Anti-EGFR therapy effective for certain patients with BRAF-mutant colorectal cancer
Click Here to Manage Email Alerts
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.
Perspective
Back to TopDavid H. Ilson, MD, PhD
Not all BRAF mutations are V600E. Up to one-fourth of these mutations may be non-V600E and have distinct biologic and potentially clinical implications.
BRAF V600E mutations are class 1, are considered kinase activating and are independent of activated RAS upstream, explaining resistance to EGFR inhibition of RAS signaling. These occur more commonly in right-sided tumors and are associated with poorer prognosis. Non-V600E mutations are more common in left-sided tumors and in younger patients, and some may convey a more favorable prognosis compared with BRAF wild-type tumors. Class 2 mutations are kinase activating and RAS independent, whereas class 3 mutations are weakly kinase activating and retain RAS signaling dependence and, therefore, may retain sensitivity to EGFR-targeted agents, as they are dependent on upstream RAS activation by the EGFR pathway.
Yaeger and colleagues report an ambitious multicenter collaborative analysis of BRAF non-V600E mutations in metastatic colorectal cancer. Out of 40 of these patients who underwent therapy with an EGFR inhibitor, alone or with chemotherapy, 30% were class 2 and 70% were class 3. Response to EGFR therapy occurred among 8% of patients with class 2 and 50% of those with class 3 mutations. Responses in class 3 occurred in first-, second- and third-line settings, but response occurred in only one patient treated first-line with class 2. Researchers also observed responses in right-sided and left-sided cancers with class 3 mutations.
This intriguing study indicates that patients with rarer, BRAF non-V600E mutations who are RAS wild-type may benefit from therapy with EGFR-targeted agents if they are class 3, but those with class 2 mutations may not derive benefit. Patients with a BRAF V600E mutation may benefit, however, from EGFR-targeted agents combined with a BRAF inhibitor and with or without a MEK inhibitor.
Read more about
Click Here to Manage Email Alerts