Preliminary safety and efficacy of tinengotinib tablets as monotherapy and combination therapy in advanced solid tumors: A phase Ib/II clinical trial.
Authors: Piha-Paul Sarina A. , Goel Sanjay , Liao Chih-Yi , Gabrail Nashat Y. , Dayyani Farshid , Kazmi Syed Mohammad Ali , Yuan Yuan , Lavasani Sayeh Moazami , Fan Jean , Peng Peng , Sun Caixia , Wang Hui , Hennessy Katie , Fu Ximei , Ni Shumao , Tan Hui Xian , Ngo Brenda , Ru Qinhua Cindy , Wu Frank , Javle Milind M. 
Published: June 2023

3019 Background: Tinengotinib is a spectrum-selective multi-kinase inhibitor that targets cell proliferation, angiogenesis, and immune-oncology pathways by inhibiting Aurora kinases A/B, Janus kinases (JAK), and receptor tyrosine kinases (FGFRs, VEGFRs). Tinengotinib has shown preliminary efficacy in prostate cancer (PC), hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BC), triple-negative BC (TNBC) and cholangiocarcinoma (CCA) in Phase (Ph) 1 trial. Here we present the preliminary safety, pharmacokinetics (PK), and efficacy of tinengotinib in a Ph Ib/II trial. Methods: Eligible patients (pts) with advanced or metastatic solid tumors were assigned to: Arm A (tinengotinib 12 mg QD), Arm B (tinengotinib 8/10/12 mg QD in combination with 100 mg/m2 Abraxane, HER2- BC); Arm C PK Run-in (tinengotinib 5/8/10/12 mg QD, or 4/6 mg BID). Objectives include safety (CTCAE v5.0) and tolerability, PK profile, efficacy (RECIST v1.1) and exploratory biomarker(s). Results: As of 30 Jan 2023, 157 pts with solid tumors were enrolled and treated. In monotherapy (Arm A and Arm C, N=153), median age was 62.5 years (23-83), 56% were female, 69% had ≥ 3 prior lines of therapy. In combination (Arm B, N=4), median age was 40 years (25-46), 100% were female, 100% had ≥3 prior lines of therapy. The treatment-related AEs (TRAE) in monotherapy arms were reported in 110 (71.9%) pts. 53 (34.6%) were Grade (G) 1-2, 55 (35.9%) were G3, 2 (1.3%) were G4, no G5 was observed; the most common TRAEs were hypertension (29.4%), stomatitis (20.9%), diarrhea (16.3%), nausea (13.7%) and palmar-plantar erythrodysesthesia syndrome (12.4%). In the combination arm, 4 treated pts at dose level 1 experienced G3 TRAEs, and the most common TRAEs were neutropenia (75%), stomatitis (50%), hyponatremia (50%), hypokalemia (50%) and hypertension (50%). In 108 efficacy-evaluable pts of monotherapy arms, the overall response rate (ORR) and disease control rate (DCR) were 16% and 60%, respectively. The ORR in PC, HR+/HER2- BC, TNBC and CCA were 50% (5/10), 40% (2/5), 50% (3/6) and 20% (3/15), respectively. Preliminary PK analysis showed a linear increase on exposure in terms of geometric mean Cmax,ss and AUC0-24h,ss from 5 mg QD to 12 mg QD. No significant difference in exposure was observed in QD vs BID. Conclusions: Tinengotinib monotherapy was well-tolerated. The tolerability assessment in combination with chemotherapy is underway. The PK results may support dose recommendation for subsequent trials. Encouraging anticancer activity of tinengotinib monotherapy were observed in pts with heavily pre-treated solid tumors, including PC, HR+/HER2- BC, TNBC and CCA. The ongoing Ph II study of tinengotinib continues to evaluate clinical benefit and safety in pts with PC. Clinical trial information: NCT04742959 .