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.This article is highlighted in the In This Issue feature, p. 305.

• Authors: Alexander Drilon, Siqing Fu, Manish R Patel, Marwan Fakih, Ding Wang, Anthony J Olszanski, Daniel Morgensztern, Stephen V Liu, Byoung Chul Cho, Lyudmila Bazhenova, Cristina P Rodriguez, Robert C Doebele, Antoinette Wozniak, Karen L Reckamp, Tara Seery, Petros Nikolinakos, Zheyi Hu, Jennifer W Oliver, Denise Trone, Katherine McArthur, Rupal Patel, Pratik S Multani, Myung-Ju Ahn
• Journal: Cancer discovery (Cancer Discov) Vol. 9 Issue 3 Pg. 384-395 (03 2019) ISSN: 2159-8290 [Electronic] United States
• PMID: 30487236 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• KIF5B-RET fusion protein, human
• Oncogene Proteins, Fusion
• Phenylurea Compounds
• Protein Kinase Inhibitors
• Quinazolines
• agerafenib
• FLT1 protein, human
• Proto-Oncogene Proteins c-ret
• RET protein, human
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Adult
• Aged
• Aged, 80 and over
• Dose-Response Relationship, Drug
• Female
• Humans
• Male
• Middle Aged
• Neoplasms (drug therapy, genetics, metabolism, pathology)
• Oncogene Proteins, Fusion (antagonists & inhibitors, genetics)
• Patient Safety
• Phenylurea Compounds (administration & dosage, pharmacokinetics)
• Protein Kinase Inhibitors (administration & dosage, pharmacokinetics)
• Proto-Oncogene Proteins c-ret (antagonists & inhibitors, genetics, metabolism)
• Quinazolines (administration & dosage, pharmacokinetics)
• Tissue Distribution
• Treatment Outcome
• Vascular Endothelial Growth Factor Receptor-1 (metabolism)