Safety and Activity of Anti-PD-L1 Antibody in Patients with Advanced Cancer.
Brahmer, Julie R. M.D.; Tykodi, Scott S. M.D., Ph.D.; Chow, Laura Q.M. M.D.; Hwu, Wen-Jen M.D., Ph.D.; Topalian, Suzanne L. M.D.; Hwu, Patrick M.D.; Drake, Charles G. M.D., Ph.D.; Camacho, Luis H. M.D., M.P.H.; Kauh, John M.D.; Odunsi, Kunle M.D., Ph.D.; Pitot, Henry C. M.D.; Hamid, Omid M.D.; Bhatia, Shailender M.D.; Martins, Renato M.D., M.P.H.; Eaton, Keith M.D., Ph.D.; Chen, Shuming Ph.D.; Salay, Theresa M. M.S.; Alaparthy, Suresh Ph.D.; Grosso, Joseph F. Ph.D.; Korman, Alan J. Ph.D.; Parker, Susan M. Ph.D.; Agrawal, Shruti Ph.D.; Goldberg, Stacie M. M.D.; Pardoll, Drew M. M.D., Ph.D.; Gupta, Ashok M.D., Ph.D.; Wigginton, Jon M. M.D.
[Article]
New England Journal of Medicine.
366(26):2455-2465, June 28, 2012.
(Format: HTML, PDF)
Background: Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models.
Methods: In this multicenter phase 1 trial, we administered intravenous anti-PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti-PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression.
Results: As of February 24, 2012, a total of 207 patients - 75 with non-small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer - had received anti-PD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 toxic effects that investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with non-small-cell lung cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up.
Conclusions: Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.)
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