In recent years, immune checkpoint inhibitors in the treatment of mesothelioma have been a keen area of investigation for this immunogenic solid tumor. With recent publications, principally findings from CheckMate 743 by Baas et al1 (reviewed in this issue of The ASCO Post), combination immune checkpoint inhibitor therapy with nivolumab and ipilimumab is now approved by the U.S. Food and Drug Administration (FDA) as a first-line therapy for patients with malignant pleural mesothelioma.
Samuel Rosner, MD
Patrick M. Forde, MBBCh
Long Search for Treatment With Long-Term Benefit
Prior to these recent developments, treatment for unresectable malignant pleural mesothelioma relied on combination chemotherapy with cisplatin plus pemetrexed. In 2003, a phase III study evaluated cisplatin plus pemetrexed vs cisplatin monotherapy. It showed superior outcomes in time to disease progression, response rates, and overall survival, and as such the combination became the primary treatment option for patients with unresectable pleural mesothelioma. Still, results from the study showed response rates of approximately 41% and overall survival of just over 1 year (12.1 months), leaving the majority of patients without significant or long-term benefit.2 From its FDA approval in February 2004 until October 2020, cisplatin plus pemetrexed remained the only FDA-approved option for treatment of unresectable malignant pleural mesothelioma.
During this nearly 16-year period, trials evaluating various additions to this doublet chemotherapy were largely disappointing. In one exception, the MAPS trial, reported by Zalcman et al, looked at the benefit of bevacizumab in combination with standard-of-care cisplatin plus pemetrexed for patients with unresectable malignant pleural mesothelioma.3 The study showed a statistically significant improvement in overall survival, achieving 18.8 months in the triplet group vs 16.1 months in control arm; however, the triplet group increased toxicity, including grade 3 or higher hypertension and thrombotic events, compared with the control. The study did not reach regulatory standards in the United States and did not lead to FDA approval.
The Promise of Immune Checkpoint Inhibitors
With the advent of immune checkpoint inhibitors in the past decade and their increased effectiveness in immunogenic solid malignancies such as melanoma and non–small cell lung cancer, it was postulated that similar efficacy might be seen in mesothelioma, which often arises because of asbestos-induced chronic inflammation. Additional results from preclinical studies added to this theory, with evidence of high PD-L1 expression seen in samples of resected mesothelioma4 along with a rich tumor microenvironment with high CD8-positive T-cell infiltration,5 particularly noted in mesothelioma of sarcomatoid and biphasic histology.6
We still have much to uncover regarding effective and reliable biomarkers to help decide between these various regimens [for malignant pleural mesothelioma].— Samuel Rosner, MD, and Patrick M. Forde, MBBCh
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In light of this biologic rationale, various single-agent immune checkpoint inhibitors were initially tested in the salvage or platinum-resistant setting. Results were mixed, although there were some promising findings. The phase III placebo-controlled CONFIRM trial evaluated nivolumab vs placebo in relapsed malignant pleural mesothelioma; the findings, which were reported at the virtual edition of the 2020 International Association for the Study of Lung Cancer World Conference on Lung Cancer, showed improved overall and progression-free survival with nivolumab.7 This was the first ever placebo-controlled phase III trial of an agent targeting PD-1 in relapsed mesothelioma and the first trial to show an improvement in overall survival following the standard first-line doublet of pemetrexed and cisplatin or carboplatin. The largest study to date of salvage combination immune checkpoint inhibitors was the MAPS2 trial, a randomized phase II noncomparative trial in which patients received either nivolumab/ipilimumab or nivolumab alone. The combination group, including 62 patients, experienced an overall survival of 15.9 months.8
With a growing body of evidence favoring immune checkpoint inhibitors in relapsed disease, there was increased interest in studying these agents in the first line. CheckMate 743, an open-label randomized phase III study, looked to compare nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks) for up to 2 years vs standard-of-care platinum doublet chemotherapy. The study met its primary endpoint of overall survival with nivolumab/ipilimumab, showing a median overall survival of 18.1 months vs 14.1 months in the control arm, at median follow-up time of 29.7 months. In a subgroup analysis, improvement in overall survival was noted to be primarily driven by patients with a nonepithelioid histology (~25% of patients), in whom combination immune checkpoint inhibitors achieved a median overall survival of 18.1 months, compared with 8.8 months with chemotherapy. The duration of response was also longer with dual immune checkpoint inhibitors, reported at 11 months vs 6.7 months with chemotherapy, again highlighting the durable nature of response with combination anti–PD-1 and anti–CTLA-4 agents, as seen in other malignancies. Grade 3 or 4 treatment-related adverse events were comparable between the two arms, notably with three treatment-related deaths in the dual immune checkpoint inhibitors group and one treatment-related death in the chemotherapy arm. It is important to note, and as the authors mentioned, evaluation of biomarkers such as PD-L1 expression was limited in this study, as it was not a stratification factor; the percentage of patients with PD-L1 expression less than 1% was low, making it difficult to draw insightful comparisons.1
Emerging Data and Ongoing Studies
There are several exciting areas of research incorporating dual checkpoint blockade for treatment of both unresectable and resectable malignant pleural mesotheliomas. Encouraging phase II data from DREAM9 and PrE050510 have revealed the benefit of combination durvalumab with doublet chemotherapy in the first-line setting. Results from PrE0505 included a median overall survival of 20.4 months, exceeding that of historical controls of first-line chemotherapy alone. The phase III DREAM3R/PrE0506 (ClinicalTrials.gov identifier NCT04334759) study is now active in the United States, Australia, and New Zealand. Additionally, efforts are under way to explore the utility of immune checkpoint inhibitors in resectable disease, with ongoing trials such as NCT03918252 incorporating combination nivolumab/ipilimumab in the neoadjuvant setting followed by adjuvant maintenance therapy with immune checkpoint inhibitors.11
What Next?
