Anti-EGFR therapy effective for certain patients with BRAF-mutant colorectal cancer
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Anti-EGFR therapy showed promising efficacy for certain patients with non-V600 BRAF-mutated metastatic colorectal cancer, according to results of a multicenter, pooled analysis published in Clinical Cancer Research.
Specifically, half of patients with kinase-impaired and RAS-dependent BRAF mutations responded to the therapy, whereas almost none of those with kinase-activating and RAS-independent mutations responded.
“Our study provides guidance on which patients with BRAF alterations are most likely to respond to EGFR-based therapy — half of patients with hypoactive, class 3 BRAF alterations responded to EGFR-based therapy alone or with chemotherapy,” Rona Yaeger, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, told HemOnc Today.
BRAF mutations occur in between 8% and 12% of metastatic colorectal cancer cases, most commonly at the V600 amino acid, according to study background. Identification of non-V600 BRAF alterations has increased with the use of next-generation sequencing. However, how these alterations affect treatment response has not been well-examined.
For this reason, Yaeger and colleagues conducted a multicenter, pooled analysis of 40 patients with non-V600 BRAF-mutated metastatic colorectal cancer who received anti-EGFR antibody therapy. Researchers divided non-V600 BRAF mutations into two functional classes, kinase activating and RAS independent (class 2, n = 12) and kinase impaired and RAS dependent (class 3, n = 28).
“This functional classification suggests that BRAF alterations that belong to class 2 — where the mutants activate signaling independent of RAS — should be resistant to upstream inhibitors, such as EGFR. On the other hand, those that belong to class 3, where the mutants depend on RAS activation to amplify signaling, could be sensitive to upstream inhibitors,” Yaeger told HemOnc Today.
Researchers did not observe significant differences in clinical characteristics of patients according to mutation class. However, 50% (n = 14) of those with class 3 BRAF mutations responded to EGFR-based therapy compared with only 8% (n = 1) of patients with class 2 BRAF mutations (P = .02).
Moreover, 78% of patients with class 3 BRAF mutations responded to first- or second-line treatment, compared with only 17% of those with class 2 BRAF mutations (P = .04). Thirty-seven percent of patients with class 3 BRAF mutations and no patients with class 2 BRAF mutations responded to third- or later-line EGFR-based therapy.
Researchers reported median PFS of 4.4 months (95% CI, 0.9-7.9) among those treated with third- or later-line EGFR-based therapy.
Results of a subgroup analysis of patients stratified by mutation class showed median duration of response to EGFR-based therapy of 4 months (95% CI, 2.1-5.9) among those with class 2 BRAF-mutant disease compared with 6.1 months (95% CI, 0.8-11.4) for those with class 3 BRAF-mutant disease.
The small number of patients in the cohort and its retrospective nature served as the study’s primary limitations, according to the researchers.
“Our study highlights the need for better targeted therapies for patients with non-V600-activating BRAF alterations,” Yaeger told HemOnc Today. “This is an area of active research, with preclinical data suggesting activity for MEK inhibitors or newer RAF inhibitors. Our study also indicates that a significant portion of patients with class 3, low-activity BRAF-mutant colorectal cancer do not respond to EGFR antibodies. We are currently studying what other receptors may be important in these tumors and if there is a broad way to inhibit upstream activation in these tumors.” – by Jennifer Southall
For more information:
Rona Yaeger, MD, can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: yaegerr@mskcc.org.
Disclosures: Yaeger reports receiving commercial research grants from Array Biopharma, GlaxoSmithKline and Novartis. Please see the study for all other authors’ relevant financial disclosures.