Naing, Aung , Gainor, Justin F., Gelderblom, Hans, Forde, Patrick M., Butler , Marcus O., Lin, Chia-Chi, Sharma, Sunil, Ochoa del Olza, Maria, Varga, Andreea, Taylor, Matthew, Schellens, Jan HM, Wu, Hongqian, Sun, Haiying, Silva, Antonio, Faris, Jason, Mataraza, Jennifer, Cameron, Scott and Bauer, Todd M. (2020) A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti-PD-1 antibody, in patients with advanced solid tumors. Journal for ImmunoTherapy of Cancer, 8 (1). pp. 1-9. ISSN 20511426

Abstract

Background Spartalizumab is a humanized IgG4κ monoclonal antibody that binds programmed death-1 (PD-1) and blocks its interaction with PD-L1 and PD-L2. This phase 1/2 study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of spartalizumab in patients with advanced or metastatic solid tumors. Methods In the phase 1 part of the study, 58 patients received spartalizumab, intravenously, at doses of 1, 3, or 10 mg/kg, administered every 2 weeks (Q2W), or 3 or 5 mg/kg every 4 weeks (Q4W). Results Patients had a wide range of tumor types, most commonly sarcoma (28%) and metastatic renal cell carcinoma (10%); other tumor types were reported in ≤3 patients each. Most patients (93%) had received prior antineoplastic therapy (median three prior lines) and two-thirds of the population had tumor biopsies negative for PD-L1 expression at baseline. The maximum tolerated dose was not reached. The recommended phase 2 doses were selected as 400 mg Q4W or 300 mg Q3W. No dose-limiting toxicities were observed, and adverse events included those typical of other PD-1 antibodies. The most common treatment-related adverse events of any grade were fatigue (22%), diarrhea (17%), pruritus (14%), hypothyroidism (10%), and nausea (10%). Partial responses occurred in two patients (response rate 3.4%); one with atypical carcinoid tumor of the lung and one with anal cancer. Paired tumor biopsies from patients taken at baseline and on treatment suggested an on-treatment increase in CD8+ lymphocyte infiltration in patients with clinical benefit. Conclusions Spartalizumab was well tolerated at all doses tested in patients with previously treated advanced solid tumors. On-treatment immune activation was seen in tumor biopsies; however, limited clinical activity was reported in this heavily pretreated, heterogeneous population. The phase 2 part of this study is ongoing in select tumor types. Trial registration number NCT02404441.

Item Type:	Article
Keywords:	clinical trials as topic immunotherapy programmed cell death 1 receptor
Date Deposited:	09 Jun 2020 00:45
Last Modified:	09 Jun 2020 00:45
URI:	https://oak.novartis.com/id/eprint/41816