A first-in-human phase I study of the PD-1 inhibitor, retifanlimab (INCMGA00012), in patients with advanced solid tumors (POD1UM-101)

Abstract

Background: Retifanlimab is a humanized, hinge-stabilized immunoglobulin G4κ monoclonal antibody against human programmed cell death protein 1 (PD-1). This first-in-human, phase I study assessed the safety and efficacy of retifanlimab in patients with advanced solid tumors and identified optimal dosing.

Patients and methods: POD1UM-101 was conducted in two parts: (i) dose escalation-evaluated retifanlimab [1 mg/kg every 2 weeks (q2w), 3 or 10 mg/kg q2w or every 4 weeks (q4w)] in patients with relapsed/refractory, unresectable, locally advanced or metastatic solid tumors; (ii) cohort expansion-biomarker-unselected tumor-specific cohorts [endometrial, cervical, sarcoma, non-small-cell lung cancer (NSCLC)] received retifanlimab 3 mg/kg q2w, and tumor-agnostic cohorts received flat dosing [375 mg every 3 weeks (q3w), or 500 and 750 mg q4w]. Primary objectives were safety and tolerability; secondary objective was efficacy in selected tumor types.

Results: Thirty-seven patients were enrolled in dose escalation, 134 in PD-1 therapy-naïve tumor-specific cohort expansion (endometrial, n = 29; cervical, NSCLC, soft tissue sarcoma, each n = 35), and 45 in flat dosing (375 mg q3w, 500 and 750 mg q4w, each n = 15). No dose-limiting toxicities occurred during dose escalation; maximum tolerated dose was not reached and 3-mg/kg q2w expansion dose was selected based on safety and pharmacokinetic data. Immune-related adverse events were experienced by 40 patients (30%) in tumor-specific cohorts (most frequently hypothyroidism, hyperthyroidism, colitis, nephritis) and 6 (13%) in flat dosing (most frequently hypothyroidism, hyperthyroidism). Objective response rate (95% confidence interval) was 14% (4.8 to 30.3), 14% (3.9 to 31.7), 20% (8.4 to 36.9), and 3% (0.1 to 14.9) in advanced NSCLC, endometrial, cervical, and sarcoma tumor-specific cohorts that progressed after multiple prior systemic therapies.

Conclusions: Retifanlimab demonstrated clinical pharmacology, safety, and antitumor activity consistent with the programmed death (ligand)-1 inhibitor class. POD1UM-101 results support further exploration of retifanlimab as monotherapy and backbone immunotherapy in combination treatments, with recommended doses of 500 mg q4w and 375 mg q3w.

Keywords: PD-1 inhibitor; checkpoint inhibitor; first-in-human; retifanlimab; solid tumor.

Figure 1

Change in target lesion size and duration of treatment in patients with solid tumors receiving retifanlimab. Waterfall plots represent best percentage change from baseline in target lesion size for individual patients receiving retifanlimab 3 mg/kg q2w in tumor-specific cohorts: (A) NSCLC, (B) cervical cancer, (C) endometrial cancer, and (D) soft tissue sarcoma. Swimlane plots represent duration of treatment and best objective responses for individual patients receiving retifanlimab 3 mg/kg q2w in tumor-specific cohorts: (E) NSCLC, (F) cervical cancer, (G) endometrial cancer, and (H) soft tissue sarcoma. Confirmed best objective response is shown for each patient in the figure. CR, complete response; NE, not evaluable; NSCLC, non-small-cell lung cancer; PD, progressive disease; PR, partial response; q2w, every 2 weeks; SD, stable disease.

Figure 2

Increased proliferation in T cell subsets following treatment with retifanlimab. Fold-change in the frequency of proliferating (Ki67+) cells in different T-cell subsets (left panel: CD3+/CD8+; center panel: CD3+/CD4+; right panel: CD3+/CD4+/CD25+/FoxP3+). Analysis included 28 patients enrolled in the tumor-specific cohorts receiving retifanlimab 3 mg/kg q2w. ∗P < 0.05 by Wilcoxon matched pairs test with each time point compared with C1D1. C1D1, cycle 1 day 1; FC, fold change; q2w, every 2 weeks; Treg cells, regulatory T cells.