RXDX-105 is a VEGFR-sparing potent RET inhibitor (RETi) with IC50 of 0.3 nM, 0.3-0.8 nM, and 5-15 nM against wt RET, RET fusions, and RET mutations, respectively. RXDX-105 has demonstrated potent antitumor activity in PDX models harboring RET fusions, which occur predominantly in NSCLC (1-2% of adenocarcinomas). More than half of these involve the KIF5B gene as the fusion partner, and pooled efficacy experience with other RET-active agents suggests a lower response rate in this pt population.
Pts with advanced solid tumors were enrolled in a Phase 1/1b dose escalation study followed by dose expansion at the RP2D. RXDX-105 was given orally at doses ranging from 20 - 350 mg QD. Tumor response was assessed every 8 weeks by RECIST v1.1. Adverse events (AEs) were recorded per NCI CTCAE v4.03.
As of 30Jun2017, 144 (55 Ph 1; 89 Ph 1b) pts (73F; 71M) received RXDX-105; 28 pts remain on treatment. Median age was 63 yrs. Based on safety and PK data, the RP2D was determined to be 275 mg, QD, fed. The most common treatment-related AEs were mostly Grades 1 or 2 and reversible with dose modifications. The most common G3 treatment-related AEs (>5%) were rash (10%), hypophosphatemia (8%), elevated ALT (7%) and anemia (7%). As previously reported, one pt experienced Grade 3 rash complicated by fatal alveolar hemorrhage. No other treatment-related Grade ≥4 AEs were observed. Of the 91 pts treated in Ph 1b, 21 pts had NSCLC harboring RET fusions confirmed by NGS, were RETi naïve, and evaluable for efficacy. Of these, 13 harbored the KIF5B-RET fusion. The other 8 pts had a variety of non-KIF5B-RET fusions; 6 of these 8 pts achieved a confirmed PR for an ORR of 75%. Median DOR has not yet been reached. None of the 13 pts with KIF5B-RET fusions had a RECIST response, although 4 had SD lasting ≥ 6 months. Overall, time on treatment ranges from 0.5+ to 14.5+ months.
RXDX-105 has demonstrated antitumor activity across multiple fusion partners in RET-positive NSCLC pts with a manageable safety profile. However, responses were not observed in pts whose tumors harbored a KIF5B-RET fusion, consistent with previous evidence with other agents, suggesting that this RET fusion may be less susceptible to RET inhibition.
Clinical trial identification
Legal entity responsible for the study
S. Liu: Consultant/Ad board: Genentech, Ignyta, Pfizer, Bristol-Myers Squibb, Lilly, Celgene, Ariad, Boehringer Ingelheim, AstraZeneca. R. Doebele: Advisory Board, Travel reimbursement, and Sponsored Research Agreement from Ignyta. B.C. Cho: Research funding: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST Consulting role: Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, Yuhan, Pfizer, Eli Lilly. E. Kowack, J. Oliver, P. Multani: Employee of Ignyta, Inc. All other authors have declared no conflicts of interest.