Revolution releases the latest interim data on SHP2 plus MEK inhibitors

On October 24, Revolution Medicines announced at the 32nd International Symposium on Molecular Targeting and Cancer Therapy (EORTC-NCI-AACR) the latest I.b/II.
clinical trials of RAS mutant tumors have found that upstream activation of the subject tyrosine kinase (RTK) may induce drug resistance, making it difficult for MEK inhibitor monotherapy to show effective therapeutic results.
RMC-4630 is an effective selective inhibitor of SHP2 and has shown anti-tumor activity against RAS mutant NSCLC in phase I clinical trials (NCT03634982).
preclinical studies have shown that RMC-4630, in combination with MEK inhibitors, has combined activity in RAS mutated cancers and tumor models with neurofibrin 1 (NF1LOF) or BRAFclass3 mutations missing.
Ongoing Phase I.b/II. Clinical Trials (RMC-4630-02, NCT03989115) is an open label dose increment and dose extension study designed to evaluate RMC-4630 and Corbyn The safety, toerability, pharmacodynamics, pharmacodynamics, and pharmacodynamic characteristics in adult patients with RES signal path changes (KRASG12x, KRASamp, NF1LOF, BRAFclass3).
using RMC-4630 twice a week (d1, d4 or d1, d2) and corbedinib daily (21 days on, 7 off) or twice a week (d1, d2).
as of May 18, 2020, 33 patients had been treated in four different dosage groups/schedules.
the maximum dose level of RMC-4630 tested to date was 140 mg (d1, d2 or d1,d4 twice a week) and the maximum dose level of corbedinib was 40 mg or 60 mg (d1,d2) per day.
treatment-related adverse events (TRAEs) were diarrhea (63.6%), edema (33.3%) and plate plate plate reduction (24.2%).
3-4 levels were diarrhea (9.1%) and plate plate plate reduction (6.1%).
4 patients (1 for level 2 and 1 for level 3 adverse reactions) reported reversible vision blur and retinal lesions after continuous drugation and reversed after discontinuation of the giving of corbedinib.
pharmacodynamic profile of RMC-4630 co-corbedinib was consistent with monotherapy and no pharmacodynamic interaction was detected.
at all dose levels and programmes tested, exposure was within the range that led to tumor subsidion in preclinical models.
preliminary evidence of anti-tumor activity has been observed in KRASmut colorectal cancer, with 3 tumor reductions in 7 patients, including 1 unproven PR at the end of the data (tumor reduction range 10%-30%, treatment time 1.9-5.1 months).
interim data from this disclosure show that intermittent RMC-4630 is acceptable to be given in association with daily or intermittent cobitinib.
the combination will further evaluate anti-tumor activity in RAS-activated tumors in Phase II recommended dosages and dosing options.
Revolution has entered into an exclusive global research, development and commercialization agreement with Sanofi for the SHP2 inhibitor program, including RMC-4630.
RMC-4630 (SAR442720) is currently conducting a number of studies, including monodrides (code RMC-4630-01), with KRASG12C inhibitor AMG5 10 (code CodeBreaK 101), Cobitinib, PD-1 antibody Pabliju monoantigenic joint clinical study to evaluate the anti-tumor activity of RMC-4630 in different specific tumor species.