Sitravatinib is a spectrum-selective TKI which targets TAM receptors (Axl, MER), split family receptors (VEGFR2 and KIT), and MET. Inhibition of these receptor tyrosine kinases may enhance antitumor activity by reducing Type 2 tumor-associated macrophages, regulatory T cells and myeloid-derived suppressor cells and enhancing a T cell-mediated anti-tumor immune response. Thus, this combination is a rational approach to enhancing or restoring the clinical activity of checkpoint inhibitor therapy (CIT) in pts with immunotherapy resistant NSCLC.
Study objectives include evaluation of safety and efficacy in pts with non-squamous NSCLC who have progression of disease (PD) on or after treatment with CIT. Sitravatinib is administered orally in continuous 28-Day cycles; nivolumab is administered via IV, 240 mg every 2 weeks. Treatment arms are stratified by prior clinical benefit (PCB) vs no prior clinical benefit (NPCB [PD in ≤ 12 weeks]). A predictive probability design is used for assessment of enrollment expansion in each stage. Other objectives include PK and correlative biomarkers.
Enrollment in Stage 2 of the CIT-experienced cohorts is complete and enrollment is ongoing. As of April 13, 2018, the CIT-experienced cohorts enrolled 46 pts and 25/46 have had at least one on-study tumor assessment. Twenty-one out of 25 pts have demonstrated tumor reductions. Seven pts out of the 25 have achieved a partial response (PR); 4 confirmed and 3 unconfirmed (1 PR/3 uPR in PCB; 3 PRs in NPCB cohorts, respectively); with the longest treatment duration exceeding 50 weeks. Sitravatinib-related AEs (>10% of pts; all grades) included diarrhea, nausea, vomiting, decreased appetite, fatigue, mucosal inflammation, dysphonia, AST/ALT increase, weight decrease, hypertension, and palmar-plantar erythrodysaesthesia syndrome. Updated safety and efficacy data will be presented.
The combination of sitravatinib with nivolumab is clinically active with manageable side effects. Correlation of clinical activity with molecular analyses, including specific gene alterations and tumor mutation burden, is underway and will be presented.
Clinical trial identification
Legal entity responsible for the study
Mirati Therapeutics, Inc.
Mirati Therapeutics, Inc.
T.A. Leal: Advisory board (consulting): Takeda, AstraZeneca, Novartis, AbbVie, BMS. A.I. Spira: Consulting and research support (to institution): Mirati Therapeutics. C. Blakely: Research funding: Mirati, Novartis, Ignyta, Medimmune, Clovis; Consulting: Jazz Pharmaceuticals. E. Massarelli: Speakers bureau: AstraZeneca, Merck; Consultant: Genetech; Grants and research support: BMS, Genetech, I. Chen: Employment: Mirati Therapeutics. J. Christensen, P. Olson: Employment and stock ownership: Mirati Therapeutics. V. Tassell: Employment and stock ownership: Mirati Therapeutics; Stock ownership: Pfizer. L. Horn: Consulting: Abbvie, AstraZeneca, BMS, Genentech, Merck, Incyte, Xcovery. All other authors have declared no conflicts of interest.