Until recently, no randomized phase III trials have demonstrated OS improvement in patients with relapsed malignant mesothelioma [1, 2]. PD-1 inhibition with single-agent nivolumab has shown activity in three phase II studies, one of which led to the approval of nivolumab in Japan [3-5]. The CONFIRM trial is the first placebo-controlled, randomized, phase III trial investigating an anti-PD-1 antibody in relapsed mesothelioma. Patients after > 1 prior line of standard chemotherapy were randomized to either nivolumab 240 mg on day 1 of a 14-day cycle (n = 221) or placebo (n = 111). Approximately 60 % in each arm were treated in the third line. In 37 % and 29 %, respectively, PD-L1 assessment revealed TPS ≥ 1 %. OS and investigator-reported PFS constituted the co-primary endpoint. At WCLC 2020, Fennell et al. reported the preliminary results .
OS difference of almost 3 months
The study met its primary endpoint. Nivolumab therapy gave rise to a 28 % reduction in mortality risk, with median OS of 9.2 vs. 6.6 months (HR, 0.72; p = 0.018). At 12 months, 39.5 % vs. 26.9 % of patients were alive. Median PFS was 3.0 vs. 1.8 months (HR, 0.61; p < 0.001), with 12-month rates of 14.5 % vs. 4.9 %. Subgroup analyses according to PD-L1 TPS demonstrated that this biomarker did not predict OS. In contrast, histology mattered, as patients with the epithelioid subtype derived a significant survival benefit from nivolumab treatment (9.4 vs. 6.6 months; HR, 0.71; p = 0.021), whereas those with the non-epithelioid type showed similar outcomes across the arms (5.9 vs. 6.7 months; HR, 0.79; p = 0.572).
Favorable safety results
Median duration of treatment was 84 and 43 days for nivolumab and placebo, respectively. Grade ≥ 3 AEs were observed in 45 % vs. 42 %, and serious grade ≥ 3 AEs in 36 % vs. 39 %. Deaths attributable to serious AEs occurred in 3.6 % vs. 5.3 %. Overall, the findings obtained in the CONFIRM study identified nivolumab as safe and effective in patients with relapsed mesothelioma. The authors emphasized that the PD-1 inhibitor should be considered a new treatment option in this setting.
- Popat S et al., A multicentre randomised phase III trial comparing pembrolizumab versus single-agent chemotherapy for advanced pre-treated malignant pleural mesothelioma: the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial. Ann Oncol 2020; 31(12): 1734-1745
- Krug LM et al., Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Oncol 2015; 16(4): 447-456
- Scherpereel A et al., Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial. Lancet Oncol 2019; 20(2): 239-253
- Quispel-Janssen J et al., Programmed death 1 blockade with nivolumab in patients with recurrent malignant pleural mesothelioma. J Thorac Oncol 2018; 13(10): 1569-1576
- Okada M et al., Clinical efficacy and safety of nivolumab: results of a multicenter, open-label, single-arm, Japanese phase II study in malignant pleural mesothelioma (MERIT). Clin Cancer Res 2019; 25(18): 5485-5492
- Fennell D et al., Nivolumab versus placebo in relapsed malignant mesothelioma: preliminary results from the CONFIRM phase 3 trial. WCLC 2020, PS01.11
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