Introduction: Patients with BRAF V600-mutant colorectal cancer (BRAFm CRC) who relapse following first-line therapy have a poor prognosis, with median overall survival of just 5–6 months. Unlike melanoma, BRAF inhibitor monotherapy has shown limited efficacy in BRAFm CRC. This limited efficacy has been attributed to reactivation of epidermal growth factor receptor (EGFR) signaling with BRAF inhibition and uninhibited phosphatidylinositol 3-kinase (PI3K) signaling. This study evaluated the efficacy and safety of the BRAF inhibitor encorafenib plus the anti-EGFR antibody cetuximab with or without the PI3K&agr; inhibitor alpelisib (BYL719) in patients with advanced BRAFm CRC.Methods: This is an ongoing phase 1b/randomized phase 2 study (ClinicalTrials.gov: NCT01719380). The phase 1b portion confirmed the safety and tolerability of the combination of encorafenib and cetuximab or encorafenib and cetuximab with alpelisib, and did not identify a maximum tolerated dose. Based on the general tolerability of the triplet, the phase 2 encorafenib dose was chosen to be the same in both arms: 200 mg orally (PO) once daily (QD). In the phase 2 portion, patients with advanced BRAFm CRC failing ≥1 prior therapy were randomized 1:1 to the doublet (encorafenib and cetuximab per label) or the triplet (encorafenib, cetuximab, and alpelisib 300 mg PO QD). The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), disease control rate (DCR), and overall survival (OS).Results: Of 102 study patients, 52 were randomized to receive the triplet and 50 to receive the doublet. Patients in each group received a median of 2 prior therapies. A planned PFS analysis comparing the triplet to the doublet after 73 events showed a hazard ratio (HR; 95% confidence interval [CI]) of 0.69 (0.43–1.11; P = 0.064), with median PFS (95% CI) of 5.4 (4.1–7.2) months and 4.2 (3.4–5.4) months, respectively. Confirmed ORR (95% CI) and DCR (95% CI) were 27% (16%–41%) and 79% (65%–89%), respectively, with the triplet, and 22% (12%–36%) and 78% (64%–89%), respectively, with the doublet. With 35 events, interim OS analysis (triplet vs doublet) showed an HR (95% CI) of 1.21 (0.61–2.39); median OS was 15.2 months with the triplet and was not reached with the doublet. Grade 3/4 adverse events (AEs), regardless of causality, were reported in 79% of patients who received the triplet and in 58% who received the doublet. Grade 3/4 AEs in >10% of patients in either arm (triplet vs doublet) were anemia (17% vs 6%), hyperglycemia (13% vs 2%), and increased lipase (8% vs 18%).Conclusion: In comparison with historical data, the combination of encorafenib and cetuximab with or without alpelisib showed promising clinical activity in patients with advanced BRAFm CRC, including improved PFS and OS. Addition of alpelisib to the doublet showed a trend toward a PFS benefit, albeit with additional toxicity. Introduction: Patients with BRAF V600-mutant colorectal cancer (BRAFm CRC) who relapse following first-line therapy have a poor prognosis, with median overall survival of just 5–6 months. Unlike melanoma, BRAF inhibitor monotherapy has shown limited efficacy in BRAFm CRC. This limited efficacy has been attributed to reactivation of epidermal growth factor receptor (EGFR) signaling with BRAF inhibition and uninhibited phosphatidylinositol 3-kinase (PI3K) signaling. This study evaluated the efficacy and safety of the BRAF inhibitor encorafenib plus the anti-EGFR antibody cetuximab with or without the PI3K&agr; inhibitor alpelisib (BYL719) in patients with advanced BRAFm CRC. Methods: This is an ongoing phase 1b/randomized phase 2 study (ClinicalTrials.gov: NCT01719380). The phase 1b portion confirmed the safety and tolerability of the combination of encorafenib and cetuximab or encorafenib and cetuximab with alpelisib, and did not identify a maximum tolerated dose. Based on the general tolerability of the triplet, the phase 2 encorafenib dose was chosen to be the same in both arms: 200 mg orally (PO) once daily (QD). In the phase 2 portion, patients with advanced BRAFm CRC failing ≥1 prior therapy were randomized 1:1 to the doublet (encorafenib and cetuximab per label) or the triplet (encorafenib, cetuximab, and alpelisib 300 mg PO QD). The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), disease control rate (DCR), and overall survival (OS). Results: Of 102 study patients, 52 were randomized to receive the triplet and 50 to receive the doublet. Patients in each group received a median of 2 prior therapies. A planned PFS analysis comparing the triplet to the doublet after 73 events showed a hazard ratio (HR; 95% confidence interval [CI]) of 0.69 (0.43–1.11; P = 0.064), with median PFS (95% CI) of 5.4 (4.1–7.2) months and 4.2 (3.4–5.4) months, respectively. Confirmed ORR (95% CI) and DCR (95% CI) were 27% (16%–41%) and 79% (65%–89%), respectively, with the triplet, and 22% (12%–36%) and 78% (64%–89%), respectively, with the doublet. With 35 events, interim OS analysis (triplet vs doublet) showed an HR (95% CI) of 1.21 (0.61–2.39); median OS was 15.2 months with the triplet and was not reached with the doublet. Grade 3/4 adverse events (AEs), regardless of causality, were reported in 79% of patients who received the triplet and in 58% who received the doublet. Grade 3/4 AEs in >10% of patients in either arm (triplet vs doublet) were anemia (17% vs 6%), hyperglycemia (13% vs 2%), and increased lipase (8% vs 18%). Conclusion: In comparison with historical data, the combination of encorafenib and cetuximab with or without alpelisib showed promising clinical activity in patients with advanced BRAFm CRC, including improved PFS and OS. Addition of alpelisib to the doublet showed a trend toward a PFS benefit, albeit with additional toxicity.

