A phase I study of rivoceranib combined with nivolumab in patients with unresectable or metastatic cancer

BackgroundRivoceranib (Rivo) is an oral small molecular receptor tyrosine kinase inhibitor that selectively inhibits VEGFR. Preclinical studies have demonstrated increased PD-L1 expression after initial treatment with anti-VEGF inhibitors as well as an increase in effector T cells (Zhao et al., 2017). This phase 1 study (NCT03396211) evaluated safety, tolerability, preliminary efficacy, and selected immunologic effects of the combination of Rivo and nivolumab (Nivo) in patients (pts) with advanced or metastatic solid tumors.MethodsPart 1 evaluated the safety of increasing oral daily doses of Rivo (400, 500, 600, and 700 mg/day) with Nivo 240 mg administered IV q2w until the MTD was determined. Part 2 evaluated the safety of the MTD or 700 mg/day of Rivo, whichever was lower, with Nivo in an expansion cohort of up to 20 pts. The primary outcome measures included safety, tolerability, and efficacy measures.Results30 pts enrolled in the study (n=10 in Part 1, n=20 in Part 2). Rivo 400 mg/day was the starting dose in cohort 1 and was de-escalated to 300 mg following a DLT of grade (Gr) 3 nausea, vomiting, and diarrhea in 2 patients. The second cohort evaluated Rivo 300 mg, and 1 pt experienced DLTs of uncontrolled hypertension and Gr 3 nausea, vomiting, and diarrhea; therefore, the MTD was Rivo 300 mg/day combined with Nivo 240 mg IV q2w. The most common (≥20%) Gr ≥3 treatment-emergent adverse events (TEAEs) were hypertension (66.7%), generalized rash (33.3%), ALT increased (33.3%), neutropenia (33.3%) (Part 1 400 mg cohort); anemia (42.9%) (Part 1 300 mg cohort); anemia and hypophosphatemia (20% each) (Part 2 300 mg cohort). 46.7% of pts experienced a serious AE. Efficacy results are displayed in the table. Table: 1013P Efficacy results Part 1 400 mgcohort (n=3) Part 1 300 mgcohort (n=7) Part 2 300 mgcohort (n=20) Overall (n=30) ORR, n (%) 0 1 (14.3) 4 (20.0) 5 (16.7) CR, n (%) 0 0 0 0 PR 0 1 (14.3) 4 (20.0) 5 (16.7) SD, n (%) 3 (100.0) 3 (42.9) 13 (65.0) 19 (63.3) PD, n (%) 0 1 (14.3) 2 (10.0) 3 (10.0) Not evaluable, n (%) 0 0 0 0 Missing, n (%) 0 (0) 2 (28.6) 1 (5.0) 3 (10.0) Time to response, months N/A 5.6 4.5 5.3 DoR, months N/A 1.8 2.8 2.0 DCR, n (%) 3 (100) 4 (57.1) 17 (85.0) 24 (80.0) ConclusionsRivo 300 mg + Nivo 240 mg IV q2w demonstrated a manageable safety profile and promising antitumor efficacy in pts with advanced or metastatic solid tumors. Further studies are needed to confirm the safety and efficacy of this combination.Clinical trial identificationNCT03396211.Editorial acknowledgementOlivia Adams, The Phillips Group Oncology Communications, Inc.Legal entity responsible for the studyElevar Therapeutics.FundingElevar Therapeutics.DisclosureC.H. Park: Financial Interests, Personal, Full or part-time Employment: Elevar Therapeutics. S.P. Chawla: Financial Interests, Personal, Research Grant: Amgen, Roche, GSK, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, Sarcoma Alliance for Research through Collaboration (SARC), Janssen, Advenchen Laboratories, Bayer, Inhibrx, NKMax, Thyme; Financial Interests, Personal, Speaker’s Bureau: Amgen, Roche, GSK, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, Sarcoma Alliance for Research through Collaboration (SARC), Janssen, Advenchen Laboratories, Bayer, Inhibrx, NKMax, Thyme; Financial Interests, Personal, Speaker, Consultant, Advisor: Amgen, Roche, GSK, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, Sarcoma Alliance for Research through Collaboration (SARC), Janssen, Advenchen Laboratories, Bayer, Inhibrx, NKMax, Thyme; Financial Interests, Personal, Stocks/Shares: AADi, Cellestia Biotech, CounterPoint, Immix, BioPharma. X. Meng, W.R. Strickland, L.A. Finis, C. Galloway: Financial Interests, Personal, Full or part-time Employment: Elevar Therapeutics. All other authors have declared no conflicts of interest.