Entrectinib Approved in Europe for NTRK+ Tumors and ROS1+ NSCLC

The European Commission has approved entrectinib for the treatment of adult and pediatric patients ≥12 years of age with solid tumors that harbor an NTRK fusion, as well as for the treatment of adult patients with ROS1-positive, advanced non—small cell lung cancer not previously treated with ROS1 inhibitors.

The European Commission has approved entrectinib (Rozlytrek) for the treatment of adult and pediatric patients ≥12 years of age with solid tumors that harbor an NTRK fusion, as well as for the treatment of adult patients with ROS1-positive, advanced non—small cell lung cancer not previously treated with ROS1 inhibitors.

The approval was based on data from the phase 2 STARTRK-2, phase 1 STARTRK-1, phase 1 ALKA-372-001, and phase 1/1b STARTRK-NG trials. The findings demonstrated that entrectinib showed durable responses across several NTRK gene fusion-positive solid tumors, including sarcoma, NSCLC, salivary mammary analogue secretory carcinoma, secretory and non-secretory breast, thyroid cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, ovarian cancer, endometrial carcinoma, cholangiocarcinoma, gastrointestinal cancers, and neuroblastoma, as well as ROS1-positive NSCLC.

The NTRK fusion indication is specifically for patients who have disease that is locally advanced, metastatic, or where surgical resection is likely to result in severe morbidity; and who have not received a prior NTRK inhibitor and have no satisfactory treatment options.

“We are excited to announce the approval of Rozlytrek in Europe for two indications, bringing patients with NTRK and ROS1 gene fusions a new effective treatment even when their cancer has spread to the brain,” Levi Garraway, MD, PhD, Roche’s chief medical officer and head of Global Product Development, stated in a press release. “This advance represents another important step forward in cancer care by allowing us to treat certain genetic drivers of cancer irrespective of the location of the tumor within the body. Roche is deeply committed to driving personalized healthcare and addressing the high unmet need in patients around the world with rare cancers.”

The FDA approved entrectinib for these indications in August 2019 based on findings from an integrated analysis of the STARTRK-2, STARTRK-1, and ALKA-372-001 trials, which demonstrated a 57% overall response rate (ORR) in patients with NTRK fusion—positive solid tumors.2 The decision was also based on data from the STARTRK-NG study. The trials enrolled patients across 15 countries and 150 clinical trial sites.

The integrated analysis included data for 53 patients with ROS1-activating gene fusions and 54 patients with locally advanced or metastatic NTRK fusion—positive solid tumors from 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 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 2 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 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 1 STARTRK-1 trial (NCT02097810) evaluated a daily continuous dosing schedule of entrectinib in patients with solid tumors with NTRK1/2/3ROS1 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 2 dose of entrectinib to be 400 mg/m2 daily.

Third, the multicenter, open-label, dose-escalation, phase 1 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/CROS1 or ALK gene fusions.

Finally, the phase 1/1b 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.

The pooled findings showed that entrectinib elicited a 63.5% objective response rate (ORR); the median DOR was 12.9 months. In ROS1-positive, advanced NSCLC, entrectinib led to a 73.4% ORR at a minimum of 12 months follow-up, and the median DOR was 16.5 months. In 161 patients who had a minimum of 6 months follow-up, including 29% of patients with CNS metastases at baseline, the ORR was 67.1%.

In patients with CNS metastases at baseline, the intracranial ORR was 62.5% and 77.8% in both NTRK and ROS1 patient populations, respectively.

In pediatric patients, the ORR with entrectinib in all children and adolescents with NTRK gene fusions (n = 5), with 2 of them achieving a complete response (CR). Two patients with primary high-grade tumors in the CNS had objective responses, which included 1 patient with a CR.1

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.


  1. Rozlytrek, Roche’s first tumour-agnostic therapy, approved in Europe for people with NTRK fusion-positive solid tumours and for people with ROS1-positive advanced non-small cell lung cancer. News release. Published August 3, 2020. Accessed August 3, 2020. https://bit.ly/2D86KcW.
  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.