Health Canada approves Rozlytrek® (entrectinib) for NTRK gene fusion-positive solid tumours in locally advanced or metastatic patients(1)

Data show more than half of trial patients across all 10 tumour types studied had responses to treatment,² including in patients where cancer has spread to the central nervous system³

MISSISSAUGA, ON, April 28, 2020 /CNW/ - Hoffmann-La Roche Limited (Roche Canada) is pleased to announce that on February 10, 2020, Health Canada, under the Notice of Compliance with Conditions (NOC/c) policy, approved Rozlytrek^® (entrectinib) for adult patients with unresectable locally advanced or metastatic extracranial solid tumours, including brain metastases, that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, and with no satisfactory treatment options.⁴ 

Rozlytrek is Roche's first tumour-agnostic treatment which works by targeting the underlying gene mutation (NTRK) which is responsible for driving oncogenesis or the growth of cancer cells in tumours.⁵ 

Health Canada's Notice of Compliance with Conditions policy provides conditional authorization for new drugs with promising evidence of clinical effectiveness, for patients suffering from serious, life-threatening or severely debilitating diseases or conditions for which no drug is presently marketed in Canada or for which a significant increase in efficacy or a significant decrease in risk is demonstrated in relation to an existing drug marketed in Canada.⁶ Prior to authorization, the sponsor must undertake to design, carry out and report on confirmatory trials to verify the clinical benefit of the drug.

Rozlytrek was studied in NTRK gene fusion-positive tumours including but not limited to those located in the lung, head and neck, breast, colorectal and connective tissue (sarcomas).⁷ NTRK gene fusions are found in 90% of some rare cancers and about 1% of common cancers.⁸ In clinical studies, the presence of NTRK gene fusions has been shown to cause the formation of highly aggressive tumours.⁹ Moreover, NTRK gene fusions can be found in lung cancers and melanomas which have the tendency to spread or metastasize to the central nervous system¹⁰ and ultimately have a poorer prognosis.¹¹

"Precision medicine involves identifying novel biomarkers which would allow a more personalized delivery of cancer therapeutics," Dr. Khashayar Esfahani, Assistant Professor of Oncology, McGill University. "The approval of Rozlytrek allows physicians to target a specific mutation in tumours, regardless of its location in the body, which translates to unparalleled anti-cancer responses otherwise not attainable with historical treatments such as chemotherapy for these types of tumours." 

The presence of NTRK gene fusions in patients are confirmed by physicians through next generation sequencing (NGS) tests such as comprehensive genomic profiling (CGP).¹² Once the NTRK gene fusion is identified in a patient, treatments like Rozlytrek can specifically target it, inhibiting the growth of cancerous cells in multiple tumour types.¹³ 

"This approval is good news as it opens up more options for patients. We are moving beyond medications for specific types of tumours and are now able to test anyone with many different kinds of cancer who might have the NTRK gene fusion and then deliver more targeted treatments," said Dr. Tracy Stockley, Head, Division of Clinical Laboratory Genetics, University Healthcare Network. "Now even more patients are able to be considered for molecularly guided therapy including those who previously had very limited options."

This conditional approval is based on an integrated analysis from three open-label clinical trials evaluating Rozlytrek in the treatment of extracranial NTRK gene fusion-positive solid tumours in adult patients over 18 years of age, some of which entered the study with brain metastasis.¹⁴ Rozlytrek demonstrated objective responses in more than half of people with NTRK gene fusion-positive, locally advanced or metastatic solid tumours, including those with central nervous system (CNS) metastases at baseline.¹⁵

"The Canadian Cancer Survivor Network (CCSN) is very pleased that Roche's first tumour agnostic treatment has been approved by Health Canada," said Jackie Manthorne, President & CEO of CCSN. "This type of precision medicine provides cancer patients with important additional treatment options for cancer, which to date have not had satisfactory treatments."

About the integrated analysis
The integrated analysis included data from three open-label clinical trials in patients with advanced cancer contributed to a pre-specified integrated efficacy analysis evaluating Rozlytrek in the treatment of extracranial NTRK fusion-positive solid tumours in adult patients ≥ 18 years of age ALKA, n=1; STARTRK-1, n=2; and STARTRK-2, n=51.¹⁶ A total of 52 (96%) patients had an NTRK gene fusion detected by NGS and 2 (4%) had an NTRK gene fusion detected by other nucleic acid-based tests.¹⁷ Rozlytrek was studied in several solid tumour types, including breast, cholangiocarcinoma (bile duct), colorectal, gynaecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers.¹⁸

The primary efficacy outcome measures in the integrated analyses were objective response rate (ORR) and duration of response (DoR).¹⁹ Results from the analysis found that Rozlytrek demonstrated objective responses in 57% of patients (objective response rate [ORR] =57%; N=54), and responses were observed across 10 tumour types.²⁰ Duration of response [DoR] ranged from 1.9 to 20.0+ months (N=31 out of 54).²¹ 

