First-Line Nivolumab plus Ipilimumab in Unresectable Malignant Pleural Mesothelioma: 3-Year Update from CheckMate-743

The prognosis has been generally poor for patients with malignant pleural mesothelioma (MPM), as it is an aggressive disease and usually unresectable at the time of diagnosis.¹ Chemotherapy had been the only available treatment, but long-term survival was poor with that treatment.¹ When bevacizumab was added to the regimen, survival improved, but this option has not been widely used.¹ Nivolumab (NIVO), an anti–PD-L1 antibody, plus ipilimumab (IPI), an anti-cytotoxic T-lymphocyte 4 antibody, have been shown to produce durable overall survival (OS) for treatment of melanoma, renal-cell carcinoma, and non–small-cell lung cancer.¹ Therefore, the investigators hypothesized that NIVO plus IPI when added to chemotherapy would improve the efficacy and safety of treatment for unresectable MPM.¹

Patients (N = 605) in the CheckMate-743 study were randomized to receive NIVO 3 mg/kg intravenously (IV) every 2 weeks plus IPI IV 1 mg/kg every 6 weeks or chemotherapy (cisplatin or carboplatin plus pemetrexed).¹ The primary end point was OS. Treatment was continued until unacceptable toxicity, disease progression, or 2 years of immunotherapy.¹

The median OS was 18.1 months (95% confidence interval [CI], 16.8-21.4) in the NIVO plus IPI group, compared with 14.1 months (95% CI, 12.4-16.2) in the chemotherapy group.^1,2 The 1-year OS was 68% (95% CI, 62.3-72.8) and 58% (95% CI, 51.7-63.2) for NIVO plus IPI and chemotherapy, respectively. At 2 years, OS was 41% (95% CI, 35.1-46.5) and 27% (95% CI, 21.9-32.4) for NIVO plus IPI and chemotherapy, respectively.¹

In this 3-year update, the OS in all randomized patients was 23.2% (95% CI, 18.4-28.2) for the NIVO plus IPI group compared with 15.4% (95% CI, 11.5-19.9) for the chemotherapy group.^2,3 The OS was also evaluated by histology; the 3-year OS in patients with epithelioid histology was 24% in the NIVO plus IPI group compared with 15% in the chemotherapy group; for the non-epithelioid histology, the OS was 22% compared with 4%, respectively.²

The progression-free survival at 3 years was 14% for the NIVO plus IPI group compared with 1% for the chemotherapy group.² The percentage of patients in response, measured by overall response rate/duration of response, was 28% for the NIVO plus IPI group compared with 0% for the chemotherapy group at the 3-year follow-up.

The exploratory analysis in this study evaluated OS by several other factors, including the 4-gene inflammatory signature score, which correlated with improved survival benefit with NIVO plus IPI. OS was also better with NIVO plus IPI than chemotherapy across all lung immune prognostic index scores. Tumor mutational burden did not correlate with better survival.³

Grade 3/4 treatment-related adverse events (TRAEs) occurred in 30% of the patients treated with NIVO plus IPI and in 32% of those treated with chemotherapy. Serious TRAEs occurred in 21% of the NIVO plus IPI group and in 8% of the chemotherapy group.¹ Grade 3/4 serious TRAEs occurred in 15% of patients in the NIVO plus IPI group and in 6% of patents in the chemotherapy group.¹ Deaths due to disease progression occurred in 61% of the NIVO plus IPI group and in 70% of the chemotherapy group.¹

In the NIVO plus IPI group, discontinuation of therapy occurred due to disease progression (61%) and drug toxicity (20%).¹ In the patients treated with chemotherapy, disease progression led to discontinuation of therapy in 16% of patients and drug toxicity led to 8% stopping therapy.¹

The 3-year update on TRAEs demonstrated that safety was consistent with the past report, with no change in the overall rate of TRAEs.² At 3 years, the efficacy in patients who discontinued NIVO plus IPI due to TRAEs was 37% as measured by OS. Of the responders who discontinued treatment secondary to TRAEs, 34% maintained their responses for ≥3 years after the discontinuation.²

In conclusion, first-line NIVO plus IPI as treatment for unresectable MPM has been shown to produce sustained survival improvement over 3 years. These data confirm NIVO plus IPI as the standard of care for treatment of unresectable MPM.^2,3

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. [Published correction appears in Lancet. 2021;397:670]. Lancet. 2021;397:375-386.
2. Peters S, Scherpereel A, Cornelissen R, et al. LBA65-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: ESMO Congress 2021; September 16-21, 2021.
3. Peters S, Scherpereel A, Cornelissen R, et al. LBA65-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. Ann Oncol. 2021;32(suppl_5):S1283-S1346.