Photo Courtesy © PER/Claudio Papapietro 2013
Naiyer A. Rizvi, MD
The 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 presenter 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 the 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 doses 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.
According to an analysis presented at the 2013 World Conference on Lung Cancer in October, at a median 20.3-month follow-up, overall survival (OS) rates were 42% at 1 year and 24% at 2 years across all cohorts of NSCLC patients in the study, regardless of nivolumab dose. In that same population, median OS was 9.9 months, based on Kaplan-Meier estimates.
Rizvi said that responses continue in 10 of 22 remaining patients. He added that, among patients who discontinued the trial for reasons other than disease progression, six of the remaining seven continued to respond. These results raise questions about how long patients need to take the drug, 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.”
Additional study participants benefited from nivolumab, but were not included in data as positive responders because their benefit was delayed or they experienced initial inflammation of their tumors that mimicked progression, Rizvi pointed out.
About 5% to 10% of patients can be expected to exhibit that reaction, but an indication of eventual outcome is that those who will eventually respond tend to feel better while on nivolumab, he said.
A clue about biomarkers came in a separate analysis presented at the World Conference on Lung Cancer, which looked at PD-L1 expression and its association with clinical activity in the 129 patients from the phase I trial. The patients who tested positive for PD-L1 expression—about half the group—benefited more from nivolumab, although PD-L1-negative patients also responded.