– Marked and Durable Responses Across TRK Fusion
Cancers –
Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company
innovating the development of highly selective medicines for
patients with genetically defined cancers, and Bayer AG, Germany,
today announced a publication in the February 22nd issue of the New
England Journal of Medicine (NEJM) for larotrectinib in the
treatment of pediatric and adult patients whose tumors harbor
tropomyosin receptor kinase (TRK) gene fusions.
The NEJM publication provides additional clinical details and
patient follow-up from the 2017 American Society of Clinical
Oncology (ASCO) Annual Meeting presentation. It includes the
first 55 consecutively enrolled adult and pediatric patients with
TRK fusion cancers treated across Loxo Oncology’s Phase 1 adult
trial, Phase 2 trial (NAVIGATE), and Phase 1/2 pediatric trial
(SCOUT) and uses a July 17, 2017 data cutoff.
“Ongoing treatment with larotrectinib continues to demonstrate
striking and durable efficacy coupled with minimal side effects,
across a diverse patient population,” said David Hyman, M.D., the
NAVIGATE global principal investigator, chief of the Early Drug
Development service at Memorial Sloan Kettering Cancer Center
and senior author of the NEJM paper. “The efficacy of larotrectinib
warrants screening for TRK fusions alongside other actionable
targets in patients of all ages with advanced solid tumors.”
In December, Loxo Oncology initiated submission of a rolling New
Drug Application (NDA) to the U.S. Food and Drug Administration
(FDA) for larotrectinib, utilizing the same patient population and
data cutoff as outlined in the NEJM paper. The rolling NDA
submission is expected to be complete in early 2018 and a Marketing
Authorisation Application (MAA) submission by Bayer in the European
Union is expected in 2018. The larotrectinib program has continued
to enroll and treat newly identified patients with TRK fusion
cancers, beyond the 55 patients described in the publication. The
anti-tumor activity and safety of larotrectinib in these additional
patients are consistent with the data reported in the publication,
and will be included for supportive analyses in the NDA and MAA
submissions. Loxo Oncology expects to present these additional data
in the second half of 2018.
“It is exciting to see the NEJM share the larotrectinib
experience in TRK fusion cancers with the broader clinical and
research communities,” said Josh Bilenker, M.D., chief executive
officer of Loxo Oncology. “The class-leading data reported for
larotrectinib are a testament to the importance of building
selective medicines against all of the actionable targets
comprehensive profiling can identify. We hope to build on the
success of larotrectinib as our pipeline matures in 2018 and
beyond.”
Overview of Data Published in NEJM
The published data were based on the intent to treat (ITT)
principle, using the first 55 TRK fusion patients with
RECIST-evaluable disease enrolled to the three clinical trials,
regardless of prior therapy or tumor tissue diagnostic method. The
analysis included both adult and pediatric patients, ranging in age
from four months to 76 years, who carried 17 unique TRK
fusion-positive tumor diagnoses. Tumor types included salivary
gland, infantile fibrosarcoma, thyroid, colon, lung, melanoma,
gastrointestinal stromal tumor (GIST), and other cancers.
The primary endpoint for the analysis was overall response rate
(ORR). Secondary endpoints included duration of response,
progression-free survival, and safety. As shown below, as
previously reported, the ORR was 75% by central assessment and 80%
by investigator assessment.
|
Central Assessment
(%)(n=55) |
Investigator Assessment
(%)(n=55) |
Overall response rate (95% CI)(ORR=PR+CR) |
75% (61–85%) |
80% (67–90%) |
Partial response |
62 |
% |
64 |
%* |
Complete response |
13 |
% |
16 |
% |
Stable disease |
13 |
% |
9 |
% |
Progressive disease |
9 |
% |
11 |
% |
Could not be evaluated |
4 |
% |
0 |
|
* Data include one patient who had a partial response that was
pending confirmation at the time of the July 17, 2017 data cut-off.
The response was subsequently confirmed, and the patient’s
treatment and response were ongoing as of the data cut-off
date.
Median duration of response (DOR) and median progression-free
survival (PFS) had not been reached after median follow-up
durations of 8.3 months and 9.9, respectively. At 1 year, 71% of
responses were ongoing. As of the July 17, 2017 data cutoff, 86% of
responding patients remained on treatment or had undergone surgery
with curative intent. The first patient treated with a TRK fusion
tumor remained in response and on therapy at 27 months.
Larotrectinib was well tolerated with the majority of all
adverse events being grade 1 or 2. Few grade 3 or 4 adverse events,
regardless of attribution, were observed with the most common being
anemia (11%), alanine or aspartate aminotransferase increase (7%),
weight increase (7%), and neutrophil count decrease (7%) (all grade
3 events). There were no treatment-related grade 4 or 5 events, and
no treatment-related grade 3 adverse events occurred in more than
5% of patients. Eight patients required larotrectinib dose
reductions. Adverse events leading to dose reductions included
AST/ALT elevation, dizziness, and neutrophil count decrease, all
grade 2 or 3 events. In all cases, patients whose doses were
reduced maintained their best response at the lower dose and none
discontinued larotrectinib due to an adverse event.
Primary resistance was observed in six patients in the study. Of
the six, one patient had been previously treated with another TRK
inhibitor and tumor sequencing prior to larotrectinib dosing
revealed a solvent front mutation, a known resistance mechanism.
Tumor tissue was analyzed for three of the five remaining patients.
In all three patients, TRK immunohistochemistry failed to
demonstrate TRK expression, potentially implicating a false
positive initial TRK fusion test result and therefore explaining
the lack of response in these patients.
