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

  • J Immunother Cancer. 2020 Mar;8(1):e000530. doi: 10.1136/jitc-2020-000530.
Aung Naing  1 ,  Justin F Gainor  2 ,  Hans Gelderblom  3 ,  Patrick M Forde  4 ,  Marcus O Butler  5 ,  Chia-Chi Lin  6 ,  Sunil Sharma  7 ,  Maria Ochoa de Olza  8 ,  Andrea Varga  9 ,  Matthew Taylor  10 ,  Jan H M Schellens  11 ,  Hongqian Wu  12 ,  Haiying Sun  12 ,  Antonio P Silva  13 ,  Jason Faris  14 ,  Jennifer Mataraza  14 ,  Scott Cameron  14 ,  Todd M Bauer  15  16
Affiliations
  • 1. MD Anderson Cancer Center, Houston, Texas, USA [email protected].
  • 2. Massachusetts General Hospital, Boston, Massachusetts, USA.
  • 3. Leiden University Medical Center, Leiden, The Netherlands.
  • 4. Johns Hopkins University, Baltimore, Maryland, USA.
  • 5. Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.
  • 6. National Taiwan University Hospital, Taipei, Taiwan.
  • 7. Huntsman Cancer Institute, Salt Lake City, Utah, USA.
  • 8. Vall d'Hebron University Hospital, Barcelona, Spain.
  • 9. Gustave Roussy, Villejuif, France.
  • 10. Oregon Health & Science University, Portland, Oregon, USA.
  • 11. Utrecht University, Utrecht, The Netherlands.
  • 12. Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
  • 13. Novartis Institutes for BioMedical Research, Basel, Switzerland.
  • 14. Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
  • 15. Sarah Cannon Research Institute, Nashville, Tennessee, USA.
  • 16. Tennessee Oncology, PLLC, Nashville, Tennessee, USA.
PMID: 32179633 DOI: 10.1136/jitc-2020-000530
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.
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