1696P - A phase I/ II trial of pazopanib (Paz) alternating (alt) with bevacizumab (Bev) in treatment-naïve metastatic clear cell renal cell carcinoma (mccRCC) patients (pts): Phase II results

Background

Vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors (TKI) are widely used for the treatment of mccRCC. VEGF upregulation is postulated to be a resistance mechanism against VEGF TKI. We hypothesized that introducing Bev during scheduled breaks in Paz treatment can bind and neutralize VEGF, thereby prolonging progression-free survival (PFS) of mccRCC pts. The phase I portion of this study established the safety and recommended phase II dose (RP2D). Here we report the phase II efficacy and safety results.

Methods

This multi-center, single-arm, two-stage, phase II trial was conducted in treatment-naive mccRCC pts, utilizing the RP2D of Paz 800mg daily (days 1-28) and Bev 10mg/Kg on days 36 and 50 of a 10-week cycle. The primary endpoint was the 12-month clinical benefit rate (CBR = CR+PR+SD from RECIST 1.1). The study was designed to detect a CBR rate of 60% versus 45% at alpha = 0.10 and power = 0.80 using a two-stage design with n = 26+25 (51) pts. Under some simplifying assumptions a 45% 12-month CBR rate translated to a median PFS of 11.1 months (mos) in this study population and a 60% CBR rate translates to a median PFS of 15.7 mos. Secondary endpoints included safety, objective response rate (ORR), and overall survival (OS).

Results

This trial enrolled 51 pts across 5 cancer centers. The futility-stopping rule was not met after n = 26 pts was enrolled. Enrollment was enriched for IMDC favorable risk (31/45) pts due to FDA approval of immunotherapy regimens. The final efficacy rule of ≥28/51 pts having a CBR response at 12 months was met (40/51 = 0.78). Median age was 65.6 years with 70.6% male pts. The predominant adverse events (AE) were diarrhea (70%), hypertension (54%), fatigue (69%), and nausea (51%). Most common grade 3/ 4 AEs included hypertension (33%), ALT (14%) and AST (12%). The ORR was 54.9% with a CBR of 98%. The median PFS was 22.1 mos (95% CI, 15.9, 27.4) after a median follow-up of 33.1 mos. The median OS was 62.9 mos (95% CI 46.0, NR).

Conclusions

This phase II trial of Paz alt with Bev met its primary efficacy endpoint. This novel regimen was well tolerated and with promising efficacy and safety in treatment-naive, predominantly favorable risk mccRCC pts.

Clinical trial identification

NCT01684397.

Editorial acknowledgement

Legal entity responsible for the study

Roswell Park Comprehensive Cancer Center.

Funding

Novartis.

Disclosure

S. George: Financial Interests, Personal, Advisory Board, advisor/consultant: BMS, Bayer, Pfizer, Exelixis, Sanofi/ Genzyme, Seattle Genetics, EMD Serono, Eisai, Merck, Aveo, QED therapeutics; Financial Interests, Personal, Advisory Board, Advisor/consultant: Novartis, AstraZeneca; Financial Interests, Institutional, Local PI: Pfizer, Merck, Agensys, Novartis, BMS, Bayer, Eisai, Seattle Genetics, Surface Oncology, Exelixis, Aravive, Aveo, Gilead. U.N. Vaishampayan: Financial Interests, Personal, Advisory Board, consultant: BMS; Financial Interests, Personal, Advisory Board: Bayer, Gilead, Pfizer, Merck, Exelixis, Novartis; Financial Interests, Institutional, Research Grant, Investigator initiated trial supported by Merck: Merck; Non-Financial Interests, Member of Board of Directors: Michigan Society of Hematology/Oncology. D. Kilari: Financial Interests, Personal, Invited Speaker: Janssen, Pfizer, Aveo Oncology, Seagen, MJH - life sciences, Binayatra foundation; Financial Interests, Personal, Advisory Board: Exelixis, Eisai; Financial Interests, Institutional, Coordinating PI: Exelixis, Genentech. E. Heath: Financial Interests, Personal, Other, Consulting/Advisory Role, Paid Travel: Astellas; Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Janssen; Financial Interests, Personal, Other, Paid Travel: Caris Life Science; Financial Interests, Personal, Advisory Board, Speaker's Bureau, Paid Travel: Sanofi; Financial Interests, Personal, Advisory Board, Paid Travel: Seattle Genetics; Financial Interests, Institutional, Local PI: Arvinas, Astellas, AstraZeneca, Bayer, BioXcel, Bristol Myers Squibb, Calibr, Calithera, Corcept, Daiichi Sankyo, Eisai, Five Prime, Fortis, Gilead Sciences, GSK, Harpoon, Hoffman-La Roche, Infinity, Janssen, Merck, Merck Sharpe Dohme, Mirati, Modra, Novartis, Peloton, Pfizer, Pharmacyclics, iTeos, Point Biopharma; Financial Interests, Personal, Other, Executive Committee Member Precision Oncology Alliance: Caris Life Science; Financial Interests, Institutional, Coordinating PI: Exelixis, Oncolys; Financial Interests, Personal, Steering Committee Member: Seattle Genetics. E. Wulff-Burchfield: Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Personal, Speaker, Consultant, Advisor: Astellas, BMS, Exelixis; Financial Interests, Personal, Advisory Board: Aveo, Janssen, Bayer; Financial Interests, Personal, Stocks or ownership, family member: Immunomedics, Nektar; Financial Interests, Personal and Institutional, Funding, and non financial support: Acer therapeutics; Financial Interests, Personal, Licencing Fees or royalty for IP, Pending patent: Osanetant/ Acer. L.J. Appleman: Financial Interests, Institutional, Local PI, Site P.I: Amgen; Financial Interests, Institutional, Local PI, Local PI: BMS, Merck, Exelixis, Arvina, Surface Oncology, Novartis, Ipsen/Epizyme, Johnson & Johnson, BioNTech, Seagen, Peloton; Financial Interests, Institutional, Local PI, local PI: Pfizer, Genentech/Roche, Astellas; Financial Interests, Personal, Steering Committee Member, Pulmonary Hypertension Data Safety Monitoring Committee Chair: AAdi. All other authors have declared no conflicts of interest.