Heterogeneity of treatment effects in malignant pleural mesothelioma

The results from CheckMate 7431Baas 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. 2021; 397: 375-386Summary Full Text Full Text PDF PubMed Scopus (270) Google Scholar are a relevant advance for the systemic treatment of patients with malignant pleural mesothelioma. However, we have concerns about the presentation and interpretation of subgroup analyses. Some further clarity would be helpful for the applicability of the study results in clinical practice, beyond the unequivocal clinically relevant effect observed in the whole population. The investigators state that "benefit with nivolumab plus ipilimumab was observed in most subgroups assessed, with the exception of patients aged 75 years or older".1Baas 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. 2021; 397: 375-386Summary Full Text Full Text PDF PubMed Scopus (270) Google Scholar However, the aim of presenting a forest plot is not to show statistical significance in each subgroup but to test if any apparent heterogeneity among subgroups is compatible with chance or not. The interaction test would have been useful for interpretation. According to our calculation (RevMan, version 5·3), treatment efficacy is not significantly heterogeneous among age subgroups (p=0·12). Similarly, efficacy is not significantly heterogeneous among PD-L1 subgroups (p=0·20). On the contrary, the interaction test reveals a significant heterogeneity among histology subgroups (p=0·007). The presence of heterogeneity does not mean that the experimental treatment is not effective in epithelioid tumours, but heterogeneity should be further investigated before definitive conclusions. The tumour immune microenvironment of epithelioid and non-epithelioid mesotheliomas is reported to be very different, adding a biological basis to further investigate such results.2Awad MM Jones RE Liu H et al.Cytotoxic T cells in PD-L1-positive malignant pleural mesotheliomas are counterbalanced by distinct immunosuppressive factors.Cancer Immunol Res. 2016; 4: 1038-1048Crossref PubMed Scopus (55) Google Scholar, 3Pasello 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. 2018; 29: 1258-1265Summary Full Text Full Text PDF PubMed Scopus (57) Google Scholar As suggested by many experts, analyses of the heterogeneity of treatment effects should be on the basis of tests for interaction, which should then be presented in the forest plot.4Wang R Lagakos SW Ware JH Hunter DJ Drazen JM Statistics in medicine—reporting of subgroup analyses in clinical trials.N Engl J Med. 2007; 357: 2189-2194Crossref PubMed Scopus (926) Google Scholar, 5Sormani MP Bruzzi P Reporting of subgroup analyses from clinical trials.Lancet Neurol. 2012; 11: 747Summary Full Text Full Text PDF PubMed Scopus (9) Google Scholar MDM reports advisory board fees from Eisai, AstraZeneca, Janssen Pharmaceuticals, and Astellas Pharma, consultancy fees from Novartis, Roche, Pfizer, Takeda, and Merck Sharp & Dohme, and an institutional research grant from Tesaro–GlaxoSmithKline, unrelated to this Correspondence. MT declares travel, accommodations, and expenses supported by Roche, Bristol-Myers Squibb, AstraZeneca, and Takeda, and activity as a medical writer supported by Novartis and Amgen, unrelated to this Correspondence. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trialNivolumab plus ipilimumab provided significant and clinically meaningful improvements in overall survival versus standard-of-care chemotherapy, supporting the use of this first-in-class regimen that has been approved in the USA as of October, 2020, for previously untreated unresectable MPM. Full-Text PDF Heterogeneity of treatment effects in malignant pleural mesothelioma – Authors' replyWe thank Massimo Di Maio and Marco Tagliamento for their Correspondence regarding CheckMate 743, a global, open-label, randomised, phase 3 study of first-line nivolumab plus ipilimumab versus chemotherapy in unresectable malignant pleural mesothelioma (MPM).1 We appreciate their remarks on the interaction test to investigate heterogeneity across histological subtypes. Full-Text PDF