Pegilodecakin combined with pembrolizumab or nivolumab for patients with advanced solid tumours (IVY): a multicentre, multicohort, open-label, phase 1b trial

Abstract

Background: IL-10 has anti-inflammatory and CD8+ T-cell stimulating activities. Pegilodecakin (pegylated IL-10) is a first-in-class, long-acting IL-10 receptor agonist that induces oligoclonal T-cell expansion and has single-agent activity in advanced solid tumours. We assessed the safety and activity of pegilodecakin with anti-PD-1 monoclonal antibody inhibitors in patients with advanced solid tumours.

Methods: We did a multicentre, multicohort, open-label, phase 1b trial (IVY) at 12 cancer research centres in the USA. Patients were assigned sequentially into cohorts. Here, we report on all enrolled patients from two cohorts treated with pegilodecakin combined with anti-PD-1 inhibitors. Eligible patients were aged at least 18 years with histologically or cytologically confirmed advanced malignant solid tumours refractory to previous therapies, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with uncontrolled infectious diseases were excluded. Pegilodecakin was provided in single-use 3 mL vials and was self-administered subcutaneously by injection at home at 10 μg/kg or 20 μg/kg once per day in combination with pembrolizumab (2 mg/kg every 3 weeks or 200 mg every 3 weeks) or nivolumab (3 mg/kg every 2 weeks or 240 mg every 2 weeks or 480 mg every 4 weeks at the approved dosing), both of which were given intravenously at the study site. Patients received pembrolizumab or nivolumab with pegilodecakin until disease progression, toxicity necessitating treatment discontinuation, patient withdrawal of consent, or study end. The primary endpoints were safety and tolerability, assessed in all patients enrolled in the study who received any amount of study medication including at least one dose of pegilodecakin, and pharmacokinetics (previously published). Secondary endpoints included objective response by immune-related response criteria in all patients who were treated and had evaluable measurements. The study is active but no longer recruiting, and is registered with ClinicalTrials.gov, NCT02009449.

Findings: Between Feb 13, 2015, and Sept 12, 2017, 111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer. Data cutoff was July 1, 2018. Median follow-up was 26·9 months (IQR 22·3-31·5) for patients with non-small-cell lung cancer, 33·0 months (29·2-35·1) for those with melanoma, and 22·7 months (20·9-27·0) for those with renal cell carcinoma. At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma).

Interpretation: In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma.

Funding: ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company.

