Durvalumab in Oncology: Pioneering Advances through Recent Clinical Trials and Expanding Therapeutic Horizons

Abstract: Durvalumab, the programmed death-ligand 1 (PD-L1) targeting monoclonal antibody, has revolutionized the treatment of numerous cancers, such as Non-Small Cell Lung Cancer (NSCLC). Despite producing remarkable clinical advantages, immune-related toxicities, i.e., pneumonitis and colitis, are being closely monitored and must be treated on an individual basis. The safety profile, including immune-related toxicities, must be carefully considered. The role of Durvalumab as a consolidative treatment for unresectable stage III NSCLC, as demonstrated in the PACIFIC trial, marked a significant milestone in the adoption of immunotherapy. However, recent findings suggest that its benefit varies among patient subgroups, highlighting the need for more precise biomarkers beyond PD-L1 expression. Ongoing trials, such as PACIFIC-9 and AEGEAN, are investigating durvalumab in different settings and combination therapies with an aim to overcome resistance mechanisms. The PACIFIC-9 is an example where durvalumab is being combined with the CD73-blocking anti-CD73 antibody oleclumab and the CD94/NKG2Ablocking monalizumab in unresectable stage III NSCLC patients who maintain a stable response through chemoradiotherapy. Early findings are encouraging, but phase III efficacy data remain awaited. Heterogeneity in treatment response between tumor types, including bladder carcinoma, head and neck cancers, and cholangiocarcinoma, is one reason why it is worth aiming for tumorintrinsic and microenvironmental determinants of responsiveness to immunotherapy. Durvalumab is of landmark significance in a range of malignancies but needs further efforts in the characterization of resistance mechanisms, the optimization of combination strategies, and the development of predictive models for the guidance of personalised therapeutic regimens.