02/03/2014 05:50 PM Posted by: Dr. H. Alejandro PretiThe future of PD-1 and PD-L1 inhibition in non-small cell lung cancer (NSCLC) is bright, with ongoing studies suggesting that the strategy will lead to a “new world” in the treatment of the disease, according to a presentation at the 8th Annual New York Lung Cancer Symposium, held in New York City November 9.
Nivolumab and three other immune checkpoint inhibitors being studied in the clinic are all demonstrating similar promising activity, explained presenter, Naiyer A. Rizvi, MD, a thoracic oncologist at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York. Furthermore, Rizvi said, researchers are beginning to gather data indicating that PD-L1 expression is a biomarker for success with the drugs.
“For these patients, the single-agent response rate to second-line chemotherapy with docetaxel, for example, is 8%, and the duration of response is a few months, so we don’t have a lot of good options for advanced-stage lung cancer,” Rizvi said. “The initial data with nivolumab and other compounds is that patients who have been heavily pretreated have a response rate of over 20%, with 24% alive 2 years later, which is pretty remarkable. The responses we’ve seen with our patients have been pretty dramatic, like nothing we’ve seen before. There’s no question it’s going to change the landscape of how we treat lung cancer.”
Rizvi said excitement arose about the use of PD-1 and PD-L1 agents in the treatment of NSCLC when a study of nivolumab demonstrated durable responses in half of 129 patients, with higher dosages of the drug bringing better results.
Nivolumab and another IgG4 antibody, MK-3475, are still being explored in the clinic, as are MPDL3280A and MEDI4736, both IgG1 antibodies, Rizvi said. All have reached phase III development except for MEDI4736, which is being investigated in a phase I trial.
The drugs target PD-1, an inhibitory T-cell co-receptor, or PD-L1, a ligand expressed on the tumor. It is thought that interactions between PD-1 and the ligands PD-L1 or PD-L2 can lead to antitumor immune suppression; the compounds in development are designed to interrupt those interactions, allowing T cells to fight cancer.
Updated results from the expansion cohort of the phase I trial of PD-1 antibody nivolumab (CA209-003) included results for 129 patients with previously treated, advanced NSCLC. For those who took 3 mg/kg of nivolumab, the overall response rate (ORR) was 24.3 % and median survival was 14.9 months, Rizvi said. Many responses occurred within the first 8 to 16 weeks, he said.
“If you reset your immune system, if you turn your T cells back on, do you need to keep dosing with this drug?” he asked. “We don’t really know the answer to that.”
MK-3475, another PD-1 antibody, has demonstrated similar efficacy to nivolumab in an ongoing phase I trial (NCT01295827) of 38 patients with squamous or non-squamous NSCLC, Rizvi said. In the trial, the drug has demonstrated an ORR of 24% (9 patients) by investigator review and 21% (7 patients) by independent review.
In a phase Ia trial the PD-L1 antibody MPDL3280A demonstrated an ORR of 23% in all participants; response improved with higher PD-L1 positivity, Rizvi said.
“Smoking status is an interesting subanalysis of the trial, and may play a role in how we select patients for this drug and how we think about lung cancer,” he said. “If patients have a large mutational burden, there is a lot of antigen release, and they are more likely, over time, to turn on an adaptive immune response that will allow for tumors to escape. Patients who are smokers or ex-smokers fall into that category, and their tumors have a more inflammatory component. Those patients may be more likely to respond to these agents.”
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