Patients with malignant pleural mesothelioma who were treated with a chemoimmunotherapy regimen containing the immune checkpoint inhibitor pembrolizumab experienced significantly improved overall survival compared with those treated with chemotherapy alone, with acceptable tolerability, according to findings from a phase III study discussed at the 2023 Best of ASCO Seattle.1,2
In a session on local or regional non–small cell lung cancer (NSCLC), Christina S. Baik, MD, MPH, reviewed results from a phase III trial of platinum/pemetrexed with or without pembrolizumab in patients with malignant pleural mesothelioma. In the study (a collaboration among the Canadian Cancer Trials Group, the National Cancer Institute of Naples, and the French Cooperative Thoracic Intergroup), the improvement in survival seen with the addition of pembrolizumab to chemotherapy was evident in patients with both PD-L1–positive and PD-L1–negative tumors.
Christina S. Baik, MD, MPH
Most patients with pleural mesothelioma have unresectable disease, from comorbidities and/or advanced disease stage. Approved systemic treatments for unresectable pleural mesothelioma have historically been limited to chemotherapy regimens, with moderate survival benefit and poor outcomes, prompting the exploration of novel therapies.
According to Dr. Baik, Associate Professor in the Clinical Research Division at Fred Hutch Cancer Center in Seattle, and Associate Professor at the University of Washington School of Medicine, the CheckMate 743 trial previously established the efficacy of combination immunotherapy with ipilimumab and nivolumab in unresectable pleural mesothelioma, particularly of the nonepithelioid subtype.3 Although the impact of the immunotherapy combination on patients with the epithelioid subtype was less pronounced, patients who received ipilimumab and nivolumab overall had a clear survival benefit over patients who received a standard-of-care chemotherapy doublet. These results led to the 2020 approval of nivolumab plus ipilimumab by the U.S. Food and Drug Administration (FDA) for previously untreated and unresectable malignant pleural mesothelioma.
However, about 30% of patients treated with immunotherapy in the trial experienced grade 3 or higher toxicities. These adverse events prompted investigation into chemoimmunotherapy vs chemotherapy alone in treatment-naive patients with pleural mesothelioma.
The study discussed at the 2023 Best of ASCO Seattle randomly assigned 440 treatment-naive patients with pleural mesothelioma to receive platinum doublet chemotherapy alone or platinum doublet chemotherapy plus pembrolizumab, with a primary endpoint of overall survival. Most patients had the epithelioid subtype of mesothelioma and PD-L1–positive tumors.
“This was a fairly simple study design,” said Dr. Baik. “Patients who received chemoimmunotherapy did better. They had improved overall survival compared with chemotherapy alone, with a hazard ratio around 0.8.”
Consistent with findings from CheckMate 743, patients in this study with the nonepithelioid subtype had a greater benefit with the addition of pembrolizumab when compared with patients who had epithelioid mesothelioma. Grade 3 or higher pembrolizumab-related adverse events occurred in 19% of patients, with the most common being fatigue.
According to Dr. Baik, the ongoing phase III DREAM3R study (ClinicalTrials.gov identifier NCT04334759) in advanced pleural mesothelioma is currently investigating chemoimmunotherapy (cisplatin or carboplatin and pemetrexed given with the monoclonal anti–PD-L1 antibody durvalumab) vs physician’s choice of either a chemotherapy doublet or ipilimumab and nivolumab.
“Hopefully, this study will accrue quickly, and we can get a definitive answer to the question of which is better: chemoimmunotherapy or ipilimumab and nivolumab,” she said.
Clinical Implications by Subtype
For first-line therapy for nonepithelioid pleural mesothelioma, Dr. Baik maintains that both ipilimumab/nivolumab and chemoimmunotherapy regimens are “very active. They’re clearly better than chemotherapy alone, so patients should be offered an immunotherapy approach,” she added. “Of course, chemoimmunotherapy is not yet approved by the FDA, but it is an active option for patients.”
For the epithelioid subtype of mesothelioma, according to Dr. Baik, it remains unclear whether immune checkpoint inhibitor therapy adds much additional benefit to chemotherapy. However, a subgroup of patients likely benefits from this treatment combination.
“I personally have equipoise on all three regimens as first-line therapy: a platinum doublet with or without bevacizumab, a platinum doublet plus pembrolizumab, or ipilimumab and nivolumab,” she said.
Despite the challenges that remain in the treatment of malignant pleural mesothelioma, treatment options continue to evolve, and patient outcomes continue to improve. “In [the landscape of] early-stage NSCLC, this is very exciting,” Dr. Baik concluded.
DISCLOSURE: Dr. Baik has served as a consultant or advisor for AstraZeneca, Boehringer Ingelheim, Guardant Health, Janssen, Pfizer, Regeneron, Silverback Therapeutics, Takeda, and Turning Point Therapeutics; and has received research funding from AbbVie, AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Janssen, Lilly Oncology, Loxo, Nuvalent, Pfizer, Rain Therapeutics, Spectrum Pharmaceuticals, and TP Therapeutics.
2. Chu QS, Piccirillo MC, Greillier L, et al: IND227 phase III study of cisplatin/pemetrexed with or without pembrolizumab in patients with malignant pleural mesothelioma: A CCTG, NCIN, and IFCT trial. 2023 ASCO Annual Meeting. Abstract LBA8505. Presented June 3, 2023.
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.