Results of Combination “Triplet” of Tucatinib
with Trastuzumab and Capecitabine Published in The Lancet
Oncology
Results of Tucatinib in Combination with
Ado-trastuzumab Emtansine Published in JAMA Oncology
The second bullet point above the "About Tucatinib" boilerplate,
should read: "ORR was 47 percent (n=16/34)" (instead of "ORR was 47
percent (n=34/50)").
The corrected release reads:
SEATTLE GENETICS ANNOUNCES PUBLICATION OF
RESULTS FROM TWO TUCATINIB PHASE 1B CLINICAL TRIALS IN
HER2-POSITIVE METASTATIC BREAST CANCER
Results of Combination “Triplet” of Tucatinib
with Trastuzumab and Capecitabine Published in The Lancet
Oncology
Results of Tucatinib in Combination with
Ado-trastuzumab Emtansine Published in JAMA Oncology
Seattle Genetics, Inc. (Nasdaq:SGEN) today announced that
results of a phase 1b clinical trial of tucatinib in combination
with standard of care agents for the treatment of patients with
advanced HER2-positive (HER2+) metastatic breast cancer were
recently published in the journal The Lancet Oncology. Results
demonstrated that tucatinib in combination with trastuzumab
(Herceptin®) and capecitabine (Xeloda®) was generally
well-tolerated and had encouraging clinical activity in heavily
pre-treated patients with advanced HER2+ breast cancer, including
those with brain metastases (ONT-380-005/triplet study). A separate
phase 1b clinical trial of tucatinib in combination with
ado-trastuzumab emtansine (T-DM1, Kadcyla®) was published in JAMA
Oncology. Results showed an acceptable safety profile and
preliminary antitumor activity among heavily pretreated patients
with HER2+ metastatic breast cancer, with and without brain
metastases (ONT-380-004). Tucatinib is an oral, small molecule
tyrosine kinase inhibitor that is highly selective for HER2.
“There remains a need for a well-tolerated, oral targeted
therapy to treat patients with HER2+ metastatic breast cancer whose
disease progresses on conventional anti-HER2 treatments,
particularly for those whose cancer has metastasized to the brain,
which occurs in up to 50 percent of these patients,” said Rashmi
Murthy, M.D., MBE, Assistant Professor, Department of Breast
Medical Oncology, Division of Cancer Medicine, The University of
Texas MD Anderson Cancer Center. “In the ONT-380-005 triplet study,
durable responses were seen in heavily pretreated patients with
metastatic HER2+ breast cancer, including those with brain
metastases, after treatment with tucatinib. Importantly, in the
trial, tucatinib treatment was associated with few clinically
significant side effects, such as diarrhea or skin rash, commonly
seen with other tyrosine kinase inhibitors targeting this disease,
which may allow for prolonged use and as a result potentially
improve outcomes for patients.”
“The results of the combination tucatinib with trastuzumab and
capecitabine triplet study support the development of this regimen
in the ongoing pivotal HER2CLIMB trial to provide a meaningful
advancement in the use of targeted therapies to treat this
disease,” said Roger Dansey, M.D., Chief Medical Officer at Seattle
Genetics. “In addition, based on the results of the combination of
tucatinib with T-DM1, we are evaluating development opportunities
for this combination in earlier lines of HER2+ metastatic breast
cancer.”
The manuscript entitled “Tucatinib with capecitabine and
trastuzumab in advanced HER2-positive metastatic breast cancer with
and without brain metastases: a non-randomized, open-label, phase
1b study” was published in the July print edition of The Lancet
Oncology.
The phase 1b triplet study was an open-label dose-escalation and
expansion cohort study of tucatinib in combination with
capecitabine and/or trastuzumab in patients with HER2+ metastatic
breast cancer, including those with or without brain metastases.
