Phase I Study of Pembrolizumab (MK-3475; Anti–PD-1 Monoclonal Antibody) in Patients with Advanced Solid Tumors

Abstract

Purpose: This phase I study evaluated the safety, maximum tolerated dose, antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in patients with advanced solid tumors. Experimental Design: In a 3 + 3 dose escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg intravenously every 2 weeks until progression or intolerable toxicity. Seven additional patients received 10 mg/kg every 2 weeks. Thirteen patients participated in a 3-week intrapatient dose escalation (dose range, 0.005–10 mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: No dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma experienced complete responses of 57 and 56+ weeks' duration, respectively. Three patients with melanoma experienced partial responses. Fifteen patients with various malignancies experienced stable disease. One patient died of cryptococcal infection 92 days after pembrolizumab discontinuation, following prolonged corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab exhibited pharmacokinetic characteristics typical of humanized monoclonal antibodies. Maximum serum target engagement was reached with trough levels of doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based translational models with a focus on intratumor exposure prediction suggested robust clinical activity would be observed at doses ≥2 mg/kg every 3 weeks. Conclusions: Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks. Clin Cancer Res; 21(19); 4286–93. ©2015 AACR. See related commentary by van Elsas et al., p. 4251

Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors

“…S2. The exposure for pembrolizumab administered in combination with utomilumab was comparable with that observed with pembrolizumab alone (7).…”

Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials

“…Although conclusions drawn from cross‐study comparisons should be made with caution, and to the best of our knowledge the number of pan‐tumor clinical studies of ICI monotherapy is limited, this analysis of a large population of patients across a broad scope of tumor types suggests that avelumab was associated with an incidence of irAEs that is consistent with that of other ICIs 16, 17. Differences may be attributed to the specificity of avelumab for PD‐L1, which leaves PD‐L2/PD‐1 interactions intact and allows for maintenance of immune homeostasis18, 19; however, additional evidence is required to fully understand the contribution of PD‐L2.…”

WOMEN IN CANCER THEMATIC REVIEW: Systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine

“…Few patients with NET have been treated so far with checkpoint inhibitors. Best response was stable disease in a patient with carcinoid and a patient with pancreatic NET (Patnaik et al 2015), and it remains unclear which NET patient subgroups might potentially benefit from this therapy. In light of the activity of pembrolizumab in small-cell lung cancer and Merkel cell carcinoma (Horn et al 2016, Nghiem et al 2016, the role of immunotherapy might be particularly relevant in high-grade NEC.…”