Osimertinib plus Savolitinib to Overcome Acquired MET-Mediated Resistance in Epidermal Growth Factor Receptor-Mutated, MET-Amplified Non-Small Cell Lung Cancer: TATTON

被引：116

作者：

Hartmaier, Ryan J. ^{[1
]}

Markovets, Aleksandra A. ^{[1
]}

Ahn, Myung Ju ^{[2
]}

Sequist, Lecia, V ^{[3
]}

Han, Ji-Youn ^{[4
]}

Cho, Byoung Chul ^{[5
]}

Yu, Helena A. ^{[6
]}

Kim, Sang-We ^{[7
]}

Yang, James Chih-Hsin ^{[8
]}

Lee, Jong-Seok ^{[9
]}

Su, Wu-Chou ^{[10
]}

Kowalski, Dariusz M. ^{[11
]}

Orlov, Sergey ^{[12
]}

Ren, Song ^{[13
]}

Frewer, Paul ^{[14
]}

Ou, Xiaoling ^{[14
]}

Cross, Darren A. E. ^{[15
]}

Kurian, Nisha ^{[16
]}

Cantarini, Mireille ^{[15
]}

Jaenne, Pasi A. ^{[17
]}

机构：

[1] AstraZeneca, Oncol R&D, Res & Early Dev, Translat Med, Boston, MA USA

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

[3] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA

[4] Natl Canc Ctr, Ctr Lung Canc, Goyang, South Korea

[5] Yonsei Univ, Yonsei Canc Ctr, Div Med Oncol, Coll Med, Seoul, South Korea

[6] Mem Sloan Kettering Canc Ctr, Dept Med Oncol, 1275 York Ave, New York, NY 10021 USA

[7] Univ Uslan, Asan Med Ctr, Dept Oncol, Coll Med, Seoul, South Korea

[8] Natl Taiwan Univ, Dept Med Oncol, Canc Ctr, Taipei, Taiwan

[9] Seoul Natl Univ, Dept Internal Med, Bundang Hosp, Seoul, South Korea

[10] Natl Cheng Kung Univ Hosp, Dept Internal Med, Tainan, Taiwan

[11] Maria Sklodowska Curie Natl Res Inst Oncol, Dept Lung Canc & Thorac Oncol, Warsaw, Poland

[12] BioEq LLC, St Petersburg, Russia

[13] AstraZeneca, Clin Pharmacol & Quantitat Pharmacol, Gaithersburg, MD USA

[14] AstraZeneca, Oncol R&D, Oncol Biometr, Cambridge, England

[15] AstraZeneca, Oncol R&D, Oncol Late Dev, Cambridge, England

[16] AstraZeneca, Oncol R&D, Precis Med & Biosamples, Boston, MA USA

[17] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA

来源：

CANCER DISCOVERY | 2023年 / 13卷 / 01期

关键词：

TYROSINE KINASE INHIBITORS; PHASE-II PLATFORM; PATIENT; NSCLC; CRIZOTINIB; VOLITINIB; THERAPY; DISEASE; AZD9291; POTENT;

D O I：

10.1158/2159-8290.CD-22-0586

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

MET-inhibitor and EGFR tyrosine kinase inhibitor (EGFR-TKI) combination therapy could overcome acquired MET-mediated osimertinib resistance. We present the fi nal phase Ib TATTON (NCT02143466) analysis (Part B, n = 138/Part D, n= 42) assessing oral savolitinib 600 mg/300 mg once daily (q.d.) + osimertinib 80 mg q.d. in patients with MET-amplified, EGFR-mutated (EGFRm) advanced non-small cell lung cancer (NSCLC) and progression on prior EGFR-TKI. An accept-able safety profi le was observed. In Parts B and D, respectively, objective response rates were 33% to 67% and 62%, and median progression-free survival (PFS) was 5.5 to 11.1 months and 9.0 months. Increased antitumor activity may occur with MET copy number >= 10. EGFRm circulating tumor DNA clearance on treatment predicted longer PFS in patients with detectable baseline ctDNA, while acquired resistance mechanisms to osimertinib + savolitinib were mediated by MET, EGFR, or KRAS alterations. SIGNIFICANCE: The savolitinib + osimertinib combination represents a promising therapy in patients with MET-amplifi ed/overexpressed, EGFRm advanced NSCLC with disease progression on a prior EGFR-TKI. Acquired resistance mechanisms to this combination include those via MET, EGFR, and KRAS. On-treatment ctDNA dynamics can predict clinical outcomes and may provide an opportunity to inform earlier decision-making.

引用

页码：98 / 113

页数：16

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