Introduction
Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers that occur in a wide range of tumor types. Larotrectinib, a highly selective Food and Drug Administration and European Medicines Agency approved TRK inhibitor, demonstrated an objective response rate (ORR) of 79% and a median duration of response (DoR) of 35 months across multiple cancers (Hong et al. Lancet Oncol 2020). Here we report updated data for patients with TRK fusion lung cancer assessed by independent review committee (IRC) and investigators (INV).
Methods
Patients with lung cancer harboring an NTRK gene fusion enrolled in two clinical trials (NCT02122913 and NCT02576431) were included in this analysis. Larotrectinib 100 mg twice daily was administered on a continuous 28-day schedule. Response was assessed by IRC and by INV per RECIST v1.1.
Results
As of July 15, 2019, 14 patients with metastatic TRK fusion lung cancer were enrolled: 13 with non-small cell lung cancer (NSCLC) and 1 patient with small cell lung cancer (SCLC). Seven (6 NSCLC, 1 SCLC) patients had baseline central nervous system (CNS) metastases. The median age was 52 years (range 25–76). Eleven patients (79%) had fusions involving NTRK1 and three patients (21%) had fusions involving NTRK3. Patients were heavily pre-treated with a median of three prior therapies (range 1–5). Among 13 IRC-evaluable patients the ORR was 77% (95% confidence interval [CI] 46–95). ORR was 71% (95% CI 42–92) per INV. ORR in patients with CNS metastases was 71% (95% CI 29–96) and 57% (95% CI 18–90) per IRC and per INV, respectively (Table). The overall DoR per IRC ranged from 3.6 to 36.8+ months. The median progression-free survival (PFS) had not been reached (range 1.8 to 30.3+ months), with an estimated PFS rate at 12 months of 69%. Larotrectinib was well tolerated, with treatment-emergent adverse events being mainly Grade 1–2.
Tabled
1
| All patients (N=14) | Patients with brain metastases at baseline (n=7) | |||
|---|---|---|---|---|
| INV | IRC† | INV | IRC | |
| ORR, % (95% CI) | 71 (42–92) | 77 (46–95) | 57 (18–90) | 71 (29–96) |
| CR, n (%) | 1 (7) | 2 (15) | 0 | 0 |
| PR, n (%) | 9 (64) | 8 (62) | 4 (57) | 5 (71) |
| SD, n (%) | 3 (21) | 3 (23) | 2 (29) | 2 (29) |
| PD, n (%) | 1 (7)‡ | 0 | 1 (14)‡ | 0 |
†IRC data missing for one patient. ‡Extracranial progression detected. CI, confidence interval; CR, complete response; INV, investigator assessment; IRC, independent review committee assessment; PD, progressive disease; PR, partial response; SD, stable disease.
Conclusion
In this updated dataset, larotrectinib was shown to be highly active in patients with advanced lung cancer harboring NTRK gene fusions, including those with CNS metastases. The drug has a favorable safety profile. These results support inclusion of NTRK gene fusions in the routine molecular testing of patients with lung cancer.
Keywords
Larotrectinib, NTRK gene fusions, TRK
Article info
Identification
Copyright
© 2021 Published by Elsevier Inc.
User license
Elsevier user license | How you can reuse 
Elsevier's open access license policy
Elsevier user license
Permitted
For non-commercial purposes:
- Read, print & download
- Text & data mine
- Translate the article
Not Permitted
- Reuse portions or extracts from the article in other works
- Redistribute or republish the final article
- Sell or re-use for commercial purposes
Elsevier's open access license policy
