Phase 2 results: Encorafenib (ENCO) and cetuximab (CETUX) with or without alpelisib (ALP) in patients with advanced BRAF-mutant colorectal cancer (BRAFm CRC).

3544 Background: BRAFm CRC carries a poor prognosis, with survival of 5–6 months after failure of first-line therapy. Reactivation of epidermal growth factor receptor (EGFR) signaling with BRAF inhibition and uninhibited PI3K signaling may explain the limited efficacy of BRAF inhibitor monotherapy in patients (pts) with BRAFm CRC. This study investigated the BRAF inhibitor ENCO and the anti-EGFR antibody CETUX with or without the PI3Kα inhibitor ALP (BYL719) in pts with advanced BRAFm CRC. Methods: In this ongoing phase 1b/randomized phase 2 study (ClinicalTrials.gov: NCT01719380), phase 1b did not identify a maximum tolerated dose for either combination. Based on general tolerability of the triplet, the ENCO dose for phase 2 was chosen to be the same in both arms. In phase 2, pts with advanced BRAFm CRC failing ≥ 1 prior therapy were randomized 1:1 to a doublet (ENCO 200 mg PO QD and CETUX per label) or triplet (ENCO, CETUX, and ALP 300 mg PO QD). Progression-free survival (PFS) was the primary endpoint. Secondary endpoints included overall response rate (ORR) and overall survival (OS). Results: A total of 102 pts were randomized (triplet, n = 52; doublet, n = 50). Pts in each group had a median of 2 prior therapies. A planned PFS analysis comparing the triplet to the doublet after 73 events showed a HR (95% CI) of 0.69 (0.43–1.11; P= 0.064) with median PFS (95% CI) of 5.4 (4.1–7.2) mo and 4.2 (3.4–5.4) mo and confirmed ORR (95% CI) of 27% (16%–41%) and 22% (12%–36%), respectively. With 35 events, interim OS analysis (triplet vs doublet) showed a HR (95% CI) of 1.21 (0.61–2.39); median OS was 15.2 mo on the triplet and not reached on the doublet. Grade 3/4 adverse events (AEs), regardless of causality, were reported in 79% (triplet) and 58% (doublet) of pts. Grade 3/4 AEs in > 10% of pts in either arm were anemia (17% vs 6%), hyperglycemia (13% vs 2%), and increased lipase (8% vs 18%) for the triplet and doublet, respectively. Conclusions: Combinations of ENCO and CETUX with or without ALP showed promising clinical activity, including improved PFS and OS relative to historical data. Adding ALP to the doublet may add a PFS benefit as well as additional toxicity. Clinical trial information: NCT01719380.