Subset of BRAF non-V600-Mutant mCRC Is Potentially More Sensitive to Anti-EGFR Therapy

Patients with metastatic colorectal cancer (mCRC) who harbored BRAF non-V600, RAS-dependent mutations were more likely to respond to anti-EGFR therapy versus those with BRAF non-V600, RAS-independent mutations, according to results of a multicenter pooled analysis published in Clinical Cancer Research.¹

Among patients with BRAF non-V600 mutations, 8% with RAS-independent mutations (class 2) responded to anti-EGFR therapy, whereas 50% of patients with RAS-dependent mutations (class 3) responded to anti-EGFR therapy (P = .02).

"Through the analysis of colorectal cancer tumors with specific BRAF mutations, we identified a potential new indication for anti-EGFR treatment, highlighting the power of precision oncology," study investigator Hiromichi Ebi, MD, PhD, chief of the Division of Molecular Therapeutics at the Aichi Cancer Center Research Institute in Nagoya, Japan, stated in a press release.²

Similar findings were reported, irrespective of whether patients received anti-EGFR therapy as first- or second-line therapy, or third or later-line treatment. In the first- or second-line setting, 17% of patients with class 2 BRAF non-V600 mutations and 78% patients with class 3 BRAF non-V600 mutations responded to anti-EGFR therapy (P = .04). In the third- or later-line setting, 0% of patients with class 2 BRAF non-V600 mutations and 37% of patients with class 3 BRAF non-V600 mutations responded to anti-EGFR therapy (P = .14).

"Cancer genomic profiling is rapidly transforming the clinical management of cancer patients," Ebi stated in the press release. "Results from our study indicate that metastatic colorectal cancer patients with certain BRAF mutations should be considered for anti-EGFR treatment, a new indication for this population of patients."

Approximately 10% of patients with mCRC harbor mutations in the BRAF gene. Historically, anti-EGFR therapy is not recommended for patients with class 1 BRAF V600 mutations as they are often right-sided and confer a worse response to EGFR inhibition. Notably, BRAF non—V600-mutant tumors often originate in the left side of the colon, but only those that are class 3 rely on EGFR to trigger RAS signaling.

To assess the activity of anti-EGFR therapy among the classes of BRAF non-V600 mutations, investigators retrospectively analyzed prospectively sequenced institutional data from 40 patients with mCRC who had been treated with anti-EGFR therapy between 2010 and 2017.

Among them were 12 class 2 BRAF non-V600 mutations and 28 class 3 BRAF non-V600 mutations. Baseline characteristics were comparable between groups.

Common treatment regimens included combinations of standard FOLFOX, irinotecan, or FOLFIRI, with EGFR antibodies cetuximab (Erbitux) and panitumumab (Vectibix).

The median overall survival (OS) of patients with BRAF non—V600-mutant mCRC was 40.2 months (95% CI, 30.4-50.0). Among patients with RAS wild-type tumors, those with class 2 BRAF non-V600—mutant mCRC had a median OS of 26 months versus 44.8 months in those with class 3 BRAF non-V600—mutant mCRC (P = .21).

The median duration of response to anti-EGFR therapy was 4 months (95% CI, 2.1-5.9) and 6.1 months (95% CI, 0.8-11.4) in the class 2 and class 3 BRAF non-V600—mutant mCRC groups, respectively (P = .25).

Notably, more than half of patients with left-sided class 3 BRAF non-V600 mutations responded to anti-EGFR treatment, whereas 2 of 7 patients with right-sided tumors responded to anti-EGFR therapy.

Patient-derived tumor models were also employed. Mice were treated with cetuximab at a dose of 50 mg/kg twice weekly or placebo and observed daily. Three cases of cetuximab resistance were reported among two class 2 and one class 3 BRAF non-V600—mutant xenograft models. Both cases of EGFR sensitivity were reported in class 3 BRAF non-V600—mutant models.

Due to the small number of patients harboring class 2 or class 3 BRAF non-V600 mutations and the fact that most patients assessed in the study also received chemotherapy, additional studies will be needed to validate the signal reported in the trial and evaluate the effects of EGFR-directed monotherapy within these functional classes of BRAF-mutant mCRC.

References

1. Patients with metastatic colorectal cancer harboring certain BRAF mutations may respond to anti-EGFR therapy. American Association for Cancer Research. Published September 12, 2019. https://bit.ly/2kbkJVE. Accessed September 12, 2019.
2. Yaeger R, Kotani D. Mondaca S, et al. Response to anti-EGRR therapy in patients with BRAF non-V600-mutant metastatic colorectal cancer [published online September 12, 2019]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-19-2004.