A Phase III Study of Durvalumab (MEDI4736) With or Without Tremelimumab for Previously Treated Patients With Advanced NSCLC: Rationale and Protocol Design of the ARCTIC Study

Abstract

Anti-programmed cell death-1 and anti-programmed cell death ligand-1 (PD-L1) monotherapies have shown promising clinical activity in advanced, refractory non-small-cell lung cancer (NSCLC), but antitumor activity appears to be greater in patients with PD-L1(+) tumors compared with patients harboring PD-L1(-) tumors. Combining the anti-PD-L1 antibody durvalumab and the anti-cytotoxic T-lymphocyte antigen 4 antibody tremelimumab offers the potential for antitumor activity in patients with advanced NSCLC, regardless of PD-L1 tumor status. ARCTIC (NCT02352948) is a global, phase III, randomized, open-label multicenter study in patients with advanced NSCLC assessing the safety and clinical activity of durvalumab versus standard of care (SoC; erlotinib, gemcitabine, or vinorelbine) in patients with PD-L1(+) tumors (≥25% of tumor cells with membrane staining using VENTANA PD-L1 [SP263] CDx Assay) (Sub-study A) and the combination of durvalumab + tremelimumab or either agent as monotherapy versus SoC in patients with PD-L1(-) tumors (Sub-study B). Eligible patients are those with locally advanced or metastatic NSCLC (Stage IIIB/IV), without epidermal growth factor receptor tyrosine kinase activating mutations or anaplastic lymphoma kinase rearrangements, who have received at least 2 prior systemic regimens, including 1 platinum-based chemotherapy regimen. Co-primary endpoints are progression-free survival and overall survival. Secondary endpoints include the proportion of patients alive at 12 months, objective response rate, duration of response, progression-free survival at 6 and 12 months, safety and tolerability, pharmacokinetics, immunogenicity, and quality of life. The exploratory endpoints will assess potential biomarkers of treatment response. Recruitment started in January 2015 and is ongoing.

Utility of PD-L1 immunohistochemistry assays for predicting PD-1/PD-L1 inhibitor response

“…Clinical trials are currently underway for both metastatic NSCLC [35–37] and for urothelial carcinoma [38]. Durvalumab (an anti-PD-L1 antibody) is also being evaluated in clinical trials for the treatment of NSCLC (phase III) [39] and bladder cancer (phase III) [40, 41]. Pidilizumab (an anti PD-1 antibody) is currently being tested in the treatment of large B cell lymphoma (Phase II completed) [42].…”

Immune Checkpoint Blockade: The New Frontier in Cancer Treatment

“…Based on current labeling for the treatment of melanoma patients, ipilimumab and nivolumab are administered together only for the initial four doses; nivolumab is then given as monotherapy [12]. Alternative dosing regimens for ICBs used in combination are currently under investigation, with the goal of improving the safety profile while maximizing clinical benefit [125,142,143].…”

PD-L1 as a biomarker in NSCLC: challenges and future directions

“…The phase III ARCTIC study evaluating durvalumab in advanced NSCLC patients who have received at least two prior systemic chemotherapy regimens is ongoing, and preliminary results are not yet reported (11).…”