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Entrectinib promising for brain metastases in NTRK fusion-positive solid tumors

Clinical Cancer Research
Reuters Health - 21/02/2022 - Entrectinib, an inhibitor of tropomyosin receptor kinases (TRKA)/B/C and ROS1, showed promise in patients with metastatic NTRK fusion-positive solid tumors with central nervous system (CNS) involvement in an updated analysis.

Entrectinib, marketed as Roslytek by Genentech, is approved in the U.S. and Europe for the treatment of patients ages 12 and up with NTRK fusion-positive solid tumors and adults with ROS1 fusion-positive non-small cell lung cancer.

An earlier integrated analysis of three previous phase I/II trials showed that entrectinib yielded durable overall and intracranial responses in 54 patients with NTRK fusion-positive solid tumors, including rare tumor types, Dr. Christian Rolfo of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai in New York City and colleagues note in Clinical Cancer Research. The current study expands prior reports with additional patients and longer follow-up.

"What is interesting here is the activity in brain metastasis," Dr. Rolfo told Reuters Health by email. "The confirmation of substantial effect on metastases in the brain suggests that entrectinib could address the unmet need of an effective treatment for patients with NTRK fusions and involvement of the CNS."

The efficacy analysis included 121 adults (median age, 57; 51%, female) with 14 tumor types and at least 30 different histologies. Median follow-up was 25.8 months.

The primary endpoints were objective response rate (ORR) and duration of response (DoR); secondary endpoints included progression-free survival (PFS), intracranial efficacy, and safety.

About 61% of patients had a complete (19 patients) or partial (55) response, with a median DoR of 20 months and a median PFS of 13.8 months.

In 11 patients with CNS disease, the intracranial ORR was 63.6% and the median intracranial DoR was 22.1 months.

Safety in adults and children was similar to previous reports. Most treatment-related adverse events (TRAE) were grade 1/2 and manageable or reversible with dose modifications; 8.3% of patients discontinued entrectinib due to TRAE.

The authors conclude, "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...NTRK gene fusions occur at a low frequency (<1%) in common solid tumors but can be found in more than 90% of secretory breast carcinoma, mammary analog secretory carcinoma (MASC), and rare pediatric tumors."

Dr. Rolfo said, "The next steps are to understand better the mechanisms of resistance and how we can overcome them. There are in development several compounds against this target. Another important step is to include liquid biopsy as a tool for diagnosis and monitoring of response in the clinical practice."

"My take-home message is 'Please test your patients!' Although NTRK fusions are rare, our results should encourage broader screening for these fusions in patients with solid tumors, as they may benefit from entrectinib, particularly because the extended life expectancy of these patients may increase the likelihood of metastases in the brain," Dr. Rolfo concluded.

Dr. Arturo Loaiza-Bonilla, CTCA Enterprise Director, Clinical Research Medical Oncologist at Cancer Treatment Centers of America, Atlanta, called the findings "reassuring." He noted, "the significant PFS provides a rationale for its use in this biomarker-enriched population."

"It would be ideal to understand if any specific patients derive more or less benefit than others, including tumor types and emerging genomic variants leading to resistance," he said. "In addition, a disease/cohort comparison with the use of synthetic control arms would be helpful to measure the magnitude of benefit compared to historical well controlled data."

"Individualized, precision oncology is leading the way to optimize our patient's outcomes, particularly once a targetable biomarker is detected," he added. "We should be always in the lookout for this and other genomic drivers by performing next generation sequencing in our patients with advanced cancers; many patients are undergenotyped."

The study was funded by F. Hoffmann-La Roche Ltd. Three coauthors are employees and several received fees from the company.

SOURCE: https://bit.ly/36u59wh Clinical Cancer Research, online February 10, 2022.

By Marilynn Larkin

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