Research in context
Evidence before this study
We searched PubMed between Jan 1, 2005, and Oct 1, 2015, for published preclinical and clinical research on antibody treatments for cancer, with terms including “anti-PD-L1” or “anti-PD-1” and “anti-CTLA-4”. Most clinical studies were reported in the past 2 years. Patients with advanced non-small cell lung cancer (NSCLC) progressing after first-line treatment have a pronounced unmet need because current treatments have limited clinical use. Early clinical data suggest that blockade of multiple immune checkpoints might have greater antitumour activity than blockade of one checkpoint in melanoma and other tumour types, including NSCLC, although the incidence of adverse events also seems to be higher than with single drugs. Treatment with the PD-L1 inhibitor durvalumab has produced durable responses in patients with advanced NSCLC, with a manageable tolerability profile. We designed a study to investigate the safety and antitumour activity of durvalumab in combination with the CTLA-4 inhibitor tremelimumab in patients with locally advanced or metastatic NSCLC.
Added value of this study
In the dose-escalation part of the study, the combination of durvalumab 20 mg/kg every 4 weeks and tremelimumab 1 mg/kg had a manageable tolerability profile. Clinical activity was recorded irrespective of PD-L1 expression status, including in patients with no PD-L1 staining in the tumour cell membrane.
Implications of all the available evidence
The clinical activity of durvalumab plus tremelimumab noted in patients with PD-L1-negative tumours is an important advance, because this population is less responsive to treatment with single drugs that block the PD-1 checkpoint pathway. Based on findings of this study and previous investigations, the optimum dose of combination treatment with durvalumab and tremelimumab was selected for phase 3 studies, which are ongoing.