Sorafenib in Molecularly Selected Cancer Patients: Final Analysis of the MOST-Plus Sorafenib Cohort

Abstract

Background: 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.

Keywords: biologically driven trial; personalized medicine; randomized discontinuation design; sorafenib.

Figure 1

Trial profile. Following an induction period of 12 weeks, 145 treated and evaluable patients were categorized according to disease status: patients with objective response (OR, n = 5) continued sorafenib; patients with stable disease (SD, n = 35) were randomized (R) with a 1:1 ratio to the maintenance (blue) or interruption (red) arm; and patients with progressive disease (PD, n = 105) permanently discontinued sorafenib. Randomization was stratified according to ECOG PS: 0−1 versus 2 at randomization. Non-evaluable patients were defined as patients with less than one cycle of treatment due to a reason other than disease progression, sorafenib-related toxicities, or death. ¹ All patients with OR at W12 have permanently discontinued sorafenib due to PD at time of database cutoff. ² Five patients in the interruption arm were randomized without documented SD: PD (n = 3), PR (n = 1), and NE (n = 1), and one patient was randomized in maintenance arm despite >28 days sorafenib temporary discontinuation before randomization. ³ This subgroup also includes patients with sorafenib permanent discontinuation before or at W12 due to toxicity (n = 34), investigator or patient decision (n = 14), death (n = 10), another reason (n = 1 with abnormal ECG at time of randomization).

Figure 2

Detailed graph of molecular alteration having led to sorafenib recommendation. Molecular alterations per gene name and type of alteration according to disease status at Week 12.

Figure 3

Progression Free rate at 16 weeks post-randomisation (PFR-16W), duration of treatment and best response from randomization. (A). Bayesian estimates of the probability distribution of being progression-free (success) at 16 weeks after randomization. Prior and posterior density functions of the probability of success were updated after each successive interim analysis. Success was defined as being progression-free at 16 weeks. (B). Duration of treatment and best response from randomization. Primary tumor site and molecular alterations having led to inclusion in the sorafenib cohort are listed for each patient. In the interruption arm (red lines), patients were proposed to reinitiate sorafenib in case of PD (black star). One patient was enrolled without molecular alteration and randomized in the interruption arm.

Figure 4

Kaplan Meier plots for progression free survival and overall survival (A) PFS from randomization. (B) OS from randomization. (C) PFS from inclusion. (D) OS from inclusion.