Japanese First to Approve Entrectinib for NTRK+ Solid Tumors

The first regulatory approval has been granted to entrectinib in Japan. The Japanese&nbsp;Ministry of Health, Labour and Welfare recently&nbsp;approved the agent for the treatment of adult and pediatric patients with&nbsp;<em>NTRK&nbsp;</em>fusion&ndash;positive, advanced recurrent solid tumors.

Sandra Horning, MD

The first regulatory approval has been granted to entrectinib (Rozlytrek) in Japan. The Japanese Ministry of Health, Labour and Welfare (MHLW) recently approved the agent for the treatment of adult and pediatric patients with NTRKfusion—positive, advanced recurrent solid tumors.

The decision was based on data from the phase II STARTRK-2, phase I STARTRK-1, and phase I ALKA-372-001 trials, as well as findings from the phase I/II STARTRK-NG pediatric study. In STARTRK-2, specifically, entrectinib achieved an objective response rate (ORR) of 56.9% in patients withNTRK-positive solid tumors.1The median duration of response was 10.4 months. Among patients with CNS metastases, the intracranial ORR (IC ORR) was 50%.

Japanese regulatory authorities are also in the process of reviewing a potential indication for entrectinib for the treatment of patients withROS1fusion—positive locally advanced or metastatic non–small cell lung cancer (NSCLC).

“Today’s approval of Rozlytrek represents a new chapter in personalized healthcare, applying advanced diagnostics to deliver precision medicines that target cancers based on their molecular drivers instead of their location in the body,” said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development, Roche, the manufacturer of the multikinase inhibitor.

“We are proud to be at the forefront of personalized medicine with this novel treatment approach, and we look forward to working with regulatory agencies around the world to bring Rozlytrek to more patients withNTRKfusion—positive cancer, as well as to those withROS1fusion—positive NSCLC, as soon as possible,” added Horning.

In the United States, the FDA granted a priority review designation in February 2019 to a new drug application (NDA) for entrectinib as a treatment for select adult and pediatric patients withNTRKfusion—positive locally advanced or metastatic solid tumors, as well as patients with metastaticROS1—positive NSCLC. The FDA is expected to decide on the application by August 18, 2019.

The NDA was based on the same 4 trials the MHLW reviewed—STARTRK-2, STARTRK-1, ALKA-372-001, and STARTRK-NG. The studies enrolled patients across 15 countries and 150 clinical trial sites. 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 57.4% ORR in patients withNTRKfusion—positive solid tumors and a median duration of response of 10.4 months.2

The integrated analysis included data of 53 patients withROS1-activating gene fusions and 54 patients with locally advanced or metastaticNTRKfusion—positive solid tumors from the STARTRK-2, STARTRK-1, and 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 withNTRKfusion—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 anNTRK1-/2-/3-,ROS1- orALK-positive gene fusion. The primary endpoint is ORR; secondary endpoints include DOR, time to response, clinical benefit rate, intracranial tumor response, progression-free survival (PFS), 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 withNTRK1/2/3,ROS1orALKgene 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/m2daily.

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,orALKgene 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, orALKfusions.

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 IC ORR was 54.5%, with more than one-quarter of these patients achieving a complete response.

The responses were consistent in several subgroup analyses, including CNS metastases at baseline (50.0%; n = 12) versus none (59.5%; n = 42); andNTRKgene type—NTRK1(59.1%; n = 22),NTRK2(0%; n = 1), andNTRK3(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 77.4% ORR and a median DOR of 24.6 months in patients with locally advanced or metastaticROS1-positive NSCLC; the IC ORR was 55.0%.

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.

Updated results from the STARTRK-NG clinical trial were presented at the 2019 ASCO Annual Meeting. The results showed that entrectinib induced objective responses in 100% of pediatric patients with tumors harboringNTRK1/2/3,ROS1, orALKgene fusions or mutations.3

The multikinase inhibitor induced responses in all 11 patients with CNS and solid tumors withNTRK1/2/3,ROS1, orALKgene fusions, as well as in 1 patient withALK-mutated neuroblastoma. No responses occurred in patients with tumors lacking these genetic aberrations.

Among the 5 responders with CNS tumors, there was 1 complete response (CR; ETV6-NTRK3 gene fusion) and 4 partial responses (PR; 3 confirmed gene fusions [TPR-NTRK1,EEF1G-ROS1,EML1-NTRK2]; 1 unconfirmed gene fusion [GOPC-ROS1]).

Six of the responders had extracranial tumors, including inflammatory myofibroblastic tumors (n = 3), infantile fibrosarcomas (n = 2), and melanoma (n = 1). In this group, there was 1 CR (DCTN1-ALKgene fusion) and 5 PRs (TFG1-ROS1,EML4-NTRK3,KIF5B-ALK, and 2ETV6-NTRK3gene fusions). The other response was a CR in a patient with neuroblastoma harboring a ALKF1174L mutation.


  1. Japan becomes the first country to approve Roche&rsquo;s personalised medicine Rozlytrek. Roche. Published online June 18, 2019. Accessed June 18, 2019. https://bit.ly/2Io1Hoh.
  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. Robinson GW, Gajjar AJ, Gauvain KM, et al. Phase 1/1B trial to assess the activity of entrectinib in children and adolescents with recurrent or refractory solid tumors including central nervous system (CNS) tumors.J Clin Oncol.2019;37(suppl; abstr 10009).