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-na?ve 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% ... More
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-na?ve 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..
