In the second panel of the Advancements in Oncology event, held on Saturday, June 1, The Oncology Brothers, Rahul Gosain, MD, MBA, and Rohit Gosain, MD, sat down with Cathy Eng, MD, FACP, FASCO, of Vanderbilt-Ingram Cancer Center, to discuss gastrointestinal cancer-related data from the 2024 American Society of Clinical Oncology Annual Meeting.
Together, they highlighted the significance and evolution of genetic mutations in colon cancer, pointing to recent studies on the importance of next-generation sequencing (NGS) and specific mutations such as KRAS G12C.
The Importance of NGS, KRAS G12C
Dr. Rahul Gosain emphasized the evolving understanding of cancer genetics, particularly regarding sidedness and KRAS wild-type status. He noted that it is not just about KRAS wild type anymore, pointing out significant data on KRAS G12C. The CodeBreaK 300 study, which investigated sotorasib, initially showed promise in phase 2 trials. However, the phase 3 data did not meet expectations in lung cancer, raising questions about the future direction of KRAS G12C treatments.
Dr. Eng underscored the critical role of NGS in identifying mutations like KRAS G12C. She expressed surprise at the number of newly diagnosed patients who still lack comprehensive NGS or even microsatellite instability testing, which she deemed crucial. Dr. Eng highlighted that the CodeBreaK study utilized sotorasib for patients with a KRAS G12C mutation, marking a breakthrough as the first drug specific to KRAS. “Not all patients are G12C. It is a very small minority in colorectal cancer. It is less than 5% of our patient population,” she explained.
Presented at the European Society for Medical Oncology Congress, the CodeBreaK 300 study demonstrated that sotorasib at a 960-mg dose significantly improved progression-free survival and response rates compared with a 240-mg dose in the control arm. The control group, treated with TAS-102 or regorafenib, had a 0% response rate, highlighting the necessity of NGS in identifying candidates for KRAS G12C-targeted treatments.
Dr. Eng stressed the urgency of performing NGS as soon as possible to identify eligible patients. She also noted the excitement surrounding the development of other KRAS G12C inhibitors and the emerging KRAS G12D inhibitors, which are currently in phase 1 trials.
Role of NGS in Managing Progression
Dr. Rohit Gosain mentioned the practice of repeating NGS panels upon disease progression. Dr. Eng agreed, especially for patients who were initially KRAS wild type but then progressed on EGFR therapy. She advocates for rechecking the KRAS status when considering rechallenging with anti-EGFR therapy after a certain period. The evolving nature of these panels, now capable of evaluating over 500 molecular alterations, underscores the value of retesting. “We started off with these small 50-mutation panels and now we are going to 500-plus molecular alterations that we are evaluating and amplifying. There is just so much that we are learning,” she stated.
Dr. Eng noted that while biopsies are ideal, they are not always feasible or preferred by patients. In such cases, blood-based assays are a viable alternative.
Treatment Options Beyond KRAS G12C
Dr. Rahul Gosain pointed out the limited treatment options after disease progression, even with targeted therapies like sotorasib. He inquired about the use of TAS-102, regorafenib, and the newly approved fruquintinib from the FRESCO-2 study.
Dr. Eng explained that 3 drugs are approved for use in the third-line or later settings, requiring prior treatment with fluoropyrimidine, oxaliplatin, or irinotecan-based therapies, and anti-EGFR therapy for KRAS wild-type patients. She emphasized the importance of shared decision-making due to potential toxicities. “It is really a discussion with the patient. It is really a shared decision-making approach,” she asserted.
Regorafenib, for instance, is known for its challenging side effects but can be managed with careful monitoring and step-up dosing, as indicated by the CORRECT trial and a smaller phase 2 re-dose study.
For TAS-102, Dr. Eng highlighted its combination with bevacizumab in the United States, which is well tolerated but can cause myelosuppression. She concludes by noting that while no drug is perfect, managing side effects is crucial for improving patient outcomes.
View the next segment of this session: Navigating TAS-102, Fruquintinib for Colorectal Cancer: Insights From Dr. Cathy Eng.
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