2714 - Sitravatinib demonstrates activity in patients with novel genetic alterations that inactivate CBL

Background

Sitravatinib (MGCD516) is a small molecule inhibitor of TAM (AXL, MER) and split (VEGFR2, PDGFR, KIT) family RTKs, RET, and MET. CBL encodes an E3-ubiquitin ligase that regulates the degradation of activated RTKs that are inhibited by sitravatinib. Thus, CBL loss-of-function mutations may increase signaling of a subset of sitravatinib target RTKs in tumors and predict sensitivity to treatment with sitravatinib.

Methods

Study 516-001 is a Phase 1/1b study of sitravatinib in patients (pts) with advanced solid tumors. After determination of the MTD, pts with tumors harboring inactivating genetic alteration in CBL were enrolled into a preplanned Phase1b expansion cohort using a 2-stage Simon optimal design. Pts received sitravatinib once daily at 150mg or 120mg and were evaluated for safety, PK and clinical activity. Here we report the completion of Stage 1 for the Phase1b cohort of pts with CBL-inactivated tumors.

Results

105 pts (57 men/48 women; median age 67 years; range 36-84) with advanced solid tumors were enrolled in Phase1b cohorts, including 12 pts with malignancies harboring inactivating genetic alterations in CBL, comprising single nucleotide variants in the RING domain and indels compromising the coding region. Two partial responses (PR) were observed among the first 8 evaluable pts (melanoma 2; NSCLC 2; sarcoma 2; other 2) in Stage 1, which met criteria for enrollment of 16 additional evaluable pts for Stage 2. Confirmed PRs were observed in NSCLC (1/2) and melanoma (1/2) with response durations over 4 months for both. Prolonged stable disease for ≥17 weeks was observed in 2 additional pts (pancreatic neuroendocrine tumor and esophageal cancer). Treatment-related AEs (>20% of Phase1b pts; Grades 1-3) included diarrhea, fatigue, hypertension, nausea, vomiting and decreased appetite.

Conclusions

Stage 1 enrollment of the Study 516-001 Phase1b cohort of pts with CBL-inactivated tumors was completed. Sitravatinib treatment resulted in 2 confirmed PRs in a heavily pre-treated patient population with a manageable safety profile. CBL mutations may be a novel target. Further evaluation of sitravatinib in NSCLC, melanoma, and other tumors is ongoing, and testing for CBL mutations may be warranted.

Clinical trial identification

NCT02219711.

Legal entity responsible for the study

Mirati Therapeutics, Inc.

Funding

Mirati Therapeutics, Inc.

Editorial Acknowledgement

Disclosure

R.D. Carvajal: Consulting: BMS, Castle Biosciences, Foundation Medicine, Immunocore, Incyte, Merck, Roche/Genentech; Advisory board: Aura Biosciences, Chimeron, Rgenix. R.S. Heist: Consulting: Boehringer Ingelheim; Research funding (to institution): Mirati, Celgene, Genentech Roche, Novartis, Peregrine, Debiopharm, Corvus, Abbvie, Millenium, Incyte. T. Werner: Research support to institution as the PI for industry sponsored trials Tesaro, Abbvie, Novartis, BMS. S. Neuteboom, J. Christensen: Employee and shareholder: Mirati Therapeutics. D. Potvin: Consultant: Mirati Therapeutics, Inc. I. Chen: Employee: Mirati Therapeutics; Stock ownership: Mirati Therapeutics. R. Chao: Employee: Mirati Therapeutics; Stock ownership: Mirati, Pfizer, and Merck. A. Alva: Advisor: Merck, Genetech, Astra Zeneca; Corporate sponsored research via institution: BMS, Merck, AstraZeneca, Calithera, Celgene, Bayer. All other authors have declared no conflicts of interest.