During the 2015 Annual Meeting of the American Society of Clinical Oncology, Chicago, Scott J. Antonia, M.D., Ph.D., chair of the Thoracic Oncology Department at Moffitt Cancer Center presented the results of a phase 1b expansion and dose-escalation trial of MEDI4736 combined with tremelimumab in the treatment of advanced non-small cell lung cancer (NSCLC) patients.
MEDI4736, a monoclonal antibody is able to target the programmed cell death-1 ligand (PD-L1) expressed within tumor cells. Tremelimumab, a monoclonal antibody inhibits cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that are expressed on the surface of immune T cells.
Activation of the CTLA-4 and PD-L1 pathways does not allow the immune system to mount an appropriate anti-tumoral response.To avoid immune detection and cell death, tumour cells take advantage of this physiological mechanism. Using MEDI4736 and tremelimumab to inhibit these proteins, researchers were able to restimulate patients’ immune systems, allowing cells to identify and kill tumors.
Moffitt researchers and their colleagues found that MEDI4736 in combination with tremelimumab had manageable toxicity levels, however, 64% of patients demonstrated some type of adverse side events, with higher doses of tremelimumab and a constant dose of MEDI4736 resulting in more frequent and severe toxicity. A total of 26% of the patients experienced fatigue, 21% had diarrhea, and 13% experienced increased amylase. Furthermore, 31% had at least one drug-related adverse event of grade 3/4, mainly diarrhea (8%) and colitis (7%).
Results from the trial showed that the combination of MEDI4736 with tremelimumab showed clinical activity in patients with NSCLC, even in those who did not present expression of the PD-L1 ligand in their tumor cells. Overall, a total of 8 patients reached partial response and 11 had their disease stable. From those patients with PD-L1 negative tumors 3 had a partial response.
Currently, researchers are analyzing the maximum dose tolerated and patient enrollment is still ongoing.