Roche recently announced that the EC has conditionally approved the targeted anticancer drug Rozlytrek for the treatment of pediatric and adult patients aged 12 years and older with neurotrophic tyrosine receptor kinase (NTRK) gene fusion-positive solid tumors, specifically those with locally advanced, metastatic, or surgically resectable disease that would lead to severe illness, who have not previously received NTRK inhibitors, and who have no satisfactory treatment options. In addition, the EC has also approved Rozlytrek for the treatment of adult patients with ROS1-positive, advanced non-small cell lung cancer (NSCLC) who have not previously received ROS1 inhibitors. In the United States, Rozlytrek was approved for these two indications in August 2019.
Roche recently announced that the European Commission (EC) has conditionally approved the targeted anticancer drug Rozlytrek (entrectinib) for the treatment of pediatric and adult patients with neurotrophic tyrosine receptor kinase (NTRK) gene fusion-positive solid tumors, specifically those with locally advanced, metastatic, or surgically resectable disease that would lead to severe illness, who have not previously received NTRK inhibitors, and who have no satisfactory treatment options. Rozlytrek is Roche's first tumor-agnostic therapy, demonstrating durable responses across multiple tumor types, including those that have spread to the brain. In the US and EU, Rozlytrek was previously granted Breakthrough Therapy Designation (BTD) and Priority Therapy Designation (PRIME) for the treatment of NTRK fusion-positive solid tumors, respectively. NTRK gene fusions have been identified in a range of difficult-to-treat solid tumor types, including pancreatic cancer, thyroid cancer, salivary gland cancer, breast cancer, colorectal cancer, and lung cancer.
The EU approved Rozlytrek based on data from multiple clinical studies, including the pivotal Phase II STARTRK-2 study, the Phase I STARTRK-1 study, the Phase I ALKA-372-001 study, and the Phase I/II STARTRK-NG study in pediatric patients. These studies demonstrate that Rozlytrek provides durable responses to a variety of NTRK fusion-positive solid tumors (including sarcoma, non-small cell lung cancer, salivary gland-like secretory carcinoma (MASC), secretory and non-secreting breast cancer, thyroid cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, ovarian cancer, endometrial cancer, cholangiocarcinoma, gastrointestinal cancer, and neuroblastoma) and ROS1-positive NSCLC. The meta-analysis results are as follows:
—Treatment of NTRK fusion-positive solid tumors: The overall response rate (ORR, 74 patients) of Rozlytrek was 63.5%, with objective responses observed in 13 different solid tumor types. The median duration of response (DoR) was 12.9 months (range: 9.3–not reached).
—Treatment of ROS1-positive advanced NSCLC: The overall response rate (ORR; 94 patients, median follow-up 12 months) of Rozlytrek was 73.4%, with a median DoR of 16.5 months (range: 14.6 months–28.6 months). In 161 patients followed for 6 months, including 29% with central nervous system (CNS) metastases, the ORR was 67.1%.
—Patients with baseline CNS metastases: All patients showed a response to Rozlytrek, with intracranial ORRs of 62.5% and 79.2% in the NTRK and ROS1 patient populations, respectively.
—Treatment of pediatric patients: Rozlytrek shrank tumors in all children and adolescents with NTRK gene fusions (n=5) (ORR=100%), with 2 achieving complete remission (CR=40%). Objective responses were observed in 2 patients with primary high-grade tumors, with 1 achieving a complete remission.
Rozlytrek is well tolerated, with the most common adverse reactions including fatigue, constipation, altered taste (halitosis), swelling (edema), dizziness, diarrhea, nausea, neurological disturbances (sensory disturbances), shortness of breath (dyspnea), anemia, weight gain, increased serum creatinine, pain, cognitive impairment, vomiting, cough, and fever.
The approval of Rozlytrek demonstrates the value of combining genomic testing with precision medicine to provide personalized treatment options for patients with rare and difficult-to-treat cancers. Based on genomic testing, Rozlytrek will provide an effective first-line therapy for patients with NTRK or ROS1 gene fusions in many cancers, including those with brain metastases.
Notably, Rozlytrek is the third approved "cancer-agnostic" anticancer drug based on a common biomarker for different tumor types rather than the tissue type of tumor origin. The other two drugs approved for "cancer-agnostic" indications are: (1) Merck's anti-PD-1 therapy Keytruda (pembrolizumab), approved in 2017 for the treatment of microsatellite high instability (MSI-H) or mismatch repair deficient (dMMR) tumors, and approved in June 2020 for the treatment of solid tumors with high tumor mutation burden (TMB-H); (2) Bayer's targeted anticancer drug Vitrakvi (larotrectinib), approved in 2018 for the treatment of NTRK gene fusion tumors.
The active pharmaceutical ingredient of Rozlytrek is entrectinib, a selective tyrosine kinase inhibitor (TKI) that targets locally advanced or metastatic solid tumors carrying NTRK1/2/3 (encoding TRKA/TRKB/TRKC) or ROS1 gene fusions. Entrectinib can cross the blood-brain barrier, blocking the kinase activity of TRKA/B/C and ROS1 proteins, leading to the death of cancer cells carrying ROS1 or NTRK gene fusions. Entrectinib is effective against both primary and metastatic CNS diseases and has no adverse off-target activity. Roche is currently investigating the potential of entrectinib for treating a variety of solid tumors, including NSCLC, pancreatic cancer, sarcoma, thyroid cancer, salivary gland cancer, gastrointestinal stromal tumors, and cancer of unknown primary origin (CUP).
