Entrectinib Active Across Multiple Tumor Types

George D. Demetri, MD

More than half of patients with advanced solid tumors associated with NTRK gene fusions responded to treatment with the small-molecule inhibitor entrectinib, an integrated analysis of 3 clinical trials showed.

Overall, 31 of 54 evaluable patients had objective responses encompassing 10 types of tumors. Responses had a median duration of 10.4 months.

Among patients with brain metastases at baseline, more than half responded to entrectinib, which targets TRK A/B/C and ROS1 gene fusions, as reported at the European Society for Medical Oncology Annual Congress in Munich.

“Entrectinib treatment resulted in clinically meaningful, deep, and durable systemic responses in NTRK fusion-positive adult patients with solid tumors,” said George D. Demetri, MD, of Dana-Farber Cancer Institute in Boston. “Clinically meaningful and durable central nervous system (CNS) antitumor activity was demonstrated in patients with baseline CNS metastases, with an intracranial response rate similar to the systemic response rate.”

“Entrectinib was tolerable, with a manageable safety profile. Most adverse events were managed with dose interruption or reduction, and the discontinuation rate was low.”

Preclinical data provided solid support for clinical development of entrectinib. In preclinical studies, entrectinib demonstrated broad pan-tumor TRK inhibition and antitumor activity, including activity against CNS lesions, said Demetri.

Entrectinib was evaluated in 3 clinical studies involving patients with and without NTRK gene fusions: STARTRK-1, conducted at 10 sites in the United States, Spain, and South Korea; STARTRK-2, involving more than 150 sites in 15 countries; and ALKA-372-001 at 2 sites in Italy.

Demetri reported findings from an integrated analysis involving 54 patients from the trials with NTRK-positive solid tumors. None of the patients had prior exposure to TRK inhibitor therapy. Additionally, he reviewed safety data from a total of 355 entrectinib-treated patients, representing multiple tumor types and gene rearrangements.

The primary endpoints of the analysis were objective response rate and duration of response. Secondary endpoints included progression-free survival, overall survival, intracranial objective response, and duration of response, safety, and tolerability.

The 54 patients with NTRK fusion-positive tumors had a median age of 57.5, and women accounted for almost 60% of the patients. More than 40% of the patients had received 2 or more prior lines of therapy, and 37% had untreated cancers.

Sarcomas were the most commonly represented type of tumor (24%), followed by non—small cell lung cancer (19%), mammary analog secretory carcinoma (13%), breast cancer (11%), thyroid cancer (9%), and colorectal cancer (7%).

The data showed an overall response rate of 57.4% and stable disease in an additional 16.7% of patients. Ten patients had lesser responses or were unevaluable, and 4 patients (7.4%) had progressive disease. Objective responses were observed across the range of tumor types represented in the analysis.

The response rate remained consistent in several key subgroup analyses: CNS metastases at baseline (50.0%, n=12) versus none (59.5%, n=42); and NTRK gene type—NTRK1 (59.1%, n=22), NTRK2 (0%, n=1), and NTRK3 (58.1%, n=31).

With regard to secondary endpoints, the data showed a median duration of response in 31 evaluable patients, median PFS of 11.2 months in all 54 patients, and median overall survival in all 54 patients of 20.9 months.

Demetri said 11 patients had CNS metastases at baseline and 6 (54.5%) had objective responses with entrectinib, including 3 complete responses. Duration of response was not yet evaluable, and median intracranial PFS was 14.3 months.

The safety review included 68 patients with NTRK fusion-positive tumors. Most adverse events (AEs) were grade 1/2, led by dysgeusia (47.1%), constipation (27.9%), fatigue (27.9%), diarrhea (26.5%), peripheral edema (23.5%), and dizziness (23.5%). The most common grade 3 AEs were weight gain (10.3%) and fatigue (7.4%).

A similar safety profile emerged from an analysis of the overall safety population (n=355).

Demetri GD, Paz-Ares L, Farago AF, et al. Efficacy and safety of entrectinib in patients with NTRK fusion-positive tumors: pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA17.

<<< 2018 ESMO Congress