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Efficacy and Safety of Entrectinib in Patients with NTRK Fusion–Positive Solid Tumors

Conference Correspondent  - ASCO Highlights

Fusions involving the NTRK genes lead to transcription of chimeric tropomyosin receptor tyrosine kinase (TRK) proteins with overexpressed kinase function. Entrectinib is an orally available inhibitor of the tyrosine kinases TRKA/B/C. Entrectinib was found to be effective in patients with NTRK fusion–positive solid tumors in phase 1/2 studies including ALKA, STARTRK-1, and STARTRK-2. Updated data from a larger population with longer follow-up were presented at the 2020 ASCO Annual Meeting.

An integrated analysis of adult patients with advanced/metastatic NTRK fusion–positive solid tumors from 3 phase 1/2 trials was performed on available data through October 31, 2018. Tumors were assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors, version 1.1, at the end of cycle 1 and every 8 weeks thereafter. Primary outcome measures were overall response rate (ORR) and duration of response (DOR). Secondary end points were progression-free survival (PFS), overall survival, efficacy in patients with and without baseline central nervous system (CNS) disease, and safety.

This analysis included 74 evaluable patients with advanced/metastatic NTRK fusion–positive solid tumors. Tumor types included sarcoma, mammary analogue secretory carcinoma, non–small-cell lung cancer (NSCLC), colorectal cancer (CRC), thyroid, breast, neuroendocrine, pancreatic, gynecologic, cholangiocarcinoma, gastrointestinal non-CRC, and neuroblastoma. The median duration of survival follow-up in all patients was 14.2 months (range, 0.1-29.7 months). The BICR ORR was 63.5% (95% confidence interval [CI], 51.5%-74.4%), with 5 complete responses (6.8%). The median BICR DOR was 12.9 months (95% CI, 9.3-not estimable [NE]), and the median BICR PFS was 11.2 months (95% CI, 8.0-15.7). The median overall survival was 23.9 months (range, 16.0 months-NE).

In the 58 patients without investigator-assessed baseline CNS disease, the BICR ORR was 63.8% (95% CI, 50.1%-76.0%). The median BICR DOR in responders was 12.9 months (95% CI, 9.3-NE). Among the 16 patients with CNS disease, the BICR ORR was 62.5% (95% CI, 35.4%-84.8%) and the median BICR DOR in responders was 6.0 months (95% CI, 4.2-NE). Among 16 patients with baseline CNS metastases, the intracranial ORR was 50.0%, including 4 patients with complete response. The median intracranial DOR was 8 months (95% CI, 6.7-NE), and the median intracranial PFS was 8.9 months (95% CI, 5.9-14.3).

Safety was similar to that previously reported for entrectinib. The most common grade 3 or higher treatment-related adverse events were weight gain in 8 (7.1%) patients, anemia in 8 (7.1%) patients, and fatigue in 7 (6.2%) patients.

The investigators conclude that in this updated analysis, which includes more patients and longer follow-up, entrectinib continued to demonstrate clinically meaningful responses in patients with NTRK fusion–positive solid tumors. This was demonstrated both in patients with and without baseline CNS disease.

Source: 2020 ASCO Annual Meeting. Abstract 3605.

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