CAMBRIDGE, Mass., Nov. 10, 2017 /PRNewswire/ -- Blueprint Medicines
Corporation (NASDAQ: BPMC), a leader in discovering and developing
targeted kinase medicines for patients with genomically defined
diseases, today announced new Phase 1 clinical data for BLU-285, a
potent and highly selective KIT and PDGFRα inhibitor in development
as a potential treatment for patients with advanced
gastrointestinal stromal tumors (GIST). The data confirm and build
upon data previously presented for BLU-285 in patients with
advanced GIST, demonstrating robust clinical activity and a
favorable safety profile. The data showed 67 percent of patients
with heavily pretreated KIT-driven GIST treated with 300 to 400 mg
of BLU-285 once daily (QD) had radiographic tumor reductions. In
this population, the data also showed an objective response rate
(ORR) of 17 percent and median progression free survival (PFS) of
11.5 months. In patients with PDGFRα-D842 driven GIST, the data
showed an ORR of 71 percent and an estimated 12-month PFS of 78
percent. BLU-285 was well-tolerated, and most adverse events (AEs)
reported by investigators were Grade 1 or 2. The data will be
presented today in an oral presentation at the Connective Tissue
Oncology Society 2017 Annual Meeting in Maui, Hawaii.
As previously announced, Blueprint Medicines plans to pursue
expedited development of BLU-285 in patients with PDGFRα
D842V-driven GIST, and the Company is on track to initiate a
global, randomized Phase 3 clinical trial of BLU-285 in third-line
GIST in the first half of 2018, with the goal of supporting
registration of BLU-285 in a broader GIST patient population. In
addition, based on the strength of the data in patients with
KIT-driven GIST, Blueprint Medicines announced today an expansion
of the ongoing Phase 1 trial. The Company recently increased the
enrollment target for patients previously treated with imatinib and
at least one additional tyrosine kinase inhibitor (TKI) from 50 to
100 patients and added a new cohort to evaluate BLU-285 in
second-line GIST.
"The updated BLU-285 data show robust clinical activity in a
broad population of patients with advanced GIST," said Michael Heinrich, M.D., Professor of Medicine at
Oregon Health & Science University and an investigator on the
clinical trial. "In patients with PDGFRα-driven advanced GIST, the
data for BLU-285 continue to be remarkable, particularly
considering these patients have no effective treatment options.
Importantly, I'm also very encouraged to see radiographic tumor
reductions in two-thirds of patients with heavily pretreated GIST
across all common KIT genotypes, as well as prolonged progression
free survival in this population. Overall, these clinical results
confirm recently published preclinical data showing activity across
a spectrum of disease-relevant mutations and support clinical
development of BLU-285 in a broad patient population."
"We are grateful to the patients, families and investigators who
have contributed to the Phase 1 clinical trial to date, and we are
committed to advancing the clinical development of BLU-285 quickly
and responsibly," said Andy Boral,
M.D., Chief Medical Officer of Blueprint Medicines. "We continue to
plan for expedited development of BLU-285 in patients with PDGFRα
D842V-driven GIST, and we look forward to working with the FDA
under the Breakthrough Therapy Designation program to determine the
fastest path forward for BLU-285 in this population. In addition,
the objective responses and prolonged progression free survival we
are seeing in patients with heavily pretreated KIT-driven GIST give
us increased confidence in our approach to expand development of
BLU-285 in third- and second-line treatment. Overall, we believe
our data-driven clinical development strategy will enable
productive interactions with global regulatory authorities over the
course of 2018."
New Data from the Ongoing Phase 1 Clinical Trial of BLU-285
in Advanced GIST
As of the data cutoff date of October 11,
2017, 116 patients had been treated with BLU-285 in the dose
escalation and expansion portions of the Phase 1 clinical trial at
eight dose levels (ranging from 30 mg QD to 600 mg QD), including
76 patients with KIT-driven GIST, 39 patients with PDGFRα-driven
GIST, and one patient with KIT/PDGFRα wild-type GIST. The median
number of prior TKI regimens was four for patients with KIT-driven
GIST (ranging from two to 11), and one for patients with
PDGFRα-driven GIST (ranging from zero to six). Among patients with
KIT-driven GIST, 64 patients (83 percent) previously received
regorafenib.
Blueprint Medicines has selected 300 mg QD as the recommended
part 2 dose (RP2D) for the expansion portion of the clinical trial,
with an option for investigators to escalate patients to the
maximum tolerated dose (MTD) of 400 mg QD following two treatment
cycles.
