Phase Ib Study Of Ribociclib (R) Plus Trametinib (T) In Patients (Pts) With Metastatic/Advanced Solid Tumours

In preclinical and preliminary clinical studies, the combined inhibition of MEK and CDK4/6 showed synergistic antitumor activity. This study aimed to determine the recommended phase II regimen (RP2R) and characterize the safety and preliminary efficacy of T (MEK inhibitor) in combination with R (CDK4/6 inhibitor) in pts with advanced solid tumours. Adult pts with advanced/metastatic solid tumours who failed ≥ 1 prior line of systemic therapy were enrolled in this multicenter, open-label study (NCT02703571). Here, we report results from the phase Ib part of the study. The safety of T (dose range, 1-2 mg) + R (dose range, 200-500 mg) was assessed across 11 cohorts using 2 different treatment schedules. The initial 28-day cycle of continuous T (2 mg) + 3W on/1W off R (200 mg) was modified to an intermittent schedule for safety reasons. A 21-day schedule of 2W on/1W off T + R was then explored. The primary objective was to determine maximum tolerated dose (MTD) and/or RP2R of the combination. The secondary objectives included safety, preliminary antitumor activity, and pharmacokinetics (PK). Biomarker analyses are ongoing as part of the exploratory objectives. A total of 95 pts were enrolled between June 2016 and September 2019. The median age was 58 y; 31% of the pts were aged ≥ 65 years. The primary sites of cancer at initial diagnosis were colon (27%), rectum (13%), and pancreas (11%). The median time since most recent relapse/progression to study entry was 2 mo. In the dose-determining set (n = 79), 12 pts (15%) experienced a dose-limiting toxicity. All pts (n = 95) experienced at least 1 adverse event (AE); most common was fatigue (57%). Serious AEs were reported in 42% of the pts. RP2R was T 1 mg + R 300 mg and MTD was T 1 mg + R 400 mg (T on W 1 and 2 + R on W 2 and 3 of a 21-day schedule). The objective response rate using RECIST 1.1 was 4%. The median progression-free survival was 2.6 mo. An increasing trend in T exposure was observed with increasing R dose. RP2R and MTD for T + R oral coadministration were established. The safety and tolerability profile of T + R combination was consistent with the prior experience as single agents. The efficacy of this combination was limited; phase 2 portion of the study was not pursued.