Targeted Therapies and Drivers for Treatment Choice in Colorectal Cancer

A roundtable discussion, moderated by Shikha Jain, MD, FACP, discussed the treatment sequencing, management, and future directions of advanced colorectal cancer, as well as relevant clinical trial data from the 2024 American Society of Clinical Oncology Annual Meeting. Dr. Jain was joined by Suneel Kamath, MD; Arvind Dasari, MD, MS; and Sakti Chakrabarti, MD.

In the second segment of the roundtable series, the panel swaps opinions on recent advancements in targeted therapies for colorectal cancer, including the use of EGFR and KRAS inhibitors, the importance of next-generation sequencing (NGS) and liquid biopsies, and strategies for managing progression in metastatic patients.

View the next segment on Treatment Considerations for Oligometastatic Colorectal Cancer.

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Dr. Jain: Let us discuss targeted agents, focusing on BRAF and EGFR status. EGFR and KRAS status have been longstanding topics in colorectal cancer, but recent advancements and newer treatments targeting these agents have emerged.

Dr. Dasari: EGFR antibodies have been around for about a decade to a decade and a half. We are still refining which patients benefit most, specifically RAS wild-type patients. For a long time, patients with RAS mutations had no targeted therapies, as RAS mutations were considered undruggable. However, recent breakthroughs have produced effective therapies against KRAS G12C, affecting a small proportion (2% to 3%) of colorectal cancer patients. This is just the beginning, with extended and pan-RAS inhibitors showing very exciting data, potentially leading to significant developments in the future.

Dr. Chakrabarti: I always emphasize the importance of conducting NGS on metastatic colorectal cancer patients upfront. If tissue is nott available, a liquid biopsy can provide crucial information about the cancer’s biology.

Dr. Jain: I agree. Let us explore liquid biopsies and NGS further. I get NGS for every metastatic patient without exception. Liquid biopsies are more debated. What are your thoughts on their use?

Dr. Chakrabarti: Liquid biopsies are logistically simple and provide valuable information, complementing solid tumor NGS. My preference is to do both upfront. If tissue is not available, a liquid biopsy can still detect important markers like HER2 amplification and MSI high status, which is better than having no genomic profiling at all.

Dr. Jain: Some clinicians get both NGS and a liquid biopsy for every metastatic patient. Is that your approach?

Dr. Chakrabarti: Yes, I send both tissue and liquid biopsy samples simultaneously. If tissue is insufficient, the liquid biopsy results can be very helpful and often complementary to tissue NGS.

Dr. Jain: What about you, Dr. Kamath? What is your approach?

Dr. Kamath: I agree. For metastatic cancer patients, I do both upfront. It is simple, cost-effective, and provides results faster. It complements tissue NGS, which should not be replaced but supplemented with liquid biopsy.

Dr. Jain: How do you handle progression? Do you rebiopsy at the first progression, use a liquid biopsy, or wait?

Dr. Dasari: In colorectal cancer, rebiopsy at progression is not as established as in other cancers. However, for patients previously treated with anti-EGFR therapy, a repeat liquid biopsy can be helpful when considering rechallenge. Also, for HER2/neu amplified patients, a tissue biopsy might be necessary to confirm HER2/neu status before continuing anti-HER2 therapies.

Dr. Jain: Regarding HER2 therapies, if a patient progresses on FOLFOX plus trastuzumab, do you continue anti-HER2 therapy with the next line, like FOLFIRI?

Dr. Dasari: It depends on the progression pattern. With anti-HER2/neu therapies, isolated lesions can be managed with local therapies while continuing the same treatment. For diffuse progression, we can switch to second-line anti-HER2/neu therapy or consider clinical trials.

Dr. Chakrabarti: If the HER2 amplification is still present, I would continue some form of anti-HER2 therapy. Confirmation depends on patient characteristics. For younger, healthier patients, a rebiopsy is preferable. For older, frailer patients, a liquid biopsy might be the better option.

Dr. Kamath: The oligo-progressive paradigm is critical. I have used SBRT for single lesions while continuing HER2-targeted therapy. This approach can be very effective.