Entrectinib Effective and Safe in NTRK Fusion–Positive Solid Tumors

Wayne Kuznar

December 2018, Vol 9, No 4 - Emerging Therapies

Munich, Germany—Entrectinib, an oral, central nervous system (CNS)-­active, selective inhibitor of TRK proteins and ROS1 tyrosine kinases, induced responses in more than 50% of adults with neurotrophic tropomyosin receptor kinase (NTRK) gene fusion–positive solid tumors, according to findings released at the ESMO 2018 Congress.

An integrated analysis of 3 early-­phase clinical trials demonstrated ­responses to entrectinib regardless of tumor type or CNS spread, said George D. Demetri, MD, Director, Center for Sarcoma and Bone Oncology, Dana-­Farber Cancer Institute, Boston.

“Entrectinib treatment resulted in clinically meaningful, deep and durable systemic responses in NTRK fusion–positive adult patients with solid tumors across 10 tumor types and at least 19 distinct histopathologies in patients with and without CNS metastases,” said Dr Demetri.

NTRK1/2/3 gene fusions are oncogenic drivers across different tumor types. Entrectinib “was designed from the start to be active in the central nervous system,” Dr Demetri said. Clinically meaningful benefit of entrectinib had previously been shown for patients with non–small-cell lung cancer (NSCLC) and ROS1 mutation, with or without CNS metastases, with a 77% objective response rate (ORR) and a median duration of response of 24.6 months.

The 3 Studies

The data presented were an integrated analysis of the STARTRK-2, STARTRK-1, and ALKA-372-001 clinical trials.

STARTRK-2 was a pivotal phase 2, global, multicenter, open-label basket study in patients with solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene fusion or rearrangement. The study was conducted at 150 sites in 15 countries.

STARTRK-1 was a phase 1, multicenter, open-label dose-escalation study of a daily, continuous dosing schedule in patients with solid tumors associated with NTRK1/2/3, ROS1, or ALK gene fusions or rearrangements that was conducted in the United States and in South Korea.

ALKA-372-001 was a phase 1, multicenter, open-label dose-escalation study of an intermittent and continuous entrectinib dosing schedule in patients with advanced or metastatic solid tumors harboring TRKA/B/C, ROS1, or ALK gene fusions. The study was conducted in Italy.

The efficacy population consisted of 54 adult patients with solid tumors and NTRK fusion who have not received a TRK inhibitor. The safety population included 355 patients with all tumor types and gene rearrangements, including ROS1, who received entrectinib therapy.

The cancer types varied and included 24% of patients with sarcomas, 19% with NSCLC, 13% with mammary analog secretory carcinomas, 11% with breast cancer, 9% with thyroid cancer, and 7% with colorectal cancer. A total of 37% of patients were treatment-naïve at baseline, and 42.6% received ≥2 previous lines of systemic therapy. Overall, 22% of patients had CNS metastases at baseline.

The ORR was 57.4% per blinded independent central review. The median duration of response was 10.4 months, and the median progression-free survival (PFS) was 11.2 months. The median overall survival was 20.9 months, with an upper confidence limit that was not evaluable.

“The overall objective response rates were quite similar, whether they had CNS metastases at baseline or not,” said Dr Demetri. The ORR was 50% in patients with CNS metastases at baseline and 59.5% in those without CNS metastases at baseline.

The ORR was 59.1% in the 22 patients with NTRK1 gene fusions, 0% in the 1 patient with an NTRK2 gene fusion, and 58.1% in the 31 with NTRK3 gene fusions. The intracranial ORR for the patients who entered the study with active CNS disease was 54.5% (6 of 11), with 3 complete CNS responses and 3 partial responses. The intracranial median duration of response was not estimable, and the intracranial median PFS was 14.3 months.

Safety Results

Overall, entrectinib was well-tolerated. Most adverse events were grade 1 or 2, reversible, and managed with treatment interruption or dose reduction. Treatment-related adverse events leading to discontinuation occurred in 3.9% of patients. The most common treatment-­related adverse events were dysgeusia (47%), fatigue (35%), diarrhea (28%), constipation (28%), and dizziness (25%).

Entrectinib received a breakthrough therapy designation from the FDA in 2017 for the treatment of NTRK fusion–positive, locally advanced or metastatic solid tumors in adults and children whose disease has progressed after previous therapies or who have no acceptable standard therapies.