Roche's Rozlytrek Nears EU Approval as Tumor-Agnostic Therapy for NTRK Fusion-Positive Solid Tumors and ROS1-Positive NSCLC

Jun 03, 2020 15:15 CST Updated 15:05

Roche

Oncology Drug Research, Development, and Manufacturing

European Medicines Agency

The European Medicines Agency (EMA) is a decentralized agency of the European Union (EU), located in London. It began operations in 1995. The agency is responsible for the scientific evaluation, supervision, and safety monitoring of medicines developed by pharmaceutical companies for use in the EU. By ensuring that all medicines available on the EU market are safe, effective, and of high quality, the EMA protects public and animal health in the 28 EU Member States and countries of the European Economic Area.

Committee for Medicinal Products for Human Use

Committee for Medicinal Products for Human Use (CHMP)The Committee for Medicinal Products for Human Use (CHMP) is the committee within the European Medicines Agency (EMA) responsible for human medicines. The CHMP replaced the former Committee for Proprietary Medicinal Products (CPMP) in May 2004.The CHMP plays a vital role in the authorization of medicines in the European Union (EU). In the centralized procedure, the CHMP is responsible for: 1) conducting initial assessments of marketing authorization applications across the EU; assessing modifications or extensions to existing marketing authorizations (“variations”); considering recommendations from the Agency’s Pharmacovigilance Risk Assessment Committee regarding the safety of medicines on the market, and, where necessary, advising the European Commission to amend the marketing authorization of a medicinal product, or to suspend or withdraw it from the market.The CHMP also evaluates medicines authorized at the national level that are referred to the EMA, with the aim of maintaining a harmonized position throughout the EU.Furthermore, the CHMP and its working groups promote the development of medicines and pharmaceutical regulation by: providing scientific advice to companies researching and developing new medicines; developing scientific and regulatory guidelines to assist pharmaceutical companies in preparing marketing authorization applications for human medicines; and collaborating with international partners to harmonize regulatory requirements.

June 03, 2020 /BioValleyBIOON/ -- Roche recently announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion, recommending conditional approval of the targeted anticancer drug Rozlytrek (entrectinib) 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, this applies to patients with locally advanced or metastatic disease, or those for whom surgical resection would likely result in severe morbidity, who have not previously received an NTRK inhibitor and have no satisfactory therapeutic alternatives. Furthermore, the CHMP also recommended approving Rozlytrek for the treatment of adult patients with ROS1-positive advanced non-small cell lung cancer (NSCLC) who have not previously received a ROS1 inhibitor.

The CHMP opinion will now be submitted to the European Commission (EC) for review, which is expected to make a final decision within the next two months. Previously, the EMA had granted Rozlytrek Priority Medicines (PRIME) status for the treatment of NTRK fusion-positive solid tumors. NTRK gene fusions have been identified in a range of hard-to-treat solid tumor types, including pancreatic cancer, thyroid cancer, and salivary gland cancer,Breast Cancer, colorectal cancer and lung cancer.

In the United States, Rozlytrek had previously been granted Breakthrough Therapy Designation (BTD) for the treatment of NTRK fusion-positive solid tumors; the drug was approved in August 2019FDAAccelerated Approval: (1) For the treatment of pediatric and adult patients aged 12 years and older with advanced solid tumors harboring neurotrophic tyrosine receptor kinase (NTRK) gene fusions who have no satisfactory alternative treatments. (2) For the treatment of adult patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC).

Levi Garraway, M.D., Chief Medical Officer and Head of Global Product Development at Roche, stated, “Once approved, Rozlytrek will become Roche’s first tumor-agnostic (i.e., independent ofTumortumor-agnostic (“pan-cancer”) therapy. Thus, this milestone marks a new advance in personalized medicine. Based on genomic testing, Rozlytrek will provide an effective first-line treatment for patients with NTRK or ROS1 gene fusions across many cancer types, including those who have already developed brain metastases.”

Rozlytrek is the third marketed drug based on commonalities across different types of tumorsBiomarkerrather than anticancer drugs based on the tissue of tumor origin, marking a new paradigm in “tumor-agnostic” cancer drug development. Two other drugs approved for “tumor-agnostic” indications are: (1) In 2017, Merck’s Keytruda (pembrolizumab) was approved for the treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR)Tumor; (2) In 2018,BayerTargeted Anti-Cancer Drug Vitrakvi (Larotrectinib) Approved for the Treatment of NTRK Gene FusionsTumor。

The active pharmaceutical ingredient of Rozlytrek is entrectinib, a selective tyrosine kinase inhibitor (TKI) indicated for the targeted treatment of locally advanced or metastatic solid tumors harboring NTRK1/2/3 (encoding TRKA/TRKB/TRKC) or ROS1 gene fusions. Entrectinib can cross the blood-brain barrier and inhibit the kinase activity of TRKA/B/C and ROS1 proteins, leading to the death of cancer cells with ROS1 or NTRK gene fusions. Entrectinib demonstrates efficacy against both primary and metastatic central nervous system (CNS) diseases, without adverse off-target activity. Currently, Roche is investigating the potential of entrectinib in treating various solid tumors, including non-small cell lung cancer (NSCLC), pancreatic cancer, sarcoma, thyroid cancer, salivary gland cancer, gastrointestinal stromal tumors, and cancers of unknown primary (CUP).

The CHMP’s positive opinion was 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 conducted in pediatric patients. In the comprehensive analysis, the efficacy of Rozlytrek in treating various types of solid tumors was evaluated. The results showed:

—Treatment of NTRK fusion-positive solid tumors (n=74): The overall response rate (ORR) for Rozlytrek was 63.5%. Objective responses to Rozlytrek were observed across 14 different types of solid tumors, with a median duration of response (DoR) of 12.9 months (range: 9.3 months to not reached). Among the 31 patients who achieved a response, 61% had a duration of response ≥9 months. Importantly, treatment responses to Rozlytrek were also observed in patients with baseline central nervous system (CNS) metastases, with an intracranial response rate of 50%.

— Treatment of ROS1-positive advanced NSCLC: The overall response rate (ORR) for Rozlytrek was 73.4% (median follow-up of 12 months in 94 patients), with a median duration of response (DoR) of 16.5 months (range: 14.6–28.6 months). Among 161 patients with at least 6 months of follow-up, including 29% with central nervous system (CNS) metastases, the ORR was 67.1%.

—Responses to Rozlytrek treatment were observed in both NTRK- and ROS1-positive patient populations with baseline CNS metastases.

— In pediatric patients, Rozlytrek reduced tumor size in all children and adolescents with NTRK gene fusions (n=5) (ORR=100%), with 2 patients achieving complete response (CR=40%). Two cases had primary high-gradeTumorObjective responses were observed in all patients, including one complete response.

In these studies, Rozlytrek was evaluated for the treatment of various typesTumor, including: sarcoma, non-small cell lung cancer, 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 cancers, and neuroblastoma.

Rozlytrek was well tolerated, with the most commonAdverse ReactionsIncluding: fatigue, constipation, taste alterations (halitosis), swelling (edema), dizziness, diarrhea, nausea, neurological disorders (sensory disturbances), shortness of breath (dyspnea),Anemia, weight gain, increased serum creatinine, pain, cognitive impairment, vomiting, cough, fever. (Bioon.com)

Original source: CHMP recommends EUapproval of Roche’s Rozlytrek for people with NTRK fusion-positive solid tumours and for people with ROS1-positive, advanced non-small cell lung cancer