- Results of first of two-part phase 1 study
demonstrate that DS-8201a was well-tolerated with no dose-limiting
toxicities
- Overall preliminary efficacy results report an
objective response rate of 35 percent and a disease control rate of
90 percent in HER2 expressing breast and gastric
cancer patients
- In a subgroup analysis, preliminary efficacy results
report an objective response rate of 42 percent and a disease
control rate of 92 percent in T-DM1 treated HER2+ breast
cancer
- Daiichi Sankyo will be advancing DS-8201a to the
second part of the phase 1 study examining the safety and efficacy
of DS-8201a in four different HER2 expressing cohorts
TOKYO and PARSIPPANY, New Jersey and MUNICH, Oct. 9,
2016 /PRNewswire/ -- Daiichi Sankyo Company, Limited
(hereafter, Daiichi Sankyo) today announced safety and preliminary
efficacy data from a phase 1 study of DS-8201a, a novel
investigational HER2-targeting antibody drug conjugate, which
suggest that it was well-tolerated with no dose-limiting
toxicities. These results, from the dose escalation part of a
two-part phase 1 study of DS-8201a, will be presented today during
a late-breaking poster discussion session at the ESMO 2016
Congress, the annual meeting of the European Society for Medical
Oncology (ESMO).
DS-8201a is an investigational antibody drug conjugate comprised
of a humanized anti-HER2 antibody attached by a peptide linker to a
novel topoisomerase I inhibitor (DXd) payload, utilizing Daiichi
Sankyo's proprietary payload and linker-payload technology.
Preliminary overall efficacy results in 20 evaluable patients
demonstrated an objective response rate of 35 percent (seven
partial responses) and disease control rate of 90 percent,
including 12 patients previously treated with ado-trastuzumab
emtansine (T-DM1) and five patients with HER2 low expression
(IHC2+/FISH- or IHC1+). In 15 patients with HER2+ disease defined
as IHC3+ or IHC2+/FISH+, the disease control rate was 100 percent.
Seventeen patients are still on treatment, and five of the first 10
patients have been under active treatment (0.8 to 6.4 mg/kg)
for more than 24 weeks. Median progression free survival has not
been reached.
"Despite recent advances in treating HER2+ breast and gastric
cancer, there still remains a large unmet need for patients with
HER2+ disease whose tumors are no longer controlled by currently
approved targeted HER2 treatments or for tumors that express low
HER2," said Antoine Yver, MD, MSc,
Executive Vice President and Global Head, Oncology Research and
Development, Daiichi Sankyo. "These preliminary results are
compelling and warrant further clinical evaluation of DS-8201a in
several different patient populations expressing HER2."
"The components that make up DS-8201a are unique from any other
antibody drug conjugate currently in clinical development and may
explain the clinical activity observed at such an early phase of
development," said José Baselga, MD, PhD, Physician-in-Chief and
Chief Medical Officer at Memorial Sloan Kettering Cancer Center,
New York, NY. "While the results
of this study provide important preliminary proof-of-concept for
the novel mechanism of action of DS-8201a, additional research will
be needed to further confirm these findings."
A total of 22 patients (16 breast cancer, 5 gastric cancer, 1
gastroesphageal junction adenocarcinoma) were treated in the dose
escalation part of the study. The maximum tolerated dose was not
reached (0.8-8.0 mg/kg given every three weeks) and there have been
no dose-limiting toxicities at pharmacologically-active exposure
and a favorable pharmacokinetic profile. Seven grade 3 adverse
events were seen in three patients (1 hypokalemia, 1 anemia, 1
neutrophil count decreased, 2 lymphocyte count decrease, 1 ALP
increase and 1 cholangitis). Most common adverse events were mild
or moderate gastrointestinal and hematological events.
HER2+ Breast Cancer Subgroup Analyses
A total of 18
patients enrolled in the study received one or more prior anti-HER2
therapies (18 received trastuzumab, 13 ado-trastuzumab emtansine, 5
pertuzumab, 4 lapatinib). In 12 evaluable HER2+ breast cancer
patients previously treated with ado-tratuzumab emtansine (T-DM1),
the objective response rate was 42 percent with a disease control
rate of 92 percent.
"It is impressive that DS-8201a showed activity in these
patients since many were heavily pre-treated with more than one
HER2-targeting agent including T-DM1, and some with very
substantial tumor load or large tumors," said Kenji Tamura, MD, PhD, Chairman, Department of
Breast and Medical Oncology, National Cancer Center Hospital,
Tokyo, Japan and lead investigator
of the study. "This finding will be further evaluated in the second
part of this study where one cohort will include only advanced
breast cancer patients previously treated with T-DM1."
