Anti–PD-1 and anti–PD-L1 antibodies elicit durable objective responses in phase I trials.
Major finding: Anti–PD-1 and anti–PD-L1 antibodies elicit durable objective responses in phase I trials.
Clinical relevance: Tumors resistant to other types of immunotherapy respond to blockade of PD-1/PD-L1.
Impact: PD-1/PD-L1 immunotherapy is safe and effective in a wide spectrum of pretreated solid tumors.
Many solid tumors selectively express programmed death 1-ligand 1 (PD-L1), which suppresses T-cell functions by binding programmed death 1 (PD-1), an inhibitory receptor expressed on activated lymphocytes. Blocking the PD-1/PD-L1 interaction may therefore be a broadly effective way to stimulate antitumor immune responses while minimizing immune-related toxicity. Topalian and colleagues evaluated an anti–PD-1 antibody, and Brahmer and colleagues evaluated an anti–PD-L1 antibody in phase I dose-escalation studies in patients with advanced solid tumors. Complete or partial responses to the anti–PD-1 and anti–PD-L1 blocking antibodies were observed in non–small cell lung cancer (18% and 10% of patients, respectively), melanoma (28% and 17% of patients, respectively), and renal cell cancer (27% and 12% of patients, respectively), with stable disease lasting 24 weeks or longer in additional patients. These findings were particularly striking given that lung cancers have been resistant to other forms of immunotherapy and that many of the study patients had been heavily pretreated with cytotoxic and targeted therapies. Importantly, among responding patients with at least 1 year of follow-up, durable responses of 1 year or longer were observed in two thirds of patients treated with anti–PD-1 and half of patients treated with anti–PD-L1, indicative of a persistent antitumor immune response. Additionally, immunohistochemical analysis of a subset of pretreatment tumor biopsies indicated that objective responses to anti-PD-1 only occurred in patients whose tumors expressed PD-L1, suggesting that PD-L1 expression may be a useful marker to identify potential responders. Significant drug-related adverse events were observed in only 14% and 9% of patients treated with anti-PD-1 and anti-PD-L1 antibodies, respectively, although 3 of 296 patients died of anti–PD-1-related pulmonary toxicity. Targeting the PD-1/PD-L1 pathway may thus be a safe, effective way to induce immune responses to advanced solid tumors. Phase II trials are currently under way.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N Engl J Med 2012 Jun 2 [Epub ahead of print].
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012 Jun 2 [Epub ahead of print].
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.