The objective of the study was to assess the safety, tolerability,
pharmacokinetics and antitumor activity, and to determine the
recommended phase 2 dose of tucatinib in combination with these
agents. Once a recommended phase 2 dose of 300 mg BID was
established in the triplet combination, an expansion cohort using
that regimen was opened. The trial enrolled 60 patients with HER2+
metastatic breast cancer who had previously received a median of
three HER2-targeted agents, such as trastuzumab, pertuzumab
(Perjeta®), lapatinib (Tykerb®) or T-DM1.
Data from patients treated with the triplet combination at 300
mg BID (n=27) included:
- Median progression-free survival (PFS)
was 7.8 months.
- Objective response rate (ORR) was 61
percent (n=14/23) with a median duration of response of 11.0
months.
- Median PFS for patients with brain
metastases (n=11) was 6.7 months.
- ORR was 42 percent (n=5/12) in patients
with measurable brain metastases that had received the 300mg BID
tucatinib dose in any combination.
- The triplet combination was
well-tolerated and the majority of adverse events were grade 1,
with most patients being able to continue on the full dose of
tucatinib. Grade 3 diarrhea was infrequent without a requirement
for prophylactic anti-diarrheal medicine.
An ongoing randomized, double-blind, placebo-controlled pivotal
trial called HER2CLIMB is comparing tucatinib vs. placebo, each in
combination with capecitabine and trastuzumab in patients with
pretreated, unresectable, locally advanced or metastatic HER2+
breast cancer, including patients with or without brain
metastases.
“The combination of tucatinib and T-DM1 in the phase 1b clinical
trial was tolerable and appeared to show antitumor activity among
heavily pretreated patients with HER2+ metastatic breast cancer
with and without brain metastases,” said Virginia Borges, M.D.,
Deputy Head of the Division of Medical Oncology and the Robert F.
& Patricia Young Endowed Chair in Young Women’s Breast Cancer
Research at the University of Colorado School of Medicine. “Based
on these data, tucatinib may have the potential to be a new
therapeutic option for these patients and warrants further
investigation.”
The manuscript entitled “Tucatinib combined with ado-trastuzumab
emtansine in advanced HER2-positive metastatic breast cancer: A
phase 1b open-label clinical trial” was published in the July print
edition of JAMA Oncology.
This phase 1b, open-label dose escalation and expansion cohort
study of tucatinib in combination with T-DM1 enrolled 57 patients
with HER2+ breast cancer. The objective of the study was to assess
the safety, tolerability, pharmacokinetics and antitumor activity,
and to determine the recommended phase 2 dose of tucatinib in
combination with T-DM1. Participants in the study previously
received a median of two prior HER2-directed therapies.
Data from the phase 1b study of tucatinib and T-DM1 (n=57)
included:
- Median PFS was 8.2 months.
- ORR was 47 percent (n=16/34).
- The combination of tucatinib and T-DM1
was well-tolerated and the majority of adverse events were grade
1.
About Tucatinib
Tucatinib is an investigational, orally bioavailable, potent
tyrosine kinase inhibitor that is highly selective for HER2 without
significant inhibition of EGFR. Inhibition of EGFR has been
associated with significant toxicities, including skin rash and
diarrhea. Tucatinib has shown activity as a single agent and in
combination with both chemotherapy and other HER2 directed agents
such as trastuzumab.1,2 Studies of tucatinib in these combinations
have shown activity both systemically and in brain metastases. HER2
is a growth factor receptor that is overexpressed in multiple
cancers, including breast, ovarian and gastric cancers. HER2
mediates cell growth, differentiation and survival. Tumors that
overexpress HER2 are more aggressive and historically have been
associated with poor overall survival, compared with HER2-negative
cancers. Tucatinib has been granted orphan drug designation by the
U.S. Food and Drug Administration (“FDA”) for the treatment of
breast cancer patients with brain metastases.
