Assessment of Subcutaneous vs Intravenous Administration of Anti-PD-1 Antibody PF-06801591 in Patients With Advanced Solid Tumors: A Phase 1 Dose-Escalation Trial

Abstract

Importance: We assessed feasibility of monthly subcutaneous administration of PF-06801591, a humanized immunoglobulin G4 monoclonal antibody that binds to the programmed cell death (PD-1) receptor and blocks its interaction with PD-1 ligands.

Objective: To evaluate the safety, efficacy, and pharmacokinetics of PF-06801591 administered intravenously vs subcutaneously.

Design, setting, and participants: Ongoing phase 1, open-label, multicenter, dose-escalation study of 40 patients, 18 years or older, with locally advanced or metastatic solid tumors, enrolled between March 8, 2016, and March 5, 2018, from 4 US medical centers.

Interventions: An intravenous dose of 0.5, 1, 3, or 10 mg/kg of PF-06801591 was administered every 3 weeks or a subcutaneous dose of 300 mg was administered every 4 weeks. Dose escalation occurred after 2 to 4 patients were enrolled per dose level, with additional patients enrolled in each cohort for further assessment.

Main outcomes and measures: The primary end points were dose-limiting toxic effects and safety. Secondary end points included pharmacokinetics, immunogenicity, PD-1 receptor occupancy, and efficacy.

Results: Of 40 enrolled patients (12 men and 28 women; mean [SD] age, 61 [13] years) in this phase 1 dose-escalation trial, 25 received PF-06801591 intravenously at escalating dose levels (0.5, 1, 3, or 10 mg/kg) and 15 patients received the monoclonal antibody subcutaneously at a single dose level. No dose-limiting toxic effects were observed. Grade 3 or higher treatment-related adverse events occurred in 4 (16%) patients treated intravenously and 1 (6.7%) patient treated subcutaneously. Immune-related adverse events occurred in 10 (40%) patients treated intravenously and 3 (20%) treated subcutaneously. No dose-adverse event associations were observed during intravenous dose escalation, and no serious skin toxic effects occurred with subcutaneous delivery. Responses were seen in 5 patients receiving PF-06801591 intravenously and in 2 patients treated subcutaneously for an overall objective response rate of 18.4%. Median overall survival was not reached with intravenous dosing vs 10.7 months with subcutaneous administration. Exposure to PF-06801591 increased in a dose-proportional manner over the range of intravenous doses. Median time to maximum observed serum concentration was 8 days after subcutaneous administration. Full PD-1 receptor occupancy was seen in all dose cohorts.

Conclusions and relevance: Anti-PD-1 antibody PF-06801591 was tolerable and showed antitumor activity in a variety of tumor types across all dose levels of intravenous and subcutaneous administration. Monthly subcutaneous administration of PF-06801591 offers a convenient, effective alternative to currently available intravenously administered checkpoint inhibitors.

Trial registration: ClinicalTrials.gov identifier: NCT02573259.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Johnson reports research funding fees (to institution) from BerGenBio, Lilly, EMD Serono, Janssen, Mirati Therapeutics, Genmab, Pfizer, AstraZeneca, Genentech/Roche, Stemcentrx, Novartis, Checkpoint Therapeutics, Array BioPharma, Regeneron, Apexigen, AbbVie, Tarveda Therapeutics, Adaptimmune, Syndax, Neovia, Boehringer Ingelheim, Sanofi, Hengrui Therapeutics, INC, Merck, Daiichi–Sankyo, Lycera, G1 Therapeutics, Dynavax, LOXO Oncology, CytomX, BeiGene, Birdie Pharmaceuticals, Corvus, Incyte, Genocea, Gritstone Oncology, and Amgen; and consulting fees (to institution) from Genentech/Roche, Celgene, Boehringer Ingelheim, Sanofi, Mirati Therapeutics, LOXO Oncology, Calithera, AstraZeneca and Merck; contract lobbyist for Astellas Pharma and Otsuka Pharmaceuticals (Spouse). Dr Braiteh reports fees for speaker bureau and advisory board services from Pfizer. Dr Hu-Lieskovan reports consulting fees from Merck, Amgen, Genmab, Bristol-Myers Squibb and Vaccinex; research support from Bristol-Myers Squibb, Merck, and Vaccinex; contracted clinical research with Pfizer, Genentech, Astellas Pharma, Neon Therapeutics, F-Star, Xencore, Nektar Therapeutics. Drs Chou, Davda, Forgie, Jacobs, and Kazazi and Ruifeng Li are employees of and own stock in Pfizer Inc. No other disclosures were reported.

Figures

Figure 1.. CONSORT Flow Diagram

Figure 2.. Percent Change in Tumor Size in the Modified Intent-to-Treat Population of 38 Patients

aPatient had 30% or more reduction in target lesion tumor burden, but a new measurable lesion outside of field of the initial baseline CT scans was identified, and the patient was reported as having progressive disease (PD). A retrospective assessment showed the new measurable lesion had been noted on scans prior to study screening, and later scans showed that it regressed 40% on treatment. B, Solid lines represent patients still on treatment, and dashed lines represent patients who have discontinued treatment. IV indicates intravenous; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors version 1.1; SC, subcutaneous; SD, stable disease.

Figure 3.. Concentration-Time Profiles of PF-06801591 After Intravenous or Subcutaneous Administration and PD-1 Receptor Occupancy by PF-06801591

Concentration-time profiles (A and B) were assayed using serum and the PD-1 (programmed cell death 1) receptor occupancy (C and D), as measured by reduction in free cell surface PD-1 postdosing, was assayed using whole blood taken at the identified time points from patients treated with PF-06801591. Representative plots are shown for PD-1 receptor occupancy. Values represent mean ± SD. C indicates cycle; D, day; EOT, end of treatment; IV, intravenous; pre, predose; SC, subcutaneous.