Pilot Trial of Combined BRAF and EGFR Inhibition in BRAF Mutant Metastatic Colorectal Cancer Patients
Mené sur 15 patients atteints d'un cancer colorectal métastatique présentant un gène BRAF muté, cet essai évalue l'activité antitumorale et la toxicité d'un traitement combinant panitumumab et vemurafenib
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.