PACIFIC-9: Phase III trial of durvalumab + oleclumab or monalizumab in unresectable stage III non-small-cell lung cancer.

Evidence from the Phase III PACIFIC trial established durvalumab, a monoclonal antibody (mAb) targeting PD-L1, following concurrent chemoradiotherapy (cCRT) as a global standard of care for patients with unresectable, stage III non-small-cell lung cancer (NSCLC). There remains an unmet need to improve upon the outcomes achieved with the PACIFIC regimen. Combining durvalumab with other immunotherapies may improve outcomes further. Two such immunotherapies include oleclumab, an mAb targeting CD73, and monalizumab, an mAb targeting NKG2A. Both agents demonstrated antitumor activity in early-phase trials. PACIFIC-9 (NCT05221840) is an international, double-blind, randomized, placebo-controlled, Phase III trial comparing durvalumab plus either oleclumab or monalizumab with durvalumab plus placebo in patients with unresectable, stage III NSCLC and no disease progression following cCRT. Clinical Trial Registration: NCT05221840 (ClinicalTrials.gov) Plain Language Summary Durvalumab is a treatment that helps the body's immune system to identify and attack cancer cells by binding to a protein called PD-L1. Studies show that durvalumab lowers the risk of cancer growing or spreading, and prolongs survival, when administered after chemotherapy and radiation therapy ('chemoradiotherapy') in patients with a type of lung cancer called stage III non-small-cell lung cancer (NSCLC) for whom surgery is not an option. Two antibody treatments have been developed that may help a patient's immune system to identify and attack cancer cells. Oleclumab binds to a protein on cancer cells called CD73, which prevents the production of adenosine, a chemical that obstructs the immune system from attacking the cancer. Monalizumab binds to NKG2A, a protein on immune cells that inhibits their ability to destroy cancer cells. Early studies suggest that combining either of these treatments with durvalumab may be better than durvalumab alone for slowing the growth and spread of cancer in patients with NSCLC. PACIFIC-9 is a study that aims to recruit approximately 999 patients with stage III NSCLC for whom surgery is not an option and who have completed chemoradiotherapy without the cancer growing or spreading. Patients will be randomly assigned in equal numbers to receive up to a year of treatment with durvalumab plus oleclumab, durvalumab plus monalizumab or durvalumab plus placebo. The primary measure of efficacy is the length of time that patients remain alive without the cancer growing or spreading for each combination versus durvalumab plus placebo. Executive summary The PACIFIC regimen Durvalumab is a monoclonal antibody that binds to PD-L1 and overcomes PD-L1 mediated inhibition of T-cell activation, allowing T cells to recognize and kill tumor cells. The Phase III placebo-controlled, PACIFIC trial (NCT02125461) demonstrated significant improvements in progression-free survival (PFS) and overall survival with durvalumab in patients with unresectable, stage III non-small-cell lung cancer (NSCLC) whose disease had not progressed following platinum-based, concurrent chemoradiotherapy (cCRT); the PACIFIC regimen is now a global standard of care in this population. Oleclumab & monalizumab Extracellular adenosine can act as an immunosuppressant within the tumor microenvironment; oleclumab is a monoclonal antibody that binds to and blocks CD73, an enzyme on the surface of tumor cells that drives the production of extracellular adenosine. NKG2A is a receptor on T cells and natural killer (NK) cells that can inhibit T cell and NK cell effector function when it binds to HLA-E; monalizumab is a monoclonal antibody that binds to NKG2A, preventing it from inhibiting NK and T cell function. In the open-label, randomized, Phase II COAST trial (NCT03822351) the combination of durvalumab with oleclumab, and durvalumab with monalizumab, were both associated with encouraging clinical activity compared with durvalumab alone in patients with unresectable, stage III NSCLC and no progression after cCRT; the findings of COAST support further evaluation of these combinations in a Phase III trial. PACIFIC-9 PACIFIC-9 (NCT05221840) is an international, double-blind, randomized, placebo-controlled, Phase III trial comparing the efficacy and safety of durvalumab plus oleclumab and durvalumab plus monalizumab versus durvalumab plus placebo in patients with unresectable, stage III NSCLC. The trial is enrolling men and women aged 18 years or older with histologically or cytologically documented, unresectable, stage III NSCLC according to the TNM system as described in the International Association for the Study of Lung Cancer staging manual (8th edition), whose disease has not progressed following definitive, platinum-based cCRT. The primary end point is PFS, defined as time from randomization until progression per Response Evaluation Criteria in Solid Tumors version 1.1 as assessed by blinded independent central review, or death due to any cause. [ABSTRACT FROM AUTHOR]