Journal Article

Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: a phase 2 umbrella trial

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

2024

Overview

For patients with non-small-cell lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of-care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, not all patients derive durable benefit and resistance to immune checkpoint blockade is common. Understanding mechanisms of resistance—which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11 /LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumor microenvironment—and developing effective therapies to overcome them, remains an unmet need. Here the 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. A total of 268 patients received durvalumab (anti-PD-L1 monoclonal antibody)–ceralasertib (ATR kinase inhibitor), durvalumab–olaparib (PARP inhibitor), durvalumab–danvatirsen (STAT3 antisense oligonucleotide) or durvalumab–oleclumab (anti-CD73 monoclonal antibody). Greatest clinical benefit was observed with durvalumab–ceralasertib; objective response rate (primary outcome) was 13.9% (11/79) versus 2.6% (5/189) with other regimens, pooled, median progression-free survival (secondary outcome) was 5.8 (80% confidence interval 4.6–7.4) versus 2.7 (1.8–2.8) months, and median overall survival (secondary outcome) was 17.4 (14.1–20.3) versus 9.4 (7.5–10.6) months. Benefit with durvalumab–ceralasertib was consistent across known immunotherapy-refractory subgroups. In ATM -altered patients hypothesized to harbor vulnerability to ATR inhibition, objective response rate was 26.1% (6/23) and median progression-free survival/median overall survival were 8.4/22.8 months. Durvalumab–ceralasertib safety/tolerability profile was manageable. Biomarker analyses suggested that anti-PD-L1/ATR inhibition induced immune changes that reinvigorated antitumor immunity. Durvalumab–ceralasertib is under further investigation in immunotherapy-refractory NSCLC. ClinicalTrials.gov identifier: NCT03334617 In the phase 2 HUDSON study, patients with advanced non-small-cell lung cancer received anti-PD-L1 combined with biomarker-guided therapy targeting ATR kinase, PARP, STAT3 or CD73, leading to encouraging clinical benefit in response to combination of the ATR kinase inhibitor ceralasertib with durvalumab.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/67/1612/1350 / 631/67/1857 / Antibodies, Monoclonal / Antigen presentation / Antineoplastic Agents - therapeutic use / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Antisense oligonucleotides / B7-H1 Antigen / Biomarkers / Biomedical and Life Sciences / Biomedicine / Cancer Research / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - genetics / CD73 antigen / DNA damage / DNA repair / Enzyme inhibitors / Humans / Immune checkpoint inhibitors / Immunotherapy / Indoles / Infectious Diseases / Kinases / LKB1 protein / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Metabolic Diseases / Molecular Medicine / Monoclonal antibodies / Morpholines / Neurosciences / Non-small cell lung carcinoma / Patients / PD-L1 protein / Platinum / Platinum - therapeutic use / Poly(ADP-ribose) polymerase / Pyrimidines / Response rates / Safety management / Small cell lung carcinoma / Stat3 protein / Subgroups / Sulfonamides / Survival / Targeted cancer therapy / Therapy / Tumor Microenvironment