A combination of the anti-PD-L1 immune checkpoint inhibitor durvalumab with the anti-CTLA-4 monoclonal antibody tremelimumab showed improved tumor response in patients with advanced NSCLC.
Naiyer A. Rizvi, MD
A combination of the antiPD-L1 immune checkpoint inhibitor durvalumab (MEDI4736) with the anti–CTLA-4 monoclonal antibody tremelimumab showed improved tumor response in patients with advanced non–small cell lung cancer (NSCLC) over single-agent therapy.
The study, published in the Journal for ImmunoTherapy of Cancer, was a phase I, open-label, dose-escalation/expansion study that contained 84 patients. Of these patients, 48 had two or more prior lines of therapy. Data from the study showed improved tumor response regardless of PD-L1 status, with an overall response rate of 25% and 35% of PD-L1-negative patients receiving a response (0% tumor cell staining).
Higher response rates were observed in those with 1 prior therapy versus 2 or more.
"The rationale to do this study is that we know that single agent PD-1/PD-L1 is very active and, clearly, these drugs have a role in lung cancer as a second-line treatment with the recent approvals," said Naiyer A. Rizvi, MD, associate attending physician, Memorial Sloan Kettering Cancer Center, and lead author of the study. "To try and improve response and durability of response for more patients, we explored this immunotherapy combination. We hoped that there would be more potent T-cell activation and that we could improve beyond single-agent therapy."
All dose level coherts showed that 80% of patients experienced a greater-than grade 1 treatment-related adverse event (AE), while 42% had grade 3/4 treatment-related AE. Data also showed 28% of patients discontinuing treament due to AE, those mainly being patients with increasing doses of tremelimumab.
"The toxicities were really what one expected with tremelimumab. We did see more toxicities with the combination but, for the most part, they were predictable," said Rizvi. "The toxicities we observed were gastrointestinal-related, skin-related, liver enzyme elevation, and pancreatic enzyme elevation. Particularly with the lower dose of tremelimumab, these toxicities were treatable. Most patients did not have to discontinue therapy due to side effects; we were able to work around that."
Rizvi added that because of the results from the studies, the combination of durvalumab and tremelimumab could very well be used in the first-line setting.
"I think the data are compelling enough that we are actually setting this combination, administered every 4 weeks for 1 year, in the first-line setting. Most of the patients that we treated in this trial were pretreated and had a number of lines of chemotherapy. We now have an opportunity to give this as a first-line therapy in lung cancer, and that is where we would like to go next. There are two phase III trials with the combination that are ongoing, comparing the immunotherapy combination versus chemotherapy to see if we can position this combination as an effective first-line treatment that is better than chemotherapy," he said.
"I think that using PD-L1 testing to determine who is more likely to respond to single-agent therapy is useful. One of the limitations is that we still see some of the patients respond. Several researchers are trying to explore other ways to define treatments for patients better."