CAMBRIDGE, Mass., Nov. 15,
2018 /PRNewswire/ -- Blueprint Medicines Corporation (NASDAQ:
BPMC), a leader in discovering and developing targeted kinase
medicines for patients with genomically defined diseases, today
announced updated data for the registration-enabling NAVIGATOR
clinical trial of avapritinib, a potent and highly selective KIT
and PDGFRA inhibitor in development for patients with advanced
gastrointestinal tumors (GIST). The data showed that avapritinib
was highly active across all lines of therapy for patients with
PDGFRα D842V-driven GIST and in second-, third- and fourth-line for
other GIST patients. In addition, avapritinib was well-tolerated
with most adverse events (AEs) reported by investigators as Grade 1
or 2. These results will be presented today in an oral presentation
at the Connective Tissue Oncology Society 2018 Annual Meeting in
Rome, Italy.
The updated data from the ongoing Phase 1 NAVIGATOR trial
support Blueprint Medicines' plans to submit a New Drug Application
(NDA) in the first half of 2019 to the U.S. Food and Drug
Administration (FDA) for the treatment of PDGFRA Exon 18 mutant
GIST, which primarily includes patients with the D842V mutation,
and fourth-line GIST. There are currently no approved or effective
therapies in these patient populations. In patients with PDGFRα
D842V-driven GIST, avapritinib demonstrated an objective response
rate (ORR) of 84 percent and a 12-month duration of response (DoR)
of 76 percent. In heavily pre-treated patients with fourth-line or
later GIST, avapritinib demonstrated an ORR of 20 percent, tumor
reductions in 60 percent of patients and a median DoR of 7.3
months. ORR and DoR per central radiographic review will be the
primary endpoints for the NDA submission, consistent with
regulatory precedent for accelerated approvals based on single-arm
oncology studies. In addition, avapritinib demonstrated an ORR of
26 percent in regorafenib-naïve third- and fourth-line GIST and an
ORR of 25 percent in second-line GIST. Patients with PDGFRα
D842V-driven GIST were excluded from both of these populations.
"With an increased understanding of molecular drivers of GIST
over the last decade, it is encouraging to see an investigational
drug, like avapritinib, bring a precision therapy approach to
GIST," said Michael Heinrich, M.D.,
Professor of Medicine at Oregon Health & Science University and
an investigator on the NAVIGATOR trial. "Avapritinib has the
potential to be a significant therapeutic advance in GIST, a rare
cancer with high medical needs across lines of treatment. In
particular, the updated data demonstrate the broad clinical impact
of avapritinib for patients with PDGFRα D842V-driven GIST and
fourth-line GIST, where there are currently no effective therapies.
In addition, the data strongly support clinical development of
avapritinib in early lines, including second- and third-line
treatment."
"These data highlight the potential of avapritinib, a potent and
highly selective inhibitor of KIT and PDGFRA mutant kinases, to be
a cornerstone precision therapy in GIST," said Andy Boral, M.D., Ph.D., Chief Medical Officer
of Blueprint Medicines. "The results validate Blueprint Medicines'
approach to designing precision therapies that specifically target
genetic drivers of disease, with the goals of delivering
transformative benefit to patients and enabling rapid progress
toward registration. Avapritinib's highly potent anti-tumor
activity in PDGFRα D842V-driven GIST, combined with differentiated
activity across treatment lines in KIT-driven GIST, reflect its
promise as a potentially foundational treatment option across
multiple GIST populations. We are committed to advancing a
comprehensive and scientifically driven clinical development
program with the goal of improving the lives of GIST
patients."
Data Highlights from the Ongoing Phase 1 NAVIGATOR Clinical
Trial
As of the data cutoff date of October 15,
2018, 231 patients were treated with avapritinib in the dose
escalation and expansion portions of the Phase 1 clinical trial at
eight dose levels, ranging from 30 mg once daily (QD) to 600 mg QD.
This population consisted of 167 patients with KIT-driven GIST, 56
patients with PDGFRα D842V-driven GIST and eight patients with
other PDGFRA mutations. Patients in the expansion portion of the
clinical trial were treated at the recommended Phase 2 dose of 300
mg QD.
Safety Data
As of the data cutoff date, avapritinib was well-tolerated, and
most AEs reported by investigators were Grade 1 or 2. Across all
doses, 20 patients (8.7 percent) discontinued treatment with
avapritinib due to treatment-related AEs.
