Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Nature medicine, 2024-03, Vol.30 (3), p.716-729

Ort / Verlag

United States: Nature Publishing Group

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.