A phase Ia study of the MEK1/2 inhibitor PD-0325901 with the c-MET inhibitor crizotinib in patients with advanced solid cancers

Abstract

MEK1/2 inhibitor; C-MET inhibitor crizotinib; Advanced solid cancers

Inhibidor de MEK1/2; Inhibidor de c-MET crizotinib; Cáncer sólido avanzado

Inhibidor de MEK1/2; Inhibidor de c-MET crizotinib; Càncer sòlid avançat

Background: Single-agent MEK1/2 inhibition has been disappointing in clinical trials targeting RAS mutant (MT) cancers, probably due to upstream receptor activation, resulting in resistance. We previously found that dual c-MET/MEK1/2 inhibition attenuated RASMT colorectal cancer (CRC) xenograft growth. In this study, we assessed safety of MEK1/2 inhibitor PD-0325901 with c-MET inhibitor crizotinib and determined the optimal biological doses for subsequent clinical trials. Methods: In this dose-escalation phase I trial, patients with advanced solid tumours received PD-0325901 with crizotinib, using a rolling-6 design to determine the maximum tolerable dose (MTD) and safety/tolerability. Blood samples for pharmacokinetics and skin biopsies were collected. Results: Twenty-five patients were recruited in 4 cohorts up to doses of crizotinib 200 mg B.D continuously with PD-0325901 8 mg B.D, days 1-21 every 28 days. One in six patients exhibited a dose-limiting toxicity at this dose level. Drug-related adverse events were in keeping with single-agent toxicity profiles. The best clinical response was stable disease in seven patients (29%). Conclusions: PD-0325901/crizotinib can be given together at pharmacologically-active doses. The MTD for PD-0325901/crizotinib was 8 mg B.D (days 1-21) and 200 mg B.D continuously in a 28-days cycle. The combination was further explored with an alternate MEK1/2 inhibitor in RASMT CRC patients. Eudract-number: 2014-000463-40.

Funding was supported by MErCuRIC, funded by the European Commission’s Framework Programme 7, under contract ♯602901, research grants from Pfizer as well as the Tom Simms Memorial Fund in Queen’s University Belfast. SVS was supported by Cancer Research UK (C13749/A7261). VP was supported from Programme JAC - project SALVAGE (CZ.02.01.01/00/22_008/0004644) financed by MEYS – Co-funded by the European Union, and thanks the RECETOX Research Infrastructure (No LM2023069) financed by the Ministry of Education, Youth and Sports for supportive background. The research leading to these results has received funding from: AIRC under 5 per Mille 2018 - ID. 21091 program – P.I. Bardelli Alberto (A.B.); International Accelerator Award, ACRCelerate, jointly funded by Cancer Research UK (A26825 and A28223), FC AECC (GEACC18004TAB) and AIRC (22795) (A.B.); AIRC under IG 2023 - ID. 28922 project – P.I. Bardelli Alberto (A.B.); PRIN 2022 - Prot. 2022CHB9BA (A.B.). The study was sponsored by the University of Oxford.