Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1)

Abstract

Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the recommended phase II dose. Entrectinib was well tolerated, with predominantly Grades 1/2 adverse events that were reversible with dose modification. Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer.Significance: Gene fusions of NTRK1/2/3, ROS1, and ALK (encoding TRKA/B/C, ROS1, and ALK, respectively) lead to constitutive activation of oncogenic pathways. Entrectinib was shown to be well tolerated and active against those gene fusions in solid tumors, including in patients with primary or secondary CNS disease. Cancer Discov; 7(4); 400-9. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 339.

Figure 1. Pharmacokinetics of Entrectinib at Steady-State (Continuous Daily Dosing)

Mean steady state (Day 28) patient plasma concentration profiles at escalating dose levels were plotted over the dosing interval following once-daily continuous dosing. The target IC₅₀ and IC₉₀ values are based on entrectinib-induced tumor growth inhibition in mouse xenograft models of NTRK1-rearranged colorectal cancer.

Figure 2. Best Response to Entrectinib in TKI Treatment-Naïve Extracranial Solid Tumor Patients

Each bar represents maximal tumor regression from baseline based upon the sum of the longest diameters of target lesions (per RECIST 1.1) in the 24 “Phase 2-eligible” patients with extracranial solid tumors. The dashed line at −30% indicates the threshold for partial response. Specific molecular alterations are shown for each patient. The asterisk indicates one patient with ROS1-rearranged NSCLC, who experienced no change in tumor burden during treatment with entrectinib.

Figure 3. Duration of Treatment

Each bar indicates the duration of treatment for the 25 “Phase 2-eligible” patients at the time of data cutoff. Specific molecular alterations are shown next to each patient. Arrows indicate patients who were ongoing on study; X denotes patients who discontinued the study (all due to disease progression); black diamonds represent time of first response; black bars represent three patients who experienced disease progression but remained on study due to clinical benefit.

Figure 4. Baseline and on-study brain MRI images for a patient with SQSTM1-NTRK1-rearranged lung cancer

Baseline head CT scans show metastases (red arrows) in the left occipital lobe (top panel) and in the right thalamus (bottom panel). Restaging head CT scans show complete response at 1 month and 18 months on entrectinib (at the time of data cutoff).