Safety and activity of anti-PD-L1 antibody in patients with advanced cancer

Abstract

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.).

Figure 1. Activity of Anti–PD-L1 Antibody in Patients with Advanced Melanoma and Non–Small-Cell Lung Cancer

Shown is the tumor burden (assessed as the longest linear dimension) over time in patients with melanoma (Panel A) and non–small-cell lung cancer (Panel B) who received 10 mg of anti–PD-L1 antibody per kilogram of body weight. In most patients who had an objective response, responses were durable and were evident by the end of cycle 2 (12 weeks) of treatment, regardless of the drug dose or tumor type. The vertical dashed line marks the 24-week time point at which the rate of progression-free survival was calculated. Tumor regression followed both conventional and immune-related patterns of response, such as a prolonged reduction in the tumor burden in the presence of new lesions.

Figure 2. Computed Tomography after Receipt of Anti–PD-L1 Antibody

Panel A shows a complete response in a patient with melanoma who received 3 mg of anti–PD-L1 antibody per kilogram. Circles indicate an initial increase in the size of pulmonary nodules at 6 weeks and 3 months, followed by complete regression at 10 months (i.e., an immune-related pattern of response). Panel B shows a partial response at 15 months in the liver (arrows) and right lung pleura (arrowheads) in a patient with non–small-cell lung cancer (nonsquamous subtype) who received 10 mg of anti–PD-L1 antibody per kilogram.