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

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

Abstract 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) xenogr...

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Main Authors: Peter Gallagher, Christian Rolfo, Elena Elez, Julien Taieb, Jennifer Houlden, Linda Collins, Corran Roberts, Thierry André, Mark Lawler, Federica Di Nicolantonio, Margaret Grayson, Ruth Boyd, Vlad Popovici, Alberto Bardelli, Robbie Carson, Hajrah Khawaja, Pierre Laurent-Puig, Manuel Salto-Tellez, Bryan T. Hennessy, Tim S. Maughan, Josep Tabernero, Richard Adams, Robert Jones, Marc Peeters, Mark R. Middleton, Richard H. Wilson, Sandra Van Schaeybroeck, on behalf of the MErCuRIC Trial Consortium
Format: Article
Language:English
Published: Nature Portfolio 2025-03-01
Series:BJC Reports
Online Access:https://doi.org/10.1038/s44276-025-00133-6
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Summary:Abstract 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
ISSN:2731-9377

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