The following article features coverage from the European Society for Medical Oncology (ESMO) Congress 2021. Click here to read more of Cancer Therapy Advisor’s conference coverage.

Updated phase 3 data confirm combination nivolumab and ipilimumab (nivo-ipi) as standard care for unresectable malignant pleural mesothelioma (MPM), according to a presentation at the European Society for Medical Oncology (ESMO) Congress 2021.1

The data come from the CheckMate 743 study ( Identifier: NCT02899299), which showed superior 3-year overall survival (OS) with nivo-ipi over standard chemotherapy and no new safety signals associated with nivo-ipi.

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Advanced MPM has an extremely poor prognosis. Standard-of-care pemetrexed plus cisplatin chemotherapy produced a response rate of 41% and a median OS of 12.1 months in a phase 3 trial, but most patients experience no enduring benefit from treatment.2

Additional agents (eg, maintenance pemextrexed3, bevacizumab4, and cediranib5) have provided inconsistent and marginal improvements over standard chemotherapy alone.

Prior results from CheckMate 743 showed that OS was better with nivo-ipi than with standard chemotherapy at a median follow-up of 29.7 months.6

Until now, however, long-term data have been lacking. For that reason, the presentation of results from CheckMate 743 at a 3-year minimum follow-up — about 1 year after cessation of all therapy — was important.

The results were presented at ESMO 2021 by Solange Peters, MD, PhD, of Lausanne University Hospital in Switzerland. Dr Peters also presented an analysis of biomarkers that might predict benefit from immunotherapy.

Trial Design  

The trial included 605 patients with untreated MPM, stratified by histology (epithelioid vs non-epithelioid) and sex. They were randomly assigned to 1 of 2 regimens:

  • Nivolumab (3 mg/kg intravenously every 2 weeks) plus ipilimumab (1 mg/kg intravenously every 6 weeks) for up to 2 years
  • Chemotherapy (intravenous pemetrexed at 500 mg/m2 every 3 weeks plus either cisplatin at 75 mg/m2 or carboplatin at AUC 5 mg/ml/min) every 3 weeks for up to 6 cycles.

The primary endpoint was OS. Secondary endpoints included objective response rate, disease control rate, efficacy by PD-L1 expression, and progression-free survival (PFS) by blinded, independent central review. Safety, tolerability, and biomarker assessments were prespecified exploratory endpoints.

One potential biomarker the researchers assessed was a 4-gene inflammatory signature score, which includes CD8A, STAT1, LAG3, and CD274 (PD-L1) genes, measured via RNA sequencing performed on baseline tumor samples. Another potential biomarker was tumor mutational burden (TMB), evaluated via whole-exome sequencing of matched tumor and normal samples.

The final potential biomarker was a lung immune prognostic index (LIPI) score calculated using lactate dehydrogenase levels and baseline neutrophil-to-lymphocyte ratios. The LIPI score is a prognostic biomarker in patients receiving systemic treatment for metastatic non-small cell lung cancer.7

Long-Term OS Results

With a minimum follow-up of 35.5 months — at least 11.5 months after completion of immunotherapy — the nivo-ipi combination continued to provide OS benefit over chemotherapy.

The median OS was 18.1 months with nivo-ipi and 14.1 months with chemotherapy (hazard ratio [HR], 0.73; 95% CI, 0.61-0.87). The 3-year OS rate was 23% and 15%, respectively.

Although there was no subgroup that failed to benefit from immune blockade over chemotherapy, the difference in OS was more dramatic for certain subgroups.

The researchers observed poor efficacy of chemotherapy against non-epithelioid MPM. The median OS was 8.8 months with chemotherapy in non-epithelioid MPM, compared with 16.7 months for chemotherapy in patients with epithelioid histology.

Therefore, the OS difference for the nivo-ipi regimen over chemotherapy was more impressive for patients with non-epithelioid MPM (HR, 0.48) than for patients with epithelioid MPM (HR, 0.85).

At the 3-year landmark milestone, the OS rate was 24% with nivo-ipi and 19% with chemotherapy for the epithelioid cohort. The 3-year OS rate was 22% and 4%, respectively, for the non-epithelioid cohort.

Because chemotherapy performed poorly in the 363 patients with a performance status (PS) of 1 or higher, the HR in favor of immunotherapy was less impressive for the 242 patients with a PS of 0 (HR, 0.90) than for the group with a PS of 1 or higher (HR, 0.66). 

The HR in favor of immunotherapy was not greatly affected by sex.