Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer

Author(s): Elena Elez, M.D., Ph.D.^1,2; Takayuki Yoshino, M.D., Ph.D.³; Lin Shen, M.D.⁴; Sara Lonardi, M.D.⁵; Eric Van Cutsem, M.D., Ph.D.^6,7; Cathy Eng, M.D.⁸; Tae Won Kim, M.D., Ph.D.⁹; Harpreet Singh Wasan, M.D.¹⁰; Jayesh Desai, F.R.A.C.P.^11,12; Fortunato Ciardiello, M.D., Ph.D.¹³; Rona Yaeger, M.D.¹⁴; Timothy S. Maughan, M.D.¹⁵; Van K. Morris, M.D.¹⁶; Christina Wu, M.D.¹⁷; Tiziana Usari, B.Sc.¹⁸; Robert Laliberte, M.S.¹⁹; Samuel S. Dychter, M.D.²⁰; Xiaosong Zhang, M.D., Ph.D.²¹; Josep Tabernero, M.D., Ph.D.^1,2,22; Scott Kopetz, M.D., Ph.D.¹⁶; for the BREAKWATER Trial Investigators*;

Source: DOI: 10.1056/NEJMoa2501912

Dr. Anjan Patel's Thoughts

The BREAKWATER trial evaluated encorafenib, cetuximab, and mFOLFOX6 as a first-line therapy for BRAF V600E–mutated metastatic colorectal cancer, showing very significant improvements in progression-free survival (PFS) (12.8 vs 7.1mos) and overall survival (OS) (30.3 vs 15.1mos). The combo also achieved a higher overall response rate (ORR). (60 vs 40%), positioning it as a new standard for this challenging patient population. Of note, side effects like nausea, diarrhea, and neuropathy, which were more frequent with this regimen. I would use this in the appropriate patient.

BACKGROUND

First-line treatment with encorafenib plus cetuximab (EC) with or without chemotherapy (oxaliplatin, leucovorin, and fluorouracil [mFOLFOX6]) for BRAF V600E–mutated metastatic colorectal cancer, an aggressive subtype with a poor prognosis, was compared with standard care (chemotherapy with or without bevacizumab) in an open-label, phase 3 trial, which showed significance regarding one of the two primary end points, objective response according to blinded independent central review (odds ratio for EC+mFOLFOX6 vs. standard care, 2.44; one-sided P<0.001). This result led to accelerated Food and Drug Administration approval of this investigational combination therapy for BRAF V600E–mutated metastatic colorectal cancer, including as first-line therapy. Data on progression-free survival (the second primary end point) and an updated interim analysis of overall survival are now available.

METHODS

We randomly assigned patients with untreated BRAF V600E–mutated metastatic colorectal cancer to receive EC, EC+mFOLFOX6, or standard care. The two primary end points were objective response (reported previously) and progression-free survival according to blinded independent central review in the EC+mFOLFOX6 group and the standard-care group. The key secondary end point was overall survival.

RESULTS

Significantly longer progression-free survival was seen with EC+mFOLFOX6 than with standard care (median, 12.8 vs. 7.1 months; hazard ratio for progression or death, 0.53; 95% confidence interval [CI], 0.41 to 0.68; P<0.001). In an interim analysis, overall survival was significantly longer with EC+mFOLFOX6 than with standard care (median, 30.3 vs. 15.1 months; hazard ratio for death, 0.49; 95% CI, 0.38 to 0.63; P<0.001). The incidence of serious adverse events during treatment was 46.1% with EC+mFOLFOX6 and 38.9% with standard care. Safety profiles were consistent with those known for each agent.

CONCLUSIONS

This trial showed significantly longer progression-free survival and overall survival with first-line treatment with EC+mFOLFOX6 than with standard care among patients with BRAF V600E–mutated metastatic colorectal cancer. (Funded by Pfizer and others; BREAKWATER ClinicalTrials.gov number, NCT04607421.)

