The programmed death 1 (PD-1) receptor is expressed by activated T cells and mediates immunosuppression involved in tumor growth. Results from two phase 1 clinical trials—one evaluating an anti–PD-1 antibody (Topalian SL, et al. N Engl J Med. 2012; 366:2443-2454) and the second evaluating an anti–PD-1 ligand (PD-L1) antibody (Brahmer JR, et al. N Engl J Med. 2012;366:2455-2465)—suggest that targeting the PD-1/PD-L1 pathway may be beneficial in treating certain types of solid tumors, including advanced melanoma, non–small-cell lung cancer (NSCLC), and renal-cell cancer.
In the first study, 296 patients with advanced melanoma, NSCLC, castration-resistant prostate cancer, renalcell cancer, or colorectal cancer received the anti–PD-1 antibody for up to twelve 8-week treatment/evaluation cycles. Most patients had been heavily pretreated.
Among the 236 evaluable patients, dose-related objective responses (partial or complete) were seen in patients with melanoma (range, 19%-41%), NSCLC (range, 6%-32%), and renal cell cancer (range, 24%-31%), but no responses were seen in patients with colorectal or prostate cancer.
Objective responses of ≥1 year were seen in small but substantial proportions, ranging from 1 in 5 to 1 in 4 patients with melanoma, NSCLC, or renalcell cancer. The response in patients with NSCLC was unexpected and suggests that that drug’s activity may go beyond immunogenic tumor types.
In a secondary analysis of 25 patients with PD-L1–positive tumors, 9 (36%) had an objective response compared with no response among the 17 patients with PD-L1–negative tumors.
The adverse event profile seen in this study was consistent with immune-related causes. The incidence of grade 3 or 4 drug-related adverse events was low enough (14% of 296 patients) to suggest potential therapy delivery in an outpatient setting.
In the second study, patients with NSCLC, melanoma, colorectal cancer, renal-cell cancer, ovarian cancer, pancreatic cancer, gastric cancer, or breast cancer received an anti–PD-L1 antibody for up to sixteen 6-week treatment cycles.
Durable tumor regression as seen by objective response (range, 6%-17%) and prolonged stabilization of disease at 24 weeks (range, 12%-41%) were achieved in 160 patients, including some who had received extensive previous therapy.
As with the first study, there was an unexpected response in patients with NSCLC, but no objective responses were seen in patients with colorectal or prostate cancer. Of the 17 patients with ovarian cancer, 1 had an objective response. Most of the adverse events with the study drug were immune related. Grade 3 or 4 effects were seen in 9% of 207 patients.
Although the drugs were not compared directly, these data suggest that the anti–PD-L1 antibody may produce a smaller response than the anti-PD-1 antibody. These early results point to a potential role for this anti-PD-1 antibody as a targeted therapy.
