“It has been a long time coming to see a positive randomized phase III study with a checkpoint inhibitor in relapsed mesothelioma,” said the study’s invited discussant, Rina Hui, MBBS, PhD, Clinical Professor of Medicine, Crown Princess Mary Cancer Centre, Westmead Hospital, University of Sydney, Australia.1 “In patients who have received platinum/pemetrexed in the first-line setting, single-agent nivolumab can now be considered a treatment option in the second line or third line after second-line chemotherapy.”
As pointed out by Dr. Hui, data have been limited as to outcomes with salvage therapies. Upon relapse, patients can be re-treated with pemetrexed-based chemotherapy or single-agent vinorelbine or gemcitabine, but such salvage approaches result in short median survival times. As for immunotherapy, the large majority of trials in relapsed mesothelioma have been phase I or IIb. The only phase III trial, PROMISE-meso, showed no difference in progression-free or overall survival for pembrolizumab vs chemotherapy,2 she said.
Rina Hui, MBBS, PhD
PD-L1 Expression and Nonepithelioid Histology
“CONFIRM, which recruited 332 heavily pretreated patients, added important and encouraging data on immunotherapy in the salvage setting,” Dr. Hui noted. Although the results were positive, there were some nuances for benefit, and no clear associations were found for PD-L1 expression or histology, meaning no biomarker for selection has emerged, she said.
The lack of association between PD-L1 level and outcome might be due to the low percentage (34%) of patients with PD-L1–positive disease in this study, as compared with other trials (43%–77%). Also, just 70% of the tumors were evaluable for this biomarker, added Dr. Hui.
In addition, no benefit was found with nivolumab in patients who had nonepithelioid tumors, which are a more aggressive, chemotherapy-resistant subtype. As reflected by the small (12%) proportion of patients in CONFIRM, many patients with nonepithelioid-type tumors do not seem to go on to second-line treatment. In the first-line CheckMate 743 trial of nivolumab plus ipilimumab, patients with nonepithelioid tumors did benefit (hazard ratio = 0.46), but they made up 25% of patients in that study,3 Dr. Hui pointed out. At this time, therefore, Dr. Hui said that she “would not deny patients with nonepithelioid histology from considering nivolumab in the salvage setting.”
Dr. Hui posed a few questions still to be answered:
- Does nivolumab provide better outcomes than second-line chemotherapy or second-line gemcitabine with ramucirumab?
- Would nivolumab plus ipilimumab be superior to single-agent nivolumab in the salvage setting?
- If nivolumumab/ipilimumab is used in the first-line setting, should the second-line treatment be platinum/pemetrexed or perhaps gemcitabine/ramucirumab?
Additional Commentary on CONFIRM
Melina Marmarelis, MD, Assistant Professor and Medical Director of the Mesothelioma and Pleural Disease Program at the University of Pennsylvania, also commented on the CONFIRM trial findings for The ASCO Post.
Melina Marmarelis, MD
“The CONFIRM trial reinforces the utility of single-agent checkpoint blockade in relapsed malignant mesothelioma, but where this fits into the emerging first-line paradigms that include immunotherapy is unclear. There is a clear benefit to this approach after platinum-based chemotherapy, but we do not have a good comparison to salvage chemotherapy nor any evidence that nivolumab would be effective after first-line immunotherapy,” she pointed out.
Dr. Marmarelis agreed with Dr. Hui regarding the use of second-line nivolumab for nonepithelioid tumors. “Given the small nonepithelioid group in CONFIRM and the inferior outcomes with chemotherapy in the nonepithelioid group compared with immunotherapy in Checkmate 743,3 the use of nivolumab in the relapsed setting should not be reserved for epithelioid histology alone,” Dr. Marmarelis said. “In addition, we currently do not have evidence that PD-L1 should be used to determine candidacy for salvage immunotherapy.”
Next Steps
Dr. Marmarelis is looking forward to seeing more data from CONFIRM, particularly centrally assessed progression-free survival, “given the notorious difficulty in measuring disease volume changes in malignant mesothelioma.” Given the “surprisingly” low rate (12.6%) of crossover to subsequent immunotherapy in the placebo arm, she is also interested to learn how many patients in this group received any type of subsequent therapy.
Single-agent immunotherapy in relapsed mesothelioma may just be a building block, proposed Dr. Marmarelis. Trials are under way to find ways to improve upon immunotherapy alone in the first-line setting, including BEAT-meso (carboplatin/pemetrexed/bevacizumab plus atezolizumab), DREAM3R (carboplatin/pemetrexed plus durvalumab), and IND 227 (cisplatin/pemetrexed plus pembrolizumab). ν
DISCLOSURE: Dr. Hui has received honoraria from AstraZeneca, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, and Roche; has served as a consultant or advisor to AstraZeneca, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, and Roche; and has been reimbursed for travel, accommodations, or other expenses by Novartis and Roche. Dr. Marmarelis holds stock or other ownership interests in Bluebird Bio, Gilead Sciences, Johnson & Johnson, Merck, Pfizer, and Portola Pharmaceuticals; has received honoraria from Novocure and Targeted Oncology; has an immediate family member who has received honoraria from Health Advances; has served as a consultant or advisor to AstraZeneca and Boehringer Ingelheim; has received institutional research funding from AstraZeneca, Lilly, and Trizell; has been reimbursed for travel, accommodations, or other expenses by Boehringer Ingelheim and Novocure; and has held other relationships with Novartis.
REFERENCES
1. Fennell D, Ottensmeier C, Califano R, et al: Nivolumab versus placebo in relapsed malignant mesothelioma: The CONFIRM phase 3 trial. 2020 World Conference on Lung Cancer. Abstract PS02.11. Presented January 30, 2021.
2. Popat S, Curioni-Fontecedro A, Dafni U, et al: A multicentre randomised phase III trial comparing pembrolizumab versus single-agent chemotherapy for advanced pre-treated malignant pleural mesothelioma: The European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial. Ann Oncol 31:1734-1745, 2020.
3. Baas P, Scherpereel A, Nowak AK, et al: First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): A multicentre, randomised, open-label, phase 3 trial. Lancet 397:375-386, 2021.
