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-r...

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Veröffentlicht in:Cancer discovery 2019-03, Vol.9 (3), p.384-395
Hauptverfasser: Drilon, Alexander, Fu, Siqing, Patel, Manish R, Fakih, Marwan, Wang, Ding, Olszanski, Anthony J, Morgensztern, Daniel, Liu, Stephen V, Cho, Byoung Chul, Bazhenova, Lyudmila, Rodriguez, Cristina P, Doebele, Robert C, Wozniak, Antoinette, Reckamp, Karen L, Seery, Tara, Nikolinakos, Petros, Hu, Zheyi, Oliver, Jennifer W, Trone, Denise, McArthur, Katherine, Patel, Rupal, Multani, Pratik S, Ahn, Myung-Ju
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Sprache:eng
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Zusammenfassung: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. .
ISSN:2159-8274
2159-8290
DOI:10.1158/2159-8290.CD-18-0839