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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]

We assessed the impact of the coronavirus disease 2019 (COVID-19) pandemic on the statistical analysis of time-to-event outcomes in late-phase oncology trials. Using a simulated case study that mimics a Phase III ongoing trial during the pandemic, we evaluated the impact of COVID-19-related deaths, time off-treatment and missed clinical visits due to the pandemic, on overall survival and/or progression-free survival in terms of test size (also referred to as Type 1 error rate or alpha level), power, and hazard ratio (HR) estimates. We found that COVID-19-related deaths would impact both size and power, and lead to biased HR estimates; the impact would be more severe if there was an imbalance in COVID-19-related deaths between the study arms. Approaches censoring COVID-19-related deaths may mitigate the impact on power and HR estimation, especially if study data cut-off was extended to recover censoring-related event loss. The impact of COVID-19-related time off-treatment would be modest for power, and moderate for size and HR estimation. Different rules of censoring cancer progression times result in a slight difference in the power for the analysis of progression-free survival. The simulations provided valuable information for determining whether clinical-trial modifications should be required for ongoing trials during the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Aims: Tremelimumab, a cytotoxic T‐lymphocyte‐associated protein 4 human monoclonal antibody of the immunoglobulin G2 κ isotype, has been studied in oncology clinical trials as both monotherapy and in combination with durvalumab. This study characterized the pharmacokinetics of tremelimumab as monotherapy and in combination with durvalumab and evaluated the impact of patient covariates on pharmacokinetics. Methods: A pooled‐analysis population pharmacokinetics model was built using NONMEM methodology. Pharmacokinetic data from 5 studies spanning different tumour types and therapy regimens were pooled for model development (956 patients). A dataset pooled from 4 additional studies was used for external validation (554 patients). Demographic and relevant clinical covariates were explored during model development. Results: Tremelimumab exhibited linear pharmacokinetics, well described by a 2‐compartment model, with time‐varying clearance (0.276 L/day at baseline) associated primarily with therapy regimen and linked with changes in disease status. As monotherapy and combination therapy, tremelimumab clearance over 1 year increased by ~16% and decreased by ~17%, respectively. Pharmacokinetic behaviour was consistent across patient demographics and cancer subtypes. Patients with higher bodyweight and lower albumin levels at baseline had significantly higher clearance; however, no dosage adjustments are warranted. A flat dose (75 mg) was projected to provide comparable exposure to weight‐based dosing (1 mg/kg) in adults. Conclusion: Tremelimumab exhibited linear pharmacokinetics but consistently opposite trends of time‐varying clearance as monotherapy and in combination with durvalumab. Baseline bodyweight and albumin were significant covariates, but conversion from weight‐based dosing at 1 mg/kg to flat dosing at 75 mg had no clinically relevant impact. [ABSTRACT FROM AUTHOR]