Entrectinib in neurotrophic receptor tyrosine kinase fusion-positive (NTRK- fp) non-small cell lung cancer (NSCLC): integrated analysis of patients enrolled in STARTRK-2, STARTRK-1 and ALKA-372-001

Background: NTRK gene fusions lead to the expression of chimeric TRK proteins with constitutively activated kinase function, conferring oncogenic potential across several tumour types. Entrectinib is a central nervous system (CNS)-active, potent inhibitor of TRKA/B/C and ROS1. We present integrated efficacy and safety data for entrectinib in NTRK-fp solid tumours, focusing on patients with NSCLC.

Methods: Patients with locally advanced/metastatic NTRK-fp tumours (with or without baseline CNS disease) confirmed by nucleic acid-based methods, enrolled in global (> 150 sites, 15 countries) phase I/II entrectinib trials (ALKA-372-001 [EudraCT 2012 – 000 148 – 88], STARTRK-1 [NCT02097810], STARTRK-2 [NCT02568267]) were included. Disease burden was assessed per blinded independent central review (BICR) using RECIST v1.1, after cycle 1 (4 weeks) then every 8 weeks. Primary endpoints: objective response rate (ORR), duration of response (DOR) by BICR. Secondary endpoints: progression-free survival (PFS), overall survival (OS) and safety.

Results: Outcomes in the total efficacy-evaluable population (n = 54; 10 tumour types, > 19 histopathologies) are shown in [Table 1]; responses were seen in all tumour types, median PFS11.2 months. In the cohort of patients with NTRK-fp NSCLC (n = 10), BICR ORR was 70% (7/10). In patients with NSCLC and CNS disease per investigator at baseline (n = 6), four had an intracranial response (two complete, two partial); one had stable disease and one was not evaluable. In the safety population (68 patients with NTRK-fp solid tumours who received at least one dose of entrectinib), most treatment-related adverse events (TRAEs) were grade 1 – 2; grade 3: 32.4%, grade 4: 2.9%; no grade 5 TRAEs. TRAEs resulted in discontinuation in 4.4% and dose reduction in 39.7% of patients.

Conclusion: In this integrated analysis of global multicentre clinical trials, entrectinib was well tolerated and induced clinically meaningful, durable systemic and intracranial responses in patients with NTRK-fp solid tumours, including those with NSCLC.

Table 1 

Baseline characteristics	Patients with advanced/ metastatic NTRK-fp solid tumours (n = 54)
BICR, blinded independent central review; CI, confidence interval; CNS, central nervous system; CR, complete response; DOR, duration of response; NR, not reached; NTRK-fp, NTRK fusion-positive; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.
Median age	57.5 years
Range	21 – 83 years
Gender
Male	40.7%
Female	59.3%
CNS disease at baseline	22.2%
Efficacy outcomes
ORR (BICR)	57.4% (95% CI 43.2, 70.8) 4 CR (7.4%)
Median DOR (BICR)	10.4 months (95% CI 7.1 – NR)
Median PFS (BICR)	11.2 months (95% CI 8.0 – 14.9)
Median OS	20.9 months (95% CI 14.9 – NR)