and it did not affect patients’ ability to undergo surgery.
The event-free survival benefit among patients who received durvalumab translated to a 32% reduction in the risk of recurrence, recurrence precluding definitive surgery, or death, John V. Heymach, MD, reported in an oral abstract session at the annual meeting of the American Association for Cancer Research.
“Perioperative durvalumab plus neoadjuvant chemotherapy is a potential new treatment for patients with resectable non–small cell lung cancer,” said Dr. Heymach, chair of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center in Houston.
The AEGEAN findings confirm the benefits of neoadjuvant immunotherapy that were first seen on a large scale in the Checkmate 816 study, which was reported at last year’s AACR annual meeting.
In Checkmate 816, adding the immune checkpoint inhibitor nivolumab to chemotherapy in the neoadjuvant setting resulted in significantly longer event-free survival and a 14-fold greater likelihood of a pathologic complete response compared with chemotherapy alone.
“I’m impressed by the fact that we now have a second study that shows the benefits of immunotherapy in the neoadjuvant setting, along with several adjuvant studies,” the invited discussant, Roy S. Herbst, MD, PhD, deputy director of the Yale Cancer Center, New Haven, Conn., said in an interview. “There’s no doubt that in early lung cancer, resectable disease, immunotherapy is part of the equation.”
For the current study, Dr. Heymach and colleagues recruited 802 patients from 222 sites in North and South America, Europe, and Asia. The patients had NSCLC and were treatment-naive, regardless of programmed cell death–ligand-1 (PD-L1) expression.
After excluding patients with targetable EGFR/ALK alterations, the team randomly allocated 740 patients who had good performance status (ECOG 0 or 1) to receive either neoadjuvant chemoimmunotherapy plus adjuvant immunotherapy or neoadjuvant chemotherapy alone. Overall, 77.6% of patients in the treatment arm and 76.7% of patients in the placebo arm underwent surgery following neoadjuvant therapy.
At the trial’s first planned interim analysis, for patients assigned to preoperative durvalumab plus platinum-based chemotherapy and postoperative durvalumab, the 12-month event-free survival rate was 73.4%, compared with 64.5% for patients who received chemotherapy alone before and placebo after surgery (stratified P = .003902).
The other endpoint, pathologic complete response, was observed in 17.2% of patients in the durvalumab arm, vs. 4.3% in the control arm – a 13% difference (P = .000036). Major pathologic responses, a secondary efficacy endpoint, were seen in 33.3% and 12.3% of patients, respectively.
The benefits of durvalumab were consistent across all subgroups, including those based on age at randomization, sex, performance status, race, smoking, histology (squamous vs. nonsquamous), disease stage, baseline PD-L1 expression, and planned neoadjuvant agent.
The safety profile of durvalumab plus chemotherapy was manageable, and the addition of durvalumab did not affect patients’ ability to complete four cycles of neoadjuvant chemotherapy, Dr. Heymach said.
Are these data practice changing?
Dr. Herbst gave a “resounding ‘Yes.’ “
But while the AEGEAN protocol represents a new standard of care, it can’t yet be labeled the standard of care, Dr. Herbst explained.
Dr. Herbst emphasized that, because this regimen was not compared against the current standard of care, it’s “impossible to determine” whether this is indeed the new standard.
“The data are early, and additional maturity is needed to better understand the benefit of the extra adjuvant therapy, and we’ll await the survival results,” he said.
It will also be important to analyze why some patients have only minor responses with the addition of durvalumab and whether there are resistance mechanisms at play for these patients. That would be a great setting “to start to test new therapies in a personalized way,” Dr. Herbst said.
Dr. Heymach and Dr. Herbst disclosed ties to AstraZeneca, which funded the study.
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
In metastatic NSCLC, better QoL outcomes tied to better outcomes
The authors, including Fabio Salomone of the University of Naples Federico II, department of clinical medicine and surgery, also observed trends toward an association between QoL improvement and PFS among patients treated with chemotherapy and immunotherapy.
The new research was presented during a poster session at European Lung Cancer Congress 2023.
