Potential Biomarkers

Patients with PD-L1 expression of 1% or higher had a greater OS benefit from nivo-ipi than did patients with PD-L1 expression of less than 1% (HR, 0.71 and 0.99, respectively).   

Since PD-L1 status was not a stratification factor, unrecognized concurrent conditions could have influenced the analysis by PD-L1 status. Overall, there were 135 patients with PD-L1 expression less than 1%, so small sample size may have been a confounding factor.

Continue Reading

In the nivo-ipi arm, OS was better for patients with a high inflammatory gene signature score. The median OS was 21.8 months for patients with high scores and 16.8 months for patients with low scores. The 3-year OS was 35% and 15%, respectively. 

The inflammatory gene signature score was not associated with OS in the chemotherapy arm.

OS was not correlated with TMB, and there was only a trend toward a correlation between OS and LIPI scores.

Secondary Endpoints

When compared with prior analyses, the PFS curve was unchanged in the current analysis, with an HR of 0.92 favoring chemotherapy. The median PFS was 6.8 months with nivo-ipi and 7.7 months with chemotherapy. However, the 3-year PFS was 14% for nivo-ipi and 1% for chemotherapy.

Objective response rates were similar with immune blockade (39.6%) and chemotherapy (44%). The duration of response, however, was nearly twice as long with immunotherapy as with chemotherapy — 11.6 months and 6.7 months, respectively.

None of the chemotherapy-treated patients were still in response at 3 years, compared with 28% of patients treated with nivo-ipi.

The rate of treatment-related adverse events (TRAEs) was 80% in the nivo-ipi arm and 82% in the chemotherapy arm. The rate of grade 3/4 TRAEs was 31% and 32%, respectively. There was no increase in toxicity from the prior report of CheckMate 743.

The rate of TRAEs leading to discontinuation of all components of the regimen was 17% for immunotherapy and 8% for chemotherapy.

Toxic deaths occurred in 3 patients in the nivo-ipi arm (pneumonitis, encephalitis, and acute heart failure) and 1 patient in the chemotherapy arm (myelosuppression).

Discontinuation of all components of the nivo-ipi regimen did not seem to impact the OS endpoint. The 3-year OS rate was 37% in patients with early discontinuation and 23% in all randomized patients.

Importance and Limitations of the Data

The ESMO 2021 presentation represented the first suggestion of long-term benefit from any type of systemic therapy in unresectable MPM patients.

As more than twice as many patients prematurely stopped immunotherapy as stopped chemotherapy due to toxicity, it was encouraging that early discontinuation for TRAEs did not reduce the long-term efficacy of immune checkpoint blockade.

Nonetheless, as highlighted by ESMO discussant Pilar Garrido Lopez, MD, PhD, of Hospital Universitario Romón y Cajal in Madrid, biomarkers associated with short-term hazards (ie, early progression), long-term benefits (ie, durable response), and opportunities to limit toxicity (via early treatment discontinuation) are needed.

Unfortunately, CheckMate 743 did not really meet the important goals for predictive biomarkers, for the following reasons:

  • Patients with epithelioid and non-epithelioid histologies had similar OS outcomes from the nivo-ipi regimen 
  • The trial was enriched for PD-L1-positive tumors
  • The trial was not powered to detect differences in outcome by PD-L1 status
  • The 4-gene inflammatory signature data were exploratory and were based on a limited RNA-evaluable population
  • TMB and LIPI score showed limited value.

As a result, despite the tantalizing long-term survival and response duration in some patients who received frontline nivo-ipi for unresectable MPM, it isn’t clear which patients for whom the risks of early disease progression and higher serious TRAEs from immune blockade are warranted.

Disclosures: This research was supported by Bristol Myers Squibb. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Read more of Cancer Therapy Advisor’s coverage of the ESMO World Congress on Gastrointestinal Cancer 2021 by visiting the conference page.


  1. Peters S, Scherpereel A, Cornelissen R, et al. First-line nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) in patients (pts) with unresectable malignant pleural mesothelioma (MPM): 3-year update from CheckMate 743. Presented at: European Society for Medical Oncology (ESMO) Congress 2021; September 16-21, 2021. Abstract LBA65.
  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. 2003;21(14):2636-44. doi:10.1200/JCO.2003.11.136
  3. Dudek AZ, Wang X, Gu L, et al. Randomized Study of Maintenance Pemetrexed Versus Observation for Treatment of Malignant Pleural Mesothelioma: CALGB 30901. Clin Lung Cancer. 2020;21(6):553-561.e1. doi:10.1016/j.cllc.2020.06.025
  4. Zalcman G, Mazieres J, Margery J, et al. Bevacizumab for newly diagnosed pleural mesothelioma in the mesothelioma avastin cisplatin pemetrexed study (MAPS): A randomized, controlled, open-label, phase 3 trial. Lancet. 2016;387(10026):1405-1414. doi:10.1016/S0140-6736(15)01238-6
  5. Tsao AS, Miao J, Wistuba II, et al. Phase II trial of cediranib in combination with cisplatin and pemetrexed in chemotherapy-naïve patients with unresectable malignant pleural mesothelioma (SWOG S0905). J Clin Oncol. 2091;37(28):2537-2547. doi:10.1200/JCO.19.00269
  6. 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. 2021;397(10272):375-386. doi:10.1016/S0140-6736(20)32714-8
  7. Kazandjian D, Gong Y, Keegan P, et al. Prognostic value of the lung immune prognostic index for patients treated for metastatic non-small cell lung cancer. JAMA Oncol. 2019;5(10):1481-1485. doi:10.1001/jamaoncol.2019.1747