In this study, blockade of the immune inhibitory ligand PD-L1 by a monoclonal antibody produced both durable tumor regression (objective response rate, 6 to 17%) and prolonged (≥24 weeks) disease stabilization in patients with metastatic non–small-cell lung cancer, melanoma, renal-cell cancer, and ovarian cancer, including some who had been treated with extensive previous therapy. Grade 3 or 4 adverse events that were considered to be drug-related occurred in 9% of patients at doses up to and including 10 mg per kilogram. These findings are consistent with the mild autoimmune phenotype seen in mice that are homozygous for PD-L1 deletion.28
Although ipilimumab and anti–PD-L1 antibody have not been compared head to head, the toxic effects associated with ipilimumab are reported as more common and of higher grade, consistent with the more severe hyperproliferation seen in CTLA-4 knockout mice, as compared with PD-1 knockout mice.6,7,10
Most of the toxic effects that were associated with anti–PD-L1 were immune-related. The spectrum and frequency of adverse events are somewhat different between anti–PD-L1 and anti–CTLA-4, emphasizing the distinct biologic features of the two pathways.29
Infusion reactions were observed with anti–PD-L1 antibody, although they were mild in most patients. Severe colitis, an adverse event that is considered to be drug-related in some patients receiving ipilimumab, was infrequently noted in patients receiving anti–PD-L1.30
The objective response in 5 of 49 patients (10%) with advanced non–small-cell lung cancer who received anti–PD-L1 was quite unexpected. Although melanoma and renal-cell cancer are responsive to cancer immunotherapy (e.g., interleukin-2 and anti–CTLA-4), non–small-cell lung cancer has been considered to be nonimmunogenic and poorly responsive to immune-based therapies.31
Another important feature of anti–PD-L1 therapy was the durability of response across multiple tumor types. This was particularly notable given the advanced stage of disease and previous treatments of patients in our study. This durability appeared to be greater than that observed with most chemotherapies and kinase inhibitors used in these diseases, although no direct comparisons have been performed.
Because peripheral-blood T cells express PD-L1, it is possible to assess in vivo receptor occupancy by anti–PD-L1 antibody as a pharmacodynamic measure. Median receptor occupancy was more than 65% for the doses tested. Although these studies provide a direct assessment and evidence of target engagement in patients receiving anti–PD-L1 antibody, relationships between receptor occupancy in peripheral blood and the tumor microenvironment remain poorly understood.
A major implication of the clinical activity of immune checkpoint blockade is that significant endogenous immune responses to tumor antigens are generated, and these responses may be harnessed therapeutically to mediate clinical tumor regression on checkpoint inhibition. An emerging concept in cancer immunology is that inhibitory ligands such as PD-L1 are induced in response to immune attack, a mechanism termed adaptive resistance.22,32
This potential mechanism of immune resistance by tumors suggests that therapy directed at blocking interaction between PD-1 and PD-L1 might synergize with other treatments that enhance endogenous antitumor immunity.3,4,33
Longer follow-up will confirm whether patients continue to have tumor control after cessation of blockade of the pathway between PD-1 and PD-L1. Such tumor control could reflect a persistent antitumor immune response and the generation of effective immunologic memory to enable sustained control of tumor growth.
The concurrent clinical testing of antibodies that block an immune-regulatory receptor and one of its cognate ligands has not been reported. Our study and a companion study by Topalian et al.,34
now reported in the Journal
, show remarkable similarities between the patterns of clinical activity observed with anti–PD-L1 and anti–PD-1 antibodies, which validate the role of this pathway in tumor immune resistance and support the notion that it may be a target for therapeutic intervention. However, the molecular interactions that are potentially blocked by these two antibodies are not identical. Anti–PD-1 antibody blocks interactions between PD-1 and its ligands, PD-L1 and PD-L2, whereas anti–PD-L1 antibody blocks interactions between PD-L1 and both PD-1 and CD80; the latter interaction has also been shown to down-modulate T-cell responses in vitro and in vivo.35–39
Although the agents were not compared directly in a randomized trial, the frequency of objective responses for anti–PD-L1 antibody appears to be somewhat lower than that observed for anti–PD-1 antibody in initial trials. The significance of these findings remains to be defined. The clinically appropriate dose of anti–PD-L1 will require further definition in future testing, including additional phase 2 dose-ranging trials.
Our findings show that antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rate of 12 to 41% at 24 weeks) in patients with select advanced cancers, including non–small-cell lung cancer, a tumor that has not been considered to be responsive to immunotherapy. These findings validate the pathway between PD-1 and PD-L1 as an important target for therapeutic intervention in some patients with cancer. Additional studies are needed to identify which patients are likely to have a response, to determine an appropriate clinical dose, and to define the spectrum of tumors in which targeting of this pathway will have antitumor effects.