Author Affiliations

¹Vall d’Hebron Hospital Campus, Barcelona; ²Vall d’Hebron Institute of Oncology, Barcelona; ³National Cancer Center Hospital East, Kashiwa, Japan; ⁴Beijing Cancer Hospital, Beijing; ⁵Veneto Institute of Oncology, IRCCS, Padua, Italy; ⁶University Hospitals Gasthuisberg Leuven, Leuven, Belgium; ⁷KU Leuven, Leuven, Belgium; ⁸Vanderbilt-Ingram Cancer Center, Nashville; ⁹Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; ¹⁰Hammersmith Hospital, Division of Cancer, Imperial College London, London; ¹¹Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; ¹²University of Melbourne, Melbourne, VIC, Australia; ¹³University of Campania Luigi Vanvitelli, Naples, Italy; ¹⁴Memorial Sloan Kettering Cancer Center, New York; ¹⁵University of Liverpool, Liverpool, United Kingdom; ¹⁶University of Texas M.D. Anderson Cancer Center, Houston; ¹⁷Mayo Clinic, Phoenix, AZ; ¹⁸Pfizer, Milan; ¹⁹Pfizer, Cambridge, MA; ²⁰Pfizer, La Jolla, CA; ²¹Pfizer, South San Francisco, CA; ²²University of Vic–Central University of Catalonia, Barcelona;

Trastuzumab Rezetecan in Human Epidermal Growth Factor Receptor 2–Expressing Advanced Gastric Cancer or Gastroesophageal Junction Adenocarcinoma and Colorectal Cancer: A Multicenter, Open-Label, Phase I Trial

Encouraging phase I signal for this HER2-targeted Antibody-drug conjugate (ADC) in heavily pretreated GI cancers, 45% overall response rate (ORR) and 16.3mo median overall survival (OS) in HER2-positive gastric compares favorably with T-DXd benchmarks, and the 40.5% objective response rate (ORR) with 22.7mo OS in HER2-positive colorectal cancer (CRC) is notable. The 2% ILD rate looks meaningfully better than T-DXd’s reported range, which could be a real differentiator. Hematologic toxicity is substantial but manageable. Small China-only phase I, but worth watching closely as this advances.

Postoperative Hepatic Arterial Infusion With Oxaliplatin After Surgery of Four or More Colorectal Liver Metastases: A Randomized Phase II Trial

For high-risk patients with four or more colorectal liver metastases, adjuvant hepatic arterial infusion oxaliplatin roughly doubled hepatic recurrence-free survival versus standard IV chemotherapy (25 vs. 12 months), with recurrence-free survival (RFS) benefit as well. Overall survival (OS) didn't reach significance but the absolute difference and 5-year OS of 62% versus 47% suggest a real effect worth confirming in phase III. Toxicity was higher in the hepatic arterial infusion (HAI) arm but manageable with no treatment-related deaths. Generalizability remains the challenge, these needs specialized centers with HAI expertise, but worth keeping in mind for your highest-risk resected liver met patients.

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Tumor Debulking in Combination With Chemotherapy in Multiorgan Metastatic Colorectal Cancer: The ORCHESTRA Randomized Clinical Trial

Open-label, phase 3 clinical trial, 382 patients were randomized to receive chemotherapy alone or chemotherapy plus tumor debulking. The overall survival rates were not statistically different, with a median overall survival in the chemotherapy alone group of 27.5 m vs 30.0 m in the chemotherapy plus tumor debulking group hence tumor debulking added to palliative systemic chemotherapy did not result in significantly improved survival compared with chemotherapy alone in patients with multiorgan metastatic colorectal cancer.

Atezolizumab plus FOLFOX for Stage III Mismatch Repair–Deficient Colon Cancer

This is a strong adjuvant signal in resected stage III dMMR colon cancer, adding atezolizumab to mFOLFOX6 cut the risk of recurrence or death in half and improved 3-year DFS from 76% to 86%. OS hasn’t separated yet, but that may be confounded by immunotherapy at relapse. Toxicity was higher, as expected, with more grade 3–4 events and immune-related adverse events (AE)s, but overall manageable. This feels practice changing for stage III dMMR disease.