About DS-8201a
Pre-clinical models have demonstrated
that DS-8201a has a unique mechanism of action (MOA) where it
selectively binds to the HER2 receptor on a tumor cell surface,
triggering an antibody-dependent cell cytotoxic (ADCC)
response.1 DS-8201a is then internalized via endocytosis
(transportation into cells by an energy-using process) and the
intracellular lysosomal enzymes break down the peptide to release
the DXd payload, which then inhibits topoisomerase I activity,
causing DNA damage and cell death.1
The linker-payload combination of DS-8201a allows for a higher
drug-to-antibody ratio (DAR) of about 8 compared to a DAR of about
3.5 seen with ado-trastuzumab emtansine (T-DM1).1 The
higher DAR of DS-8201a may help target low expressing HER2 tumors
by supplying more payload per antibody to a tumor.1
About the DS-8201a Phase 1 Study
DS-8201a, given as an
intravenous infusion every three weeks, is currently being
evaluated in an open-label two-part phase 1 study in patients with
advanced/unresectable or metastatic breast cancer, gastric or
gastroesophageal junction adenocarcinoma, or other solid tumors
that is/are refractory to or intolerable with standard treatment or
for which no standard treatment is available.
The primary objective of part 1 of the study (dose escalation)
is to assess the safety and tolerability of DS-8201a and determine
the maximum tolerated dose (MTD). Secondary objectives include
evaluating the pharmacokinetics, efficacy and human anti-human
antibody (HAHA) against DS-8201a.
The second part (dose expansion) of the ongoing phase 1 clinical
trial is enrolling patients in Japan and the United
States into one of four cohorts: patients with HER2+ breast
cancer previously treated with T-DM1; patients with HER2+ gastric
or gastroesophageal junction adenocarcinoma previously treated with
trastuzumab; patients with HER2 low expressing breast cancer; and
patients with other solid cancers that express HER2. For more
information about the study visit ClinicalTrials.gov.
Unmet Need in HER2+ Metastatic Breast Cancer
HER2
(known as human epidermal growth factor receptor 2) is a tyrosine
kinase receptor growth-promoting protein found on the surface of
some cancer cells.2 About one in five breast cancers
overexpress the HER2/neu gene, which causes these cancers to
grow more aggressively.2 To be considered HER2+, cancer
cells are tested by one of two methods: immunohistochemistry (IHC)
or fluorescent in situ hybridization
(FISH).2 IHC test results are reported as: 0,
IHC1+, IHC2+ or IHC3+. A finding of IHC3+ is considered
HER2+.2 A finding of IHC2+ is borderline and
typically is confirmed by a positive FISH test.2
Several unmet needs remain today in HER2+ metastatic breast
cancer. Many tumors advance to the point where no currently
approved HER2-targeted treatment continues to control the
disease.3 Additionally, there are no existing options
indicated for HER2 low expressing tumors (IHC2+/FISH- or IHC1+) as
well as HER2 heterogeneously expressing tumors (tumors with some
tumor cells having high HER2 expression and some having low HER2
expression), which generally have poor prognosis.1,4
About Daiichi Sankyo Cancer Enterprise
The vision of
Daiichi Sankyo Cancer Enterprise is to push beyond traditional
thinking to align world-class science to create innovative
treatments for patients with cancer. The oncology pipeline of
Daiichi Sankyo continues to grow and currently includes more than
20 small molecules and monoclonal antibodies with novel targets in
both solid and hematological cancers. Compounds in phase 3
development include: quizartinib, an oral FLT3-ITD inhibitor, for
newly-diagnosed and relapsed/refractory FLT3-ITD+ acute myeloid
leukemia (AML); pexidartinib, an oral CSF-1R inhibitor, for
tenosynovial giant cell tumor (TGCT), also known as pigmented
villonodular synovitis (PVNS) and giant cell tumor of the tendon
sheath (GCT-TS), which also is being investigated in combination
with anti-PD1 immunotherapy, pembrolizumab, in a range of solid
tumors; and tivantinib, an oral MET inhibitor, for second-line
treatment in patients with MET-high hepatocellular carcinoma in
partnership with ArQule, Inc.
About Daiichi Sankyo
Daiichi Sankyo Group
is dedicated to the creation and supply of innovative
pharmaceutical products to address diversified, unmet medical needs
of patients in both mature and emerging markets. With over 100
years of scientific expertise and a presence in more than 20
countries, Daiichi Sankyo and its 16,000 employees around the world
draw upon a rich legacy of innovation and a robust pipeline of
promising new medicines to help people. In addition to a strong
portfolio of medicines for hypertension and thrombotic disorders,
under the Group's 2025 Vision to become a "Global Pharma Innovator
with Competitive Advantage in Oncology," Daiichi Sankyo research
and development is primarily focused on bringing forth novel
therapies in oncology, including immuno-oncology, with additional
focus on new horizon areas, such as pain management,
neurodegenerative diseases, heart and kidney diseases, and other
rare diseases. For more information, please visit:
www.daiichisankyo.com. Daiichi Sankyo, Inc., headquartered in
Parsippany, New Jersey, is a
member of the Daiichi Sankyo Group. For more information on Daiichi
Sankyo, Inc., please visit: www.dsi.com.
Contact
Jennifer
Brennan
Daiichi Sankyo, Inc.
jbrennan2@dsi.com
+1 973 944 2393 (office)
+1 201 709 9309 (mobile)
References:
1. Ogitani Y, et al. Clin Cancer
Res. March 29, 2016.
2. American Cancer Society. Breast Cancer Overview. 2016
3. De Melo Gagliato D, et al. Oncotarget. 2016.
4. Seol H, et al. Modern Pathology. 2012:25:938-948.
2016-10-06T085321
DSC 16 0019 October 2016