Pegilodecakin Combined with Anti-PD-1 Monoclonal Antibodies for Patients with Advanced Renal Cell Carcinoma (IVY): A Multicentre, Open-Label, Phase 1b Trial

Background: Interleukin (IL)-10 has anti-inflammatory and CD8+ T-cell-stimulating activities. Pegilodecakin (pegylated IL-10) induces oligoclonal T-cell expansion and has single-agent activity in advanced renal cell cancer (RCC). We assessed the safety and efficacy of pegilodecakin and anti-PD-1 monoclonal antibodies in advanced RCC. Methods: This study was a multicenter, open-label, phase 1b trial at ten cancer research centres in the US. Patients with advanced metastatic RCC were enrolled and treated with daily subcutaneous pegilodecakin at 10 or 20 µg/kg combined with either 3 mg/kg nivolumab twice weekly or 2 mg/kg pembrolizumab three times weekly. The primary endpoint was safety and tolerability. The secondary endpoint was clinical activity and tumour response, measured by immune-related response criteria (irRC). The study is registered with ClinicalTrials.gov (NCT02009449). Findings: From February 2015 to November 2016, 38 patients enrolled, and 35 patients were evaluable for response by investigators. Six patients had no prior therapy, and 32 patients had prior therapy (30 patients had prior therapy excluding pegilodecakin and checkpoint inhibitors). Of these 30, 27 patients were evaluable by irRC, and 12 (44%) achieved an objective response as assessed by the investigators. Median duration of response was 64·9 weeks. Median OS was not reached, mPFS was 12·5 months, and 1-year survival was 86·2%. All 38 patients were included in the survival and safety analyses; 26 (68%) patients had grade 3/4 treatment-related adverse events, including anaemia (10), thrombocytopenia (8), and hypertriglyceridemia (6). T-cell receptor clonality assessment in circulating T-cells indicated a treatment-dependent expansion of novel T-cell clones, correlating with survival. Interpretation: Pegilodecakin is a first-in-class long-acting IL-10 receptor agonist. In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and promising antitumour activity, warranting further study in phase 2 and 3 clinical trials. Clinical Trial Registration: The study is registered with ClinicalTrials.gov (NCT02009449). Funding Statement: Funding provided by ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company. Declaration of Interests: Aung Naing received research funding from NCI; EMD Serono; MedImmune; Healios Onc. Nutrition; Atterocor; Amplimmune; ARMO BioSciences; Karyopharm Therapeutics; Incyte; Novartis; Regeneron; 18 Merck; BMS; Pfizer, CytomX Therapeutics; Neon Therapeutics; Calithera Biosciences; TopAlliance Biosciences; Eli Lilly; Kymab; PsiOxus; Immune Deficiency Foundation (spouse). Aung Naing is on the advisory board for CytomX Therapeutics and Novartis and received reimbursement for travel and accommodation from ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company. Raid Aljumaily received grant funding that was paid to the institution from Eli Lilly and Company; Alliance Foundation Trials, LLC; Boston Biomedical, Inc.; Syneos Health; Array BioPharma; Bristol-Myers Squibb; Huntsman Cancer Institute; Merck Co; AstraZeneca; AbbVie Inc.; Regeneron; G1 Therapeutics, Inc.; F. Hoffman-La Roche AG; Genentech, Inc.; MedImmune, LLC; GlaxoSmithKline; Novartis; Peloton Therapeutics, Inc.; Baxalta; EMD Serono Inc.; Boehringer Ingelheim; TESARO, Inc.; Pfizer Inc.; and, Checkpoint Therapeutics, Inc. Karen Autio received research funding paid to the institution from ARMO Biosciences/Lilly; Merck; Pfizer; CytomX; and, Glaxo Smith Kline. Todd Bauer received research funding paid to the institution from ARMO Biosciences and Daiichi Sankyo; Medpacto; Incyte; Mirati Therapeutics; MedImmune; Abbvie; AstraZeneca; MabVax; Stemline Therapeutics; Merck; Lilly; GlaxoSmithKline; Novartis; Genentech; Deciphera; Merrimack; Immunogen; Millennium; Phosplatin Therapeutics; Calithera Biosciences; Kolltan Pharmaceuticals; Principa Biopharma; Peleton; Immunocore; Roche; Aileron Therapeutics; Bristol-Myers Squibb; Amgen; Onyx; Sanofi; Boehringer- Ingelheim; Astellas Pharma; Five Prime Therapeutics; Jacobio; Top Alliance BioScience; Janssen; Clovis Oncology; Takeda; Karyopharm Therapeutics; Foundation Medicine; Leap Therapeutics; Ignyta; Moderna Therapeutics; Pfizer; Loxo; and, Bayer. Todd Bauer received payment to institution for consulting services from Leap Therapeutics; Ignyta; and Moderna Therapeutics. Todd Bauer also received payment or reimbursement of exact amount of expenses from Ignyta; Moderna Therapeutics; Loxo; Bayer; and, Guardant Health; payment for consulting services from Pfizer; Loxo; Bayer; and, Guardant Health and for speakers bureau from Bayer. Navel Daver received research funding from Pfizer, BMS, Novartis, Daiichi-Sankyo, Karyopharm, Incyte, Abbvie, Sunesis, Servier, Genentech, NOHLA, Glycomimetics, Immunogen; for advisory and consulting services from Pfizer, Novartis, BMS, Otsuka, Celgene, Incyte, Jazz, Karyopharm, Sunesis, Immunogen, Abbvie, Astellas, Daiichi-Sankyo, Agios; and, 19 honoraria from BMS, Jazz, Novartis, Incyte, Otsuka, Immunogen, Pfizer, Astellas, Abbvie. Alexandra Drakaki received consulting fee from BMS. David Ferry is an employee and stock owner of Eli Lilly and Company. Jeffrey Infante received payment for consulting services from BioMed Valley and ARMO BioSciences; and, employer at Janssen Oncology; Wolfgang Korn received personal fees from Merck, Sharp & Dohme and Eli Lilly & Company; has stock ownership at Oncocyte Inc.; is an employee and has stock options at Caris Life Sciences. Martin Oft, during the period on the clinical study described in the manuscript, until February 11, 2019, was a full time employee of ARMO BioSciences, now a fully subsidy of Eli Lilly. Kyriakos Papadopoulos received funding to START for conduct of clinical trial from ARMO BioSciences, Abbvie, and MedImmune. Nazir Tannir received clinical grants from Merck Pharmaceuticals, Bristol-Myers Squibb, and Pfizer. Nazir Tannir is on the advisory board for Bristol- Myers Squibb, Pfizer, and Oncorena. Deborah Wong received research grant funding from ARMO BioSciences, Merck, Sharp & Dohme, KURA Oncology, Bristol-Myers Squibb, Genentech, AstraZeneca, and Regeneron. Deborah Wong has received personal fees from Bristol-Myers Squibb and Genentech. Scott McCauley has declared 2 patent applications, WO2017123557A1 entitled, “Interleukin-10 in production of antigen-specific cd8+ t cells and methods of use of same” and US20160068583A1 entitled, “Interleukin-10 Compositions and Uses Thereof”. Annie Hung, Shubham Pant, Navneet Ratti, Peter Van Vlasselaer, and Rakesh Verma declare no conflict of interest. Ethics Approval Statement: The study protocol was reviewed and approved by the Institutional Review Board at participating sites and was conducted in accordance with the Declaration of Helsinki and other Good Practice Guidelines. All patients signed the approved consent forms for the study.