The publication also details mechanisms of acquired resistance
to larotrectinib. Ten patients experienced disease progression
while on treatment after a documented objective response or stable
disease for at least six months, a phenomenon known as acquired
resistance. Nine of the ten patients had assessments of
post-progression tumor or plasma samples, and NTRK kinase domain
mutations were identified in all of those samples tested. In seven
of those assessed, investigators identified solvent front mutations
as a convergent mechanism of acquired resistance; other NTRK kinase
domain mutations were identified in the remaining two patients
tested. Of the 10 patients who developed acquired resistance, 80%
continued treatment with larotrectinib beyond progression due to
ongoing clinical benefit.
Loxo Oncology and Bayer are developing LOXO-195, a
next-generation TRK inhibitor, to specifically address acquired
resistance mutations, including all mutations characterized in the
study. LOXO-195 is currently being evaluated in a phase 1/2 trial
in children and adults.
About Larotrectinib (LOXO-101)Larotrectinib is
a potent, oral and selective investigational new drug in clinical
development for the treatment of patients with cancers that harbor
abnormalities involving the tropomyosin receptor kinases (TRKs).
Growing research suggests that the NTRK genes, which encode for
TRKs, can become abnormally fused to other genes, resulting in
growth signals that can lead to cancer in many sites of the body.
In an analysis of 55 RECIST-evaluable TRK fusion adult and
pediatric patients, larotrectinib demonstrated a 75 percent
independently-reviewed confirmed overall response rate (ORR) and an
80 percent investigator-assessed confirmed ORR, across many
different types of solid tumors. Larotrectinib has been granted
Breakthrough Therapy Designation Rare Pediatric Disease Designation
and Orphan Drug Designation by the U.S. FDA. For additional
information about the larotrectinib clinical trials, please refer
to www.clinicaltrials.gov. Interested patients and physicians
can contact the Loxo Oncology Physician and Patient Clinical Trial
Hotline at 1-855-NTRK-123 or
visit www.loxooncologytrials.com.
In November 2017, Loxo Oncology and Bayer entered
into an exclusive global collaboration for the development and
commercialization of larotrectinib and LOXO-195, a next-generation
TRK inhibitor. Loxo Oncology leads worldwide development
and U.S. regulatory activities. Bayer leads ex-U.S. regulatory
activities and worldwide commercial activities. In the
U.S., Loxo Oncology and Bayer will co-promote the
products.
About TRK Fusion CancerTRK fusions are
chromosomal abnormalities that occur when one of the NTRK genes
(NTRK1, NTRK2, NTRK3) becomes abnormally connected to another,
unrelated gene (e.g. ETV6, LMNA, TPM3). This abnormality results in
uncontrolled TRK signaling that can lead to cancer. TRK fusions
occur rarely but broadly in various adult and pediatric solid
tumors, including appendiceal cancer, breast cancer,
cholangiocarcinoma, colorectal cancer, GIST, infantile
fibrosarcoma, lung cancer, mammary analogue secretory carcinoma of
the salivary gland, melanoma, pancreatic cancer, thyroid cancer,
and various sarcomas. TRK fusions can be identified through various
diagnostic tests, including targeted next-generation sequencing
(NGS), immunohistochemistry (IHC), polymerase chain reaction (PCR),
and fluorescent in situ hybridization (FISH). For more information,
please visit www.TRKtesting.com.
About Loxo OncologyLoxo Oncology is a
biopharmaceutical company innovating the development of highly
selective medicines for patients with genetically defined cancers.
Our pipeline focuses on cancers that are uniquely dependent on
single gene abnormalities, such that a single drug has the
potential to treat the cancer with dramatic effect. We believe that
the most selective, purpose-built medicines have the highest
probability of maximally inhibiting the intended target, thereby
delivering best-in-class disease control and safety. Our management
team seeks out experienced industry partners, world-class
scientific advisors and innovative clinical-regulatory approaches
to deliver new cancer therapies to patients as quickly and
efficiently as possible. For more information, please visit the
company's website at www.loxooncology.com.
Forward Looking StatementsThis press release
contains "forward-looking" statements within the meaning of the
safe harbor provisions of the U.S. Private Securities Litigation
Reform Act of 1995. Forward-looking statements can be identified by
words such as: "anticipate," "intend," "plan," "goal," "seek,"
"believe," "project," "estimate," "expect," "strategy," "future,"
"likely," "may," "should," "will" and similar references to future
periods. These statements are subject to numerous risks and
uncertainties that could cause actual results to differ materially
from what we expect. Examples of forward-looking statements
include, among others, statements we make regarding the timing and
success of our clinical trials or regulatory approvals, the
potential therapeutic benefits and economic value of our lead
product candidate or other product candidates, and timing of future
regulatory filings. Further information on potential risk factors
that could affect our business and its financial results are
detailed in our most recent Quarterly Report on Form 10-Q, and
other reports as filed from time to time with the Securities and
Exchange Commission. We undertake no obligation to publicly update
any forward-looking statement, whether written or oral, that may be
made from time to time, whether as a result of new information,
future developments or otherwise.
Contacts for Loxo Oncology, Inc.
Company: Jacob S. Van Naarden Chief Business
Officerjake@loxooncology.com
Investors:Peter Rahmer The Trout Group, LLC 646-378-2973
prahmer@troutgroup.com
Media:Dan Budwick
1AB Media973-271-6085
dan@1abmedia.com
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