Updated efficacy of the MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in patients (pts) with <i>BRAF</i> V600E mutated (BRAFm) metastatic colorectal cancer (mCRC).

Abstract

103 Background: BRAF V600E mutations occur in 5–10% of mCRC and confer a poor prognosis. Unlike BRAFm melanoma, BRAF and MEK inhibitors have minimal activity in BRAFm mCRC. Preclinical data suggest that combined inhibition of the EGFR and MAPK pathways is required to maximally inhibit growth of BRAFm mCRC. This study evaluates the activity of the combination of P with D and/or T in BRAFm mCRC. Methods: Eligible pts with BRAFm mCRC received doublet, D+P or T+P, or triplet, D+T+P. Results: Doublet (D+P): 20 pts received the full doublet dose (D 150mg twice daily [BID] + P 6mg/kg every 2 weeks [Q2W]). Triplet: 35 pts received D+T+P including 24 pts that received full triplet dose (D 150mg BID + T 2mg once daily [QD] + P 6mg/kg Q2W). No dose-limiting toxicities were observed. As of October 20, 2014, the most common adverse events were dermatitis acneiform (Grade [G] 1/2 55%) and fatigue (G 1/2 45%) for D+P, and diarrhea (G1/2 60%, G3 9%) and dermatitis acneiform (G1/2 47%; G3 9%) for triplet. The confirmed response rate for D+P was 10% and for D+T+P was 26% (Table 1). Treatment with either regimen reduced levels of pERK in on-treatment biopsies relative to pre-dose biopsies (median reduction D+P 23%; D+T+P 54%). Pts are currently being enrolled to T+P. Updated results including progression-free survival and duration of response will be presented. Conclusions: Encouraging clinical activity with acceptable tolerability is seen with the triplet D+T+P in BRAFm mCRC. Clinical trial information: NCT01750918.Investigator–assessed best response with confirmation (RECIST 1.1). D 150 mg BID+ P 6mg/kg Q2W N = 20 D 150 mg BID, T 1.5 mg QD, P 4.8 mg/kg Q2W N = 3 D 150 mg BID, T 2 mg QD, P 4.8 mg/kg Q2W N = 4 D 150 mg BID, T 1.5 mg QD, P 6 mg/kg Q2W N = 4 D 150 mg BID, T 2 mg QD, P 6 mg/kg Q2W N=24 D+T+P Total N = 35 Complete response, n (%) 1 (5) 0 1 (25) 0 0 1 (3) Partial response, n (%) 1 (5) 2 (67) 1 (25) 0 5 (21) 8 (23) Stable disease, n (%) 16 (80) 1 (33) 2 (50) 2 (50) 15 (63) 20 (57) Progressive disease, n (%) 2 (10) 0 0 2 (50) 3 (13) 5 (14) Not evaluable, n (%) 0 0 0 0 1 (4) 1 (3) Response rate (CR+PR), n (%) 2 (10) 2 (67) 2 (50) 0 5 (21) 9 (26) 95% confidence interval, % 1.2–31.7 9.4–99.2 6.8–93.2 0.0–60.2 7.1–42.2 12.5–43.3