Roche's Tumor-Agnostic Therapy Rozlytrek (Entrectinib) Receives Conditional Marketing Authorization from European Commission

Compiled by Keke

On August 3, Roche announced that the European Commission (EC) had granted conditional marketing authorization for Rozlytrek (entrectinib) for adult and pediatric patients aged 12 years and older with solid tumors harboring neurotrophic tyrosine receptor kinase (NTRK) gene fusions. This indication applies to patients with locally advanced or metastatic solid tumors, or those for whom surgical resection may lead to severe complications, who have not previously received an NTRK inhibitor and have no satisfactory treatment options. Meanwhile, the EC also approved Rozlytrek for adult patients with ROS1-positive advanced non-small cell lung cancer (NSCLC) who have not previously been treated with a ROS1 inhibitor.

Previously, Rozlytrek was granted the Priority Medicines (PRIME) designation by the European Medicines Agency for the treatment of adult and pediatric patients with locally advanced or metastatic solid tumors harboring NTRK fusions.

It is reported that this approval was based on the integrated analysis results from the pivotal Phase 2 STARTRK-2 study, the Phase 1 STARTRK-1 study, and the Phase 1 ALKA-372-001 study, as well as data from the Phase 1/2 STARTRK-NG study. These studies enrolled patients across 15 countries and more than 150 clinical trial sites. The safety and efficacy of Rozlytrek were evaluated through an integrated analysis of 504 patients from these four trials. The studies demonstrated durable responses to Rozlytrek in various NTRK gene fusion-positive solid tumors, including sarcoma, non-small cell lung cancer (NSCLC), mammary analogue secretory carcinoma (MASC) of the salivary gland, secretory and non-secretory breast cancer, thyroid cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, ovarian cancer, endometrial cancer, cholangiocarcinoma, gastrointestinal tumors, and neuroblastoma, as well as in ROS1-positive NSCLC.

Specific results analysis shows:

In patients with NTRK fusion-positive, locally advanced or metastatic solid tumors, Rozlytrek reduced tumor size in more than half of the patients (ORR=63.5%; N=74), and objective responses were observed across 14 tumor types (median duration of response [DoR]=12.9 months [9.3 months–not reached], N=21 out of 47 patients defined by ORR).

In patients with ROS1-positive advanced NSCLC, Rozlytrek reduced tumor size in 73.4% of patients (ORR; N=94, with at least 12 months of follow-up), with a median DoR of 16.5 months [14.6–28.6 months]. In 161 patients with at least 6 months of follow-up, including 29% of patients with central nervous system (CNS) metastases, an ORR of 67.1% was observed.

In patients with central nervous system metastases, objective responses to Rozlytrek were observed, with intracranial ORRs of 62.5% and 77.8% in patients harboring NTRK and ROS1 gene alterations, respectively.

In pediatric patients, Rozlytrek reduced tumors in all children and adolescents with NTRK gene fusions (N=5) (as reflected by the ORR), with two patients achieving complete response (CR). Two patients with primary high-grade CNS tumors had objective responses, including one patient who achieved CR.

Currently, NTRK gene fusions have been identified across a spectrum of solid tumor types. While the prevalence exceeds 90% in certain rare cancers, it remains below 1% in more common malignancies such as lung cancer and colorectal cancer. NTRK fusion-positive tumors arise when NTRK1, NTRK2, or NTRK3 genes fuse with other partner genes, resulting in altered TRK proteins that activate signaling pathways involved in the proliferation of certain cancer types. NTRK gene fusions are present within tumors irrespective of the tissue or organ of origin.

ROS1 is a tyrosine kinase that plays a crucial role in regulating cell growth and proliferation. When ROS1 gene fusions occur, cancer cells grow and proliferate in an uncontrolled manner. Blocking this aberrant signaling leads to tumor cell shrinkage or death. ROS1 gene fusions occur in 1%–2% of patients with non-small cell lung cancer (NSCLC).

Biomarker testing for NTRK and ROS1 gene fusions is the most effective method to determine which patients are best suited for Rozlytrek treatment. It is reported that Roche is developing a companion diagnostic assay to help identify patients with NTRK and ROS1 gene fusions.

Rozlytrek is a selective tyrosine kinase inhibitor designed to inhibit the kinase activity of TRKA/B/C and ROS1 proteins, whose activating fusions can promote the proliferation of certain types of cancer. The drug received accelerated approval from the U.S. FDA in August 2019 for the treatment of adult and pediatric patients aged 12 years and older with solid tumors, as well as adults with ROS1-positive metastatic non-small cell lung cancer (NSCLC). In June 2019, Japan’s Ministry of Health, Labour and Welfare approved Rozlytrek for the treatment of adult and pediatric patients with NTRK fusion-positive, advanced or recurrent solid tumors, and subsequently approved it in February 2020 for the treatment of ROS1-positive NSCLC. To date, Rozlytrek has also been approved by health regulatory authorities in Australia, Canada, Israel, New Zealand, South Korea, and other regions.

Reference source: 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