TY - JOUR
T1 - A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti-PD-1 antibody, in patients with advanced solid tumors
AU - Naing, Aung
AU - Gainor, Justin F.
AU - Gelderblom, Hans
AU - Forde, Patrick M.
AU - Butler, Marcus O.
AU - Lin, Chia Chi
AU - Sharma, Sunil
AU - Ochoa De Olza, Maria
AU - Varga, Andrea
AU - Taylor, Matthew
AU - Schellens, Jan H.M.
AU - Wu, Hongqian
AU - Sun, Haiying
AU - Silva, Antonio P.
AU - Faris, Jason
AU - Mataraza, Jennifer
AU - Cameron, Scott
AU - Bauer, Todd M.
N1 - Funding Information:
The authors would like to thank the patients who participated in the trial and their families. The authors would also like to thank the physicians, nurses, research coordinators, and other staff at each site who assisted with the study. The authors would also like to thank Geraldine Bostel, Victor Antona, and Dominique Pinet for their important contributions to this study. The study was sponsored by Novartis Pharmaceuticals Corporation. Editorial assistance was provided by Laura Hilditch, PhD, and was funded by Novartis Pharmaceuticals Corporation.
Publisher Copyright:
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2020/3/15
Y1 - 2020/3/15
N2 - 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.
AB - 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.
KW - clinical trials as topic
KW - immunotherapy
KW - programmed cell death 1 receptor
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U2 - 10.1136/jitc-2020-000530
DO - 10.1136/jitc-2020-000530
M3 - Article
C2 - 32179633
AN - SCOPUS:85082024869
SN - 2051-1426
VL - 8
JO - Journal for immunotherapy of cancer
JF - Journal for immunotherapy of cancer
IS - 1
M1 - e000530
ER -