Safety Data:
As of the data cutoff date, BLU-285 was generally
well-tolerated. Most AEs reported by investigators were Grade 1 or
2. Across all grades, the most common treatment-emergent AEs
reported by investigators (≥20 percent) included nausea (56
percent), fatigue (53 percent), periorbital edema (43 percent),
vomiting (41 percent), edema peripheral (34 percent), anemia (31
percent), diarrhea (31 percent), increased lacrimation (30
percent), cognitive effects (30 percent), decreased appetite (28
percent), dizziness (23 percent), constipation (22 percent) and
hair color changes (22 percent). Cognitive effects are an
aggregated category of individual cognitive events, each of which
was observed in fewer than 20 percent of patients. Investigators
reported treatment-related Grade ≥3 AEs in 39 patients (34
percent), including anemia (9 percent), fatigue (7 percent),
hypophosphatemia (4 percent), nausea (4 percent) and cognitive
effects (3 percent). Six patients (5 percent) discontinued
treatment with BLU-285 due to AEs. An additional 43 patients
discontinued treatment, with 40 patients due to progressive disease
and three patients who withdrew consent. Among all 116 enrolled
patients, 67 remained on treatment as of the data cutoff date.
Clinical Activity Data:
As of the data cutoff date, 30 patients with KIT-driven GIST
treated at 300 to 400 mg QD were evaluable for response
assessments. In addition, 31 patients with PDGFRα D842-driven GIST
at all doses were evaluable for response assessments, including 29
patients with a D842V mutation and two patients with other D842
mutations. Two patients with a PDGFRα exon 14 mutation were
excluded from analyses of clinical activity. Patients were
evaluable if they had at least one centrally reviewed radiographic
scan, and all reported data are based on blinded central radiology
review as per modified Response Evaluation Criteria in Solid Tumors
version 1.1 (mRECIST 1.1 criteria) for GIST. Radiographic scans
were also assessed by Choi criteria, a supportive method of
response assessment in soft tissue sarcomas that has been shown to
be predictive of improved prognosis in patients with advanced
GIST.
Patients with heavily pretreated KIT-driven GIST treated at
doses of 300 to 400 mg QD
- Centrally assessed radiographic tumor reductions were observed
in 20 of 30 evaluable patients (67 percent) across all common KIT
genotypes, including mutations in exons 9, 11, 13, 14 and 17,
confirmed by archival tumor biopsy and circulating tumor DNA.
- By mRECIST 1.1 criteria, five patients had a partial response
(PR) (three confirmed, two pending confirmation), and 18 patients
had stable disease (SD), representing an ORR of 17 percent and a
disease control rate (DCR) of 77 percent.
- By Choi criteria, 16 patients had a PR and seven patients had
SD, representing an ORR of 53 percent and a DCR of 77 percent.
- Median PFS was 11.5 months.
- In contrast, historical data showed a zero percent ORR and
median PFS of 1.8 months in patients with TKI-resistant advanced
GIST re-treated with imatinib in a third-line or later
setting.1
Patients with PDGFRα-driven GIST
- Centrally assessed radiographic tumor reductions were observed
in all 31 evaluable patients.
- By mRECIST 1.1 criteria, one patient had a complete response
(CR) (pending confirmation), 21 patients had a PR (18 confirmed,
three pending confirmation), and nine patients had SD, representing
an ORR of 71 percent and a DCR of 100 percent.
- By Choi criteria, one patient had a CR and 30 patients had a
PR, representing an ORR of 100 percent.
- Median PFS was not reached, and 12-month PFS was estimated to
be 78 percent.
- In contrast, historical data showed a zero percent ORR and
median PFS of 2.8 months in patients with PDGFRα D842V-driven GIST
treated with imatinib.2
About the Phase 1 Clinical Trial for BLU-285 in PDGFRα-Driven
and KIT-Driven GIST
The Phase 1 clinical trial of BLU-285 is designed to evaluate
the safety and tolerability of BLU-285 in adults with advanced
GIST. The trial consists of two parts, a dose-escalation portion
and an expansion portion. The dose-escalation portion is complete,
and the MTD was determined to be 400 mg QD. Blueprint Medicines has
selected 300 mg QD as the RP2D for the dose expansion portion of
the trial. The expansion portion is actively enrolling patients in
three defined cohorts at the RP2D consisting of (1) a cohort of
patients with a PDGFRα D842V mutation, regardless of line of
therapy, (2) a cohort of patients who have received imatinib and at
least one other KIT-directed TKI and (3) a cohort of patients who
have received imatinib and no other TKI. Trial objectives include
assessing response, pharmacokinetics and pharmacodynamic measures.
