Pilot Trial of Combined BRAF and EGFR Inhibition in BRAF-Mutant Metastatic Colorectal Cancer Patients

Abstract

Purpose BRAF mutant metastatic colorectal cancer (mCRC) forms an aggressive subset of colorectal cancer with minimal response to selective RAF inhibitors. Preclinical data show that reactivation of epidermal growth factor receptor (EGFR) signaling occurs in colorectal tumor cells treated with RAF inhibitors and that the addition of an EGFR inhibitor enhances antitumor activity. These data suggest that combined therapy with RAF and EGFR inhibitors could be an effective strategy for treating BRAF V600E mCRC. Experimental Design We undertook a pilot trial to assess the response rate and safety of the BRAF inhibitor vemurafenib combined with anti-EGFR antibody panitumumab in patients with BRAF mutant mCRC. Patients received standard approved doses of panitumumab and vemurafenib. Results Fifteen patients were treated. Performance status was ECOG 0 in four patients (27%) and ECOG 1 in 11 patients (73%). All patients had progressed through at least one standard treatment regimen, and eight (53%) had received previous fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy. Treatment was well tolerated, with less cutaneous toxicity than would be expected with either agent, and no cases of keratoacanthomas/squamous cell carcinomas. Tumor regressions were seen in 10 of 12 evaluable patients with partial responses in two patients (100% and 64% regression lasting 40 and 24 weeks, respectively), and stable disease lasting over six months in two patients. Conclusion Combined RAF and EGFR inhibition is well tolerated, with less cutaneous toxicity than would be expected with either agent, and results in modest clinical activity in this highly aggressive and chemo-resistant subset of CRC.

Prospective Comprehensive Genomic Profiling of Advanced Gastric Carcinoma Cases Reveals Frequent Clinically Relevant Genomic Alterations and New Routes for Targeted Therapies

“…At present, most suggestion of benefit from targeted therapy in gastric carcinoma is guided by analogy to other tumor types. Such reasoning highlights the limitations of this approach, for example, BRAF V600E-mutant colorectal www.TheOncologist.com adenocarcinoma has not suggested benefit from vemurafenib monotherapy [53,54]. Because new approaches such as the combination of vemurafenib and erlotinib confer some benefit to similar patients, as noted, it is hoped that analogous approaches can also benefit gastric carcinoma patients [54].…”

BRAF mutation as a biomarker in colorectal cancer

“…These responses, however, have been transient, with median progression-free survival of 3.2 months (95% CI: 1.6-5.3 months). 27 Preliminary findings from another study and a case report evaluating cetuximab and vemurafenib demonstrated similar results. 52,53 Preliminary findings from other studies have also noted modest activity with combination therapies targeting EGFR, BRAF, and MEK.…”

“…1,[24][25][26] In CRC, BRAF mutations have been found to be mutually exclusive with RAS mutations. 23,27 Additionally, the pattern of metastatic spread at diagnosis appears unique in this patient population compared to that in patients with BRAF-WT tumors. Liver involvement at the time of diagnosis was less common (60% vs 80%, P,0.01), and peritoneal involvement was more common (26% vs 14%, P,0.01).…”

“…Yaeger et al 27 recently published findings from a pilot trial in which 15 patients with BRAF-mutant CRCs were treated with a combination of BRAF and EGFR inhibition. Of 12 evaluable patients, disease shrinkage was noted in ten patients, including two with a partial response.…”

A Blueprint to Advance Colorectal Cancer Immunotherapies

“…MEK inhibitors can enhance T-cell function and improve checkpoint blockade as demonstrated in murine melanoma models (44). Clinical studies are investigating combinations between these inhibitors as well as with other modalities (45,46). Data from a trial using atezolizumab in combination with the MEK inhibitor cobimetinib show the combination was well tolerated, and patients had an ORR of 17% (4 PR and 5 SD;ref.…”