Platinum-based doublets are standard of care (SoC) first-line treatment for advanced NSCLC, but durable benefit is observed infrequently, with resistance to chemotherapy invariably developing. The blockade of immune checkpoints is a promising novel approach in cancer treatment. Blocking co-inhibitory molecules, such as programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), from binding with their ligands can restore T-cell responses against tumors. As these pathways are non-redundant, dual targeting may have additive or synergistic antitumor activity. Durvalumab (MEDI4736) is a selective, high affinity human IgG1 mAb that blocks programmed cell death ligand-1 (PD-L1) binding to PD-1 (IC₅₀ 0.1 nM) and CD80 (IC₅₀ 0.04 nM), and tremelimumab is a selective human IgG2 mAb inhibitor of CTLA-4. Durvalumab monotherapy has shown durable responses in a NSCLC cohort from a Phase I/II study in heavily pre-treated patients with solid tumors[1] and durvalumab plus tremelimumab has shown encouraging clinical activity and a manageable safety profile in a Phase Ib study in patients with NSCLC[2]. A comprehensive clinical development program of durvalumab +/- tremelimumab in NSCLC is underway. MYSTIC (NCT02453282) is a global Phase III study to determine the efficacy and safety of durvalumab plus tremelimumab combination therapy or durvalumab monotherapy versus SoC platinum-based doublets in the first-line treatment of patients with advanced or metastatic NSCLC.

ClinicalTrials.gov identifier NCT02453282.