Conflict of interest statement

Declaration of Interests

AN received research funding from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor, Amplimmune, ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol-Meyers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera BioSciences, TopAlliance BioSciences, PsiOxus, Immune Deficiency Foundation (spouse). AN 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. RA reports grants from 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, Eli Lilly and Company, EMD Serono Inc., Boehringer Ingelheim, TESARO, Inc., Pfizer Inc., and Checkpoint Therapeutics, Inc., outside the submitted work. KAA received research funding from ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company, Merck, Pfizer, CytomX, and Glaxo Smith Kline. TBB received payment for clinical trial from Daiichi Sankyo, Medpacto, Incyte, Mirati Therapeutics, MedImmune, Abbvie, AstraZeneca, MabVax, Stemline Therapeutics, Merck, Eli Lilly and Company, GlaxoSmithKline, Novartis, Genentech, Deciphera, Merrimack, Immunogen, Millenium, Phosplatin Therapeutics, Calithera Biosciences, Koltan 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, and Foundation Medicine; grants and other from Leap Therapeutics; grants, nonfinancial support and other from Ignyta; grants, nonfinancial support and other from Moderna Therapeutics; grants and personal fees from Pfizer; grants, personal fees and nonfinancial support from Loxo; grants, personal fees and nonfinancial support from Bayer; and personal fees and nonfinancial support from Guardant Health, outside the submitted work. NGD received research funding from Pfizer, BMS, Novartis, Daiichi-Sankyo, Karyopharm, Incyte, Abbvie, Sunesis, Servier, Genentech, NOHLA, Glycomimetics, and Immunogen; advisory/consulting fees from Pfizer, Novartis, BMS, Otsuka, Celgene, Incyte, Jazz, Karyopharm, Sunesis, Immunogen, Abbvie,Astellas, Daiichi-Sankyo, and Agios. AD received travel reimbursement from Eli Lilly and Company, provided consulting services for Bristol-Myers Squibb and Astra Zeneca; received equity from Kynan Pharma, Allogene, and Urogen; and received research funding from KITE Pharma. DF is an employee and stockholder of Eli Lilly and Company. AH, SM, NR, and RV were employed by ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company. WMK reports personal fees from Merck, Sharp & Dohme and Eli Lilly & Company, stock ownership from Oncocyte Inc., and employment and ownership interest in Caris Life Sciences, outside the submitted work. SM has a patent Mumm, J., Chan, I., McCauley, S., Ogg, S., Oft, M. Interleukin-10 in Production of Antigen-Specific CD8+ T-Cells and Methods of Use of Same. Publication No. PCT/US2017/012882. Publication Date July 20, 2017 pending, a patent McCauley, S. and Van Vlasselaer, P. Interleukin-10 Compositions and Uses Thereof. Publication No. US 2016/0068583 A1. Publication Date March 10, 2016 pending, and a patent null pending. MO was a full-time employee during the period on the clinical study described in the manuscript, until February 11 2019, of ARMO BioSciences, now a fully owned subsidy of Eli Lilly. KPP reports funding to START for conduct of this clinical trial from ARMO Biosciences; Abbvie, MedImmune, Daiichi Sankyo, Regeneron, Sanofi, ArQule, other from Amgen, other Calithera Biosciences, Curegenix, Incyte, Merck, Peloton Therapeutics, ADC Therapeutics, 3D Medicines, Formation Biologics, EMD Serono, Syros Pharmaceuticals, Mersana, OncoMed, MabSpace Biosciences and Jounce Therapeutics; KPP has advisory board fees from Arqule and Bayer. NMT reports grants from Merck Pharmaceuticals, Nektar Therapeutics, and Calithera Bioscience; grants and personal fees from Bristol-Myers-Squibb, Exelisis, Inc., and Pfizer; and personal fees from Oncorena and Eisai Medical Research, outside the submitted work DJW reports research funding from ARMO Biosciences, KURA Oncology, Merck, AstraZeneca, Bristol-Myers Squibb, Genentech, Regeneron, EMD Serono, Astellas, and FSTAR and consulting for Bristol-Myers Squibb and Genentech; grants from ARMO Biosciences, Merck, Sharp & Dohme, and KURA Oncology; grants and personal fees from Bristol-Myers Squibb and Genentech; and grants from AstraZeneca and Regeneron, outside the submitted work. EBG reports grants from Eli Lilly and Company, AstraZeneca, BMS, Genentech, Merck, Novartis, Neon, Dynavax, Iovance, and Mirati; other from Dracen and EMD Serono, outside the submitted work. MO, SM, and PVV are former employees of ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company. JRI, SP and ADiab report having no conflicts of interest.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Figures

Figure 1.

IVY Trial Profile of Cohorts H and I. The CONSORT diagram depicts the composition of Cohorts H and I. Patient disposition and reasons for discontinuation as well as the number of patients still on treatment are indicated. CA=cancer; DLT =dose-limiting treatment; NSCLC= non-small cell lung cancer; RCC=renal cell carcinoma; SAE=serious adverse event; TNBC=triple negative breast cancer. * Only 1 bladder cancer patient and 1 triple negative breast cancer (TNBC) patient enrolled, such that the breast and bladder cancer subcohorts were not further recruited. Therefore, these two patients were excluded from the manuscript discussion.

Figure 2.

Patient response. Swimmer plot depicting best overall response, duration of therapy, and overall survival from pegilodecakin (AM0010) + anti-PD-1 therapy in renal cell cancer (RCC), non-small cell lung cancer (NSCLC), and melanoma patients. OS=overall survival.