Entrectinib

Previous Page   Next Page


Efficacy

Adult patients

Two phase 1 studies (ALKA-372-001 [EudraCT 2012-000 148-88] and STARTRK-1 [NCT02097810) assessed the safety and efficacy of entrectinib in 119 adult patients with advanced or metastatic solid tumours, including patients with active CNS disease [3].  

Of the phase 2 eligible population from these two trials, four were molecularly characterised as having cancers with NTRK gene fusion and 14 with ROS1 gene mutations [3]. In three patients with cancers with NTRK gene fusion, the objective response rate was 100% (95% CI, 44–100). An additional patient with an NTRK gene fusion experienced stable disease, but further analysis showed a 60% reduction in total tumour burden. In the 14 patients with ROS1 gene mutations, the objective response rate was 86% (95% CI, 60–96) and included two patients with a complete response. 

Integrated data across three phase 1/2 clinical trials (STARTRK-2, STARTRK-1, and ALKA-372-001) in adults reported that entrectinib treatment produced clinically meaningful, durable responses (objective response rate 57.4% [95% CI, 43.2–70.8]) by blinded independent central review in 54 patients with cancers with NTRK gene fusion after a median follow-up of 15.5 months [4].  In patients with CNS metastases at baseline (n = 12), the overall response rate was 50.0% versus 59.5% in patients with no metastases at baseline (n = 42).

In patients with cancers with NTRK gene fusion, median progression-free survival was 11.2 months (95% CI, 8.0–14.9 months) and median overall survival was 20.9 months (95% CI, 14.9–not estimable). For patients with CNS metastases at baseline, the median progression-free survival was 14.3 months (95% CI 5.1 months–not estimable) [4].

Clinical data for development of acquired resistance to entrectinib are also emerging. For instance, one patient with colorectal cancer presented with a previously unreported LMNA-NTRK1 gene fusion that responded to entrectinib [5]. However, this was rapidly followed by acquired resistance  associated with acquisition of two point mutations in the NTRK1 gene (i.e. p.G595R and p.G667C) that were not present before the initiation of therapy [6]. These mutations have been functionally characterized in vitro as causing insensitivity of the TRKA protein kinase to the drug inhibitor [6].

Paediatric patients

A phase 1 study (STARTRK-NG) in 16 paediatric and young adult patients (2–21 years of age) with recurrent or refractory solid tumours reported objective responses in three patients with cancers with gene fusions (i.e. NTRK, ROS1 or ALK gene fusions) [2].

References

  1. Demetri GD, Paz-Ares L, Farago AF et al. Efficacy and safety of entrectinib in patients with NTRK fusion-positive (NTRK-fp) Tumors: Pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Annals of Oncology 2018; 29: mdy424.017-mdy424.017, https://doi.org/410.1093/annonc/mdy1424.1017 .
  2. Desai AV, Brodeur GM, Foster J et al. Phase 1 study of entrectinib (RXDX-101), a TRK, ROS1, and ALK inhibitor, in children, adolescents, and young adults with recurrent or refractory solid tumors. Journal of Clinical Oncology 2018; 36: 10536-10536.
  3. Drilon A, Siena S, Ou SI et al. Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1). Cancer Discov 2017; 7: 400-409.
  4. Demetri GD, Paz-Ares L, Farago AF et al. LBA17Efficacy and safety of entrectinib in patients with NTRK fusion-positive (NTRK-fp) Tumors: Pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Annals of Oncology 2018; 29: mdy424.017-mdy424.017.
  5. Sartore-Bianchi A, Ardini E, Bosotti R et al. Sensitivity to Entrectinib Associated With a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer. J Natl Cancer Inst 2016; 108.
  6. Russo M, Misale S, Wei G et al. Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer. Cancer Discov 2016; 6: 36-44.

Next Page »

Last update: 24 June 2019