The combination of the BRAF inhibitor encorafenib with cetuximab and nivolumab produced responses in 50% of patients and disease control in 96% of patients with microsatellite-stable BRAF V600E–mutated metastatic colorectal cancer in a phase I/II trial reported at the 2022 ASCO Gastrointestinal Cancers Symposium. The findings were presented by Van K. Morris, MD, Associate Professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston.1
“Encorafenib, cetuximab, and nivolumab appears to be a safe and well-tolerated combination for patients with microsatellite-stable BRAF-mutated metastatic colorectal cancer.”— Van K. Morris, MD
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“Encorafenib, cetuximab, and nivolumab appears to be a safe and well-tolerated combination for patients with microsatellite-stable BRAF-mutated metastatic colorectal cancer. The efficacy of this combination appears promising when considering the precedent of encorafenib and cetuximab alone from the previously reported BEACON study,2” Dr. Morris said.
As Dr. Morris explained, most BRAF V600E–mutated metastatic colorectal tumors are microsatellite-stable/mismatch repair–proficient and derive no clinical benefit from anti–PD-1/PD-L1 therapies alone. Microsatellite-stable BRAF V600E–mutated disease is also characterized by higher levels of immune activation and higher tumor mutational burden than microsatellite-stable BRAF wild-type colorectal tumors. In vitro, the treatment of microsatellite-stable BRAF V600E–mutated colorectal cancer with inhibitors of BRAF and the epidermal growth factor receptor (EGFR) triggers a switch from a mismatch repair–proficient state to a mismatch repair–deficient state.
Study Details
The study has enrolled 26 patients with microsatellite-stable BRAF V600E–mutant metastatic colorectal cancer who had received one or two prior lines of therapy but no prior targeted drugs (BRAF, MEK, ERK, or EGFR inhibitors) or immunotherapy. The median age of patients was 58; most were female (58%), White (85%), had right-sided primary colon tumors (62%), and had received one prior line of treatment (62%).
Patients received oral encorafenib at 300 mg daily, cetuximab at 500 mg/m2 every 14 days, and nivolumab at 480 mg every 28 days. The primary endpoints of the phase I/II study were radiographic response and safety/tolerability.
KEY POINTS
- In patients with metastatic colorectal cancer harboring BRAF V600E mutations whose tumors are microsatellite stable, the triplet of encorafenib, cetuximab, and nivolumab led to responses in 50% of patients and disease control in 96%.
- At a median follow-up of 16.3 months, the median progression-free survival was 7.4 months, median overall survival was 15.1 months, and median duration of response was 7.7 months.
- The addition of the PD-1 blocker, nivolumab, appeared to improve outcomes over those achieved with encorafenib and cetuximab alone in the landmark BEACON trial.
At a median follow-up of 16.3 months, the median progression-free survival was 7.4 months, median overall survival was 15.1 months, and median duration of response was 7.7 months with this triplet, Dr. Morris reported.
“For patients who are experiencing responses, there is continued reduction in tumor size across the period of treatment,” he further noted. “For the 11 patients who continue to remain on study, 2 remain on treatment with encorafenib, cetuximab, and nivolumab beyond 70 weeks.”
Outcomes Better Than Beacon Results
Putting these data into context, he pointed to the results of the phase III BEACON study, whose results led to the approval of encorafenib plus cetuximab for previously treated BRAF V600E–mutated metastatic colorectal cancer.2 In BEACON, the encorafenib/cetuximab doublet led to responses in 20% of patients and yielded a median progression-free survival of 4.2 months and a median overall survival of 9.3 months.
In the dose-finding phase of the current study, no dose-limiting toxicities were seen. Common adverse effects of any grade included headache (65%), nausea (35%), maculopapular rash (31%), arthralgia (27%), acneiform rash (27%), chills (23%), and precancerous skin lesions (23%). Grade 3 toxicities, seen in one patient each, included colitis, maculopapular rash, asymptomatic elevated amylase/lipase, and leukocytosis. One grade 4 adverse event, myositis, was observed.
Future Directions
Could the inclusion of a MEK inhibitor have potentially enhanced the immune response and further improved outcomes? “This is a good question,” Dr. Morris said. “There are findings that do support the combination of BRAF/MEK inhibitors and anti–PD-1, but because the standard of care for now is encorafenib/cetuximab, this was the combination we were initially interested in combining with an anti–PD-1 partner. How we can deepen this response and do better for this population in need is something we will look at in the future.”
The phase II SWOG 2107 trial will be evaluating encorafenib and cetuximab with or without nivolumab in this population.
DISCLOSURE: Dr. Morris has received honoraria from Projects in Knowledge; has served as a consultant or advisor to Array Biopharma, Axiom Healthcare Strategies, Bicara Therapeutics, BioMedical Insights, Boehringer Ingelheim, Incyte, and Servier; and has received institutional research funding from BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono, Immatics, and Pfizer.
REFERENCES
1. Morris VK, Parseghian CM, Escano M, et al: Phase I/II trial of encorafenib, cetuximab, and nivolumab in patients with microsatellite stable, BRAF V600E metastatic colorectal cancer. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 12. Presented January 22, 2022.
2. Kopetz S, Grothey A, Yaeger R, et al: Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med 381:1632-1643, 2019.