Suddenly, a disease with just one FDA-approved therapy through as late as September 2020 may soon have up to three options to offer patients. We still have much to uncover regarding effective and reliable biomarkers to help decide between these various regimens. Unlike in non–small cell lung cancer, PD-L1 expression has not yet been demonstrated to be a reliable and dependable marker in either a predictive or prognostic fashion in malignant pleural mesothelioma. It is clear that patients with nonepithelioid histologic subtypes derive significant benefit from dual immune checkpoint blockade, which is cited as a preferred first-line therapy for such patients in the National Comprehensive Cancer Network (NCCN®) Clinical Practice Guidelines in Oncology for Malignant Pleural Mesothelioma. Beyond this stratification point, clinicians are still in great need of further patient- or tumor-specific characteristics to help determine optimal treatment strategies for patients with this rare and deadly malignancy.
Dr. Rosner and Dr. Forde work in the Thoracic Oncology Program at the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore.
DISCLOSURE: Dr. Rosner reported no conflicts of interest. Dr. Forde has served as a consultant or advisor to AbbVie, Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, Daiichi Sankyo/UCB Japan, and Janssen; has received research funding from Corvus Pharmaceuticals; and has received institutional research funding from AstraZeneca/MedImmune, Bristol Myers Squibb, Kyowa Hakko Kirin, and Novartis.
REFERENCES
1. 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.
2. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al: Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21:2636-2644, 2003.
3. Zalcman G, Mazieres J, Margery J, et al: Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): A randomised, controlled, open-label, phase 3 trial. Lancet 387:1405-1414, 2016.
4. Currie AJ, Prosser A, McDonnell A, et al: Dual control of antitumor CD8 T cells through the programmed death-1/programmed death-ligand 1 pathway and immunosuppressive CD4 T cells: Regulation and counterregulation. J Immunol 183:7898-7908, 2009.
5. Khanna S, Thomas A, Abate-Daga D, et al: Malignant mesothelioma effusions are infiltrated by CD3(+) T cells highly expressing PD-L1 and the PD-L1(+) tumor cells within these effusions are susceptible to ADCC by the anti-PD-L1 antibody avelumab. J Thorac Oncol 11:1993-2005, 2016.
6. Pasello G, Zago G, Lunardi F, et al: Malignant pleural mesothelioma immune microenvironment and checkpoint expression: Correlation with clinical-pathological features and intratumor heterogeneity over time. Ann Oncol 29:1258-1265, 2018.
7. 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 PS01.11. Presented January 30, 2021.
8. Scherpereel A, Mazieres J, Greillier L, et al; French Cooperative Thoracic Intergroup: Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): A multicentre, open-label, randomised, non-comparative, phase 2 trial. Lancet Oncol 20:239-253, 2019.
9. Nowak A, Kok P, Lesterhuis W, et al: DREAM: A phase 2 trial of durvalumab with first line chemotherapy in mesothelioma: Final result. J Thorac Oncol 13:S338-S339, 2018.
10. Forde PM, Sun Z, Anagnostou V, et al: PrE0505: Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma—A PrECOG LLC study. 2020 ASCO Virtual Scientific Program. Abstract 9003.
11. Reuss JE, Sepesi B, Rolfo CD, et al: Trial in progress: Neoadjuvant immune checkpoint blockade in resectable malignant pleural mesothelioma. 2020 ASCO Virtual Scientific Program. Abstract TPS9078.
