536MO A phase I, first-in-human, safety, pharmacokinetic, and pharmacodynamic study of oral dubermatinib (TP-0903) in patients with advanced solid tumours

Abstract

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.