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

被引：22

作者：

Besse, Benjamin ^{[1
]}

Pons-Tostivint, Elvire ^{[2
]}

Park, Keunchil ^{[3
,32
]}

Hartl, Sylvia ^{[4
,33
]}

Forde, Patrick M. ^{[5
]}

Hochmair, Maximilian J. ^{[6
]}

Awad, Mark M. ^{[7
]}

Thomas, Michael ^{[8
]}

Goss, Glenwood ^{[9
]}

Wheatley-Price, Paul ^{[9
]}

Shepherd, Frances A. ^{[10
]}

Florescu, Marie ^{[11
]}

Cheema, Parneet ^{[12
]}

Chu, Quincy S. C. ^{[13
]}

Kim, Sang-We ^{[14
]}

Morgensztern, Daniel ^{[15
]}

Johnson, Melissa L. ^{[16
]}

Cousin, Sophie ^{[17
]}

Kim, Dong-Wan ^{[18
]}

Moskovitz, Mor T. ^{[19
,34
]}

Vicente, David ^{[20
]}

Aronson, Boaz ^{[21
]}

Hobson, Rosalind ^{[22
]}

Ambrose, Helen J. ^{[23
]}

Khosla, Sajan ^{[24
]}

Reddy, Avinash ^{[25
]}

Russell, Deanna L. ^{[26
]}

Keddar, Mohamed Reda ^{[27
]}

Conway, James P. ^{[28
]}

Barrett, J. Carl ^{[26
]}

Dean, Emma ^{[29
]}

Kumar, Rakesh ^{[30
]}

Dressman, Marlene ^{[30
]}

Jewsbury, Philip J. ^{[29
]}

Iyer, Sonia ^{[26
]}

Barry, Simon T. ^{[29
]}

Cosaert, Jan ^{[29
]}

Heymach, John V. ^{[31
]}

机构：

[1] Paris Saclay Univ, Inst Gustave Roussy, Villejuif, France

[2] Nantes Univ, CHU Nantes, Med Oncol, Nantes, France

[3] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Seoul, South Korea

[4] Clin Penzing, Ludwig Boltzmann Inst Lung Hlth, Vienna, Austria

[5] Johns Hopkins Univ, Bloomberg Kimmel Inst Canc Immunotherapy, Sch Med, Baltimore, MD USA

[6] Klin Floridsdorf, Karl Landsteiner Inst Lung Res & Pulm Oncol, Dept Resp & Crit Care Med, Vienna, Austria

[7] Dana Farber Canc Inst, Boston, MA USA

[8] Heidelberg Univ Hosp, Natl Ctr Tumor Dis NCT, Translat Lung Res Ctr Heidelberg TLRC H, German Ctr Lung Res DZL, Heidelberg, Germany

[9] Univ Ottawa, Ottawa Hosp Res Inst, Ottawa, ON, Canada

[10] Univ Hlth Network, Princess Margaret Canc Ctr, Dept Med Oncol & Hematol, Toronto, ON, Canada

[11] Ctr Hosp Univ Montreal, Div Hematol Oncol, Montreal, PQ, Canada

[12] Univ Toronto, William Osler Hlth Syst, Toronto, ON, Canada

[13] Cross Canc Inst, Edmonton, AB, Canada

[14] Asan Med Ctr, Dept Oncol, Seoul, South Korea

[15] Washington Univ, Sch Med, Dept Med, Div Med Oncol, St Louis, MO USA

[16] Tennessee Oncol, Sarah Cannon Res Inst, Nashville, TN USA

[17] Inst Bergonie, Reg Comprehens Canc Ctr, Dept Med Oncol, Bordeaux, France

[18] Seoul Natl Univ, Seoul Natl Univ Hosp, Coll Med, Seoul, South Korea

[19] Rambam Med Ctr, Inst Oncol, Haifa, Israel

[20] Hosp Univ Virgen Macarena, Dept Med Oncol, Seville, Spain

[21] AstraZeneca, Oncol Early Global Dev, Gaithersburg, MD USA

[22] AstraZeneca, Oncol Biometr, Cambridge, England

[23] AstraZeneca, Res & Early Dev, Oncol R&D, Cambridge, England

[24] AstraZeneca, Real World Evidence, Oncol R&D, Cambridge, England

[25] AstraZeneca, Oncol Data Sci, Oncol R&D, Boston, MA USA

[26] AstraZeneca, Oncol R&D, Translat Med, Boston, MA USA

[27] AstraZeneca, Oncol Data Sci Res & Early Dev, Oncol R&D, Cambridge, England

[28] AstraZeneca, Oncol Data Sci, Oncol R&D, Gaithersburg, MD USA

[29] AstraZeneca, Oncol R&D, Cambridge, England

[30] AstraZeneca, Oncol R&D, Gaithersburg, MD USA

[31] MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA

[32] MD Anderson Canc Ctr, Houston, TX USA

[33] Sigmund Freud Univ, Vienna, Austria

[34] Rabin Med Ctr, Davidoff Canc Ctr, Thorac Canc Serv, Beilinson Campus, Tikva, Israel

来源：

NATURE MEDICINE | 2024年 / 30卷 / 03期

关键词：

2-YEAR FOLLOW-UP; SOLID TUMORS; OPEN-LABEL; ACQUIRED-RESISTANCE; DOCETAXEL; NIVOLUMAB; ADENOCARCINOMA; IMMUNOTHERAPY; PEMBROLIZUMAB; ATEZOLIZUMAB;

D O I：

10.1038/s41591-024-02808-y

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：716 / 729

页数：14

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