Background: BRAF V600 mutations occur in 5–10% of CRC and confer poor prognosis. Unlike in BRAF mutant (BRAFm) melanoma, BRAF and MEK inhibitors show limited activity in BRAFm CRC. Preclinical data suggest that EGFR can mediate resistance in BRAFm CRC, which can be overcome by combined inhibition of BRAF and EGFR. Therefore, combined inhibition of the BRAF pathway (with D or D + T and with anti-EGFR agent P) to prevent EGFR-mediated resistance is a rational and promising approach to treat BRAFm CRC. Methods: Eligible pts with BRAFm CRC enrolled in Parts 1 and 2 of the ongoing 3-part study, dose escalation (DE; Part 1), cohort expansion (CE; Part 2) and a planned randomized comparison (Part 3), received either the doublet (D + P) or triplet (D + P + T) combination. Results: 19 pts received D + P ± T in DE or CE. Doublet: 6 pts received the full doublet dose (D 150 mg twice daily [BID] + P 6 mg/kg every 2 weeks [Q2W]) in Cohort 1 DE and 3 pts received the doublet in Part 2 CE. Triplet: 3 pts received the lowest combination dose of the triplet (D 150 mg BID + P 4.8 mg/kg Q2W + T 1.5 mg once daily [QD]) in Cohort 2. DE Cohorts 3A (D 150 mg BID + P 4.8 mg/kg Q2W + T 2 mg QD), n = 4 and 3B (D 150 mg BID + P 6 mg/kg Q2W + T 1.5 mg QD), n = 3 were opened simultaneously. No dose-limiting toxicities have been seen in any cohorts. Most common drug-related adverse event (AE) was dermatitis acneiform for doublet (5/9 pts, all Grade [Gr] 1) and triplet (5/10 pts, 3 Gr 1 and 2 Gr 2) pts. In the doublet group, no possibly drug-related Gr > 3 events were reported. In the triplet group, Gr > 3 events at least possibly drug-related, included vomiting (n = 1), rash (n = 1) and skin fissures (n = 1). In preliminary efficacy data, partial responses have been seen in 4/6 evaluable pts on the triplet dose (3/4 ongoing, 1 > 7 months) with 2 pts with stable disease (SD; 1 ongoing and 1 discontinued due to AE). Of the 8 evaluable pts on the doublet dose, 7/8 achieved SD (lasting 6–26 weeks; 2 pts ongoing) as the best overall response. Updated results will be presented. Conclusions: P can be safely combined with D or D/T. Encouraging evidence of clinical activity has been seen. Clinical trial information: NCT01750918.