Secondary efficacy outcome measures included intracranial (IC) ORR and IC-DOR in patients presenting with measurable CNS metastases at baseline.²² Results from the analysis demonstrated that 57% of patients with intracranial metastases achieved intracranial objective responses to Rozlytrek.²³

For the clinical development program of Rozlytrek, a total of 355 patients, including 16 pediatric and young adult patients, have received Rozlytrek in four clinical trials (ALKA, STARTRK-1, STARTRK-2, and STARTRK-NG). The safety of Rozlytrek was evaluated as integrated analyses of these four ongoing clinical trials. The median duration of exposure to Rozlytrek was 5.5 months.

In this safety population, the most common tumours were lung (56%), sarcoma (8%), and colon (5%). ROS1 gene fusions were present in 42% and NTRK gene fusions were present in 20%. Most patients (75%) received Rozlytrek 600 mg orally once daily. The doses ranged from 100 mg/m2 to 1600 mg/m2 once daily in adults and 250mg/m2 to 750 mg/m2 once daily in pediatric patients. Health Canada has not authorized an indication for pediatric use.

Grade 3-4 adverse reactions occurred in 60% of patients; the most common (≥2%) were lung infection (5%), increased weight (7%), dyspnea (6%), fatigue/asthenia (5%), cognitive disorders (4.5%), syncope (2.5%), pulmonary emboli (3.4%), hypoxia (3.4%), pleural effusion (3.1%), hypotension (2.8%), diarrhea (2%), and urinary tract infection (2.5%).

Fatal events included dyspnea (0.6%), pneumonia (0.6%), sepsis (0.6%), completed suicide (0.3%), large intestine perforation (0.3%), and tumour lysis syndrome (0.3%).

Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received Rozlytrek. The most frequent adverse reaction (<1% each) that resulted in permanent discontinuation were pneumonia, cardio-respiratory arrest, dyspnea, and fatigue.²⁴ 

About NTRK gene fusion-positive cancer
Neurotrophic tyrosine receptor kinase (NTRK) gene fusion-positive cancer occurs when the NTRK1/2/3 genes fuse with other genes, resulting in altered TRK proteins (TRKA/TRKB/TRKC) that can activate signalling pathways involved in the growth of certain types of cancer. NTRK gene fusions are present in tumours irrespective of site of origin.²⁵

About Rozlytrek
Rozlytrek (entrectinib) is an oral medicine for the treatment of adult patients with unresectable locally advanced or metastatic extracranial solid tumours, including brain metastases, that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, and with no satisfactory treatment options.²⁶ It is a selective tyrosine kinase inhibitor designed to inhibit the kinase activity of the TRK A/B/C proteins, whose activating fusions drive cell division and growth in certain types of cancer.²⁷ Rozlytrek can block NTRK kinase activity and may result in the death of cancer cells with NTRK gene fusions.²⁸

About Roche
Roche is a global pioneer in pharmaceuticals and diagnostics focused on advancing science to improve people's lives. The combined strengths of pharmaceuticals and diagnostics under one roof, combined with a focus on innovation, have made Roche the leader in personalized healthcare - a strategy that aims to provide patients with timely access to their best possible healthcare solution.

Roche is the world's largest biotech company, with truly differentiated medicines in oncology, immunology, infectious diseases, ophthalmology and diseases of the central nervous system. Roche is also the world leader in in vitro diagnostics and tissue-based cancer diagnostics, and a frontrunner in diabetes management. 

Founded in 1931, Roche Canada is committed to searching for better ways to prevent, diagnose and treat diseases while making a sustainable contribution to society. The company employs more than 1,200 people across the country through its Pharmaceuticals division in Mississauga, Ontario and Diagnostics, as well as Diabetes Care divisions in Laval, Quebec.

Roche aims to improve patient access to medical innovations by working with all relevant stakeholders. Roche Canada is actively involved in local communities through its charitable giving and partnerships with organizations and healthcare institutions that work together to improve the quality of life of Canadians. For more information, please visit www.RocheCanada.com.

All trade-marks mentioned are the property of their respective owners.

© Copyright 2020; Hoffmann-La Roche Limited

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11 Rick JW, Shahin M, Chandra A, et al. Systemic therapy for brain metastases. Crit Rev Oncol Hematol. 2019;142:44-50. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746616/.

12 Nesline MK, Depietro P, Dy GK, et al. Oncologist uptake of comprehensive genomic profile guided targeted therapy. Oncotarget. 2019;10(45):4616-4629. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659802/

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SOURCE Roche Canada

Bridget Wells, Roche Canada, T: 905-542-5072, E: [email protected]; Courtney McNamara, Proof Inc., T: 416-969-1673, E: [email protected]