A phase I/Ib trial of the VEGFR-sparing multikinase RET inhibitor RXDX-105 Journal Article
| Authors: | Drilon, A.; Fu, S.; Patel, M. R.; Fakih, M.; Wang, D.; Olszanski, A. J.; Morgensztern, D.; Liu, S. V.; Cho, B. C.; Bazhenova, L.; Rodriguez, C. P.; Doebele, R. C.; Wozniak, A.; Reckamp, K. L.; Seery, T.; Nikolinakos, P.; Hu, Z.; Oliver, J. W.; Trone, D.; McArthur, K.; Patel, R.; Multani, P. S.; Ahn, M. J. |
| Article Title: | A phase I/Ib trial of the VEGFR-sparing multikinase RET inhibitor RXDX-105 |
| Abstract: | RET 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 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 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). SIGNIFICANCE: Although KIF5B-RET is the most common RET fusion in NSCLCs, RET inhibition with RXDX-105 resulted in responses only in non– KIF5B–RET- containing cancers. Novel approaches to targeting KIF5B-RET- containing tumors are needed, along with a deeper understanding of the biology that underlies the differential responses observed. © 2018 American Association for Cancer Research. |
| Keywords: | adult; human tissue; human cell; major clinical study; fatigue; bevacizumab; cisplatin; diarrhea; drug dose reduction; drug safety; hypertension; hypophosphatemia; gemcitabine; colorectal cancer; carboplatin; vasculotropin receptor; phase 2 clinical trial; skin biopsy; thrombocytopenia; vomiting; qt prolongation; lung cancer; antineoplastic activity; drug dose escalation; drug hypersensitivity; maculopapular rash; gene fusion; vandetanib; thyroid cancer; stereotactic radiosurgery; liver function test; phase 1 clinical trial; muscle spasm; pemetrexed; proteinuria; non small cell lung cancer; decreased appetite; human; male; female; article; pembrolizumab; durvalumab; cobimetinib; atezolizumab; ba/f3 cell line; agerafenib; adenosine a2a receptor antagonist |
| Journal Title: | Cancer Discovery |
| Volume: | 9 |
| Issue: | 3 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2019-03-01 |
| Start Page: | 384 |
| End Page: | 395 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-18-0839 |
| PUBMED: | 30487236 |
| PROVIDER: | scopus |
| PMCID: | PMC6397691 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 May 2019 -- Source: Scopus |