All response assessments use blinded, central radiology review. The
three 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. Please refer
to www.clinicaltrials.gov for additional details related
to this Phase 1 clinical trial (NCT02508532). Patients and
physicians may contact the study director for more information
about this Phase 1 clinical trial
at studydirector@blueprintmedicines.com.
About GIST
GIST is the most common 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 50-80, and diagnosis is
typically triggered by GI bleeding, incidental findings during
surgery or imaging and, in rare cases, tumor rupture or GI
obstruction. Approximately 80 percent of GIST patients have
KIT-driven GIST, and Blueprint Medicines estimates that
KIT exon 17 mutations occur in approximately 90 percent of GIST
patients with KIT-driven GIST following treatment with at least two
TKIs. Approximately five percent of all advanced GIST cases are
driven by D842V mutant PDGFRα. Patients diagnosed with GIST at
an early stage may undergo surgery. For patients with
KIT-driven GIST, treatment with the currently approved frontline
therapy typically leads to treatment resistance and disease
progression. Treatment options for KIT-driven GIST patients whose
disease progresses or develops resistance are currently limited,
with approved therapies providing a progression free survival of up
to six months and a response rate between five percent and seven
percent. There are no effective treatment options for patients with
PDGFRα D842V-driven GIST, and progression often occurs in as little
as three months with available treatment options.
About BLU-285
BLU-285 is an orally available, potent and highly selective
inhibitor of KIT and PDGFRα. Preclinical data have shown that
BLU-285 is active across a broad spectrum of KIT and PDGFRα
mutations, including PDGFRα D842V and KIT exon 17 mutations for
which there are limited or no effective treatment options.
Blueprint Medicines is initially developing BLU-285, an
investigational medicine, for the treatment of patients with
advanced GIST and advanced systemic mastocytosis. BLU-285 was
discovered by Blueprint Medicines' research team
leveraging its proprietary compound library, and the
Company retains worldwide development and commercialization
rights for BLU-285.
In June 2017, BLU-285 received Breakthrough Therapy
Designation from the FDA for the treatment of patients with
unresectable or metastatic GIST harboring the PDGFRα D842V
mutation. The FDA's Breakthrough Therapy Designation is
intended to expedite the development and review of a drug candidate
intended to treat a serious or life-threatening disease or
condition, when preliminary clinical evidence indicates that the
drug candidate may demonstrate substantial improvement over
existing therapies on one or more clinically significant endpoints.
Previously, the FDA granted orphan drug designation to
BLU-285 for the treatment of GIST. The FDA also granted
Fast Track designation to BLU-285 for the treatment of patients
with unresectable or metastatic GIST that progressed following
treatment with imatinib and a second TKI and for the treatment of
patients with unresectable or metastatic GIST in patients with the
PDGFRα D842V mutation regardless of prior therapy. In addition, the
European Medicines Agency has granted orphan drug designation to
BLU-285 for the treatment of GIST.
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 four 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.
References
1 Kang YK, Ryu MH, Ryoo BY, et al. Resumption of
imatinib to control metastatic or unresectable gastrointestinal
stromal tumours after failure of imatinib and sunitinib (RIGHT): a
randomised, placebo-controlled, phase 3 trial. Lancet Oncol.
2013;14(12):1175–82.
2 Cassier PA, Fumagalli E, Rutkowski P, et al. Outcome
of Patients with Platelet-Derived Growth Factor Receptor
Alpha–Mutated Gastrointestinal Stromal Tumors in the Tyrosine
Kinase Inhibitor Era. Clin Cancer Res.
2012;18(16):4458–64.
Cautionary Note 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
BLU-285, including plans and timelines for pursuing expedited
development in patients with a PDGFRα D842V mutation and plans and
timelines for the initiation of a global, randomized Phase 3
clinical trial of BLU-285 in third-line GIST; Blueprint Medicines'
ability to implement its clinical development plans for BLU-285 in
advanced GIST; expectations regarding current and future
interactions with global regulatory authorities, including the FDA,
and the impact of Breakthrough Therapy Designation on the
development of BLU-285; 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 BLU-285, BLU-554 and BLU-667;
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; and 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 BLU-554 for FGFR4-driven HCC, BLU-285 for PDGFRα
D842V-driven GIST and BLU-667 for RET-driven non-small cell lung
cancer; and the success of Blueprint Medicines' cancer
immunotherapy collaboration with F. Hoffmann-La Roche Ltd and
Hoffmann-La Roche Inc. 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, 2017, as
filed with the Securities and Exchange Commission (SEC) on
October 31, 2017, and other filings
that Blueprint Medicines 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. Blueprint Medicines explicitly disclaims any
obligation to update any forward-looking statements.
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