Across all grades, the most common treatment-emergent AEs
(regardless of relationship to avapritinib) reported by
investigators (≥20 percent) included nausea (61 percent), fatigue
(55 percent), anemia (46 percent), periorbital edema (40 percent),
diarrhea (39 percent), vomiting (38 percent), decreased appetite
(35 percent), peripheral edema (33 percent), increased lacrimation
(31 percent), memory impairment (26 percent), constipation (23
percent), face edema (23 percent), hair color changes (21 percent)
and dizziness (20 percent).
Investigator-reported Grade 3 or 4 treatment-related AEs (≥2
percent) included anemia, fatigue, hypophosphatemia, increased
bilirubin, decreased white blood count/neutropenia and
diarrhea.
Clinical Activity Data
As of the data cutoff date, the following patients were
evaluable for response assessments: 56 patients with PDGFRα
D842V-driven GIST, 109 patients with fourth-line or later GIST, 23
patients with third- or fourth-line GIST who did not receive prior
regorafenib (which is comparable to the VOYAGER trial population)
and do not harbor the PDGFRα D842V mutation, and 20 patients with
second-line GIST who do not harbor the PDGFRα D842V mutation.
Patients were evaluable if they had at least one centrally reviewed
radiographic scan, and data are based on modified Response
Evaluation Criteria in Solid Tumors version 1.1 (mRECIST 1.1
criteria) for GIST.
Across multiple lines of therapy, avapritinib demonstrated
important clinical activity in patients with PDGFRA- and KIT-driven
GIST.
GIST
Population
|
Evaluable
Patients
|
ORR
|
Clinical Benefit
Rate
at Four Months
(≥Two Scans)
|
Median
DoR
|
Median
PFS
Central Review
(Investigator Review)
|
PDGFRα
D842Va
|
56
|
84%f
|
96%
|
Not estimable;
76% at 12 months
|
Not
reached
|
Fourth-line or
laterb,c
|
109
|
20%g
|
40%
|
7.3 months
|
3.7 months
(5.4 months)
|
Regorafenib-naïve
third-
or fourth-lineb,d
|
23
|
26%
|
70%
|
10.2
months
|
8.6 months
(10.2 months)
|
Second-lined,e
|
20
|
25%h
|
NRi
|
NRi
|
NRi
|
Notes: (a) Treated at all doses; (b) Treated at doses of 300
or 400 mg QD; (c) Included patients with the PDGFRα D842V mutation,
whose proportion was consistent with the known mutational
prevalence in this GIST population; (d) Did not include patients
with the PDGFRα D842V mutation, whose proportion was greater than
the known mutational prevalence in this GIST population; (e)
Treated at doses up to and including 300 or 400 mg QD; (f) Four PR
pending confirmation; (g) One PR pending confirmation; (h) Three PR
pending confirmation; (i) NR, not reported, as data are too early
to estimate.
Additional Data Support Clinical Development Strategy in
Earlier Lines of Therapy
Third- and Fourth-Line GIST
Preliminary data showed robust clinical activity in
regorafenib-naïve third- and fourth-line GIST patients lacking the
PDGFRα D842V mutation. As of the data cutoff date, the ORR was 26
percent, tumor reductions were demonstrated in 78 percent of
patients, and the median PFS was 8.6 months per central
radiographic review and 10.2 months per investigator review. In
contrast, historical data showed a 5 percent ORR and a median PFS
of 4.8 months for regorafenib, the current standard-of-care
treatment in third-line GIST.
In regorafenib-naive patients with PDGFRα D842V-driven third- or
fourth-line GIST, the ORR was 80 percent (eight out of 10 evaluable
patients, with one response pending confirmation). Blueprint
Medicines' ongoing Phase 3 VOYAGER trial of avapritinib versus
regorafenib in third- or fourth-line GIST permits enrollment of
patients with both KIT- and PDGFRA-driven GIST, including patients
with the PDGFRα D842V mutation. Blueprint Medicines anticipates
completing enrollment of the VOYAGER trial in the second half of
2019.
Second-Line GIST
Preliminary data showed a 25 percent ORR in second-line GIST,
excluding patients with the PDGFRα D842V mutation. In patients with
second-line PDGFRα D842V-driven GIST, the ORR was 94 percent (15
out of 16 evaluable patients, with two responses pending
confirmation).
In addition, analyses of circulating tumor DNA (ctDNA) from the
NAVIGATOR trial across all lines showed increased activity for
avapritinib in patients without the secondary KIT V654A or T670I
mutations, which are estimated to occur in about 20 to 25 percent
of GIST patients following treatment with imatinib (second-line or
later). Independently published data for sunitinib, the current
standard of care therapy for second-line GIST, have shown activity
against these mutations.
