This phase 2 umbrella HUDSON study evaluated rational combination regimens for advanced NSCLC following failure of anti-PD-(L)1-containing immunotherapy and platinum-doublet therapy. 268 patients received durvalumab with ceralasertib, olaparib, danvatirsen, or oleclumab. Durvalumab-ceralasertib showed greatest clinical benefit (ORR 13.9% vs 2.6% for other regimens); median PFS was 5.8 months vs 2.7 months; median OS was 17.4 months vs 9.4 months. Benefit was consistent across immunotherapy-refractory subgroups. In ATM-altered patients, ORR was 26.1%. Durvalumab-ceralasertib's safety profile was manageable. Biomarker analyses suggested immune changes reinvigorating antitumor immunity. Durvalumab-ceralasertib is under further investigation.

Benjamin Besse, Elvire Pons-Tostivint, Keunchil Park, Sylvia Hartl, Patrick M. Forde, Maximilian J. Hochmair, Mark M. Awad, Michael Thomas, Glenwood Goss, Paul Wheatley-Price, Frances A. Shepherd, Marie Florescu, Parneet Cheema, Quincy S. C. Chu, Sang-We Kim, Daniel Morgensztern, Melissa L. Johnson, Sophie Cousin, Dong-Wan Kim, Mor T. Moskovitz, David Vicente, Boaz Aronson, Rosalind Hobson, Helen J. Ambrose, Sajan Khosla, Avinash Reddy, Deanna L. Russell, Mohamed Reda Keddar, James P. Conway, J. Carl Barrett, Emma Dean, Rakesh Kumar, Marlene Dressman, Philip J. Jewsbury, Sonia Iyer, Simon T. Barry, Jan Cosaert, John V. Heymach