Dr. Weiss on the Rationale for the KRYSTAL-1 Trial in KRAS G12C–Mutated CRC

Jared Weiss, MD, associate professor of medicine, Division of Oncology, Department of Medicine, University of North Carolina (UNC) School of Medicine, associate director of finance, UNC Lineberger Clinical Protocol Office, UNC Lineberger Comprehensive Cancer Center, discusses the rationale for the phase 1/2 KRYSTAL-1 trial (NCT03785249) in patients with KRAS G12C–mutated colorectal cancer (CRC).

KRAS G12C mutations are present in approximately 3% to 4% of patients with CRC. Moreover, the presence of these mutations in patients with CRC predicts for poor responses to cetuximab (Erbitux), Weiss explains. The KRAS protein cycles between GTP-on and GDP-off states and has a protein resynthesis of approximately 24 hours.

Adagrasib is a covalent and selective inhibitor of KRAS G12C that irreversibly binds to the inactive GDP-bound mutational state, Weiss explains. The agent was optimized for desirable properties including a long half-life of around 1 day, dose-dependent pharmacokinetics, and the potential for brain penetrance.

Preclinically, EGFR signaling was found to be the dominant resistance mechanism to KRAS G12C inhibition in CRC cells. Moreover, dual inhibition of EGFR and KRAS G12C demonstrated greater phospho-ERK modulation. In vivo cell line–derived and patient-derived xenograft models experienced deeper and more durable tumor regressions with the dual-inhibition strategy vs single-inhibition strategies, Weiss explains.

As such, the hypothesis of the KRYSTAL-1 trial was that combining adagrasib with cetuximab, an EGFR inhibitor, would improve outcomes for patients with CRC by enhancing inhibition of KRAS G12C–dependent signaling or overcoming adaptive feedback, Weiss concludes.