Table 1 |.
Clinical activity and safety profile of first-generation TRK inhibitors
| Drug | NTRK fusion-positive cancers treated (n; % of total) | ORR (95% CI; n) |
PR rate (n) | CR rate (n) | Most common drug-related AEs of any gradea |
|---|---|---|---|---|---|
| Larotrectinib10 | MASC or other salivary gland cancer (12; 22%) | 75% (61–85%; 41/55) | 62% (34/55) | 13% (7/55) | Increased serum AST and/or ALT levels (38%) |
| Non-GIST STS (11; 20%) | Dizziness (25%) | ||||
| Infantile fibrosarcoma (7; 13%) | Fatigue (16%) | ||||
| Thyroid cancer (5; 9%) | Nausea (16%) | ||||
| CRC (4; 7%) | Constipation (16%) | ||||
| NSCLC (4; 7%) | Vomiting (11%) | ||||
| Melanoma (4; 7%) | Weight gain (11%) | ||||
| GIST (3; 5%) | Decreased neutrophil counts (9%) | ||||
| Cholangiocarcinoma (2; 4%) | |||||
| Appendix cancer (1; 2%) | |||||
| Breast cancer (1; 2%) | |||||
| PDAC (1; 2%) | |||||
| Entrectinib11 | CRC (1; 25%) | 100% (44–100%; 3/3b) | 100% (3/3b) | 0% (0/3) | Fatigue (46%) |
| Glioneuronal tumour (1; 25%) | Dysgeusia (42%) | ||||
| MASC (1; 25%) | Paresthesia (29%) | ||||
| NSCLC (1; 25%) | Nausea (28%) | ||||
| Myalgia (23%) | |||||
| Diarrhoea (19%) | |||||
| Vomiting (17%) | |||||
| Arthralgia (16%) | |||||
| Dizziness (16%) | |||||
| Constipation (12%) | |||||
| Weight gain (10%) |
Data on the activity of larotrectinib in NTRK fusion-positive tumours were derived with regulatory input from three trials: a phase I trial in adult patients (NCT02122913), a phase I/II trial in paediatric patients (SCOUT; NCT02637687), and an phase II basket trial in adult or adolescent patients (NAVIGATE; NCT02576431). Data on the activity of entrectinib in NTRK fusion-positive tumours were derived from two phase I trials in adult patients (ALKA-372-001 and STARTRK-1; EudraCT 2012-000148-88 and NCT02097810, respectively). AEs, adverse events; ALT, alanine transaminase; AST, aspartate transaminase; CI, confidence interval; CR, complete response; CRC, colorectal carcinoma; GIST, gastrointestinal stromal tumour; MASC, mammary analogue secretory carcinoma; NSCLC, non-small-cell lung cancer; ORR, objective response rate; PDAC, pancreatic ductal adenocarcinoma; PR, partial response; STS, soft-tissue sarcoma.
The frequencies indicated for entrectinib refer to those observed in all 119 adult patients enrolled in the ALKA-372–001 and STARTRK-1 phase I trials, only 4 of whom had tumours harbouring NTRK fusions).
The patient with glioneuronal tumour with stable disease by RECIST was excluded from the analysis but had unconfirmed disease regression according to an exploratory volumetric assessment and a clinical response (improvement in symptoms).