Jun 18, 2019

Anti-Cancer Agent Rozlytrek, Approved for the Treatment of NTRK Fusion Gene Positive Advanced/Recurrent Solid Tumors

  • Rozlytrek has been approved for the treatment of adult and pediatric patients with NTRK fusion gene positive advanced/recurrent solid tumors in Japan ahead of the rest of the world
  • In the STARTRK-2 study, 29 out of 51 patients (56.9%) with NTRK fusion gene positive solid tumors across ten cancer types responded to Rozlytrek

TOKYO, June 18, 2019 -- Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) announced today that the new drug application was approved by the Ministry of Health, Labour and Welfare (MHLW) for a ROS1/TRK inhibitor, Rozlytrek® Capsules 100 mg and 200 mg (generic name: entrectinib) (hereafter, Rozlytrek) for the treatment of NTRK fusion gene positive advanced and recurrent solid tumors. Rozlytrek was granted both Sakigake and orphan drug designations.

“We are pleased that Rozlytrek has been approved in Japan ahead of the rest of the world for the treatment of patients with NTRK fusion gene positive solid tumors, an extremely rarely observed condition, to be used regardless of their age and cancer type. It is a milestone in our pursuit of personalized healthcare,” said Dr. Yasushi Ito, Chugai’s Executive Vice President, Co-Head of Project & Lifecycle Management Unit. “Chugai will promote proper use of Rozlytrek as the most advanced personalized medicine to contribute to the treatment of each patient according to genetic mutations.”

This approval is mainly based on the results from the open-label, multicenter, global phase II study (the STARTRK-2 study). Efficacy was evaluated in 51 adult patients with NTRK fusion gene positive solid tumors, as well as in five pediatric patients with NTRK fusion gene positive solid tumors enrolled in overseas phase I/Ib study (the STARTRK-NG study). In addition, safety was assessed in mainly 339 patients enrolled in three studies consisted of the STARTRK-2 study and two overseas phase I studies (the STARTRK-1 study and the ALKA study).

Efficacy Evaluation
- The response rate per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) estimated by the independent review committee was 56.9% (95%CI: 42.3-70.7%) in the STARTRK-2 study.
- Four out of five patients responded to the drug according to the attending investigator assessment per RECIST v1.1 and Response Assessment in Neuro-Oncology (RANO) criteria in the STARTRK-NG study.

Age Tumor type Assessed by investigator
0 Infantile fibrosarcoma stable disease
3 Epithelioid glioblastoma complete response
4 High-grade glioma partial response
4 Malignant melanoma partial response
4 Infantile fibrosarcoma partial response

Safety Summary

- The most commonly reported adverse reactions included fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, pain, anemia, cognitive disorders, weight increase, vomiting, cough, blood creatinine increase, joint pain, fever and muscle pain.

All adverse events (AE) 205 (99.5) 75 (98.7) 57 (100)
AE of grade 3 or higher 131 (63.6) 51 (67.1) 27 (47.4)
AE leading to death 13 (6.3) 6 (7.9) 1 (1.8)
Serious AE 81 (39.3) 30 (39.5) 24 (42.1)
AE leading to discontinuation 21 (10.2) 6 (7.9) 2 (3.5)
AE leading to withdrawal 93 (45.1) 39 (51.3) 25 (43.9)
AE leading to dose reduction 72 (35.0) 19 (25.0) 5 (8.8)

[Reference information]
Media release issued by Chugai on December 19, 2018
Title: Chugai Files a New Drug Application for a ROS1/TRK Inhibitor Entrectinib for the Treatment of NTRK Fusion-Positive Solid Tumors

About Rozlytrek
Rozlytrek is an oral tyrosine kinase inhibitor that blocks ROS1 (c-ros oncogene 1) and TRK (neurotrophin receptors) family strongly and selectively. It blocks ROS1 and TRK kinase activity, and inhibits proliferation of cancer cells with ROS1 or NTRK gene fusions. Rozlytrek has been granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration and Priority Medicines designation by the European Medicines Agency for the treatment of NTRK fusion gene positive, locally advanced or metastatic solid tumors in adult and pediatric patients who have either progressed following prior therapies or have no acceptable standard therapies. FDA has granted priority review for Rozlytrek for the treatment of NTRK fusion-positive solid tumors and ROS1 fusion-positive non-small cell lung cancer (NSCLC). In Japan, Chugai filed an application for approval of ROS1 fusion gene positive NSCLC in March 2019.

About NTRK fusion gene positive cancer
NTRK fusion gene is an abnormal gene that can be formed by fusing the NTRK genes (NTRK1, NTRK2, NTRK3 encode TRKA, TRKB, TRKC protein, respectively) and other genes (ETV6, LMNA, TPM3, etc.) as a result of chromosomal translocation1-3). The TRK fusion kinase made from NTRK fusion gene is thought to promote cancer cell proliferation. There is very rare expression of NTRK fusion but in various adult and pediatric solid tumors, including infantile fibrosarcoma, glioma, glioblastoma, diffuse intrinsic pontine glioma (DIPG), congenital mesoblastic nephroma, melanoma, inflammatory myofibroblastic tumor (IMT), uterus sarcoma, soft tissue tumor, gastrointestinal stromal tumor (GIST), secretory carcinoma of breast, secretory carcinoma of salivary gland, cancer of unknown primary, lung cancer, colorectal cancer, appendiceal cancer, breast cancer, gastric cancer, ovarian cancer, thyroid cancer, cholangiocarcinoma, pancreatic cancer, head and neck cancer, and various sarcomas.

Trademarks used or mentioned in this release are protected by law.

  1. Martin-Zanca D, Hughes SH, Barbacid M. A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences. Nature 1986; 319(6056): 743-8.
  2. Martin-Zanca D, Oskam R, Mitra G, Copeland T, Barbacid M. Molecular and iochemical Characterization of the Human trk Proto-Oncogene. Molecular and Cellular Biology 1989; 9(1): 24-33.
  3. Lange AM, Lo HW. Inhibiting TRK Proteins in Clinical Cancer Therapy. Cancers 2018; 10: 105.


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