A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer

Abstract

Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in BRAF^V600E colorectal cancer models. Patients with refractory BRAF^V600-mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab), with (n = 28) or without (n = 26) a PI3Kα inhibitor (alpelisib). The primary objective was to determine the maximum tolerated dose (MTD) or a recommended phase II dose. Dose-limiting toxicities were reported in 3 patients receiving dual treatment and 2 patients receiving triple treatment. The MTD was not reached for either group and the phase II doses were selected as 200 mg encorafenib (both groups) and 300 mg alpelisib. Combinations of cetuximab and encorafenib showed promising clinical activity and tolerability in patients with BRAF-mutant mCRC; confirmed overall response rates of 19% and 18% were observed and median progression-free survival was 3.7 and 4.2 months for the dual- and triple-therapy groups, respectively.Significance: Herein, we demonstrate that dual- (encorafenib plus cetuximab) and triple- (encorafenib plus cetuximab and alpelisib) combination treatments are tolerable and provide promising clinical activity in the difficult-to-treat patient population with BRAF-mutant mCRC. Cancer Discov; 7(6); 610-9. ©2017 AACR.See related commentary by Sundar et al., p. 558This article is highlighted in the In This Issue feature, p. 539.

Figure 1. Waterfall plot of best percentage change of tumor size from baseline by best response

Data cutoff date: February 1, 2015. *Patients treated at the RP2D; Abbreviations: CR, complete response; DCR, disease control rate; ENC + ALP + CTX, encorafenib combined with alpelisib and cetuximab; ENC + CTX, encorafenib combined with cetuximab; ORR, overall response rate; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; RP2D, recommended phase 2 dose; SD, stable disease.

Figure 2. Progression-free survival for all patients

Abbreviations: ENC + ALP + CTX, encorafenib combined with alpelisib and cetuximab; ENC + CTX, encorafenib combined with cetuximab; PFS, progression-free survival. The two cohorts were recruited sequentially.

Figure 3. Progression-free survival vs genetic alterations and allele frequency by gene pathways

Abbreviations: APC, adenomatous polyposis coli; EGFR, epidermal growth factor receptor; ENC + ALP + CTX, encorafenib combined with alpelisib and cetuximab; ENC + CTX, encorafenib combined with cetuximab; KRAS, Kirsten rat sarcoma viral oncogene homolog; LOH1, copy-loss loss of heterozygosity; LOHx, copy-neutral loss of heterozygosity; MAPK, mitogen-activated protein kinase; MET, MET proto-oncogene, receptor tyrosine kinase; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog; RNF43, ring finger protein 43; RTK, receptor tyrosine kinase.