Switch maintenance gemcitabine after first-line chemotherapy in patients with malignant mesothelioma: A multicenter open label phase II trial (NVALT19)

Abstract

Background: All malignant mesothelioma (MM) patients progress after first‐line therapy. We examined whether switch maintenance gemcitabine in patients, who did not show progression after first‐line platinum‐pemetrexed, could prolong time to disease progression. Methods: NVALT19 was an open label, randomized phase II trial, conducted in The Netherlands. Main eligibility criteria were pathologically proven MM, ECOG‐PS 0‐2 and completion of 4‐6 cycles of first‐line platinum‐pemetrexed without progression. Patients were randomized 1:1 between gemcitabine (1250 mg/m2 day 1 and 8 of 3 weekly schedule) or best supportive care (BSC). Gemcitabine was given until disease progression, severe toxicity or patient request for discontinuation. Primary endpoint was progression free survival (PFS) determined by local physician according to modified RECIST (mRECIST) or death in the intention‐to‐treat population. It was computed that 118 events would yield 90% power to detect an increase in PFS from median 3.5 months to median 6 months at 90% confidence level. Results: Between March 2014 and February 2019, 130 patients were randomized, 65 in each arm. PFS was significantly longer with gemcitabine (median 6.2 months [range 4.6‐8.7m]) than in the BSC arm (3.2 [2.8‐4.2m]; hazard ratio 0.42; 95% confidence interval [CI], 0.28‐0.63; p<0.0001). The PFS probability at 12 months was 25% for Maintenance Gemcitabine (95% CI: 16.3‐38.5%) and 3.3%for BSC (95% CI: 0.8‐13%). Central revision of PFS, by a blinded radiologist, also showed significant benefit for gemcitabine (median 5.3 months [4.2‐7.1m]) above BSC (2.8 [2.5‐3.3m]; hazard ratio 0.42; 95% CI 0.28 to 0.62; p<0.0001). Grade 3‐4 adverse events (AE) occurred more in the gemcitabine arm (57% of patients) vs 13% in the BSC‐arm. Neutropenia (22%), nausea (6%) and lung infection (5%) were most common treatment related grade III AE's. Three patients (5%) experienced grade IV neutropenia. One patient died in the gemcitabine arm due to treatment related sepsis. Data on dose intensity will follow at ESMO 2019. Conclusions: Switch maintenance gemcitabine after first‐line chemotherapy significantly improves the PFS in malignant mesothelioma, with a manageable toxicity profile.