Entrectinib Shows Intracranial Response in NTRK+ Tumors and CNS Metastases | OncLive

Entrectinib Shows Intracranial Response in NTRK+ Tumors and CNS Metastases

September 20, 2020

Entrectinib demonstrated durable intracranial activity in a small subset of patients with NTRK fusion–positive solid tumors and baseline central nervous system metastases.

Entrectinib (Rozlytrek) shows durable intracranial activity in a small subset of patients with NTRK- fusion-positive solid tumors and baseline CNS metastases, according to a presentation at the 2020 ESMO Virtual Congress.

In this analysis of patients with NTRK fusion-positive, TRK inhibitor-naïve solid tumors treated with entrectinib, intracranial objective response rate (ORR) was 50% in all patients with baseline metastases and median intracranial duration of response (DOR) was 8.0 months. Median intracranial progression-free survival (PFS) was 8.9 months.1

“The results of this updated analysis confirm entrectinib is associated with clinically meaningful and durable intracranial responses in patients with NTRK fusion-positive tumors and baseline CNS metastases,” said Thomas John, MBBS, PhD, associate professor, senior clinical research fellow at the Olivia Newton-John Cancer Research Institute in Victoria, Australia.

NTRK gene fusions are clinically actionable oncogenic drivers in solid tumors. CNS metastases are diagnosed in 10% to 30% of solid tumors and associated with poor outcome. Entrectinib is a potent inhibitor of TRK, ROS1, and ALK tyrosine kinases designed to cross the blood-brain barrier and achieve therapeutic levels in CNS.

Entrectinib is an oral medication that was approved, to treat adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1-positive, as well as adult and pediatric patients 12 years of age and older with solid tumors that have a NTRK gene fusion.2

In this analysis, intracranial tumor assessments were performed at the end of week 4 and every 8 weeks thereafter and were evaluated by blinded independent central review (BICR) using RECIST v1.1. Study endpoints were intracranial ORR, intracranial DOR, and intracranial PFS.

John previously presented data on 54 patients, which showed an intracranial ORR of 55% and non-estimable intracranial DOR. This updated analysis was conducted to confirm these findings in a larger cohort of patient.

In this analysis, data were analyzed for 74 patients with metastatic NTRK fusion-positive, TRK-inhibitor-naïve solid tumors from 3 phase 1 and phase 2 trials: 1 patient from ALKA-372-001 (EudraCT 2012-000148-88), 2 patients from the dose-escalation STARTRK-1 (NCT02097810), and 71 patients from the STARTRK-2 (NCT02568267).

The data cut off for this analysis was October 31, 2018. This is a very heavily pre-treated population, and the majority had ECOG performance status. Of the 74 patients, 19 patients had investigator-assessed CNs metastases at baseline, and 16 were confirmed to have CNS metastases at baseline per BICR of 5 different tumor types, including NSCLC (8), thyroid (4), sarcoma (1), salivary (1), and breast (1). Of these 16 patients, 8 had measurable CNS metastases and were evaluable for response.

Entrectinib lead to high intracranial ORRs: 50.0% (95% CI, 24.7-75.4) in the analysis set of 16 patients and 62.5% (95% CI, 24.5-91.5) in the 8 patients with measurable CNS disease. The median intracranial DOR in the set of 16 patients was 8.0 months (95% CI, 6.7-NE) and was not estimable in measurable patients with CNS metastases.

Among patients who had baseline measurable disease, nearly all patients responded, John said during his presentation. The complete response was high, with 4 patients have a complete response, and 4 patients achieving a partial response. “Entrectinib has high intracranial activity across different tumor types,” he said.

Only 1 patient had disease progression. The patient with thyroid cancer had a reduction in the target lesion but had progression in non-target lesions, John said.

The PFS in the set of 16 patients was 8.9 months (95% CI, 5.9-14.3) and 10.1 months (95% CI, 2.8-NE) in the set of 8 patients who had measurable baseline disease.

There was a low rate of CNS disease progression. Only 3 out of 74 patients evaluated showed evidence of detected, scan-confirmed CNS progression. “This suggests that entrectinib may provide protection against the development of CNS metastases including some of these patients who had non-small cell lung cancer and breast cancer where there is a high rate of CNS progression,” John said.

Entrectinib was generally well tolerated in patients both with and without baseline CNS metastases, said John. In patients who had any type of neurologic adverse effects (AEs), the most common effects were dysgeusia, dizziness, and paresthesia. The safety population that was evaluated included all patients from these 3 studies and included 504 patients with NTRK, ALK, and ROS1 who received at least 1 dose of entrectinib.

References

  1. John T. Intracranial efficacy of entrectinib in patients with NTRK fusion-positive solid tumours and baseline CNS metastases. Oral presentation European Society of Medical Oncology (EMSO) Virtual Congress 2020. September 17-21. Abstract #3640 https://bit.ly/35Q0r9K
  2. Rozlytrek. Prescribing information. Genentech. Revised August 2019. Accessed September 20, 2020. https://bit.ly/3mCrifs

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