Combination of Immune Checkpoint Blockers Shows Promise in Lung Cancer
Combination therapy with durvalumab and tremelimumab demonstrated antitumor activity in 23% of 102 patients with lung cancer in a phase 1b trial, and toxicity was manageable, according to a recent study.1
Lung cancer kills more patients with cancer than any other type of cancer in the United States, causing more than 158 000 deaths per year and 5-year survival is only 18%. This multicenter phase 1b clinical trial sought to determine the safety and efficacy of a new drug combination for non-small cell lung cancer (NSCLC) that stimulates a patient's immune system to target and kill cancer cells.
The protein PD-L1 is expressed by tumor cells to evade detection by the immune system. PD-L1 downregulates immune cells by binding to its receptor, PD-1. Also, the activation of immune cells is inhibited by the molecule known as CTLA-4.
Durvalumab blocks the PD-1/PD-L1 pathway, and tremelimumab blocks the CTLA-4 pathway. These drugs restimulate the immune system to target tumor cells. Each has shown activity as a single agent, and this study explored the hypothesis that combining them may increase the clinical benefit.
This phase 1b study had the primary goals of determining the safety profile of the drug combination and the maximum tolerated dose of each drug.
The combination of durvalumab and tremelimumab resulted in manageable toxicity. The most common overall adverse events were diarrhea, fatigue, and itching, and the most common high grade adverse events were diarrhea, colitis, and altered pancreas activity. Most toxicities could be reversed by administering immunosuppressive drugs.
A complete or partial response occurred in 23% of the 102 patients who were treated with durvalumab 10 to 20 mg/kg and tremelimumab 1 mg/kg. The combination was found to be active in patients with and without expression of PD-L1.
"The results suggest that this combination has potential as a treatment option for patients with PD-L1-negative tumors whose needs are not addressed by current therapies, including immunotherapies," said Scott J. Antonia, MD, PhD, chair of the Thoracic Oncology Department at H Lee Moffitt Cancer Center in Tampa, Florida, and co-lead author of the study. "It also reinforces the benefits of combination therapy in oncology."
The combination of the 2 drugs appears to have greater activity than either drug alone in patients with non-small cell lung cancer. The data still needs to be confirmed in larger trials.
The clinical study was funded by MedImmune, a subsidiary of AstraZeneca.
1. Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study [published online ahead of print February 5, 2016]. Lancet Oncol. doi:10.1016/S1470-2045(15)00544-6.