“The findings of the study support the thesis that QoL and survival in patients with NSCLC are linked. Although this is documented in the literature, this study sums up the evidence of a large number of RCTs, and provides detail in the QoL/survival relationship by treatment type. The subgroup analysis by treatment type is a key strength of the study showing that the QoL/survival link is stronger and more reliable in target(ed) therapies,” George Kypriotakis, PhD, who was not involved with the study, said in an interview.
Combining efficacy and quality of life improvement is an important consideration in clinical practice. “It is important that clinicians provide therapies that are also palliative and improve QoL,” said Dr. Kypriotakis, assistant professor of behavioral sciences at University of Texas MD Anderson Cancer Center, Houston. He noted that the finding of a PFS benefit is a good indicator of overall benefit, which is important since OS outcomes require a larger number of patients and longer follow-up to determine.
“PFS can still be a valid surrogate for OS, especially when it is positively associated with QoL,” noted Dr. Kypriotakis.
The study included 81 trials. Sixteen of the studies investigated immunotherapy, 50 investigated targeted therapy, and 17 investigated chemotherapy regimens. Thirty-seven percent of the trials found an improvement in QoL in the treatment arm compared with the control arm, 59.3% found no difference between arms, and 3.7% found a worse QoL in the treatment arm. There was no statistically significant association between an improvement in OS and QoL among the trials (P = .368).
Improved QoL tied to improved PFS
The researchers found an association between improved QoL and improved PFS. Among 60 trials that showed improved PFS, 43.3% found a superior QoL in the treatment arm, 53.3% showed no difference, and 3.3% showed reduced QoL. Among 20 trials that found no improvement in PFS, 20% demonstrated an improved QoL, 75% found no change, and 5% showed worse QoL (P = .0473).
A subanalysis of 48 targeted therapy trials found a correlation between PFS and QoL improvement (P = .0196). Among 25 trials involving patients receiving epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitors showing an improved PFS, 60% showed improved QoL, 36% showed no difference, and 4% showed worsening (P = .0077). Seven of these trials showed no PFS benefit and no change in QoL.
Industry sponsorship may affect QOL results
The researchers found potential evidence that industry sponsorship may lead to a spin on QoL outcomes. Among 51 trials that showed no QoL benefit associated with treatment, the description of the QoL outcome in 37 industry-sponsored was judged to be neutral and coherent with the study findings in 26 cases, but unjustifiably favorable in 11 cases. Among 14 with nonprofit support, descriptions of QoL results were found to be neutral in all cases (P = .0232).
“Obviously, industry may be motivated to overemphasize treatment benefits, especially in measures that also have a qualitative/subjective dimension such as QoL. Assuming that the authors used a reliable criterion to evaluate “inappropriateness,” industry may be more likely to emphasize QoL improvements as a surrogate for OS, especially when seeking drug approval,” Dr. Kypriotakis said.
The study is retrospective and cannot prove causation.
Dr. Salomone and Dr. Kypriotakis have no relevant financial disclosures.
The authors, including Fabio Salomone of the University of Naples Federico II, department of clinical medicine and surgery, also observed trends toward an association between QoL improvement and PFS among patients treated with chemotherapy and immunotherapy.
The new research was presented during a poster session at European Lung Cancer Congress 2023.
“The findings of the study support the thesis that QoL and survival in patients with NSCLC are linked. Although this is documented in the literature, this study sums up the evidence of a large number of RCTs, and provides detail in the QoL/survival relationship by treatment type. The subgroup analysis by treatment type is a key strength of the study showing that the QoL/survival link is stronger and more reliable in target(ed) therapies,” George Kypriotakis, PhD, who was not involved with the study, said in an interview.
Combining efficacy and quality of life improvement is an important consideration in clinical practice. “It is important that clinicians provide therapies that are also palliative and improve QoL,” said Dr. Kypriotakis, assistant professor of behavioral sciences at University of Texas MD Anderson Cancer Center, Houston. He noted that the finding of a PFS benefit is a good indicator of overall benefit, which is important since OS outcomes require a larger number of patients and longer follow-up to determine.
“PFS can still be a valid surrogate for OS, especially when it is positively associated with QoL,” noted Dr. Kypriotakis.
