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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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