Mirati may have been beaten to the punch by Amgen after it nabbed a speedy FDA approval for its KRAS drug Lumakras this year, but it’s still pushing to try to wring the most efficacy out of its rival therapy.
To this end, the little biotech is teaming up with French pharma giant Sanofi, wedding its experimental KRAS inhibitor adagrasib with Sanofi’s investigational SHP2 inhibitor SAR442720 in patients who have already had some treatment in KRAS G12C-positive non-small lung cell cancers (NSCLCs) .
Mirati is hoping to rival Amgen in NSCLC and colorectal cancer (where it recently got a boost). In lung cancer, it recently dropped top-line results from a phase 2 cohort at the European Society for Medical Oncology's 2021 meeting from its KRYSTAL-1 study, with adagrasib showing a response rate of 43% in second-line or later patients with metastatic NSCLC with a KRAS-G12C mutation.
This is broadly in line with what we’ve seen with Lumakras, and Mirati hopes the data can be good enough to register for an FDA approval. In the meantime, combos, as so often in cancer, may boost what a drug can do on its own, and that’s why it’s teaming up with Sanofi.
Sanofi is offering up its SHP2 inhibitor SAR442720, which came out of a 2018 deal with Revolution Medicines that saw the Big Pharma pay $50 million (with $500 million in biobucks) for access to work on the small-molecule drug.
RELATED: Mirati switches up leadership as KRAS drug speeds toward FDA filing
SHP2, the tyrosine phosphatase encoded by oncogene PTPN11, drives a subset of cancers and has a role in the RTK-RAS-MAPK cascade and other pathways that are dysregulated in tumors.
Knowledge of these links led Revolution to work on inhibitors that block these signaling cascades, slowing tumor growth. The inhibitors may be effective in cancers of the lung, colon and skin with mutations in KRAS, NF1 or BRAF.
SHP2 is upstream of KRAS and referees cellular signaling through the RAS/MAP kinase pathway; it's often overactive in various types of cancer. KRAS G12C inhibition and SHP2 inhibition have “complementary mechanisms of action and have demonstrated additive anti-tumor activity in preclinical models,” the pair said in a statement, and the companies will now take this idea into the clinic to see whether it pans out.
Under the deal, Sanofi is responsible for sponsoring and operating the phase 1/2 study, and, jointly with Mirati, “will oversee and share costs of the study,” though no other financial terms were disclosed.
“Mirati is aggressively advancing a broad adagrasib development program, which includes pursuing novel combination approaches including through this collaboration with Sanofi,” said Charles Baum, M.D., Ph.D., president, founder and head of R&D at Mirati.
“There is strong scientific rationale for combining a SHP2 inhibitor with adagrasib, which may help optimize clinical outcomes for patients with KRASG12C-dependent tumors.”
A growing number of biotechs and pharmas are also working on this target, including Navire Pharma; Genentech and Relay Therapeutics; Novartis; Erasca; and others.