Switch Maintenance Gemcitabine after First Line Chemotherapy in Patients with Malignant Mesothelioma: A Randomized Open Label Phase II Trial (NVALT19)

Abstract

Background: All patients with malignant mesothelioma develop progressive disease after first line therapy. Some studies have addressed maintenance therapy, none showed a great impact. Gemcitabine, an active drug in mesothelioma, was tested in the NVALT19 study in a switch maintenance setting. Methods: This open label randomized phase II study in 18 Dutch hospitals, recruited patients with unresectable mesothelioma who did not progress after first line chemotherapy (platinum-pemetrexed), World Health Organization performance status ≤ 2 and an adequate organ function. Key exclusion criteria were seriously disabling conditions or symptomatic central nervous system metastases. Patient were 1:1 randomised to maintenance gemcitabine (1250 mg/m2, intravenous, day 1 and 8, 3 weeks schema) or best supportive care (BSC,) using minimisation method. Primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Safety was analysed in all participants who received one dose of study drug. Findings: From March 20, 2014, to February 27, 2019, 130 patient were randomized (65 to gemcitabine and 65 to BSC). PFS was significant longer with gemcitabine (median 6.2) than with BSC (3·2 months; hazard ratio (HR) 0·46; 95% confidence interval [CI], 0·31 to 0·68; p<0·001). The benefit was confirmed by independent central review (HR 0·47; 95% CI, 0·32 to 0·69; p<0·001). Grade 3- 4 adverse events occurred in 33 (51%) patients in the gemcitabine arm and in 10 (16%) patients in the BSC arm. One patient died likely due to a gemcitabine related infection. Interpretation: Switch maintenance gemcitabine, after first line chemotherapy, significantly prolonged progression free survival compared to BSC alone among patients with malignant mesothelioma. The study confirmed the activity of gemcitabine in malignant mesothelioma. Trial Registration: This study is registered in the Netherlands Trial registry; NTR4132/NL3847. Funding Statement: Dutch Cancer Society (KWF Kankerbestrijding) and the NVALT Study Group. Declaration of Interests: PB participated in advisory boards of Merck Sharp & Dohme and Bristol-Myers Squibb. RC participated in advisory boards of Merck Sharp & Dohme and Roche, and received speakers fee from Roche, Pfizer and BristolMyers Squibb. HJMG has received research funding from Lilly, Novartis, Roche-Genentech, and Takeda (all to institution). JGA reports personal fees and non-financial support from msd, personal fees from bms, personal fees from boehringer ingelheim, personal fees from amphera, personal fees from eli-lilly, personal fees from takeda, personal fees from bayer, personal fees from roche, personal fees from astra zeneca, outside the submitted work; In addition, JGA has a patent allogenic tumor cell lysate licensed to amphera, a patent combination immunotherapy in cancer pending, and a patent biomarker for immunotherapy pending. JAB reports reimbursement from Bristol-Myers Squibb and F Hoffmann-La Roche for the Netherlands Cancer Institute, and financial support for an investigator initiated trial from Merck Sharp & Dohme. CJG, VvdN, JAS, BB, NvW, RvH, MYES, AJS, WAB, GPB, FD, HvT, FL declare no competing interests. Ethics Approval Statement: The research protocol has been approved by the central ethical committee and local institutional review boards. All patients provided written informed consent.