CRC Yields Most Prevalent Data at Recent GI Meeting

According to Michael J. Pishvaian, MD, PhD, a single disease type emerged as the most prominent at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancer Symposium––colorectal cancer.

In an interview with CancerNetwork® Pishvaian, director of Gastrointestinal, Developmental Therapeutics, and Clinical Research Programs, and associate professor of Oncology at Johns Hopkins School of Medicine, discussed presentations from ASCO GI that were most notable to him and that he believed would impact clinical practice.

He suggested that keeping in line with precedent, a single disease type appeared to have a greater degree of prominence than others, with colorectal cancer assuming this role. He initially highlighted results from the phase 3 BREAKWATER trial (NCT04607421), which assessed encorafenib (Braftovi) in combination with cetuximab (Erbitux) as a first-line treatment in patients with newly-diagnosed BRAF V600E-mutated colorectal cancer.1 The results, he stated, were so overwhelmingly positive that the FDA gave the combination an approval a month before the results were presented at ASCO GI.2

Pishvaian also mentioned the phase 3 CheckMate 8HW trial (NCT04008030) which assessed the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) vs ipilimumab alone as a first-line treatment for microsatellite instability (MSI)-high colorectal cancer.3 In a similar trial, the phase 3 KEYNOTE-177 trial (NCT02563002), he remarked that pembrolizumab (Keytruda) elucidated a benefit for immunotherapy in this patient population.4

He further highlighted efficacy data from the CheckMate 8HW trial, which showed a benefit with the 2-drug combination vs nivolumab alone. Additionally, Pishvaian expressed excitement regarding a 68% to 78% rate of progression-free survival (PFS) after several years for this patient group. He concluded by explaining that these patients could be classified as “cured”, seeing as they sustained a PFS benefit, even after treatment with immunotherapy ended after 2 years.

Transcript:

There were some big presentations at the ASCO GI meeting this year. Every year, it seems to change––what disease type seems to be most prominent at an individual ASCO GI meeting. This year, it was colorectal cancer that stood out. First of all, most surprisingly, but a pleasant surprise, were the results of the [phase 3] BREAKWATER study. This was a newly diagnosed patient population with a specific mutation called a BRAF V600E mutation, which exists in about 7% to 12% of all colorectal cancers. We have known for years that it is a subgroup that has a poor prognosis ... even with our best chemotherapy.

There is a biomarker-based therapeutic combination of encorafenib and cetuximab that we have known for a few years that works well in this subgroup, but it was only tested in patients who had had 1 prior line of therapy. The [phase 3] BREAKWATER trial now moved that up to the first-line therapy, and everybody was surprised at how effective it was as first-line therapy compared with standard-of-care chemotherapy. In fact, it was such an overwhelmingly positive study that the FDA gave approval [to the combination] a month before the presentation even happened. That arguably, should be the new standard of care. It is encorafenib plus cetuximab and chemotherapy [fluorouracil, leucovorin, and oxaliplatin (FOLFOX)] for patients with BRAF V600E-mutated colorectal cancer.

In fact, 1 presentation later, there was another exciting study, which was immunotherapy for microsatellite instability [MSI]-high colorectal cancer. We have known for a decade plus––in fact, it was the Johns Hopkins team [in the phase 3 KEYNOTE-177 trial] that demonstrated that pembrolizumab has a dramatic impact on patients with MSI-high colorectal cancer, leading to a significant response rate and improvement in survival times. Over the years, it was never clear whether pembrolizumab was better than chemotherapy. There was a pivotal study about 3 or 4 years ago that proved once and for all that immunotherapy should be the way to go as first-line therapy for metastatic MSI-high colorectal cancer.

This next version of the study, [the phase 3 CheckMate 8HW trial] was looking at a similar drug, nivolumab, but compared it with a second drug, ipilimumab. The combination of the 2 was better than the 1 immunotherapy. Long story short, the combination of nivolumab and ipilimumab is arguably now the frontline standard of care. The most exciting [aspect of] that presentation was they have survival data that goes out several years, and what you see is, as we call a tail on the curve, you see a percentage of patients somewhere in the 50% to 60% range whose cancer never grows, and one could argue that they might be cured because the study stopped the therapy at 2 years. After 2 years, they [experienced] no cancer growth. That is our definition of a cure. We are excited about those data.

References

1. Kopetz S, Yoshino T, Cutsem EV, et al. BREAKWATER: analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer. J Clin Oncol. 2025;43(suppl 4):16. doi:10.1200/JCO.2025.43.4_suppl.16
2. FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. News release. FDA. December 20, 2024. Accessed March 31, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-encorafenib-cetuximab-and-mfolfox6-metastatic-colorectal-cancer-braf
3. André T, Elez E, Lenz HJ, et al. Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial. Lancet. 2025;405(10476):383-395. doi:10.1016/S0140-6736(24)02848-4
4. André T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability–high advanced colorectal cancer. N Engl J Med. 2020;383(23):2207-2218. doi:10.1056/NEJMoa2017699