Simple SummaryUsing a randomized discontinuation design, sorafenib was tested on patients with advanced/metastatic solid tumors previously treated by standard treatments and harboring sorafenib-targeted genes. Patients with stable disease after 12 weeks of sorafenib induction treatment were randomized equally between continuation or interruption of sorafenib. Continuing sorafenib when stable disease is achieved, after a 12-week induction treatment, improves progression free rate compared to interruption. Sorafenib has tumor-agnostic efficacy in patients with tumors harboring genomic alterations in PDGFRA/B, VEGF-Rs, Flt-3, KIT, FGFR1 or the RAF/MEK/ERK pathway.AbstractBackground: MOST-plus is a multicenter, randomized, open-label, adaptive Phase II trial evaluating the clinical benefit of targeted treatments matched to molecular alteration in advanced/metastatic solid tumors. Sorafenib was tested on patients with tumors harboring sorafenib-targeted genes. Methods: The MOST-plus trial used a randomized discontinuation design. After 12 weeks of sorafenib (400 mg, po BID), patients with progressive disease discontinued study, patients with objective response were proposed to continue sorafenib, whereas patients with stable disease (SD) were randomly assigned (1:1) to the maintenance or interruption of treatment. The primary endpoint was RECIST version 1.1 progression-free rate at 16 weeks after randomization (PFR-16w). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Statistical analyses used a sequential Bayesian approach with interim efficacy analyses. The enrolment could be stopped in the case of a 95% probability for the estimated PFR-16w to be higher in the maintenance than in the interruption arm (NCT02029001). Results: 151 patients were included, of whom 35 had SD at 12 weeks of Sorafenib. For the 35 patients with SD on sorafenib, the PFR-16w was 65% [95% credibility interval 43.4–83.7] in the continuation arm and 25% [7.8–48.1] in the interruption arm. Median PFS and OS were improved in the maintenance versus the interruption arm (mPFS: 5.6 [95%CI 1.97–6.77] months versus 2.0 [95%CI 1.61–3.91] months (p= 0.0231) and mOS: 14.3 [95%CI 8.9–23.8] versus 8.0 months [95%CI 3.5–15.2] (p= 0.0857)). Conclusion: Sorafenib showed activity in progressive patients with solid tumors harboring somatic genomic alterations in sorafenib-targeted genes. Continuing sorafenib when SD is achieved improves PFR compared to interruption.