Entrectinib

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Safety

Adult patients

As shown below, entrectinib was well tolerated in the phase 1 ALKA-372-001 and STARTRK-1 studies in adults, and adverse events were mostly grade 1 or 2 [2]. Of the phase 2-eligibile population from these two trials, four patients had cancers with NTRK gene fusion and 14 had cancers with ROS1 gene mutations [2].

Table 10: Adverse Events Occurring in 10% of the 119 Adult Patients [2]a

Adverse event All-cause
  Any grade
(%)
Grade ≥3
(%)
  General disorders  
  Fatigue/asthenia     46     4  
  Metabolism and nutrition disorders  
  Dysgeusia     42     0  
  Weight increase     10     2  
  Nervous system disorders  
  Paresthesia     29     0  
  Dizziness     16     0  
  Gastrointestinal disorders  
  Nausea     28     0  
  Diarrhoea     19     1  
  Vomiting     17     0  
  Constipation     12     0  
  Musculoskeletal and connective tissue disorders  
  Myalgia     23     0  
  Arthralgia     16     1  

aDeemed to be related to study drug.

The safety profile in the integrated data across three phase 1/2 clinical trials (STARTRK-2, STARTRK-1, and ALKA-372-001) in adults with cancers with NTRK gene fusion is shown below.

Table 11: Treatment-related Adverse Events Occurring in ≥10% of the 68 Adult Patients With Cancers With NTRK gene fusion [3]

Adverse event Grade 1/2 (%) Grade 3 (%)
Dysgeusia 47.1 0
Constipation 27.9 0
Fatigue 27.9 7.4
Diarrhoea 26.5 1.5
Oedema peripheral 23.5 1.5
Dizziness 23.5 1.5
Blood creatinine increase 17.6 1.5
Parathesia 16.2 0
Nausea 14.7 0
Vomiting 13.2 0
Arthralgia 11.8 0
Myalgia 11.8 0
Weight increased 11.8 10.3
AST increasea 10.3 0
Muscular weakness 8.8 1.5
Anaemia 7.4 11.8

aOne grade 4 treatment-related adverse event.

AST, aspartate aminotransferase.

Pediatric patients

The phase 1 study in 16 paediatric and young adult patients (2–21 years of age) with recurrent or refractory solid tumours reported similar adverse events to adult patients [1].

References

  1. 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.
  2. 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.
  3. 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.

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Last update: 24 June 2019