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Phase Ib study of PF-05082566 in combination with pembrolizumab in patients with advanced solid tumors.
Background: PF-05082566 (PF-2566) is a fully human IgG2 monoclonal antibody (mAb) that binds to human 4-1BB (CD137). Pembrolizumab is a humanized IgG4/kappa isotype mAb targeting PD-1. This Phase 1 study was designed to assess the overall safety, pharmacokinetics, pharmacodynamics (PD) and anti-tumor activity of this novel combination in patients with advanced solid tumors. Methods: Patients received PF-2566 (0.45 to 5.0 mg/kg) and pembrolizumab (2 mg/kg) intravenously on day 1 of 21-day cycles. Maximum tolerated dose was defined as the highest combination dose with a dose limiting toxicity (DLT) rate <25% during the first 2 cycles per the TITE-CRM method. Results: Tumor types treated included non-small cell lung cancer (NSCLC) (n=6), renal cell carcinoma (RCC) (n=5), head & neck (H&N) (n=3), pancreatic (n=2), thyroid (n=2), and one each of small cell lung cancer (SCLC), colon, sarcoma, thymoma, and melanoma. All patients received between 0 and 9 lines of previous anticancer treatment. No DLTs were reported and 6 patients remain on therapy in this ongoing study. The number of cycles patients have received across all doses ranged from 2 to 19. Treatment emergent adverse events (AEs) were mostly Grade 1/2, with no apparent relationship between increasing doses of PF-2566 and frequency or severity of AEs. No patients discontinued study medication due to treatment related AEs. No substantial changes in inflammatory cytokines or its association with clinical symptoms were noted. The PF-2566 concentrations were above the preclinical predicted efficacious concentration and appeared to increase with increasing doses. Circulating PD responses (lymphocyte subsets) were observed across all doses of PF-2566. Six out of 23 treated patients (26%, 95% CI: 10.2%, 48.4%) had confirmed complete (CR) or partial response (PR) per RECIST 1.1: CR in SCLC (n=1), PRs in RCC (n=2), NSCLC (n=1), H&N (n=1) and anaplastic thyroid (n=1). Median duration of response has not been reached. Conclusions: The safety and efficacy profile of PF-2566 in doses up to 5.0 mg/kg in combination with pembrolizumab supports further investigation in patients with advanced solid tumors. Clinical trial information: NCT02179918
Abstracts by Anthony W. Tolcher:
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