The study included 81 trials. Sixteen of the studies investigated immunotherapy, 50 investigated targeted therapy, and 17 investigated chemotherapy regimens. Thirty-seven percent of the trials found an improvement in QoL in the treatment arm compared with the control arm, 59.3% found no difference between arms, and 3.7% found a worse QoL in the treatment arm. There was no statistically significant association between an improvement in OS and QoL among the trials (P = .368).
Improved QoL tied to improved PFS
The researchers found an association between improved QoL and improved PFS. Among 60 trials that showed improved PFS, 43.3% found a superior QoL in the treatment arm, 53.3% showed no difference, and 3.3% showed reduced QoL. Among 20 trials that found no improvement in PFS, 20% demonstrated an improved QoL, 75% found no change, and 5% showed worse QoL (P = .0473).
A subanalysis of 48 targeted therapy trials found a correlation between PFS and QoL improvement (P = .0196). Among 25 trials involving patients receiving epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitors showing an improved PFS, 60% showed improved QoL, 36% showed no difference, and 4% showed worsening (P = .0077). Seven of these trials showed no PFS benefit and no change in QoL.
Industry sponsorship may affect QOL results
The researchers found potential evidence that industry sponsorship may lead to a spin on QoL outcomes. Among 51 trials that showed no QoL benefit associated with treatment, the description of the QoL outcome in 37 industry-sponsored was judged to be neutral and coherent with the study findings in 26 cases, but unjustifiably favorable in 11 cases. Among 14 with nonprofit support, descriptions of QoL results were found to be neutral in all cases (P = .0232).
“Obviously, industry may be motivated to overemphasize treatment benefits, especially in measures that also have a qualitative/subjective dimension such as QoL. Assuming that the authors used a reliable criterion to evaluate “inappropriateness,” industry may be more likely to emphasize QoL improvements as a surrogate for OS, especially when seeking drug approval,” Dr. Kypriotakis said.
The study is retrospective and cannot prove causation.
Dr. Salomone and Dr. Kypriotakis have no relevant financial disclosures.
The authors, including Fabio Salomone of the University of Naples Federico II, department of clinical medicine and surgery, also observed trends toward an association between QoL improvement and PFS among patients treated with chemotherapy and immunotherapy.
The new research was presented during a poster session at European Lung Cancer Congress 2023.
“The findings of the study support the thesis that QoL and survival in patients with NSCLC are linked. Although this is documented in the literature, this study sums up the evidence of a large number of RCTs, and provides detail in the QoL/survival relationship by treatment type. The subgroup analysis by treatment type is a key strength of the study showing that the QoL/survival link is stronger and more reliable in target(ed) therapies,” George Kypriotakis, PhD, who was not involved with the study, said in an interview.
Combining efficacy and quality of life improvement is an important consideration in clinical practice. “It is important that clinicians provide therapies that are also palliative and improve QoL,” said Dr. Kypriotakis, assistant professor of behavioral sciences at University of Texas MD Anderson Cancer Center, Houston. He noted that the finding of a PFS benefit is a good indicator of overall benefit, which is important since OS outcomes require a larger number of patients and longer follow-up to determine.
“PFS can still be a valid surrogate for OS, especially when it is positively associated with QoL,” noted Dr. Kypriotakis.
The study included 81 trials. Sixteen of the studies investigated immunotherapy, 50 investigated targeted therapy, and 17 investigated chemotherapy regimens. Thirty-seven percent of the trials found an improvement in QoL in the treatment arm compared with the control arm, 59.3% found no difference between arms, and 3.7% found a worse QoL in the treatment arm. There was no statistically significant association between an improvement in OS and QoL among the trials (P = .368).
Improved QoL tied to improved PFS
The researchers found an association between improved QoL and improved PFS. Among 60 trials that showed improved PFS, 43.3% found a superior QoL in the treatment arm, 53.3% showed no difference, and 3.3% showed reduced QoL. Among 20 trials that found no improvement in PFS, 20% demonstrated an improved QoL, 75% found no change, and 5% showed worse QoL (P = .0473).
A subanalysis of 48 targeted therapy trials found a correlation between PFS and QoL improvement (P = .0196). Among 25 trials involving patients receiving epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitors showing an improved PFS, 60% showed improved QoL, 36% showed no difference, and 4% showed worsening (P = .0077). Seven of these trials showed no PFS benefit and no change in QoL.
