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

<i>RET</i> 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 <i>RET</i> fusion-positive NSCLCs, the objective response rate (ORR) was 19% (95% CI, 8%-38%, <i>n</i> = 6/31). Interestingly, the ORR varied significantly by the gene fusion partner (<i>P</i> < 0.001, Fisher exact test): 0% (95% CI, 0%-17%, <i>n</i> = 0/20) with <i>KIF5B</i> (the most common upstream partner for <i>RET</i> fusion-positive NSCLC), and 67% (95% CI, 30%-93%, <i>n</i> = 6/9) with non-<i>KIF5B</i> partners. The median duration of response in all <i>RET</i> fusion-positive NSCLCs was not reached (range, 5 to 18+ months). SIGNIFICANCE: Although <i>KIF5B-RET</i> is the most common <i>RET</i> fusion in NSCLCs, RET inhibition with RXDX-105 resulted in responses only in non-<i>KIF5B-RET</i>-containing cancers. Novel approaches to targeting <i>KIF5B-RET</i>-containing tumors are needed, along with a deeper understanding of the biology that underlies the differential responses observed.<i>This article is highlighted in the In This Issue feature, p. 305</i>.