Phase I/II, open-label, multiple ascending dose trial of AGEN2034, an anti–PD-1 monoclonal antibody, in advanced solid malignancies: Results of dose escalation in advanced cancer and expansion cohorts in subjects with relapsed/refractory cervical cancer (2018)

Background: AGEN2034 is a fully-human immunoglobulin (IgG)-4 monoclonal antibody antagonist targeting programmed death protein 1 (PD-1). The objective was to assess safety, maximum tolerated dose, preliminary efficacy, and pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of AGEN2034 in patients (pts) with advanced malignancies. Methods: 30 pts were enrolled at dose cohorts of 1, 3, and 10 mg/kg. AGEN2034 is given intravenously Q2w for ≤2 years with cohorts at Q3w dosing at 6 and 10 mg/kg. A phase 2 expansion of AGEN2034 3 mg/kg Q2w in pts with relapsed/refractory cervical cancer is under way. Results: 10 pts were enrolled at each dose level. Median age was 58 y, with ECOG scores 0–1. No dose-limiting toxicities were observed. Immune-related adverse events (AEs) consistent with this drug class were observed, including pneumonitis, colitis, diarrhea, rash, and pruritus. 21 of 30 pts had treatment-related AEs (TRAEs). 13 (43%) subjects discontinued (d/c) due to disease progression and 1 patient each d/c due to TRAEs of hepatitis and pneumonitis. At the time of data cutoff, in 25 evaluable heavily pretreated pts, 3 partial responses (2 confirmed) were noted in pts with cervical, ovarian, and breast cancers in the 1 and 3 mg/kg cohorts. 13 patients had stable disease, including 5 of 5 patients with ovarian cancer. AGEN2034 demonstrates a dose-proportional Cmax of 19.6 µg/mL at 1 mg/kg and 73.6 µg/mL at 3 mg/kg in 12 pt samples analyzed in the first 2 cohorts. Average PD-1 receptor occupancy (RO) on circulating CD8+ and CD4+ effector memory T lymphocytes (n = 18) demonstrated >59% saturation at all dose levels at day 15 post infusion. Conclusions: AGEN2034 is pharmacologically active, well-tolerated PD-1 antagonist antibody, demonstrating early signals of clinical activity in cervical and ovarian cancers. PK and RO results are comparable to commercial PD-1 antagonists. Updated safety and efficacy results for the dose escalation and the relapsed cervical cancer cohorts will be presented. (NCT03104699). A phase 2 combination study of AGEN2034 and AGEN1884 (CTLA-4) is under way. Clinical trial identification: NCT03104699. Editorial acknowledgement: Editorial support was provided by The Medicine Group, LLC (New Hope, PA, USA) and funded by Agenus Inc. (Lexington, MA, USA). Legal entity responsible for the study: The licensed antibody AGEN2034 was originally developed under a Collaborative Research and Development Agreement between Ludwig Cancer Research, 4-Antibody AG (now Agenus Switzerland Inc.) and Recepta Biopharma S.A. This antibody is partnered with Recepta Biopharma S.A. for certain South American rights. Funding: Agenus Inc. (Lexington, MA, USA). Disclosure: K.N. Moore: Consulting or advisory role: Genentech/Roche, Immunogen, Advaxis, AstraZeneca, Clovis Oncology, Tesaro, VBL Therapeutics, Janssen Oncology; Travel, accomodations, expenses: Genentech/Roche; Research funding: PTC Therapeutics Lilly. J.F. Liu: Consulting or advisory role: Tesaro, AstraZeneca; Research funding: Genentech/Roche, AstraZeneca, Merrimack, Boston Biomedical, Atara Biotherapeutics, Acetylon Pharmaceuticals, Bristol-Myers Squibb, Agenus, CytomX Therapeutics. D.M. O’Malley: Consulting or advisory role: Janssen Oncology, AstraZeneca, Clovis Oncology, Amgen, Tesaro, Novocure, Myriad Genetics; Research funding: Amgen, VentiRx, AstraZeneca, Genentech/Roche, Regeneron, Immunogen,Janssen Research & Development, Clovis Oncology, EMD Serono, Ergomed, Ajinomoto, Immunogen, Cerulean Pharma, PharmaMar, Array BioPharma, Bristol-Myers Squib, Agenus, Tesaro, Tracon Pharma, Stem CentRx; Honoraria: Clovis Oncology. J.S.-Z. Wang: Speakers’ bureau: AstraZeneca/MedImmune. V. Subbiah: Consulting or advisory role: MedImmune; Travel, accomodations, expenses: PharmaMar, Bayer; Research funding: Novartis, GlaxoSmithKline, NanoCarrier, Northwest, Biotherapeutics, Genentech/Roche, Berg Pharma, Bayer, Incyte, Fujufilm, PharmaMar, D3 Oncology Solutions, Pfizer, Amgen, Abbvie, Multivir, Blueprint Medicines, Loxo, Vegenics, Takeda, Alfasigma, Agensys, Idera, Boston Biomedical. B.A. Wilky: Consulting or advisory role: Novartis, Janssen Oncology, Lilly; Travel, accomodations, expenses: Novartis, Lilly, Advenchen Laboratories; Research Funding: Novartis, Merck Sharp & Dohme, Daiichi Sankyo, ArQule, Agenus. G. Yuan, A.M. Gonzalez, D. Savitsky, S. Coulter, E. Dow, H. Youssoufian: Agenus Inc. or subsidiary there of (current or former employee). C.D. Dupont: Agenus Inc. or subsidiary there of (current or former employee); Vertex -An Immediate Family Member Rochester Eye Associates- An Immediate Family Member Travel, Accomodations, Expenses: Agenus Research Funding: Agenus; Vertex; Pfizer; Sanofi Stock and other ownership: Agenus O. Shebanova: Agenus Inc. or subsidiary there of (current or former employee); Travel, Accomodations, Expenses: Agenus; Stock and other ownership: Agenus. W. Ortuzar: Full time contracted consultant: Agenus Bio, Inc. J.S. Buell: Agenus Inc. or subsidiary there of (current or former employee); Travel, Accommodations, Expenses: Agenus. R.B. Stein: Agenus Inc. or subsidiary there of (current or former employee); Stock and other ownership: Agenus. All other authors have declared no conflicts of interest.