Elizabeth Stankevich

Phase I Study of Single-Agent Anti–Programmed Death-1 (MDX-1106) in Refractory Solid Tumors: Safety, Clinical Activity, Pharmacodynamics, and Immunologic Correlates

PURPOSE Programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, may suppress antitumor immunity. This phase I study sought to determine the safety and tolerability of anti-PD-1 blockade in patients with treatment-refractory solid tumors and to preliminarily assess antitumor activity, pharmacodynamics, and immunologic correlates. PATIENTS AND METHODS Thirty-nine patients with advanced metastatic melanoma, colorectal cancer (CRC), castrate-resistant prostate cancer, non-small-cell lung cancer (NSCLC), or renal cell carcinoma (RCC) received a single intravenous infusion of anti-PD-1 (MDX-1106) in dose-escalating six-patient cohorts at 0.3, 1, 3, or 10 mg/kg, followed by a 15-patient expansion cohort at 10 mg/kg. Patients with evidence of clinical benefit at 3 months were eligible for repeated therapy. RESULTS Anti-PD-1 was well tolerated: one serious adverse event, inflammatory colitis, was observed in a patient with melanoma who received five doses at 1 mg/kg. One durable complete response (CRC) and two partial responses (PRs; melanoma, RCC) were seen. Two additional patients (melanoma, NSCLC) had significant lesional tumor regressions not meeting PR criteria. The serum half-life of anti-PD-1 was 12 to 20 days. However, pharmacodynamics indicated a sustained mean occupancy of > 70% of PD-1 molecules on circulating T cells > or = 2 months following infusion, regardless of dose. In nine patients examined, tumor cell surface B7-H1 expression appeared to correlate with the likelihood of response to treatment. CONCLUSION Blocking the PD-1 immune checkpoint with intermittent antibody dosing is well tolerated and associated with evidence of antitumor activity. Exploration of alternative dosing regimens and combinatorial therapies with vaccines, targeted therapies, and/or other checkpoint inhibitors is warranted.

Responses of metastatic basal cell and cutaneous squamous cell carcinomas to anti-PD1 monoclonal antibody REGN2810

BackgroundBasal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (CSCC) share exposure to UV light as the dominant risk factor, and these tumors therefore harbor high mutation burdens. In other malignancies, high mutation burden has been associated with clinical benefit from therapy with antibodies directed against the Programmed Death 1 (PD-1) immune checkpoint receptor. Highly mutated tumors are more likely to express immunogenic tumor neoantigens that attract effector T cells, which can be unleashed by blockade of the PD-1 immune checkpoint.Case presentationsThis report describes a patient with metastatic BCC and a patient with metastatic CSCC who were treated with REGN2810, a fully human anti-PD-1 monoclonal antibody, in an ongoing phase 1 trial (NCT02383212). The CSCC patient has experienced an ongoing complete response (16+ months), and the BCC patient has experienced an ongoing partial response (12+ months).ConclusionsThese case reports suggest that UV-associated skin cancers, beyond melanoma, are sensitive to PD-1 blockade.Trial registrationClinicaltrials.gov NCT02383212. Registered 2 February 2015.

PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma

Background No systemic therapies have been approved for the treatment of advanced cutaneous squamous‐cell carcinoma. This cancer may be responsive to immune therapy, because the mutation burden of the tumor is high and the disease risk is strongly associated with immunosuppression. In the dose‐escalation portion of the phase 1 study of cemiplimab, a deep and durable response was observed in a patient with metastatic cutaneous squamous‐cell carcinoma. Methods We report the results of the phase 1 study of cemiplimab for expansion cohorts of patients with locally advanced or metastatic cutaneous squamous‐cell carcinoma, as well as the results of the pivotal phase 2 study for a cohort of patients with metastatic disease (metastatic‐disease cohort). In both studies, the patients received an intravenous dose of cemiplimab (3 mg per kilogram of body weight) every 2 weeks and were assessed for a response every 8 weeks. In the phase 2 study, the primary end point was the response rate, as assessed by independent central review. Results In the expansion cohorts of the phase 1 study, a response to cemiplimab was observed in 13 of 26 patients (50%; 95% confidence interval [CI], 30 to 70). In the metastatic‐disease cohort of the phase 2 study, a response was observed in 28 of 59 patients (47%; 95% CI, 34 to 61). The median follow‐up was 7.9 months in the metastatic‐disease cohort of the phase 2 study. Among the 28 patients who had a response, the duration of response exceeded 6 months in 57%, and 82% continued to have a response and to receive cemiplimab at the time of data cutoff. Adverse events that occurred in at least 15% of the patients in the metastatic‐disease cohort of the phase 2 study were diarrhea, fatigue, nausea, constipation, and rash; 7% of the patients discontinued treatment because of an adverse event. Conclusions Among patients with advanced cutaneous squamous‐cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT02383212 and NCT02760498.)

1151PCemiplimab, a human monoclonal anti-PD-1, in patients (pts) with advanced or metastatic hepatocellular carcinoma (HCC): Data from an expansion cohort in a phase I study

M.J. Pishvaian, G.J. Weiss, G.S. Falchook, N. Yee, M. Gil-Martin, S. Shahda, V. Moreno, I. Brana, M. Crittenden, S. Formenti, R. Al-Rajabi, K.P. Papadopoulos, E. Stankevich, M. Feng, J. Li, M. Mathias, G. Kroog, I. Lowy, M.G. Fury Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA, Department of Internal Medicine, University of Arizona College of Medicine, Phoenix, AZ, USA, Drug Development, Sarah Cannon Research Institute at HealthONE, Denver, CO, USA, Hematology/Oncology, Penn State Cancer Institute, Hershey, PA, USA, Institut Catal a d’Oncologia, L’Hospitalet de Llobregat, Spain, Indiana University School of Medicine, Indiana University Melvin Bren Simon Cancer Center, Indianapolis, IN, USA, START Madrid-FJD, Hospital Fundaci on Jiménez D ıaz, Madrid, Spain, Department of Medical Oncology, Vall D’Hebron Institute of Oncology, Barcelona, Spain, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center and The Oregon Clinic, Portland, OR, USA, Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA, Department of Internal Medicine, Division of Hematology/Oncology, University of Kansas Cancer Center, Kansas City, KS, USA, Clinical Research, START, San Antonio, TX, USA, Clinical Sciences, Regeneron Pharmaceuticals, Inc., Basking Ridge, NJ, USA, Biostatistics & Data Management, Regeneron Pharmaceuticals, Inc., Basking Ridge, NJ, USA, Clinical Sciences, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA