Basel, 19 February 2019 - Roche (SIX: RO, ROG;
OTCQX: RHHBY) today announced that the US Food and Drug
Administration (FDA) has accepted the company's New Drug
Applications (NDAs) and granted Priority Review for entrectinib for
the treatment of adult and paediatric patients with neurotrophic
tropomyosin receptor kinase (NTRK) fusion-positive, locally
advanced or metastatic solid tumours who have either progressed
following prior therapies or as an initial therapy when there are
no acceptable standard therapies, and for the treatment of people
with metastatic, ROS1-positive non-small cell lung cancer (NSCLC).
These NDAs are based on results from the integrated analysis of the
pivotal Phase II STARTRK-2, Phase I STARTRK-1 and Phase I
ALKA-372-001 trials, and data from the Phase I/Ib STARTRK-NG study.
The FDA is expected to make a decision on approval by 18 August
2019.
"Entrectinib represents a unique approach to cancer treatment that
can potentially target a range of hard-to-treat and rare NTRK
fusion-positive tumours regardless of their site of origin, as well
as treat ROS1-positive non-small cell lung cancer," said Sandra
Horning, MD, Roche's Chief Medical Officer and Head of Global
Product Development. "By combining comprehensive genomic profiling
with actionable targeted therapies, like entrectinib, we are
advancing our personalised healthcare goal to find the right
treatment for each patient. We are working closely with the FDA to
make this potential new option available as soon as
possible."
The FDA grants Priority Review to medicines determined to have the
potential to provide significant improvements in the treatment,
prevention or diagnosis of a serious disease. Entrectinib was also
granted Breakthrough Therapy Designation (BTD) by the US Food and
Drug Administration (FDA); Priority Medicines (PRIME) designation
by the European Medicines Agency (EMA); and Sakigake designation by
the Japanese health authorities for the treatment of NTRK
fusion-positive, locally advanced or metastatic solid tumours in
adult and paediatric patients who have either progressed following
prior therapies or have no acceptable standard
therapies.1 BTD is
designed to expedite the development and review of medicines
intended to treat serious or life-threatening diseases and to help
ensure people have access to them through FDA approval as soon as
possible.
Roche is leveraging its expertise in developing personalised
medicines and advanced diagnostics, in conjunction with Foundation
Medicine, to develop a companion diagnostic that will help identify
people with ROS1 and NTRK gene fusions.
About the integrated analysis
The integrated analysis included data from 53 people with
ROS1-activating gene fusions and 54 people with locally advanced or
metastatic NTRK fusion-positive solid tumours (10 tumour types,
>19 histopathologies) from the Phase II STARTRK-2, Phase I
STARTRK-1 and Phase I ALKA-372-001 trials.2,3 In
addition, data from the Phase I/Ib STARTRK-NG study in paediatric
patients were also included in the NDAs. The studies enrolled
people across 15 countries and more than 150 clinical trial
sites.2,3 Tumour
types evaluated in the studies to date included breast,
cholangiocarcinoma, colorectal, gynaecological, neuroendocrine,
non-small cell lung, salivary gland, pancreatic, sarcoma and
thyroid cancers.3
-
STARTRK-2 is a Phase II,
global, multicentre, open-label basket study in people with solid
tumours that harbour an NTRK1/2/3, ROS1 or ALK-positive gene
fusion.4 The primary
endpoint is objective response rate (ORR), and duration of response
(DoR) is a secondary endpoint.4 Other
secondary outcome measures include time to response, clinical
benefit rate, intracranial tumour response, progression-free
survival (PFS), central nervous system (CNS) PFS and overall
survival (OS).4
-
STARTRK-1 is a Phase
I, multicentre, open-label dose escalation study of a daily
continuous dosing schedule in people with solid tumours with
NTRK1/2/3, ROS1 or ALK gene fusions in the US and South
Korea.5 The trial
assessed the safety and tolerability of entrectinib via a standard
dose escalation scheme and determined the recommended Phase II
dose.5
-
ALKA-372-001 is Phase
I, multicentre, open-label dose escalation study of an intermittent
and continuous entrectinib dosing schedule in people with advanced
or metastatic solid tumours with TRKA/B/C, ROS1 or ALK gene fusions
in Italy.1
-
STARTRK-NG is a Phase
I/II dose-escalation and expansion study evaluating the safety
and efficacy of entrectinib in children and adolescent patients
with no curative first-line treatment option, recurrent or
refractory extracranial solid tumours or primary CNS tumours, with
or without TRK, ROS1 or ALK fusions.6
Results from the integrated analysis showed entrectinib shrank
tumours (ORR) in more than half (57.4 percent) of people with
NTRK fusion-positive solid tumours. 3 Objective
responses to entrectinib were seen across 10 different solid tumour
types (median DoR = 10.4 months), including in people with and
without CNS metastases at baseline.3 In these
studies, entrectinib shrank tumours that had spread to the brain in
more than half of people (intracranial response [IC ORR] = 54.5
percent), with more than a quarter of these people having a
complete response.3
Entrectinib shrank tumours in 77.4 percent of people with locally
advanced or metastatic ROS1-positive NSCLC.2 In
addition, entrectinib demonstrated a durable response of more than
two years (median DoR = 24.6 months).2 Importantly,
entrectinib was shown to shrink intracranial tumours in more than
half of people with CNS metastases at baseline (IC ORR = 55.0
percent).2
The safety profile of entrectinib was consistent with that seen in
previous analyses.2,3 The most
commonly reported adverse reactions included fatigue, constipation,
altered sense of taste (dysgeusia), swelling (edema), dizziness,
diarrhea, nausea, nervous system disorders (dysesthesia), shortness
of breath (dyspnea), pain, anemia, cognitive disorders, weight
increased, vomiting, cough, blood creatinine increase, joint pain
(arthralgia), fever (pyrexia), and muscle pain
(myalgia).2,3
About entrectinib
Entrectinib (RXDX-101) is an investigational, oral medicine in
development for the treatment of locally advanced or metastatic
solid tumours that harbour NTRK1/2/3 or ROS1 gene fusions. It is a
selective tyrosine kinase inhibitor designed to inhibit the kinase
activity of the TRK A/B/C and ROS1 proteins, whose activating
fusions drive proliferation in certain types of cancer.7,8 Entrectinib
can block ROS1 and NTRK kinase activity and may result in the death
of cancer cells with ROS1 or NTRK gene fusions.7,8
Entrectinib is being investigated across a range of solid tumour
types, including breast, cholangiocarcinoma, colorectal,
gynaecological, neuroendocrine, non-small cell lung, salivary
gland, pancreatic, sarcoma and thyroid cancers.1,4-6
About NTRK fusion-positive
cancer
Neurotrophic tyrosine receptor kinase (NTRK) 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 signaling
pathways involved in proliferation of certain types of cancer. NTRK
gene fusions are tumour-agnostic, meaning they are present in
tumours irrespective of site of origin. These fusions have been
identified in a broad range of solid tumour types, including
breast, cholangiocarcinoma, colorectal, gynaecological,
neuroendocrine, non-small cell lung, salivary gland, pancreatic,
sarcoma and thyroid cancers.3 There is a
high unmet medical need for treatments for people with
life-threatening and hard-to-treat NTRK fusion-positive
tumours.
About ROS1-positive NSCLC
ROS1 is a tyrosine kinase, which plays a role in controlling how
cells grow and proliferate. When a ROS1 gene fusion occurs, cancer
cells grow and proliferate in an uncontrolled manner. Blocking this
abnormal signalling can cause tumour cells to shrink or
die.9
ROS1 gene fusions account for 1-2% of NSCLC.9 Lung
cancer is the leading cause of cancer-related death across the
world.10 Each year,
more than one and a half million people die as a result of the
disease globally, equating to more than 4,000 deaths every
day.10 NSCLC is the
most common type of lung cancer and accounts for 85% of all lung
cancer diagnoses.11 While the
ROS1 gene fusion can be found in any patient with NSCLC, young
never-smokers with NSCLC have the highest incidence of ROS1 gene
fusions.9
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 have made Roche
the leader in personalised healthcare - a strategy that aims to fit
the right treatment to each patient in the best way
possible.
