Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With NTRK Fusion-Positive Solid Tumors.

2022-04-01

Demetri, George D

De Braud, Filippo

Drilon, Alexander

Siena, Salvatore

Patel, Manish R

Cho, Byoung Chul

Liu, Stephen V

Ahn, Myung-Ju

Chiu, Chao-Hua

Lin, Jessica J

Goto, Koichi

Lee, Jeeyun

Bazhenova, Lyudmila

John, Thomas

Fakih, Marwan

Chawla, Sant P

Dziadziuszko, Rafal

Seto, Takashi

Heinzmann, Sebastian

Pitcher, Bethany

Chen, David

Wilson, Timothy R

Rolfo, Christian

Journal Article

0000-0002-0045-4809

0000-0001-6806-9061

0000-0002-2681-2846

0000-0003-2752-945X

0000-0002-5562-270X

0000-0002-4852-3914

0000-0002-5740-9654

0000-0001-7373-3916

0000-0002-3023-2510

0000-0001-8764-4359

0000-0003-3399-5342

0000-0002-2960-4364

0000-0002-2341-974X

10.1158/1078-0432.CCR-21-3597

Entrectinib potently inhibits tropomyosin receptor kinases (TRKAs)/B/C and ROS1, and previously induced deep [objective response rate (ORR) 57.4%] and durable [median duration of response (DoR) 10.4 months] responses in adults with NTRK fusion-positive solid tumors from three phase I/II trials. This article expands prior reports with additional patients and longer follow-up. Patients with locally advanced/metastatic NTRK fusion-positive solid tumors and ≥12 months' follow-up were included. Primary endpoints were ORR and DoR by blinded independent central review (BICR); secondary endpoints included progression-free survival (PFS), intracranial efficacy, and safety. The safety-evaluable populations included all patients who had received ≥1 entrectinib dose. At clinical cut-off (August 31, 2020), the efficacy-evaluable population comprised 121 adults with 14 tumor types and ≥30 histologies. Median follow-up was 25.8 months; 61.2% of patients had a complete (n = 19) or partial response (n = 55). Median DoR was 20.0 months [95% confidence interval (CI), 13.0-38.2]; median PFS was 13.8 months (95% CI, 10.1-19.9). In 11 patients with BICR-assessed measurable central nervous system (CNS) disease, intracranial ORR was 63.6% (95% CI, 30.8-89.1) and median intracranial DoR was 22.1 (95% CI, 7.4-not estimable) months. The safety profile of entrectinib in adults and pediatric patients was aligned with previous reports. Most treatment-related adverse events (TRAEs) were grade 1/2 and manageable/reversible with dose modifications. TRAE-related discontinuations occurred in 8.3% of patients. With additional clinical experience, entrectinib continues to demonstrate durable systemic and intracranial responses and can address the unmet need of a CNS-active treatment in patients with NTRK fusion-positive solid tumors.

link

Clinical Cancer Research : An Official Journal of the American Association for Cancer Research 2022; 28(7): 1302-1312

Clinical Cancer Research : An Official Journal of the American Association for Cancer Research