Encorafenib/Cetuximab/Binimetinib Triplet Safe and Effective in BRAF V600E–Mutant mCRC

Eric Van Cutsem, MD, PhD

Treatment with the BRAF inhibitor encorafenib (Braftovi) in combination with cetuximab (Erbitux) and binimetinib (Mektovi) was active with a manageable safety profile in the first-line setting for patients with BRAF V600E–mutated metastatic colorectal cancer (mCRC), according to findings from the phase 2 ANCHOR CRC study (NCT03693170) published in the Journal of Clinical Oncology.¹

At the April 12, 2021, data cutoff of the efficacy analysis, patients who received the combination and were included in the full efficacy set (n = 95) achieved a confirmed objective response rate (cORR) of 47.4% (95% CI, 37.0%-57.9%), which met the study’s primary end point. All responses were partial responses. Additionally, at a median follow-up of 20.1 months, the median progression-free survival (PFS) was 5.8 months (95% CI, 4.6-6.6) and the estimated median overall survival (OS) was 18.3 months (95% CI, 14.1-21.1).

“These results highlight the benefit of the triplet regimen in previously untreated patients with BRAF V600E–mutated mCRC, suggesting that it may be an option for patients not eligible to receive standard first-line therapy,” the study authors wrote.¹

Positive findings from the safety lead-in of the phase 3 BEACON CRC trial (NCT02928224) led to the design of ANCHOR CRC. Updated results from BEACON CRC presented during the 2019 Gastrointestinal Cancer Symposium showed that patients with BRAF V600E–mutated mCRC who received encorafenib plus binimetinib and cetuximab (n = 30) in the second- or third-line setting experienced a cORR of 48% (95% CI, 29.4%-67.5%), a median PFS of 8.0 months (95% CI, 5.6-9.3), and a median OS of 15.3 months (95% CI, 9.6-not reached). The combination was also found to be well-tolerated with no new safety signals.²

ANCHOR CRC was an open-label, multicenter, single-arm trial that enrolled adult patients with BRAF V600E-mutated mCRC with an ECOG performance status of 0 or 1. Patients who were previously treated with a RAF or MEK inhibitor, cetuximab, or any other EGFR inhibitor, as well as those with symptomatic brain metastases were not eligible for enrollment.¹

Oral encorafenib was given at a dose of 300 mg once daily in 28-day cycles and oral binimetinib was administered twice daily at a dose of 45 mg. Intravenous cetuximab 400 mg/m² was administered once on day 1 of cycle 1, then at a dose of 250 mg/m² once every week for the first 7 cycles, and 500 mg/m² once on days 1 and 15 from cycle 8 onward. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, initiation of subsequent anticancer therapy, or death.¹

Most patients who received the triplet were women (54%), 65 years or older (55%), and had an ECOG performance status of 1 (54.7%). The median age was 65 years (range, 30-84) and the median time since initial diagnosis was 66 days (range, 19-3235). The most common metastatic site locations included liver (54.7%), lymph node (51.6%), peritoneum/omentum (48.4%), and lung (36.8%), with most patients having at least 2 organs affected by metastasis (75.8%).¹

The primary end point was cORR by local tumor assessments. Secondary end points included cORR by central tumor assessments, duration of response (DOR), time to response (TTR), PFS, OS, and safety and tolerability. Patient assessment occurred every 6 weeks for the first 12 weeks, followed by every 8 weeks thereafter.

Additional findings from the trial showed that the median DOR was 5.1 months (95% CI, 3.8-8.5) by local review and 5.1 months (95% CI, 3.4-6.8) by central review. The median TTR was 1.4 months by both local (95% CI, 1.4-1.5) and central review (95% CI, 1.3-1.4).¹

The estimated 12-, 18-, and 24-month OS rates were 65%, 50%, and 35%, respectively. The median time to subsequent therapy or death was 6.9 months (95% CI, 5.5-8.3). Most patients received at least 1 additionally antineoplastic therapy after progression (60%), including FOLFOX with or without bevacizumab (Avastin) or cetuximab (n = 29), FOLFOXIRI with or without bevacizumab (n = 16), FOLFIRI with or without bevacizumab or aflibercept (Eylea; n = 15), and immunotherapy (n = 5).

In terms of patient quality of life, treatment with the combination did not result in any significant changes in 5-Level EuroQol 5-Dimension or European Organization for Research and Treatment of Cancer QoL Questionnaire Core 30 scores. Substantial improvements in symptoms by Patient Global Impression of Changes scale were reported by at least 30.4% of patients in the full analysis set between day 1 of cycle 3 and day 1 of cycle 10 (range, 30.4%-52.0%). Notably, there were no patients who reported symptoms getting much worse or very much worse up to day 1 of cycle 22.¹

The median durations of exposure to encorafenib, binimetinib, and cetuximab were 4.96 months (range, 0.09-15.40), 4.67 months (range, 0.07-14.95), and 4.96 months (range, 0.23-15.15), respectively. Safety results showed that 99% of patients experienced an adverse event (AE) of any grade, 52% of which were serious AEs (SAEs). AEs leading to death were reported in 3 patients.

The most common any-grade AEs included diarrhea (67%), nausea (45%), dermatitis acneiform (40%), and rash (40%). AEs that were at least grade 3 in severity included anemia (11%), asymptomatic lipase increase (11%), diarrhea (10%), and nausea (8%).¹

Common any-grade serious AEs (SAEs) included intestinal obstruction (17%), renal failure (8%), nausea (5%), abdominal pain (4%), diarrhea (4%), and vomiting (4%). The most frequent grade 3 or greater SAEs were intestinal obstruction (15%), renal failure (7%), nausea (5%), and abdominal pain (4%).

Study authors noted that ANCHOR CRC was, to their knowledge, the largest prospective study with BRAF inhibitor–based therapy, without chemotherapy, in the first-line treatment of patients with BRAF V600E–mutant mCRC. They added that the study was limited by a lack of randomization and the unknown number of patients with microsatellite instability–high or mismatch repair deficient cancers.¹

Other ongoing trials in the first-line setting include the phase 3 BREAKWATER trial (NCT04607421), which will compare the safety and efficacy of encorafenib plus cetuximab, with or without FOLFOX, with standard-of-care treatment. The study will enroll approximately 705 patients with BRAF V600E–mutant mCRC whose disease is not microsatellite instability high or mismatch repair deficient. The study is recruiting patients and primary results are expected by the end of 2024.^1,3

References

1. Van Cutsem E, Taieb J, Yaeger R, et al. ANCHOR CRC: results from a single-arm, phase ii study of encorafenib plus binimetinib and cetuximab in previously untreated BRAFV600E-mutant metastatic colorectal cancer. J Clin Oncol. 2023;41(14):2628-2637. doi:10.1200/JCO.22.01693
2. Kopetz S, Grothey A, Yaeger R, et al. Updated results of the BEACON CRC safety lead-in: encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) for BRAFV600E-mutant metastatic colorectal cancer (mCRC). J Clin Oncol. 2019;37(suppl 4):688. doi:10.1200/JCO.2019.37.4_suppl.688
3. Astudy of encorafenib plus cetuximab with or without chemotherapy in people with previously untreated metastatic colorectal cancer. ClinicalTrials.gov. Updated April 28, 2023. Accessed May 15, 2023. https://www.clinicaltrials.gov/ct2/show/NCT04607421