Combined PD-1, BRAF and MEK inhibition in BRAF V600E colorectal cancer

February's paper of the month looks at the treatment of patients with metastastic colorectal cancer patients with BRAF^V600E mutations.

Tian, J., Chen, J.H., Chao, S.X. et al.
Combined PD-1, BRAF and MEK inhibition in BRAF^V600E colorectal cancer: a phase 2 trial. Nat Med (2023)
https://doi.org/10.1038/s41591-022-02181-8

What is known about the subject?

BRAF^V600E mutations occur in approximately 10% of colorectal cancers, resulting in activation of MAPK signaling. Patients with BRAF^V600E CRC show unfavourable clinical outcomes and respond poorly to standard therapies. The role of surgical treatment, especially in metastatic setting, is questionable. The median overall survival is half that of BRAF wild-type colorectal cancer. [1,2] The Food and Drug Administration recently approved the combination of the anti-EGFR antibody cetuximab and the BRAFi encorafenib for use in this patient population. The response rate of this treatment regimen is 20% and the clinical effects are not durable with a median progression-free survival of 4.3 months. [3,4]

What the study adds?

This phase II clinical trial of 37 patients was designed to test the safety and effectiveness of dabrafenib and trametinib combined with the anti-PD-1 antibody PDR001 in patients with BRAF^V600E mutated metastatic colorectal cancer. Patients at the Dana-Farber Cancer Institute and the Massachusetts General Hospital Cancer Center were treated with spartalizumab (PDR001) 400 mg iv every 28 days, and the combination of oral dabrafenib 150 mg and trametinib 2 mg daily for 28 consecutive days. The primary end point was overall response rate, and the secondary end points were disease control rate, progression-free survival, duration of response and overall survival.

The study met its primary end point: the response rate was 24.3% and 25% in microsatellite stable patients. Response rate and durability were favourable compared to historical controls treated with BRAF-targeted combinations alone. Single-cell RNA sequencing of paired pre-treatment and treatment day 15 tumour biopsies showed more favorable responses in patients with better clinical outcomes.

Implications for colorectal practice

This trial showed that prognosis of patients with BRAF^V600E mutated colorectal cancer can be improved by this new treatment regimen. This may impact clinical decision making with regard to surgery in this patient group, which historically has shown very poor clinical outcomes. These study results call for future optimization of targeted and immune combinations in colorectal cancer patients.

References

1. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).
2. Richman, S. D. et al. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J. Clin. Oncol. 27, 5931–5937 (2009)
3. Kopetz, S. et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N. Engl. J. Med. 381, 1632–1643 (2019).
4. Corcoran, R. B. et al. Combined BRAF, EGFR, and MEK inhibition in patients with BRAF(V600E)-mutant colorectal cancer. Cancer Discov. 8, 428–443 (2018)