Expansion of Targeted Therapies Into Earlier Lines Reinforces Need for Upfront Biomarker Testing in mCRC

With data from trials such as the phase 3 BREAKWATER study (NCT04607421) strongly supporting the use of targeted therapy combinations upfront in colorectal cancer (CRC), and efforts to move RAS inhibitors, HER2-directed therapies, and other targeted approaches into earlier lines expected to further complicate therapeutic sequencing, early biomarker testing has become even more vital for optimized therapeutic decision-making, according to Shubham Pant, MD, MBBS.

Results from BREAKWATER showed that encorafenib (Braftovi) plus cetuximab (Erbitux) and fluorouracil-based chemotherapy significantly improved progression-free survival and meaningfully prolonged overall survival (OS) vs standard FOLFIRI (leucovorin calcium [folinic acid], fluorouracil, and irinotecan hydrochloride) with or without bevacizumab (Avastin) in previously untreated metastatic CRC (mCRC) harboring a BRAF V600E mutation.¹

Of note, updated data from the overall population and cohort 3 of BREAKWATER supported the FDA’s decision to grant traditional approval to this combination in February 2026.² In cohort 3, which was initiated upon amendment to the trial to limit randomization to arms B and C, patients in the encorafenib arm (n = 73) achieved an objective response rate of 64% (95% CI, 53%-74%) vs 39% (95% CI, 29%-51%) in the control arm (n = 74; P = .0011).

“As we know from the BREAKWATER trial, it’s important to remember that we need to sequence patients with CRC up front when they come [into the clinic],” Pant shared in an interview with OncLive®. “We really should be trying—unless there is some other reason, like if they’re just too sick to get any therapy—to use a biomarker-driven approach in the front line.”

In addition to spotlighting the benefit of giving patients targeted therapies up front in CRC, Pant highlighted therapeutic goals and factors influencing third-line strategies, as well as the growing complexity of sequencing decisions amid ongoing targeted therapy development. Pant is a professor in the Department of Gastrointestinal (GI) Medical Oncology and director of Clinical Research at The University of Texas MD Anderson Cancer Center in Houston.

OncLive: How do BREAKWATER trial data justify the use of encorafenib plus cetuximab and fluorouracil-based chemotherapy as a new standard for first-line BRAF V600E–mutant mCRC and reinforce the importance of biomarker testing at diagnosis?

Pant: If you really look at the data, they’re very strong [in favor of] using targeted therapy up front, and I think that’s what we are doing. What we found out in CRC and other solid tumor malignancies is that if we hit the target early and hard, we can really improve the OS of these patients just by getting access to therapies, even if there is some crossover. We know that a good percentage of patients fall off after frontline therapy and are not able to access any therapies in the second-line setting. I strongly believe that we should—if they’re fit enough—try to give patients the benefit of these therapies up front.

Obviously, if [a patient has] KRAS wild-type [disease] and has a left-sided tumor, then they could be a candidate for EGFR antibody therapy. If they have a BRAF mutation, then they could get a BRAF[-targeted] agent up front with chemotherapy. We really need to be looking to move biomarker [identification] in CRC to the time of diagnosis in these patients because it can impact which path they take toward their therapy.

Once patients have progressed on standard first- and second-line regimens, which clinical and molecular factors influence your approach to third-line sequencing in mCRC?

Third-line treatment is very different in CRC than the first few lines of treatment. We look for clinical trials for our patients who we think would be ideal for third-line treatments, essentially. But we also have TKIs [tyrosine kinase inhibitors] like fruquintinib (Fruzaqla) and other agents out there that we could treat patients in the third line with. Normally, what we look at is the performance status of the patient, the burden of disease, and the availability of any clinical trials [to inform these strategies].

How do you expect the third-line treatment landscape to evolve as targeted therapies and biomarker-driven strategies continue to move earlier in the treatment paradigm?

I think it’s going to be complicated. Nowadays, we are looking at chemotherapy plus targeted agents, and they’re being moved up quickly to the frontline setting. We are looking at these new RAS inhibitors, which are not only being tested in pancreatic cancer but also in CRC. We already have HER2 inhibitors, which started in the later lines, and they were quickly moved to the frontline. It’s just a very evolving field. I think we’ll see more of these targeted therapies being tried in later lines, but then quickly moving to frontline settings.

[There will be] a need for new therapies to take their place, but there are so many different therapeutics, like c-MET[–targeted] antibody-drug conjugates, which are ways to tackle CRC. It’s a fairly exciting [landscape] right now.

References

1. Pfizer’s Braftovi regimen improves progression-free survival in metastatic colorectal cancer. News release. Pfizer. February 17, 2026. Accessed March 3, 2026. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-braftovi-regimen-improves-progression-free-survival
2. FDA grants traditional approval to encorafenib for metastatic colorectal cancer with a BRAF V600E mutation. FDA. February 24, 2026. Accessed March 3, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-encorafenib-metastatic-colorectal-cancer-braf-v600e-mutation?utm_medium=email&utm_source=govdelivery