Dr Kopetz on the Background of the KRYSTAL-1 Trial in KRAS G12C+ mCRC

Scott Kopetz, MD, PhD, FACP, professor, gastrointestinal medical oncology, associate vice president, Translational Integration, The University of Texas MD Anderson Cancer Center, discusses the rationale for evaluating adagrasib (Krazati) in combination with cetuximab (Erbitux) in the phase 1/2 KRYSTAL-1 trial (NCT03785249) in patients with locally advanced or metastatic colorectal cancer (mCRC) harboring KRAS G12C mutations.

This research investigates the use of adagrasib, a covalent inhibitor of KRAS G12C, in patients with mCRC, Kopetz begins. Previous studies have revealed that the CRC response rate to single-agent adagrasib or other KRAS G12C inhibitors has been suboptimal due to adaptive resistance mechanisms and feedback involving receptor tyrosine kinases, he reports. Therefore, the rationale behind KRYSTAL-1 is to assess the efficacy of adding cetuximab to adagrasib, Kopetz says, adding that earlier evidence from the phase 1 portion of the study demonstrated that this combination is active in patients with mCRC.

During the 2024 AACR Annual Meeting, researchers presented data from the phase 1 and phase 2 portions of KRYSTAL-1 evaluating the efficacy of adagrasib plus cetuximab in patients with KRAS-mutated mCRC, he continues. KRAS G12C mutations are found in approximately 3% to 4% of CRC cases, which accounts for approximately 40% of mCRC cases; thus, these patients have a significant unmet medical need, Kopetz explains.

Developing effective inhibitors that can target KRAS G12C has been challenging, he expands. Advances in understanding the molecular structure of KRAS have led to the development of covalent inhibitors capable of binding to the cysteine residue unique to KRAS mutations, according to Kopetz. These breakthroughs have facilitated significant progress in addressing KRAS-mutated CRC, despite the lower prevalence of KRAS mutations in this disease compared with in other cancers, such as lung cancer, Kopetz reports. This ongoing research highlights the potential of this combination therapy in improving outcomes for this patient population, Kopetz concludes.