A Phase I/Ib Trial of the VEGFR-Sparing Multikinase RET Inhibitor RXDX-105 [Research Articles]

RET fusions are oncogenic drivers of various tumors, including non-small cell lung cancers (NSCLCs). The safety and antitumor activity of the multikinase RET inhibitor RXDX-105 were explored in a phase I/Ib trial. A recommended phase 2 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 non-maculopapular rash (17%). In the phase 1b cohort of RET inhibitor-naive patients with RET fusion-positive NSCLCs, the objective response rate (ORR) was 19% (95% CI 8%-38%, n=6/31). Interestingly, the ORR varied significantly by the gene fusion partner (p<0.001, Fisher's exact test): 0% (95% CI 0% - 17%, n=0/20) with KIF5B (the most common upstream partner for RET fusion-positive NSCLC), and 67% (95% CI 30% - 93%, n=6/9) with non-KIF5B partners. The median duration of response in all RET fusion-positive NSCLCs was not reached (range 5 to 18+ months).

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