Entrectinib May Be Effective, Well Tolerated Against ROS1-, NTRK-Positive Cancers


Integrated analyses showed entrectinib to be both effective and well tolerated in patients with rare ROS1 and NTRK gene fusions.

Treatment with entrectinib (Rozlytrek) induced durable and clinically meaningful responses in over three-fourths of patients with ROS1 fusion-positive non-small cell lung cancer (NSCLC), and half of patients with NTRK fusion-positive solid tumors, according to 2 studies published in Lancet Oncology.1,2

The studies, which presented an integrated analysis of 3 ongoing phase I or II clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), showed that 41 (77%; 95% CI, 64–88) of 53 patients with ROS1 fusion-positive NSCLC had an objective response, while 31 (57%; 95% CI, 43.2–70.8) of 54 patients with NTRK fusion-positive solid tumors achieved an objective response. Both studies showed entrectinib to be well tolerated with a manageable safety profile.

The FDA had previously granted accelerated approval to entrectinib for both NTRK fusion-positive solid tumors and ROS1 fusion-positive NSCLC on August 15, 2019, based on the early promise shown in all 3 trials.


ROS1-Positive NSCLC

The ROS1 fusion-positive study was led by Alexander Drilon, MD, of the Memorial Sloan Kettering Cancer Center in New York. Primary endpoints for the analysis were objective response (defined as the proportion of patients with a complete or partial response), and duration of response, measured from the date of first objective response to first documentation of disease progression. Progression-free survival (PFS) was listed as a key secondary endpoint.

The efficacy analysis population included 53 patients with ROS1 fusion-positive NSCLC. In addition to the demonstrated response rate of 77%, the median duration of response was 24.6 months (95% CI, 11.4–34.8), with a median PFS of 19.0 months (95% CI, 12.2–36.6).1

“These outcomes exceed the activity of first-line chemotherapy and immunotherapy in NSCLC, supporting the current standard of care for ROS1 fusion-positive NSCLC,” noted the researchers. “Despite the fact that study populations in this pooled analysis were enriched with patients with poorer prognoses, the proportion of patients having a response and median progression-free survival with entrectinib remained similar to the outcomes previously achieved with crizotinib (Xalkori).”

In the safety-evaluable population, 79 (59%) of 134 patients experienced grade 1 or 2 treatment-related adverse events (TRAEs), 46 (34%) experienced grade 3 or 4 TRAEs, with weight gain (8%) and neutropenia (4%) being the most common. Fifteen (11%) patients experienced serious TRAEs, with nervous system disorders (3%) and cardiac disorders (2%) occurring most commonly.

“The drug has shown both systemic and intracranial activity,” wrote the researchers. “The safety profile is favorable, making it amenable to long-term dosing.”


NTRK-Positive Solid Tumors

The NTRK fusion-positive analysis was led by Robert C. Doeblele, MD, Phd, director of the University of Colorado Cancer Center Thoracic Oncology Research Initiative, utilizing the same primary and secondary endpoints as the ROS1 analysis. Fifty-four patients with advanced or metastatic NTRK fusion-positive solid tumors were included in the efficacy-evaluable population. Of the 31 patients to show an objective response, 4 (7%) were complete responses, with the remaining 27 (50%) demonstrating a partial response. The median duration of response was 10.4 months (95% CI, 7.1 to not estimable) and median PFS was 11.2 months (95% CI, 8.0-14.9).2

“These results are especially encouraging for patients with tumor types with few treatment options such as sarcomas,” noted the researchers. “We show that entrectinib is active in multiple tumor types, showing both systemic anti-tumor activity and activity in CNS metastases.”

The median number of entrectinib cycles received was 9.5, with most grade 1 or 2 TRAEs being short-term and reversible. The most commonly reported grade 3 or 4 TRAE was weight gain (7 [10%] of 68), and anemia (8 [12%]). Nervous system disorders occurred in 3 (4%) patients.

“Overall, the safety profile of entrectinib…was consistent with that previously reported with other drugs of the same class,” wrote the researchers.

Data cutoff for both studies was May 31, 2018, and the trials are ongoing. While the additional data left to be collected will help improve strategies for identifying patients who might benefit from tyrosine kinase inhibitors, both studies called out the need to more routinely test for both ROS1 and NTRK fusions in order to broaden the therapeutic options for patients with these rare gene fusions.



1. Drilon A, Siena S, Dziadziuszko R, et al. Entrectinib in ROS1 fusion-positive, non-small-cell lung cancer: integrated analysis of three phase 1–2 trials. Lancet Oncol 2019 published online Dec 11. https://doi.org/10.1016/S1470- 2045(19)30690-4.

2. Doebele RC, Drilon A, Paz-Ares L, et al Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1–2 trials. Lancet Oncol 2019; published online Dec 11. https://doi.org/10.1016/S1470-2045(19)30691-6.

3.Lassen U. Entrectinib for ROS1 fusion-positive and NTRK fusion-positive solid tumors. Lancet Oncol 2019; published online Dec 11. https://doi.org/10.1016/S1470-2045(19)30789-2.

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