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Stand Up To Cancer, Mirati Fund Research into KRAS G12C Inhibitor Resistance


NEW YORK – Stand Up To Cancer and Mirati Therapeutics in May provided $3 million in funding to researchers at three cancer centers to investigate why some patients do not respond to the drugmaker's KRAS G12C inhibitor adagrasib.

The research will be conducted over three years at Massachusetts General Hospital Cancer Center, MD Anderson Cancer Center, and Dana-Farber Cancer Institute. Ryan Corcoran, director of the gastrointestinal cancer center program and the scientific director of the Termeer Center for Targeted Therapy at Mass General, and Scott Kopetz, deputy chair of gastrointestinal medical oncology at MD Anderson, will co-lead the research effort.

The funding was awarded through Stand Up To Cancer's Catalyst program, which facilitates partnerships between the pharma industry and academics on research to accelerate drug development and explore combination therapies. The translational research supported through the $3 million grant will span preclinical studies in tumor models to clinical trials exploring adagrasib combinations. Through this work, Corcoran said, researchers hope to expand adagrasib's benefit to more patients.

Recent data from the Phase II KRYSTAL-1 study of adagrasib in KRAS G12C-mutant non-small cell lung cancer showed that 43 percent of patients responded to monotherapy treatment, and the disease control rate, including patients who responded and had stable disease, was 80 percent. Based on this data, Mirati submitted a new drug application to the US Food and Drug Administration in February seeking adagrasib's marketing approval.

Mirati's main competitor in the KRAS G12C space, Amgen, launched its KRAS inhibitor Lumakras (sotorasib) for KRAS G12C-mutated advanced NSCLC last year. Amgen, however, is also exploring resistance to Lumakras and earlier this year partnered with researchers from Memorial Sloan Kettering to begin a master protocol trial exploring Lumakras combinations with a MEK inhibitor, a SHP2 allosteric inhibitor, a PD-L1 inhibitor, a pan-ErbB tyrosine kinase inhibitor, and an EGFR inhibitor, in patients with advanced KRAS G12C-mutant solid tumors.

In the effort supported by Mirati and Stand Up To Cancer, the researchers are exploring several forms of resistance to KRAS inhibition with adagrasib including acquired resistance, which occurs after patients initially respond to treatment but then stop, and primary resistance, in which patients don't respond to treatment at all.

"Therapeutic resistance is probably one of the biggest hurdles we face with any therapy," Corcoran said. "The reports of clinically acquired resistance to KRAS inhibition in patients [have found] almost all of these resistance mutations seem to cluster within the RAS pathway and lead to the reactivation of RAS and its downstream effectors."

Based on previous research by Corcoran's lab and other institutions, the researchers will explore the activity of adagrasib with an ERK inhibitor being developed by Erasca, ERAS-007, in a Phase Ib clinical trial involving KRAS G12C-mutated colorectal cancer and NSCLC. Preclinical data suggests KRAS and ERK inhibition together could address both primary and acquired resistance. Corcoran explained that resistance mutations often occur in genes downstream of KRAS in the RAS/MAPK pathway, allowing the cancer to continue growing despite the presence of a KRAS inhibitor.

Resistance can often occur due to other KRAS variants, such as G12D or G12V, and due to alterations in other genes downstream on the RAS pathway, such as BRAF, MEK, or ERK.

"The goal of our clinical trial is to intercept all of these mutations, both the rapid, adaptive switch that turns the pathway back on in primary resistance, as well as the eventual emergence of these mutations in acquired resistance, by intercepting that signal at the most downstream point in the pathway, which is ERK," Corcoran said.

The researchers will also explore other combination strategies. Corcoran's team will perform single-cell sequencing on tumor biopsies from patients before treatment with adagrasib and about two weeks after treatment. They will analyze that sequencing data to study changes in the tumor cells and immune cells and improve their understanding of the interaction between KRAS inhibition and immune response.

They will then explore the combination of adagrasib and immune checkpoint inhibitors in mouse models, Corcoran said, a strategy that seems to work against cancers driven by mutations in other RAS pathway genes, such as BRAF-mutated colorectal cancer.

"In a different subtype of colorectal cancer that has a BRAF mutation, we have very strong evidence that … in addition to driving cancer growth and cancer survival, [the alteration] also drives strong immunosuppressive signals within the cancer cell that make it harder for the immune system to recognize and less likely for the immune system to be able to kill," he said. "Preclinical as well as early clinical data have suggested that combining inhibitors of the RAS pathway with immunotherapy, such as immune checkpoint inhibitors, can have a strong cooperative effect."

Mirati is already exploring several combination studies with adagrasib including a Phase II trial combining the drug with Merck's checkpoint inhibitor Keytruda (pembrolizumab) in KRAS G12C-mutated NSCLC.

The company also has ongoing studies combining adagrasib with other RAS pathway inhibitors including Eli Lilly's EGFR inhibitor Erbitux (cetuximab), Novartis' SHP2 inhibitor TNO155, and Boehringer Ingelheim's SOS1 inhibitor BI 1701963.

"We're aiming to cross the full spectrum of translational research to bring multiple modalities to bear on this problem," Corcoran said. "We hope to really understand mechanistically why patients are responding and why some patients are not responding and use that information to design even more effective therapies down the road."