A Phase I/Ib Trial of the VEGFR-Sparing Multikinase RET Inhibitor RXDX-105.

fusions are oncogenic drivers of various tumors, including non-small cell lung cancers (NSCLC). The safety and antitumor activity of the multikinase RET inhibitor RXDX-105 were explored in a phase I/Ib trial. A recommended phase II dose of 275 mg fed daily was identified. The most common treatment-related adverse events were fatigue (25%), diarrhea (24%), hypophosphatemia (18%), maculopapular rash (18%), and nonmaculopapular rash (17%). In the phase Ib cohort of RET inhibitor-naïve patients with fusion-positive NSCLCs, the objective response rate (ORR) was 19% (95% CI, 8%-38%, = 6/31). Interestingly, the ORR varied significantly by the gene fusion partner ( < 0.001, Fisher exact test): 0% (95% CI, 0%-17%, = 0/20) with (the most common upstream partner for fusion-positive NSCLC), and 67% (95% CI, 30%-93%, = 6/9) with non- partners. The median duration of response in all fusion-positive NSCLCs was not reached (range, 5 to 18+ months). SIGNIFICANCE: Although is the most common fusion in NSCLCs, RET inhibition with RXDX-105 resulted in responses only in non--containing cancers. Novel approaches to targeting -containing tumors are needed, along with a deeper understanding of the biology that underlies the differential responses observed..