Dr Bekaii-Saab on Treatment Evolutions in KRAS G12C–Mutant and HER2-Overexpressing CRC

Tanios Bekaii-Saab, MD, FACP, professor, medicine, senior associate consultant, Hematology and Oncology, co-leader, Gastrointestinal Cancer Program, Mayo Clinic, discusses the evolution of treatment for patients with KRAS G12C–mutant and HER2-overexpressing colorectal cancer (CRC).

The CRC field has become increasingly intriguing because of the emergence of various actionable genomic alterations and their corresponding therapeutic matches, Bekaii-Saab begins. Two significant updates that occurred in the realm of CRC in 2023 revolved around KRASG12C mutations and HER2 overexpression, which have garnered substantial attention, he states. The combination of adagrasib (Krazati) and cetuximab (Erbitux) is effective against KRASG12C mutations, which are found in a small percentage of patients, Bekaii-Saab says.

Notable, although less striking, outcomes have occurred with sotorasib (Lumakras) and panitumumab (Vectibix) treatment combinations, which yield response rates ranging from 30% to approximately 50%, along with durable responses, Bekaii-Saab expands. These developments represent a significant shift in the approach of targeting a specific RAS mutation subtype within CRC. Consequently, these advances have been incorporated into the National Comprehensive Cancer Network guidelines, transforming the armamentarium of clinical practice for this patient subgroup, he emphasizes.

Another exciting focus within CRC is the subgroup of patients characterized by HER2 amplification, which accounts for approximately 3% to 4% of metastatic CRC cases, Bekaii-Saab continues. This subgroup has seen much progress in the past year. Notably, in January 2023, the FDA granted approval to the combination of tucatinib (Tukysa) and trastuzumab (Herceptin)for patients with RAS wild-type disease with HER2 overexpression, he explains. This approval followed the promising results of the phase 2 MOUNTAINEER trial (NCT03043313), which demonstrated high response rates, enduring responses, and favorable outcomes in patients who received this treatment approach, Bekaii-Saab explains.

Currently, the combination of tucatinib and trastuzumab is progressing into the phase 3 research arena with the MOUNTAINEER-03 trial (NCT05253651), which aims to randomly assign patients to receive mFOLFOX6 (5-Fluorouracil, leucovorin, and oxaliplatin) with or without the treatment combination. This trial promises further insights into the efficacy of this treatment approach, Saab concludes.