NEW YORK – Revolution Medicines announced today that it has dosed the first patient in a Phase Ib clinical trial evaluating its investigational SHP2 inhibitor, RMC-4630, in combination with Amgen's KRAS G12C inhibitor AMG510.
The open-label, dose escalation and expansion study, sponsored and conducted by Amgen, is evaluating the combination in patients with advanced solid tumors characterized by KRAS G12C mutations. Revolution is supplying RMC-4630 for the trial, in which researchers will also track the safety, efficacy, and pharmacokinetics of the combination.
As seen in preclinical studies, tumor cells driven by mutations in the RAS pathway become addicted to RAS signaling for survival. Suppressing this signaling by simultaneously targeting KRAS G12C mutations and by inhibiting SHP2, which also plays a role in cell survival, appears to be a promising strategy based on early studies in non-small cell lung cancer. The addition of a SHP2 inhibitor may also block a key resistance pathway that RAS-dependent tumor cells use to proliferate and avoid shut down by a KRAS inhibitor.
Revolution CEO Mark Goldsmith highlighted in a statement that RMC-4630 monotherapy has shown promising activity in lung cancers with KRAS G12C mutations. The company presented this data earlier this year at a medical conference. Based on insights from that study, "it is compelling to pair this investigational drug with KRAS G12C inhibitors such as AMG 510," Goldsmith said in a statement.
Revolution has an exclusive research, development and commercialization agreement with Sanofi for its SHP2 inhibitor program, including RMC-4630. Under that collaboration, the drug is being studied as a single agent in a Phase I trial involving patients with various tumor types and oncogenic mutations; and in a Phase Ib/II study in combination with cobimetinib (Genentech/Exelixis' Cotellic) in relapsed or refractory solid tumors with RTK, KRAS, BRAF class 3, or NF1 loss of function mutations.
In March, Revolution announced that in collaboration with the Netherlands Cancer Institute, RMC-4630 and an investigational ERK inhibitor would also be studied in the Phase I/IB SHERPA trial in RAS-mutated solid tumors.