364 First-in-human phase 1 study of MLN2480, an investigational oral pan-RAF kinase inhibitor, in patients (pts) with relapsed or refractory solid tumors, including BRAF/NRAS-mutant melanoma

Background: Activating mutations in the MAPK pathway are common in many solid tumors. RAF kinases play a key role in this pathway and represent a valid target for therapy. This study (NCT01425008) evaluated the safety, MTD, preliminary antitumor activity and pharmacokinetics (PK) of MLN2480. Methods: Pts aged ≥18 yrs with advanced solid tumors (dose-escalation [DE] and PK cohorts) and inoperable stage 3/4 melanoma (expansion [ME] cohorts) received oral MLN2480 every other day (Q2D) in 22- or 28-d cycles. Dose escalation was based on cycle 1 DLTs. PK and ME cohorts received the MTD; ME cohorts were defined by treatment history (naïve vs treated) and mutation status (NRAS vs BRAF). Results: At data cut-off, 75 pts had enrolled, 30 to DE cohorts, 25 to ME cohorts and 20 to the PK cohort. DE pts received MLN2480 20–280 mg Q2D in 22-d cycles or 200 mg Q2D in 28-d cycles. 2 pts (280 mg Q2D, 22-d cycles) had cycle 1 DLTs of grade 3 periorbital edema and maculopapular rash. Drug-related AEs of interest included arthralgia in 23% of pts and nevi in 10% (only at low doses 20 mg and 40 mg). PK data from the DE cohorts indicated dose-proportional (d21) exposure with MLN2480 20–280 mg Q2D. MLN2480 MTD was 200 mg Q2D. In 45 pts of the ME/PK cohorts, median cycles received were 2 (1–12) and 7 pts received ≥6 28-d cycles. Common drug-related AEs in ME/PK pts included maculopapular rash (40%), fatigue (31%) and anemia (22%); grade ≥3 (29% of pts) included maculopapular rash (7%) and anemia (4%). At 200 mg, frequency of drug-related arthralgia and nevi decreased to 7% and 0%, respectively; CPK elevations were seen in 11%. No squamous cell carcinomas were reported. In ME/PK pts, 11% discontinued due to AEs; 2 pts died on study (1 drug-related: respiratory failure at 280 mg). In naïve BRAF-mut RECIST-evaluable ME pts (n=10), there were 4 PRs, 1 SD and 5 PDs. In naïve NRAS-mut ME pts (n=7), there were 1 PR, 3 SDs and 3 PDs. Response duration ranged from 1.5–5.4+ mos. A pt with NRAS-mut thyroid cancer has been on study for 24 cycles with SD. 6 pts overall had SD for 4.7–18.9+ mos. Conclusions: The safety profile of MLN2480 at up to 200 mg Q2D (MTD) was acceptable. Safety observations at low and high doses support the hypothesis that MLN2480 may overcome the paradoxical activation of the MAPK pathway in the clinic and may block RAF heterodimerization, unlike BRAF-specific inhibitors. Preliminary response data suggest evidence of antitumor activity in BRAF- and NRAS-mut melanoma. Conflict of interest: Advisory board: GSK, BMS, Amgen, Merck, Roche Corporate-sponsored research: GSK, AZ, Eisai, Clovis, BMS, Amgen, Roche, Merck, Vertex, Immunocore, Pfizer, Medimmune