AXL is upregulated in many solid tumors and may drive resistance to targeted cancer therapeutics, traditional chemotherapies, and immuno-oncology agents. Dubermatinib is a novel, orally administered small molecule AXL kinase inhibitor affecting mesenchymal-epithelial transition while targeting oncogenesis and chemoresistance.
Ph I enrolled 45 pts with advanced solid tumors across 9 dose levels (1.5-37mg/m2) and 50mg flat dose. The RPh2D was determined as 50mg dubermatinib QD 21/28 days based on dose-proportionate drug accumulation including metabolites, and thrombocytopenia. Five expansion cohorts enrolled 1) dubermatinib plus IO with progression after response (n=19); 2) dubermatinib plus EGFR inhibitor in EGFR+ NSCLC with progression after response (n=18); 3) KRAS+ CRC (n=47); 4) platinum refractory/resistant ovarian cancer (n=22); 5) BRAFmut/wt melanoma (n=13).
In 125 patients receiving at least one 50mg dose the most frequently observed Gr3/4 AEs were anemia, diarrhea (7/5.6%); hyponatremia, dyspnea (5/4.0%); vomiting, ascites, fatigue, incr alkphos, decr potassium, PE (3/2.4%). PK values for plasma dubermatinib and active metabolites rose incrementally with dose (t½ 12-20hrs). Day 1 Cmax and AUC0-24 (50mg) were 14.8 ng/mL and 160.9 ng*hr/mL, respectively. Increases were observed at Day 21. Clinical activity included 4 PRs: 2 NSCLC (1 pt 37mg/m2 dubermatinib+TKI, 1 pt 50mg dubermatinib+nivolumab), 1 melanoma pt. 9mg/m2 and 1 cholangiocarcinoma pt. 50mg, both single agent dubermatinib. Dose reduction rate at RP2D was <10% with overall CBR observed in 18.4% (23/125) of pts including 4 PRs and SD>4 months in heavily pretreated patients. PD evaluation of pre, post-treatment tumor biopsies and PBMCs correlated with drug activity (dose dependent sAXL reduction and GAS6 increase on treatment Day 8). Changes in immune cell infiltration, activity of antigen presenting cells and polarization of macrophages will be presented.
Dubermatinib at 50mg orally once daily was tolerated, with evidence of AXL engagement in surrogate tissues and preliminary evidence of clinical activity. Combination studies with TKIs and IO agents are being analyzed.
NCT02729298 JAPIC ID: JapicCTI-194793.
Tolero Pharmaceuticals, Inc.
Tolero Pharmaceuticals, Inc.
A.A. Adjei: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc. M. Beg: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc. J. Melear: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc; Speaker Bureau/Expert testimony: Janssen; Speaker Bureau/Expert testimony: AstraZeneca. J. Thompson: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc; Advisory/Consultancy: Pfizer. F.Y-C. Tsai: Advisory/Consultancy: Tempus Lab; Leadership role: Caremission LLC; Shareholder/Stockholder/Stock options: Salarius Pharmaceuticals; Research grant/Funding (institution): Tolero Pharmaceuticals, Inc. J.C. Baranda: Research grant/Funding (institution): Exelixis; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Tolero Pharmaceuticals; Research grant/Funding (institution): Xencor; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi; Research grant/Funding (institution): Nektar; Research grant/Funding (institution): SQZ; Shareholder/Stockholder/Stock options: Forty-Seven Inc; Shareholder/Stockholder/Stock options: Moderna; Shareholder/Stockholder/Stock options: Zymeworks; Shareholder/Stockholder/Stock options: Morphosys AG. B. Bastos: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc; Speaker Bureau/Expert testimony: Regeneron; Speaker Bureau/Expert testimony: Sanofi Genzyme. A. Spira: Honoraria (self), Research grant/Funding (self): Cytomx; Honoraria (self), Research grant/Funding (self): Amgen; Honoraria (self), Research grant/Funding (self): Novartis; Honoraria (self), Research grant/Funding (self): Merck; Honoraria (self), Research grant/Funding (self): AstraZeneca; Honoraria (self), Research grant/Funding (self): Bristol-Myers-Squibb; Research grant/Funding (self): EMD Serono; Research grant/Funding (self): Turning Point; Research grant/Funding (institution): Tolero Pharmaceuticals, Inc. Y. Lou: Advisory/Consultancy: Novocure; Research grant/Funding (institution): Tolero Pharmaceuticals, Inc; Research grant/Funding (institution): Tesaro; Research grant/Funding (institution): Merck Sharp & Dohme; Research grant/Funding (institution): Blueprint Medicines; Research grant/Funding (institution): Vaccinex; Advisory/Consultancy: AstraZeneca; Research grant/Funding (institution): Macrogenics; Advisory/Consultancy: Clarion Healthcare; Research grant/Funding (institution): Kyowa Hakko Kirin Pharma; Research grant/Funding (institution): Harpoon Therapeutics; Research grant/Funding (institution): Sun Pharma Advanced Research Company Limited. M. Seetharam: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc; Advisory/Consultancy: Daiichi-Sankyo; Honoraria (self): CME Horizon. M. Uemura: Shareholder/Stockholder/Stock options: Abbott Laboratories; Advisory/Consultancy: Seattle Genetics; Shareholder/Stockholder/Stock options, Spouse/Financial dependant: Regeneron Pharmaceuticals. D.R. Camidge: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc; Advisory/Consultancy: Anchiarno; Advisory/Consultancy: Amgen; Advisory/Consultancy, Research grant/Funding (institution): Takeda; Advisory/Consultancy, Research grant/Funding (institution): Roche / Genentech; Advisory/Consultancy: EMD Serono; Advisory/Consultancy: Sanofi; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: CBT Pharmaceuticals; Advisory/Consultancy: Daiichi-Sankyo; Advisory/Consultancy: G1 Therapeutics; Advisory/Consultancy, Research grant/Funding (institution): AbbVie; Advisory/Consultancy: Achilles; Advisory/Consultancy: BeyondSpring; Advisory/Consultancy: Apollomics; Advisory/Consultancy: 14ner / Elevation; Advisory/Consultancy: Archer; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Glaxo-Smith-Kline; Advisory/Consultancy, Research grant/Funding (institution): Hansoh; Research grant/Funding (institution): InhibRx; Research grant/Funding (institution): Lycera; Research grant/Funding (institution): MedImmune; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Phosplatin; Research grant/Funding (institution): Psioxus; Research grant/Funding (institution): Rain; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Symphogen. N. Yamamoto: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc; Research grant/Funding (institution): Astellas; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Chugai; Advisory/Consultancy, Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Taiho; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bristol-Myers-Squibb; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Novartis; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Daiichi-Sankyo; Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): Boehringer-Ingelheim; Research grant/Funding (institution): Kyowa-Hakko Kirin; Advisory/Consultancy, Research grant/Funding (institution): Takeda; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Ono; Research grant/Funding (institution): Janssen Pharma; Research grant/Funding (institution): Merck Sharp & Dohme; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Glaxo-Smith-Kline; Research grant/Funding (institution): Sumitomo Dainippon; Advisory/Consultancy: Otsuka; Advisory/Consultancy: Cimic; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Sysmex. C.L. Cowey: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc. T. Doi: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc; Honoraria (self), Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self): Astellas; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AbbVie; Honoraria (self): Ono; Honoraria (self): Oncolys BioPharma; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Taiho; Advisory/Consultancy: Amgen; Advisory/Consultancy, Research grant/Funding (institution): Sumitomo Dainippon; Advisory/Consultancy: Rakuten Medical; Advisory/Consultancy, Research grant/Funding (institution): Daiichi Sankyo; Advisory/Consultancy: Takeda; Advisory/Consultancy: Bayer; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Merck, Sharp and Dohme; Research grant/Funding (institution): Merck Serono; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Kyowa Hakko Kirin; Research grant/Funding (institution): IQVIA; Research grant/Funding (institution): Pfizer. S.P. Anthony: Full/Part-time employment: Tolero Pharmaceuticals, Inc; Advisory/Consultancy: Paradigm. M. Janat-Amsbury: Full/Part-time employment: Tolero Pharmaceuticals, Inc. M. Wade: Full/Part-time employment: Tolero Pharmaceuticals, Inc. D.J. Bearss: Officer/Board of Directors: Tolero Pharmaceuticals, Inc. J. Sarantopoulos: Research grant/Funding (institution): Tolero Pharmaceuticals, Inc.