Based on the totality of data, Blueprint Medicines believes a
precision medicine approach has the potential to optimize patient
outcomes in second-line GIST. The company plans to initiate the
registration-enabling Phase 3 COMPASS-2L clinical trial in the
second half of 2019 using a ctDNA-guided patient selection
strategy. The planned trial will select patients with PDGFRA- and
KIT-driven second-line GIST who do not have the KIT V654A or T670I
mutations, and randomize them to receive avapritinib or sunitinib
with an anticipated primary endpoint of PFS.
Conference Call Information
Blueprint Medicines will host a live conference call and webcast
on November 15, 2018 at 7:30 a.m. ET to review the updated data for
avapritinib in GIST. The conference call may be accessed by dialing
(855) 728-4793 (domestic) or (503) 343-6666 (international) and
referring to conference ID 3479587. A live webcast of the
conference call will be available under "Events and Presentations"
in the Investors section of Blueprint Medicines' website at
http://ir.blueprintmedicines.com. The archived webcast will be
available on Blueprint Medicines' website approximately two hours
after the conference call and will be available for 30 days
following the call.
About the Avapritinib Clinical Development Program in
GIST
Blueprint Medicines is pursuing a broad clinical development
program for avapritinib across all lines of GIST. Avapritinib is
currently being evaluated in two ongoing registration-enabling
clinical trials for GIST: the Phase 1 NAVIGATOR trial and the Phase
3 VOYAGER trial.
The NAVIGATOR trial is designed to evaluate the safety and
tolerability of avapritinib in patients with advanced GIST. The
trial consists of two parts, a dose escalation portion and an
expansion portion. The dose escalation portion is complete, and
trial objectives include assessing response, pharmacokinetics and
pharmacodynamic measures. Response assessments use blinded, central
radiology review. The expansion cohorts of the trial are designed
to enroll a total of approximately 200 patients at multiple sites
in the United States, United Kingdom and European Union.
The VOYAGER trial is a global, open-label, randomized, Phase 3
trial designed to evaluate the safety and efficacy of avapritinib
versus regorafenib in patients with third- or fourth-line advanced
GIST. The trial is designed to enroll approximately 460 patients
randomized 1:1 to receive either avapritinib or regorafenib at
multiple sites in the United
States, United Kingdom,
European Union, Australia and
Asia.
In the second half of 2019, Blueprint Medicines plans to
initiate COMPASS-2L, a global, randomized, Phase 3 precision
medicine trial. The trial will evaluate the safety and efficacy of
avapritinib versus sunitinib in patients with second-line advanced
GIST and pre-specified disease genotypes.
Patients and physicians interested in the Phase 3 VOYAGER trial
can contact the Blueprint Medicines study director at
VOYAGER@blueprintmedicines.com or 1-617-714-6707. For more
information about the VOYAGER trial, please visit
www.voyagertrial.com. Additional details are available on
www.clinicaltrials.gov (ClinicalTrials.gov Identifier:
NCT03465722).
About GIST
GIST is a sarcoma, or tumor of bone or connective tissue, of the
gastrointestinal (GI) tract. Tumors arise from cells in the wall of
the GI tract and occur most often in the stomach or small
intestine. Most patients are diagnosed between the ages of 50 to
80, and diagnosis is typically triggered by GI bleeding, incidental
findings during surgery or imaging and, in rare cases, tumor
rupture or GI obstruction.
Most GIST cases are caused by a spectrum of clinically relevant
mutations that force the KIT or PDGFRA protein kinases into an
increasingly active state. Because currently available therapies
only bind to the inactive protein conformations, certain primary
and secondary mutations typically lead to treatment resistance and
disease progression.
Treatment options for KIT-driven GIST patients whose disease
progresses or develops resistance are currently limited. There are
no effective treatment options for patients with PDGFRA-driven
GIST, and progression often occurs in as little as three months
with available therapies. In advanced GIST, clinical benefits from
existing treatments can vary by mutation type. Early testing is
critical to help guide therapy that effectively treats the
underlying driver of disease and is recommended in expert
guidelines.
About Avapritinib
Avapritinib is a potent and selective oral inhibitor of KIT and
PDGFRA mutant kinases. It is a type 1 inhibitor designed to target
the active kinase conformation; all oncogenic kinases signal via
this conformation. Avapritinib has demonstrated broad inhibition of
KIT and PDGFRA mutations associated with GIST, and the most potent
activity against activation loop mutations, which currently
approved therapies do not inhibit. In contrast with existing
multi-kinase inhibitors, avapritinib has shown marked selectivity
for KIT and PDGFRA over other kinases. In addition, avapritinib is
uniquely designed to bind and inhibit the KIT D816V mutation, the
primary driver of disease in up to 95 percent of systemic
mastocytosis (SM) patients. Preclinical studies have shown
avapritinib potently inhibited KIT D816V at sub-nanomolar potencies
with minimal off-target activity.
