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.
Subject(s)
Neoplasms , Humans , Female , Male , Middle Aged , Aged , Neoplasms/drug therapy , Adult , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Aged, 80 and overABSTRACT
Background: Head and neck cancer (HNC) has a poor prognosis at advanced stages. Given the immunosuppressive tumor microenvironment in HNC, inhibition of the programmed death-ligand 1/programmed death-1 (PD-L1/PD-1) signaling pathway represents a promising therapeutic approach. Atezolizumab (anti-PD-L1) is efficacious against many tumor types. Here we report the clinical safety and activity from the HNC cohort of the phase Ia PCD4989g clinical trial. Patients and methods: Patients with previously treated, advanced HNC received atezolizumab i.v. every 3 weeks for 16 cycles, up to 1 year or until loss of clinical benefit. Patients were monitored for safety and tolerability and evaluated for response at least every 6 weeks. Baseline PD-L1 expression level and human papillomavirus (HPV) status were evaluated. Results: Thirty-two patients were enrolled; 7 patients (22%) had a primary tumor in the oral cavity, 18 (56%) in the oropharynx, 1 (3%) in the hypopharynx, 2 (6%) in the larynx, and 4 (13%) in the nasopharynx. Seventeen patients (53%) had ≥2 prior lines of therapy. Twenty-one patients (66%) experienced a treatment-related adverse event (TRAE), with three experiencing grade 3 TRAEs and one experiencing a grade 4 TRAE (per CTCAE v4.0). No grade 5 TRAEs were reported. Objective responses by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) occurred in 22% of patients, with a median duration of response of 7.4 months (range 2.8-45.8 months). Median progression-free survival was 2.6 months (range 0.5-48.4 months), and median overall survival was 6.0 months (range 0.5-51.6+ months). Responses showed no association with HPV status or PD-L1 expression level. Conclusions: In this heavily pre-treated advanced HNC cohort, atezolizumab had a tolerable safety profile and encouraging activity, with responses observed regardless of HPV status and PD-L1 expression level. These findings warrant further investigation of atezolizumab in HNC. ClinicalTrials.gov number: NCT01375842.
