Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With NTRK Fusion-Positive Solid Tumors

Abstract

Purpose: Entrectinib potently inhibits tropomyosin receptor kinases (TRKAs)/B/C and ROS1, and previously induced deep [objective response rate (ORR) 57.4%] and durable [median duration of response (DoR) 10.4 months] responses in adults with NTRK fusion-positive solid tumors from three phase I/II trials. This article expands prior reports with additional patients and longer follow-up.

Patients and methods: Patients with locally advanced/metastatic NTRK fusion-positive solid tumors and ≥12 months' follow-up were included. Primary endpoints were ORR and DoR by blinded independent central review (BICR); secondary endpoints included progression-free survival (PFS), intracranial efficacy, and safety. The safety-evaluable populations included all patients who had received ≥1 entrectinib dose.

Results: At clinical cut-off (August 31, 2020), the efficacy-evaluable population comprised 121 adults with 14 tumor types and ≥30 histologies. Median follow-up was 25.8 months; 61.2% of patients had a complete (n = 19) or partial response (n = 55). Median DoR was 20.0 months [95% confidence interval (CI), 13.0-38.2]; median PFS was 13.8 months (95% CI, 10.1-19.9). In 11 patients with BICR-assessed measurable central nervous system (CNS) disease, intracranial ORR was 63.6% (95% CI, 30.8-89.1) and median intracranial DoR was 22.1 (95% CI, 7.4-not estimable) months. The safety profile of entrectinib in adults and pediatric patients was aligned with previous reports. Most treatment-related adverse events (TRAEs) were grade 1/2 and manageable/reversible with dose modifications. TRAE-related discontinuations occurred in 8.3% of patients.

Conclusions: With additional clinical experience, entrectinib continues to demonstrate durable systemic and intracranial responses and can address the unmet need of a CNS-active treatment in patients with NTRK fusion-positive solid tumors.

Figure 1.

Responses and time on entrectinib treatment in patients with NTRK fusion-positive solid tumors, by tumor type (BICR assessed). A, Best individual patient responses [n = 103; 18 patients with missing sum of the longest diameter (SLD) change were excluded from the plot]. B, Time on entrectinib treatment. Data cut-off August 31, 2020. The minimum shrinkage in the SLD of target lesions that defined an OR was 30%. Gastrointestinal (GI)-other, adenocarcinoma of upper GI tract; CRC, colorectal carcinoma; CUP, cancer of unknown primary; Inv, investigator; ND, not determined; SD, stable disease.

Figure 2.

Time-to-event analyses for A, DoR in responding patients; B, PFS per BICR; C, OS in patients with NTRK fusion-positive solid tumors (N=121). Data cut-off August 31, 2020.

Figure 3.

Best intracranial responses to entrectinib in patients with NTRK fusion-positive solid tumors and measurable CNS metastases (BICR assessed) at baseline. Data cut-off August 31, 2020. Response assessed by BICR. Patients with new CNS lesions or unequivocal progression of nontarget lesions had overall response classified as PD, even if the SLD of all lesions was reduced. ND, not determined; SD, stable disease.