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First-line Nivolumab plus Ipilimumab versus chemotherapy in unresectable malignant pleural mesothelioma: CheckMate 743

Malignant pleural mesothelioma ( MPM ) is a highly aggressive cancer; most patients are diagnosed with unresectable disease, and the 5-year survival rate is less than 10%.
Standard of care treatment is Platinum / Pemetrexed chemotherapy and was approved in 2004; since then, limited treatment advances have been made.
More favorable outcomes have been associated with epithelioid versus non-epithelioid histology.

Previous reports of programmed death-1 ( PD-1 ) pathway blockade with Nivolumab ( Opdivo ) alone or in combination with cytotoxic T-lymphocyte–associated antigen 4 blockade with Ipilimumab ( Yervoy ) have shown activity in previously-treated malignant pleural mesothelioma.

The results of a prespecified interim analysis of the primary endpoint were presented.

CheckMate 743 is a phase 3 randomized study of first-line Nivolumab + Ipilimumab versus Platinum doublet chemotherapy in unresectable malignant pleural mesothelioma.

Adult patients with previously untreated, unresectable, histologically confirmed malignant pleural mesothelioma and ECOG performance status 0-1 were randomized ( 1:1; stratified by histology [ epithelioid vs nonepithelioid ] and sex ) to receive Nivolumab 3 mg/kg once every 2 weeks + Ipilimumab 1 mg/kg once every 6 weeks for up to 2 years or Platinum doublet chemotherapy ( Cisplatin [ 75 mg/m2 ] or Carboplatin [ AUC 5 ] plus Pemetrexed [ 500 mg/m2 ] for 6 cycles ).

The primary endpoint was overall survival ( OS ); key secondary endpoints included objective response rate ( ORR ), disease control rate, and progression-free survival ( PFS ), all per blinded independent central review.
Exploratory endpoints included safety and tolerability.

In total, 303 patients were randomized to Nivolumab + Ipilimumab and 302 to chemotherapy.

Baseline characteristics were balanced between arms, with an epithelioid histology reported for approximately 75% of patients in each treatment arm.

With a minimum follow-up of 22 months, the primary endpoint of overall survival was significantly improved with Nivolumab + Ipilimumab versus chemotherapy ( median, 18.1 vs 14.1 months; hazard ratio, HR, 0.74; 95% CI, 0.61–0.89; P = 0.002 ); 2-year OS rates were 40.8% vs 27.0%.

An OS benefit was seen with both epithelioid ( median, 18.7 vs 16.5 months; HR, 0.86; 95% CI, 0.69–1.08 ) and non-epithelioid ( median, 18.1 vs 8.8 months; HR, 0.46; 95% CI, 0.31–0.68 ) histologies; as expected, outcomes in the chemotherapy arm were better in patients with epithelioid histology.

Progression-free survival was similar between treatment arms ( HR, 1.00; 95% CI, 0.82–1.21 ); ORR ( 95% CI ) were 39.6% ( 34.1–45.4% ) vs 42.7% ( 37.1–48.5% ).

Grade 3-4 treatment-related adverse events were reported in 30.3% of patients on Nivolumab + Ipilimumab and in 32.0% of patients on chemotherapy, and led to discontinuation in 15.0% of patients on Nivolumab + Ipilimumab and 7.4% of patients on chemotherapy.

In conclusion, CheckMate 743 met its primary endpoint of statistically improved overall survival with Nivolumab + Ipilimumab versus standard of care chemotherapy in first-line treatment of unresectable malignant pleural mesothelioma.
The safety profile of Nivolumab + Ipilimumab was consistent with the known profile of this combination regimen, and no new safety signals were observed.
These clinically meaningful data represent the first positive phase 3 trial of immunotherapy in malignant pleural mesothelioma and may be considered as a new standard of care. ( Xagena )

Source: IASLC Virtual Presidential Symposium, 2020