Industry sponsorship may affect QOL results
The researchers found potential evidence that industry sponsorship may lead to a spin on QoL outcomes. Among 51 trials that showed no QoL benefit associated with treatment, the description of the QoL outcome in 37 industry-sponsored was judged to be neutral and coherent with the study findings in 26 cases, but unjustifiably favorable in 11 cases. Among 14 with nonprofit support, descriptions of QoL results were found to be neutral in all cases (P = .0232).
“Obviously, industry may be motivated to overemphasize treatment benefits, especially in measures that also have a qualitative/subjective dimension such as QoL. Assuming that the authors used a reliable criterion to evaluate “inappropriateness,” industry may be more likely to emphasize QoL improvements as a surrogate for OS, especially when seeking drug approval,” Dr. Kypriotakis said.
The study is retrospective and cannot prove causation.
Dr. Salomone and Dr. Kypriotakis have no relevant financial disclosures.
FROM ELCC 2023
ESMO guidelines provide ‘clear blueprint’ for managing immunotherapy toxicities
This transcript has been edited for clarity.
I’m David Kerr, professor of cancer medicine at the University of Oxford. I’d like to talk to you today about something specific and generic around guidelines.
It’s around the management of toxicities from immunotherapy, and it’s the ESMO Clinical Practice Guideline for diagnosis, treatment, and follow-up, delivered by Dr. Haanen and, of course, a number of colleagues on behalf of the wider committee.
Have a look at it. I’m not going to talk about the details of it. It’s very well written. It’s very clear and evidence based, of course. There are many helpful hints and a very clear blueprint as to how we should better manage the myriad of potential side effects from immunotherapy.
It tells us a little about the basis of the science, some of the mechanistic work that’s going on in allowing us to understand why some people react in such different ways, almost as if the immune systems are primed to overreact. It gives a very helpful, stepwise look at how we best diagnose, manage, and, in the longer term, follow up patients who have problems with these very important drugs.
All of us recognize the extraordinary impact they’ve made across a wide range of different tumor types, and therefore, as practicing oncologists and health care professionals in the field, all of us need to understand better the details as to how we better care for our patients on these drugs.
Have a look at it. It’s well written and useful, and I think it’s a document that I’ll turn to when I’m looking for a refresher or advice in the future.
The generic focus is about guidelines. Many years ago, I was one of the architects of the British National Cancer Plan, and for me, there were four simple principles at that stage in our development of how we would improve the delivery of cancer control in the United Kingdom. It was around site specialization, particularly of our surgical colleagues who embraced this with vigor. God bless them.
It was using guidelines to help level up the quality of treatment that we were giving, of course underpinned by research, and using – one would hope – modern IT and telecommunications to improve the networking that we use to deliver multidisciplinary cancer care, one of the key elements. Guidelines were embedded in that.
A couple of years ago, we did a survey of cancer physicians around the world. Almost 30 different countries were represented, and we asked which guidelines were most used. It was a very interesting set of responses. The three dominant guidelines – this will surprise no one – are the NCCN (National Comprehensive Cancer Network) guidelines, the ESMO guidelines, and the ASCO (American Society of Clinical Oncology) guidelines.
Rather than selecting one and one being completely dominant, what seemed to be the case is that our colleagues around the world dipped in and used all three. They may prefer NCCN for some particular tumor type or some particular aspect of how they’re structured, but at the same time, we would dip into the ESMO guidelines for specific bits of help, as well as the ASCO guidelines.
I find this fascinating. I assume that in different regions, depending on how they were affiliated in terms of additional training or links to Europe or links to the United States, that one or other of these guideline groups would predominate, but no. In each country, in each region, given the large data bank that we have of guidelines now, it’s a sort of pick-and-mix situation.
I was initially surprised but then took comfort from it. There’s nothing I hate more than the wasted energy of reduplication and saying, well come on, if there is one guideline set that does truly command the attention of the world, then the other should stop. It’s wasted energy, which is something that none of us can afford.
The fact that each of these trusted, evidence-based, beautifully presented guidelines is used in different ways was important. A message to the guideline groups from me is: “Thank you for your professionalism, for the hard work of hundreds of cancer specialists from all different specialties, and for their contribution to developing these guidelines.”