Abstract Introduction: Somatic mutations in the metabolic enzymes isocitrate dehydrogenase (IDH) 1 and 2 occur in a spectrum of solid and hematologic malignancies. Mutant IDH1/2 in cancer cells results in the neomorphic production of the oncometabolite, D-2-hydroxyglutarate (2-HG), which impairs cellular differentiation via an epigenetic mechanism. AG-120 is a first-in-class, oral, potent, reversible and selective inhibitor of mutated IDH1 protein. We report preliminary results from the ongoing, first-in-human, phase 1, open-label, single-arm study of AG-120 (NCT02073994). Aims: Key objectives are to evaluate the safety, tolerability, and maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity. Key exploratory objectives include an analysis of tumor tissue samples in non-glioma subjects and magnetic resonance imagining/spectroscopy (MRI/MRS) in glioma subjects, pre and on AG-120 treatment. Methods: Patients with advanced, IDH1-mutant solid tumors, including glioma, who have recurred or progressed following standard therapy, or who have not responded to standard therapy, are eligible to receive continuous, single-agent, oral AG-120 dosed daily in 28-day cycles. Informed consent is obtained prior to entry. Sequential dose cohorts are being enrolled, with expansion cohorts planned. Blood and tumor biopsies are collected for PK/PD assessment. Objective responses are investigator assessed using either RECIST or RANO criteria for subjects with solid tumors and gliomas, respectively. Results: As of 1 July 2015, 55 patients (glioma: 20, non-glioma: 35) were treated with AG-120. Median age was 54 years (range, 23-88) and median number of prior systemic regimens 3 (range, 1-6). Doses administered were 100 mg BID (n = 4), 300 mg QD (n = 9), 400 mg QD (n = 5), 500 mg QD (n = 17), 600 mg QD (n = 5), 800 mg QD (n = 6), 900 mg QD (n = 4), and 1200 mg QD (n = 5). Median treatment duration was 1.9 months (range, 0.1-12.5). The MTD was not reached. PK analyses showed high plasma exposure and drug accumulation following oral administration and a mean half-life of 73.1 ± 66.6 hr. Overall, treatment was well tolerated: 49 patients experienced treatment-emergent adverse events (AEs), regardless of causality. Most frequently occurring AEs (%) were nausea (21.8), diarrhea (16.4), vomiting (14.5), anemia (12.7), and abdominal pain (10.9). There were no treatment-related serious AEs. Summary/Conclusion: AG-120 is a first-in-class, oral, potent, selective inhibitor of mutant IDH1 in development for solid and liquid tumors. Updated safety and clinical activity, as well as exploratory PD analyses will be presented. Future development plans for AG-120 in solid tumors will also be highlighted. Citation Format: Howard Burris, Ingo Mellinghoff, Elizabeth Maher, Patrick Wen, Murali Beeram, Mehdi Touat, Jason Faris, Nilofer Azad, Timothy Cloughesy, Lia Gore, Jonathan Trent, Daniel Von Hoff, Meredith Goldwasser, Bin Fan, Sam Agresta. The first reported results of AG-120, a first-in-class, potent inhibitor of the IDH1 mutant protein, in a Phase I study of patients with advanced IDH1-mutant solid tumors, including gliomas. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL04-05.