Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various cancers, including lung cancer. Larotrectinib, a highly selective, central nervous system (CNS)-active tropomyosin receptor kinase (TRK) inhibitor, demonstrated a 73% objective response rate (ORR) in 15 patients (pts) with TRK fusion lung cancer (Drilon et al. JCO Precis Oncol 2022). We report efficacy and safety with circulating tumour DNA (ctDNA) analysis in pts with TRK fusion lung cancer treated with larotrectinib.
Pts treated with larotrectinib in 2 clinical trials (NCT02122913, NCT02576431) were analysed. NTRK gene fusions were determined by local testing before enrolment. Larotrectinib was administered at 100 mg twice daily. Response was assessed by an independent review committee (IRC) per RECIST v1.1. ctDNA was analysed using Guardant360 and GuardantOMNI.
As of 20 July 2021, 26 pts (12 pts with CNS metastases) were enrolled. Among 23 pts (10 pts with CNS metastases) evaluable per IRC, ORR was 83% (95% confidence interval [CI] 61–95; 2 complete response, 17 partial response, 4 stable disease). Median duration of response (DoR) was not reached (95% CI 9.5–not estimable [NE]), with a 12-month DoR rate of 72%. Median progression-free survival was not reached (95% CI 9.9–NE). Median overall survival was 40.7 months (95% CI 19.4–NE). Treatment-related adverse events were mostly Grade 1–2. ctDNA data were available for 14 pts. ctDNA analysis detected NTRK gene fusions in 6 of the 14 pts at treatment start. Assessment of baseline co-occurring mutations revealed the inclusion of 3 patients with mutation-positive NSCLC who had failed prior anti-EGFR therapy. By the data cut-off, 6 pts had progressed, with ctDNA data available for 5 pts. Potential acquired mutations were identified in 3 pts.
Larotrectinib demonstrated durable responses, extended survival benefit, and a favourable safety profile in patients with advanced lung cancer harbouring NTRK gene fusions, including those with treatment-naive NSCLC or with prior EGFR inhibitor therapy. ctDNA next-generation sequencing represents a promising technology to test NTRK gene fusions or resistance mutations.
NCT02122913
NCT02576431
Editorial acknowledgement: Editorial assistance was provided by Anastasija Pesevska, PharmD, and Joe Alling, BSc, (Scion, London UK) funded by Bayer HealthCare Pharmaceuticals, Inc.