FDA Approves Entrectinib for NTRK+ Tumors and ROS1+ NSCLC

The FDA has granted an accelerated approval to entrectinib for the treatment of adult and pediatric patients ≥12 years of age with solid tumors that harbor a NTRK fusion, and has also approved the agent for the treatment of adults with ROS1-positive, metastatic non–small cell lung cancer.

The FDA has granted an accelerated approval to entrectinib (Rozlytrek) for the treatment of adult and pediatric patients ≥12 years of age with solid tumors that harbor an NTRK fusion, and has also approved the agent for the treatment of adults with ROS1-positive, metastatic non—small cell lung cancer (NSCLC).

The NTRK fusion indication is specific to patients who have a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed on therapy or have no alternative treatments.

The approval is based on findings from an integrated analysis of the phase II STARTRK-2, phase I STARTRK-1, and the phase I ALKA-372-001 trials, which demonstrated a 57% overall response rate (ORR) in patients with NTRK fusion—positive solid tumors.2 The decision is also based on data from the phase I/Ib STARTRK-NG study. The trials enrolled patients across 15 countries and 150 clinical trial sites.

“We are in an exciting era of innovation in cancer treatment as we continue to see development in tissue agnostic therapies, which have the potential to transform cancer treatment. We’re seeing continued advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine,” FDA Acting Commissioner Ned Sharpless, MD, stated in a press release. “Using the FDA’s expedited review pathways, including breakthrough therapy designation and accelerated approval process, we’re supporting this innovation in precision oncology drug development and the evolution of more targeted and effective treatments for cancer patients. We remain committed to encouraging the advancement of more targeted innovations in oncology treatment and across disease types based on our growing understanding of the underlying biology of diseases.”

The integrated analysis included data of 53 patients with ROS1-activating gene fusions and 54 patients with locally advanced or metastatic NTRK fusion—positive solid tumors from the phase II STARTRK-2, phase I STARTRK-1 and phase I ALKA-372-001 trials—comprising 10 tumor types with more than 19 histopathologies. Tumor types included breast cancer, cholangiocarcinoma, colorectal cancer, gynecological cancer, neuroendocrine tumors, NSCLC, salivary gland cancer, pancreatic cancer, sarcoma and thyroid cancer.

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.

In the international, multicenter, open-label, ongoing phase II STARTRK-2 basket trial (NCT02568267), investigators are enrolling 300 patients with solid tumors that harbored an NTRK1-/2-/3-, ROS1- or ALK-positive gene fusion. The primary endpoint is ORR; secondary endpoints include duration of response (DOR), time to response, clinical benefit rate, intracranial tumor response, progression-free survival (PFS), central nervous system (CNS) PFS, and overall survival (OS).

The multicenter, open-label, dose-escalation, phase I STARTRK-1 trial (NCT02097810) evaluated a daily continuous dosing schedule of entrectinib in patients with solid tumors with NTRK1/2/3, ROS1 or ALK gene fusions in the United States and South Korea. Investigators evaluated the safety and tolerability of entrectinib via a standard dose escalation and determined the recommended phase II dose of entrectinib to be 400 mg/m2 daily.

Third, the multicenter, open-label, dose-escalation, phase I ALKA-372-001 study (NCT02097810) evaluated an intermittent and continuous entrectinib dosing schedule in patients in Italy with advanced or metastatic solid tumors with TRKA/B/C, ROS1 or ALK gene fusions.

Finally, the phase I/Ib dose-escalation and dose-expansion STARTRK-NG study is investigating the safety and efficacy of entrectinib in pediatric and adolescent patients with no curative first-line treatment option, recurrent or refractory extracranial solid tumors or primary CNS tumors, with or without TRK, ROS1 or ALK fusions.

Results from the integrated analysis showed that the responses were observed across 10 solid tumor types, including in patients with and without CNS metastases at baseline. Moreover, the intracranial ORR (IC ORR) was 54.5%, with more than one-quarter of these patients achieving a complete response. The median DOR ranged from 2.8 to 26.0+ months.

The responses were consistent in several subgroup analyses, including 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). Furthermore, the median PFS was 11.2 months and the median OS was 20.9 months.

Additionally, the pooled findings from STARTRK-2, STARTRK-1, and ALKA-372-001, showed that entrectinib demonstrated a 78% ORR and a median DOR of 24.6 months in patients locally advanced or metastatic ROS1-positive NSCLC; the IC ORR was 55.0%. Moreover, the DOR ranged from 1.8 to 36.8+ months.

Regarding safety, adverse events (AEs) with entrectinib was consistent with that seen in prior studies. The most commonly reported AEs included fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, pain, anemia, cognitive disorders, weight increased, vomiting, cough, blood creatinine increase, arthralgia, pyrexia, and myalgia.

Results of the STARTRK-NG trial were presented at the 2018 ASCO Annual Meeting, demonstrating that 3 pediatric and young adult patients with advanced, previously treated CNS tumors with targeted gene fusions—DCTN1-ALK inflammatory myofibroblastic tumors (IMT), TFG-ROS1 IMT, and EML4-NTRK3 infantile fibrosarcoma—responded to entrectinib.3 Based on these data, investigators identified the recommended phase II dose for children, adolescents, and young adults with solid tumors at 550 mg/m2 of daily entrectinib.

In June 2018, entrectinib was approved by the Japan’s Ministry of Health, Labour and Welfare for the treatment of adult and pediatric patients with NTRK fusion—positive, advanced recurrent solid tumors.


  1. FDA Approves Third Oncology Drug That Targets a Key Genetic Driver of Cancer, Rather Than a Specific Type of Tumor. FDA. Published August 15, 2019. https://bit.ly/2TDORX1. Accessed August 15, 2019.
  2. 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.
  3. Desai AV, Brodeur GM, Foster J, et al. Phase I study of entrectinib (RXDX-101), a TRK, ROS1, and ALK inhibitor, in children, adolescents, and young adults with recurrent or refractory solid tumors. J Clin Oncol. 2018;36 (suppl;abstr 10536). doi: 10.1200/JCO.2018.36.15_suppl.10536.