Blueprint Medicines is initially developing avapritinib, an
investigational medicine, for the treatment of advanced GIST,
advanced SM, and indolent and smoldering SM. The FDA has granted
avapritinib two Breakthrough Therapy Designations, one for the
treatment of PDGFRα D842V-driven GIST and one for advanced SM.
Blueprint Medicines has an exclusive collaboration and license
agreement with CStone Pharmaceuticals for the development and
commercialization of avapritinib and certain other drug candidates
in Mainland China, Hong Kong,
Macau and Taiwan. Blueprint Medicines retains
development and commercial rights for avapritinib in the rest of
the world.
About Blueprint Medicines
Blueprint Medicines is developing a new generation of targeted
and potent kinase medicines to improve the lives of patients with
genomically defined diseases. Its approach is rooted in a deep
understanding of the genetic blueprint of cancer and other diseases
driven by the abnormal activation of kinases. Blueprint Medicines
is advancing multiple programs in clinical development for subsets
of patients with gastrointestinal stromal tumors, hepatocellular
carcinoma, systemic mastocytosis, non-small cell lung cancer,
medullary thyroid cancer and other advanced solid tumors, as well
as multiple programs in research and preclinical development. For
more information, please visit www.blueprintmedicines.com.
Cautionary Notes Regarding Forward-Looking Statements
This press release contains forward-looking statements within
the meaning of the Private Securities Litigation Reform Act of
1995, as amended, including, without limitation, statements
regarding plans and timelines for the clinical development of
avapritinib, including plans and timelines for initiating the Phase
3 COMPASS-2L trial and completing enrollment in the Phase 3 VOYAGER
trial; expectations regarding the potential benefits of avapritinib
in treating patients with GIST; plans and timelines for submitting
an NDA to the FDA for avapritinib for the treatment of PDGFRA Exon
18 mutant GIST and fourth-line GIST; and Blueprint Medicines'
strategy, business plans and focus. The words "may," "will,"
"could," "would," "should," "expect," "plan," "anticipate,"
"intend," "believe," "estimate," "predict," "project," "potential,"
"continue," "target" and similar expressions are intended to
identify forward-looking statements, although not all
forward-looking statements contain these identifying words. Any
forward-looking statements in this press release are based on
management's current expectations and beliefs and are subject to a
number of risks, uncertainties and important factors that may cause
actual events or results to differ materially from those expressed
or implied by any forward-looking statements contained in this
press release, including, without limitation, risks and
uncertainties related to the delay of any current or planned
clinical trials or the development of Blueprint Medicines' drug
candidates, including avapritinib, BLU-554, BLU-667 and BLU-782;
Blueprint Medicines' advancement of multiple early-stage efforts;
Blueprint Medicines' ability to successfully demonstrate the safety
and efficacy of its drug candidates; the preclinical and clinical
results for Blueprint Medicines' drug candidates, which may not
support further development of such drug candidates; actions of
regulatory agencies, which may affect the initiation, timing and
progress of clinical trials; Blueprint Medicines' ability to
develop and commercialize companion diagnostic tests for its
current and future drug candidates, including companion diagnostic
tests for avapritinib for PDGFRα D842V-driven GIST, BLU-554 for
FGFR4-driven hepatocellular carcinoma and BLU-667 for RET-driven
non-small cell lung cancer; the success of Blueprint Medicines'
current and future collaborations, including its cancer
immunotherapy collaboration with F. Hoffmann-La Roche Ltd and
Hoffmann-La Roche Inc. and its collaboration with CStone
Pharmaceuticals. These and other risks and uncertainties are
described in greater detail in the section entitled "Risk Factors"
in Blueprint Medicines' Quarterly Report on Form 10-Q for the
quarter ended September 30, 2018, as
filed with the Securities and Exchange Commission (SEC) on
October 30, 2018, and any other
filings that Blueprint Medicines has made or may make with the SEC
in the future. Any forward-looking statements contained in this
press release represent Blueprint Medicines' views only as of the
date hereof and should not be relied upon as representing its views
as of any subsequent date. Except as required by law, Blueprint
Medicines explicitly disclaims any obligation to update any
forward-looking statements.
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