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 1896, Roche continues to search for better ways to
prevent, diagnose and treat diseases and make a sustainable
contribution to society. The company also aims to improve patient
access to medical innovations by working with all relevant
stakeholders. Thirty medicines developed by Roche are included in
the World Health Organization Model Lists of Essential Medicines,
among them life-saving antibiotics, antimalarials and cancer
medicines. Moreover, for the tenth consecutive year, Roche has been
recognised as the most sustainable company in the Pharmaceuticals
Industry by the Dow Jones Sustainability Indices (DJSI).
The Roche Group, headquartered in Basel, Switzerland, is active in
over 100 countries and in 2018 employed about 94,000 people
worldwide. In 2018, Roche invested CHF 11 billion in R&D and
posted sales of CHF 56.8 billion. Genentech, in the United
States, is a wholly owned member of the Roche Group. Roche is the
majority shareholder in Chugai Pharmaceutical, Japan. For more
information, please visit www.roche.com.
All trademarks used or mentioned in this release are protected by
law.
References
[1] F. Hoffman La Roche Ltd. Data on file.
[2] Doebele R et al. Efficacy and Safety of Entrectinib in Locally
Advanced or Metastatic ROS1 Fusion-Positive Non-Small Cell Lung
Cancer (NSCLC). Presented at: IASLC 19th World Conference on Lung
Cancer; September 23-26, 2018; Toronto, Canada. Abstract
13903.
[3] Demetri GD et al. Efficacy and Safety of Entrectinib in
Patients with NTRK Fusion-Positive (NTRK-fp) Tumors: Pooled
Analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Presented at
ESMO 2018; October 19-23, 2018; Munich, Germany. Abstract
LBA17.
[4] ClinicalTrials.gov. Basket Study of Entrectinib (RXDX-101) for
the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3
(Trk A/B/C), ROS1, or ALK Gene Rearrangements (Fusions)
(STARTRK-2). [Internet; cited 2019 February 05]. Available from:
https://clinicaltrials.gov/ct2/show/NCT02568267.
[5] ClinicalTrials.gov. Study of Oral RXDX-101 in Adult Patients
With Locally Advanced or Metastatic Cancer Targeting NTRK1, NTRK2,
NTRK3, ROS1, or ALK Molecular Alterations. (STARTRK-1). [Internet;
cited 2019 February 05]. Available from:
https://clinicaltrials.gov/ct2/show/NCT02097810.
[6] ClinicalTrials.gov. Study of RXDX-101 in Children With
Recurrent or Refractory Solid Tumors and Primary CNS Tumors, With
or Without TRK, ROS1, or ALK Fusions. [Internet; cited 2019
February 05]. Available from:
https://clinicaltrials.gov/ct2/show/NCT02650401?term=NCT02650401&rank=1.
[7] Ahn M-J, Cho BC, Siena S, et al. Entrectinib in patients with
locally advanced or metastatic ROS1 fusion-positive non-small cell
lung cancer (NSCLC). Presented at: IASLC 18th World Conference on
Lung Cancer; October 15-18, 2017; Yokohama, Japan. Abstract
8564.
[8] Rolfo, et al. Entrectinib: a potent new TRK, ROS1, and ALK
inhibitor. Expert Opin Investig Drugs.
2015;24(11):1493-500.
[9] Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define
a unique molecular class of lung cancers. J Clin Oncol. 2012;
30(8):863-70.
[10] GLOBOCAN. Lung Cancer. [Internet; cited 2019 February 05].
Available from:
http://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf.
[11] American Cancer Society. What Is Non-Small Cell Lung Cancer?
[Internet; cited 2019 February 05]. Available from:
https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.html.
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Relations
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20190219-MR-FDA grants Priority
Review to Roche’s entrectinib