2277 - Phase 1/2, 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

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 C_max 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.

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).

Editorial Acknowledgement

Editorial support was provided by The Medicine Group, LLC (New Hope, PA, USA) and funded by 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.