705MO - Sitravatinib (sitra) in combination with nivolumab (nivo) demonstrates clinical activity in checkpoint inhibitor (CPI) naïve, platinum-experienced patients (pts) with advanced or metastatic urothelial carcinoma (UC)

Background

Sitra is a spectrum-selective TKI which targets TAM receptors (Tyro3, Axl, MerTK), split family receptors (VEGFR2 and c-Kit) and c-Met. Sitra has demonstrated antitumor activity as well as the reduction of Type 2 tumor-associated macrophages, regulatory T-cells and myeloid-derived suppressor cells and enhancement of T cell-mediated anti-tumor immune response in nonclinical studies and patients. Given these pleiotropic immune-enhancing effects, we hypothesized that the combination of sitra with a CPI will augment clinical activity of CPI alone in UC.

Methods

This is a multi-cohort phase 2 Study (516-003) to evaluate the efficacy and safety of the nivo+sitra combination in UC. This Cohort (C5) enrolled CPI-naïve pts who have disease progression on or after prior platinum-based chemotherapy. Sitra is administered orally, daily; nivo intravenously, 240mg every 2 weeks or 480mg every 4 weeks. Based on the Predictively Probability Design, a target sample size of 26 pts in Stage 1 allows advancement to Stage 2 if clinically active. Other objectives include pharmacokinetics (PK) and correlative biomarkers.

Results

C5 met its prespecified clinical activity with 8 confirmed responses in the first 26 evaluable pts, and advanced to Stage 2 (ongoing). As of May 8, 2020, C5 has enrolled 36 pts with 26 having had ≥1 on-study tumor assessment. Preliminary confirmed investigator-assessed ORR per RECIST 1.1 was 31% (4% CR). Disease control rate (CR/PR/SD) was 77%. With median follow-up of 6.1 months, median PFS was 3.9 months (95% CI 1.9, 7.3). Most common (≥20%) treatment-related adverse events (TRAEs) included fatigue (49%), diarrhea (43%), decreased appetite (41%), dysphonia (30%), increased ALT (30%), hypertension (24%), nausea (22%) and palmar-plantar erythrodysesthesia syndrome (22%). Grade 3/4 TRAEs occurred in 46% of pts. There were no Grade 5 TRAEs. Updated safety, PK and efficacy data will be presented.

Conclusions

Sitra with nivo combination is clinically active with manageable side effects in CPI-naïve, platinum-experienced pts with UC.

Clinical trial identification

NCT03606174.

Editorial acknowledgement

Legal entity responsible for the study

Mirati Therapeutics, Inc.

Funding

Mirati Therapeutics, Inc.

Disclosure

P. Msaouel: Honoraria (self): Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): Mirati Therapeutics; Honoraria (self): Exelixis; Research grant/Funding (institution): Takeda; Research grant/Funding (institution): Gateway for Cancer Research. A.O. Siefker-Radtke: Advisory/Consultancy: Merck; Advisory/Consultancy: Bavarian Nordic; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Genentech; Advisory/Consultancy, Speaker Bureau/Expert testimony: Janssen; Advisory/Consultancy: Mirati Therapeutics; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Nektar Therapeutics; Advisory/Consultancy: Pfizer. R. Sweis: Honoraria (self): Aduro; Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Exelixis; Honoraria (self): Eisai; Honoraria (self): Mirati; Honoraria (self): Puma. S. Mao: Speaker Bureau/Expert testimony: Bristol-Myers Squibb. J.E. Rosenberg: Advisory/Consultancy, Research grant/Funding (institution): Mirati Therapeutics; Advisory/Consultancy: Adicet Bio; Advisory/Consultancy: Agensys; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Astellas; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: BioClin Therapeutics; Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol Myers Squibb; Advisory/Consultancy: EMD Serono; Advisory/Consultancy: Fortress Biotech; Advisory/Consultancy: GlaxoSmithKline; Advisory/Consultancy: Inovio Pharma; Advisory/Consultancy: Janssen; Advisory/Consultancy: Lilly; Advisory/Consultancy: Merck; Advisory/Consultancy: Pharmacyclics; Advisory/Consultancy, Research grant/Funding (institution): QED Therapeutics; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche/Genentech; Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics; Advisory/Consultancy: Sensei Biotherapeutics; Advisory/Consultancy: Western Oncolytics; Advisory/Consultancy: Boerhinger Ingelheim; Advisory/Consultancy: Pfizer; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Jounce Therapeutics; Research grant/Funding (institution): Novartis; Travel/Accommodation/Expenses: Chugai. U.N. Vaishampayan: Advisory/Consultancy, Research grant/Funding (institution): Alkermes; Advisory/Consultancy: Bayer; Advisory/Consultancy: Exelixis; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb. A. Rezazadeh Kalebasty: Shareholder/Stockholder/Stock options: ECOM Medical; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Exelixis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bayer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony: EMD Serono; Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Janssen; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Astellas; Speaker Bureau/Expert testimony: Sanofi; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Eisai; Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony: Merck; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Macrogenics; Research grant/Funding (institution): Beyond Spring; Research grant/Funding (institution): BioClin Therapeutics; Research grant/Funding (institution): Clovis Oncology; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Epizy; Travel/Accommodation/Expenses: Prometheus Laboratories. N. Davis: Research grant/Funding (institution): Mirati Therapeutics. T. Zhang: Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Janssen; Research grant/Funding (institution): Acerta; Research grant/Funding (institution): Abbvie; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Merrimack; Research grant/Funding (institution): OmniSeq; Research grant/Funding (institution): PGDx; Advisory/Consultancy, Research grant/Funding (institution): Merck; Research grant/Funding (institution): Mirati Therapeutics; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Regeneron; Advisory/Consultancy, Speaker Bureau/Expert testimony: Genentech; Advisory/Consultancy, Speaker Bureau/Expert testimony: Exelixis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Genomic Health; Advisory/Consultancy, Speaker Bureau/Expert testimony: Sanofi Aventis; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: Foundation Medicine; Advisory/Consultancy: Amgen; Advisory/Consultancy: MJH Associates; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Pharmacyclics; Advisory/Consultancy: Seattle Genetics. J. Christensen: Shareholder/Stockholder/Stock options, Full/Part-time employment: Mirati Therapeutics. R. Shazer: Shareholder/Stockholder/Stock options, Full/Part-time employment: Mirati Therapeutics. X. Yan: Shareholder/Stockholder/Stock options, Full/Part-time employment: Mirati Therapeutics. M. Winter: Shareholder/Stockholder/Stock options, Full/Part-time employment: Mirati Therapeutics. H. Der-Torossian: Shareholder/Stockholder/Stock options, Full/Part-time employment: Mirati Therapeutics. G. Vasudeva Iyer: Honoraria (self), Research grant/Funding (institution): Mirati Therapeutics; Honoraria (self), Research grant/Funding (institution): Janssen; Research grant/Funding (institution): DeBioPharm; Research grant/Funding (institution): Novartis. All other authors have declared no conflicts of interest.