A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti-PD-1 antibody, in patients with advanced solid tumors

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.

Keywords: clinical trials as topic; immunotherapy; programmed cell death 1 receptor.

Figure 1

Median concentration–time profiles for spartalizumab, by treatment group. (A) Cycle 1. (B) Cycle 3. Q2W, once every 2 weeks; Q4W, once every 4 weeks.

Figure 2

Percentage change from baseline in target lesions and duration of exposure to spartalizumab. (A) Best percentage change from baseline in target lesions, by PD-L1 expression at baseline. Best overall response is shown for each patient according to RECIST v1.1. (B) Duration of exposure to spartalizumab, by treatment group. Best overall response and response at last assessment are shown. (C) Percentage change from baseline in target lesions over time, by PD-L1 expression at baseline. Best overall response is shown for each patient according to RECIST v1.1. * Unavailable; # Non-measurable disease. ATC, anaplastic thyroid cancer; BOR, best overall response; EMC, extraskeletal myxoid chondrosarcoma; H&N, head and neck; HCC, hepatocellular carcinoma; mRCC, metastatic renal cell carcinoma; non-CR/non-PD, non-complete response/non-progressive disease; NSCLC, non-small cell lung cancer; PD, progressive disease; PD-L1, programmed death ligand 1; PR, partial response; Q2W, once every 2 weeks; Q4W, once every 4 weeks; RECIST, Response Evaluation Criteria In Solid Tumors; SCC, squamous cell carcinoma; SCLC, small cell lung cancer; SD, stable disease; TNBC, triple-negative breast cancer; UNK, unknown.

Figure 3

Tumor response assessments and immunohistochemistry of CD8+ lymphocyte infiltration in patient with atypical carcinoid tumor of the lung with a partial response to treatment. (A) Reduction in overall tumor burden (upper) and individual lesions (lower). (B) CT scans of the liver: (i) liver metastasis pretreatment; (ii) pseudo-progression at first restaging; (iii) response at second restaging. (c) High levels of CD8 detected by immunohistochemistry during Cycle 2. PD, progressive disease; PR, partial response; Q2W, every 2 weeks; Q4W, every 4 weeks; SD, stable disease.