It’s worth it, it’s working, people are using them, and they’re making a difference. It’s all about leveling up the quality of cancer care that we deliver.
Specifically, have a look at the ESMO immune guidelines. They are great. I hope you find them helpful. Generically, thanks to all of you who are contributing and working so hard to make these data available to improve the quality of cancer care around the world.
Thanks for listening, as always. I’m interested in any comments that you might have, but for the time being, Medscapers, ahoy.
David J. Kerr, CBE, MD, DSc, is a professor of cancer medicine at the University of Oxford. He reported conflicts of interest with Celleron Therapeutics, Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Bayer, Genomic Health, and Merck Serono.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
I’m David Kerr, professor of cancer medicine at the University of Oxford. I’d like to talk to you today about something specific and generic around guidelines.
It’s around the management of toxicities from immunotherapy, and it’s the ESMO Clinical Practice Guideline for diagnosis, treatment, and follow-up, delivered by Dr. Haanen and, of course, a number of colleagues on behalf of the wider committee.
Have a look at it. I’m not going to talk about the details of it. It’s very well written. It’s very clear and evidence based, of course. There are many helpful hints and a very clear blueprint as to how we should better manage the myriad of potential side effects from immunotherapy.
It tells us a little about the basis of the science, some of the mechanistic work that’s going on in allowing us to understand why some people react in such different ways, almost as if the immune systems are primed to overreact. It gives a very helpful, stepwise look at how we best diagnose, manage, and, in the longer term, follow up patients who have problems with these very important drugs.
All of us recognize the extraordinary impact they’ve made across a wide range of different tumor types, and therefore, as practicing oncologists and health care professionals in the field, all of us need to understand better the details as to how we better care for our patients on these drugs.
Have a look at it. It’s well written and useful, and I think it’s a document that I’ll turn to when I’m looking for a refresher or advice in the future.
The generic focus is about guidelines. Many years ago, I was one of the architects of the British National Cancer Plan, and for me, there were four simple principles at that stage in our development of how we would improve the delivery of cancer control in the United Kingdom. It was around site specialization, particularly of our surgical colleagues who embraced this with vigor. God bless them.
It was using guidelines to help level up the quality of treatment that we were giving, of course underpinned by research, and using – one would hope – modern IT and telecommunications to improve the networking that we use to deliver multidisciplinary cancer care, one of the key elements. Guidelines were embedded in that.
A couple of years ago, we did a survey of cancer physicians around the world. Almost 30 different countries were represented, and we asked which guidelines were most used. It was a very interesting set of responses. The three dominant guidelines – this will surprise no one – are the NCCN (National Comprehensive Cancer Network) guidelines, the ESMO guidelines, and the ASCO (American Society of Clinical Oncology) guidelines.
Rather than selecting one and one being completely dominant, what seemed to be the case is that our colleagues around the world dipped in and used all three. They may prefer NCCN for some particular tumor type or some particular aspect of how they’re structured, but at the same time, we would dip into the ESMO guidelines for specific bits of help, as well as the ASCO guidelines.
I find this fascinating. I assume that in different regions, depending on how they were affiliated in terms of additional training or links to Europe or links to the United States, that one or other of these guideline groups would predominate, but no. In each country, in each region, given the large data bank that we have of guidelines now, it’s a sort of pick-and-mix situation.
I was initially surprised but then took comfort from it. There’s nothing I hate more than the wasted energy of reduplication and saying, well come on, if there is one guideline set that does truly command the attention of the world, then the other should stop. It’s wasted energy, which is something that none of us can afford.
The fact that each of these trusted, evidence-based, beautifully presented guidelines is used in different ways was important. A message to the guideline groups from me is: “Thank you for your professionalism, for the hard work of hundreds of cancer specialists from all different specialties, and for their contribution to developing these guidelines.”
It’s worth it, it’s working, people are using them, and they’re making a difference. It’s all about leveling up the quality of cancer care that we deliver.
Specifically, have a look at the ESMO immune guidelines. They are great. I hope you find them helpful. Generically, thanks to all of you who are contributing and working so hard to make these data available to improve the quality of cancer care around the world.
Thanks for listening, as always. I’m interested in any comments that you might have, but for the time being, Medscapers, ahoy.
David J. Kerr, CBE, MD, DSc, is a professor of cancer medicine at the University of Oxford. He reported conflicts of interest with Celleron Therapeutics, Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Bayer, Genomic Health, and Merck Serono.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
I’m David Kerr, professor of cancer medicine at the University of Oxford. I’d like to talk to you today about something specific and generic around guidelines.
It’s around the management of toxicities from immunotherapy, and it’s the ESMO Clinical Practice Guideline for diagnosis, treatment, and follow-up, delivered by Dr. Haanen and, of course, a number of colleagues on behalf of the wider committee.
Have a look at it. I’m not going to talk about the details of it. It’s very well written. It’s very clear and evidence based, of course. There are many helpful hints and a very clear blueprint as to how we should better manage the myriad of potential side effects from immunotherapy.
It tells us a little about the basis of the science, some of the mechanistic work that’s going on in allowing us to understand why some people react in such different ways, almost as if the immune systems are primed to overreact. It gives a very helpful, stepwise look at how we best diagnose, manage, and, in the longer term, follow up patients who have problems with these very important drugs.
All of us recognize the extraordinary impact they’ve made across a wide range of different tumor types, and therefore, as practicing oncologists and health care professionals in the field, all of us need to understand better the details as to how we better care for our patients on these drugs.
Have a look at it. It’s well written and useful, and I think it’s a document that I’ll turn to when I’m looking for a refresher or advice in the future.
The generic focus is about guidelines. Many years ago, I was one of the architects of the British National Cancer Plan, and for me, there were four simple principles at that stage in our development of how we would improve the delivery of cancer control in the United Kingdom. It was around site specialization, particularly of our surgical colleagues who embraced this with vigor. God bless them.
It was using guidelines to help level up the quality of treatment that we were giving, of course underpinned by research, and using – one would hope – modern IT and telecommunications to improve the networking that we use to deliver multidisciplinary cancer care, one of the key elements. Guidelines were embedded in that.
A couple of years ago, we did a survey of cancer physicians around the world. Almost 30 different countries were represented, and we asked which guidelines were most used. It was a very interesting set of responses. The three dominant guidelines – this will surprise no one – are the NCCN (National Comprehensive Cancer Network) guidelines, the ESMO guidelines, and the ASCO (American Society of Clinical Oncology) guidelines.
Rather than selecting one and one being completely dominant, what seemed to be the case is that our colleagues around the world dipped in and used all three. They may prefer NCCN for some particular tumor type or some particular aspect of how they’re structured, but at the same time, we would dip into the ESMO guidelines for specific bits of help, as well as the ASCO guidelines.
I find this fascinating. I assume that in different regions, depending on how they were affiliated in terms of additional training or links to Europe or links to the United States, that one or other of these guideline groups would predominate, but no. In each country, in each region, given the large data bank that we have of guidelines now, it’s a sort of pick-and-mix situation.
I was initially surprised but then took comfort from it. There’s nothing I hate more than the wasted energy of reduplication and saying, well come on, if there is one guideline set that does truly command the attention of the world, then the other should stop. It’s wasted energy, which is something that none of us can afford.
The fact that each of these trusted, evidence-based, beautifully presented guidelines is used in different ways was important. A message to the guideline groups from me is: “Thank you for your professionalism, for the hard work of hundreds of cancer specialists from all different specialties, and for their contribution to developing these guidelines.”
It’s worth it, it’s working, people are using them, and they’re making a difference. It’s all about leveling up the quality of cancer care that we deliver.
Specifically, have a look at the ESMO immune guidelines. They are great. I hope you find them helpful. Generically, thanks to all of you who are contributing and working so hard to make these data available to improve the quality of cancer care around the world.
Thanks for listening, as always. I’m interested in any comments that you might have, but for the time being, Medscapers, ahoy.
David J. Kerr, CBE, MD, DSc, is a professor of cancer medicine at the University of Oxford. He reported conflicts of interest with Celleron Therapeutics, Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Bayer, Genomic Health, and Merck Serono.
A version of this article first appeared on Medscape.com.
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