About HER2-Positive Metastatic Breast Cancer
Patients with HER2-positive breast cancer have tumors with high
levels of a protein called human epidermal growth factor receptor 2
(HER2), which promotes the aggressive spread of cancer cells. The
American Cancer Society estimates 268,670 new cases of invasive
breast cancer will be diagnosed in the U.S. in 2018. Approximately
15 to 20 percent of breast cancers are HER2-positive.3
Historically, HER2 disease has been associated with shorter
survival times as well as a higher risk of recurrence and CNS
disease (brain metastases). Approximately 30 to 50 percent of
HER2-positive breast cancer patients develop brain metastases over
time.4,5 Over the past two decades, the approvals of four targeted
treatments (trastuzumab, pertuzumab, lapatinib and T-DM1)
have led to improved time to progression and survival rates of
patients with HER2-positive breast cancer. Despite these advances,
there is still a significant need for new therapies that can impact
metastatic disease, including brain metastases, and be tolerated
for longer periods of time.
About Seattle Genetics
Seattle Genetics, Inc. is an emerging multi-product, global
biotechnology company that develops and commercializes
transformative therapies targeting cancer to make a meaningful
difference in people’s lives. ADCETRIS® (brentuximab vedotin)
utilizes the company’s industry-leading antibody-drug conjugate
(ADC) technology and is currently approved for the treatment of
multiple CD30-expressing lymphomas. Beyond ADCETRIS, the company
has established a pipeline of novel targeted therapies at various
stages of clinical testing, including three in ongoing pivotal
trials for solid tumors. Enfortumab vedotin for metastatic
urothelial cancer and tisotumab vedotin for metastatic cervical
cancer utilize our proprietary ADC technology. Tucatinib, a small
molecule tyrosine kinase inhibitor, is in a pivotal trial for
HER2-positive metastatic breast cancer. In addition, we are
leveraging our expertise in empowered antibodies to build a
portfolio of proprietary immuno-oncology agents in clinical trials
targeting hematologic malignancies and solid tumors. The company is
headquartered in Bothell, Washington, and has a European office in
Switzerland. For more information on our robust pipeline, visit
www.seattlegenetics.com and follow @SeattleGenetics on Twitter.
Forward-Looking Statements
Certain of the statements made in this press release are forward
looking, such as those, among others, relating to therapeutic
potential of tucatinib, its possible safety, efficacy, and
therapeutic uses and anticipated development activities including
the continued enrollment of patients in HER2CLIMB, development of
tucatinib for breast and other cancers, future clinical trials and
intended regulatory actions. Actual results or developments may
differ materially from those projected or implied in these
forward-looking statements. Factors that may cause such a
difference include the difficulty and uncertainty of pharmaceutical
product development, including the inability to show sufficient
activity in the clinical trials, the risk of adverse events or
safety signals, and the possibility of adverse regulatory actions
as tucatinib advances in clinical trials even after promising
results in earlier clinical trials. More information about the
risks and uncertainties faced by Seattle Genetics is contained
under the caption “Risk Factors” included in the company’s
Quarterly Report on Form 10-Q for the quarter ended March 31, 2018
filed with the Securities and Exchange Commission. Seattle
Genetics disclaims any intention or obligation to update or revise
any forward-looking statements, whether as a result of new
information, future events or otherwise.
References:
1. Moulder, S. et al., Phase 1 Trial of ONT-380, a HER2
Inhibitor, in Patients with HER2+ Advanced Solid Tumors, with an
Expansion Cohort in HER2+ Metastatic Breast Cancer. Clin Cancer
Res, May 2017.
2. Hamilton, E. et al., Efficacy of a Phase 1b Trial of
Tucatinib (ONT-380), an Oral HER2-Specific Inhibitor, in
Combination with Capecitabine and Trastuzumab in HER2+ Metastatic
Breast Cancer, Including Patients with Brain Metastases. Presented
at the San Antonio Breast Cancer Symposium (SABCS) Annual Meeting
2016, San Antonio, TX, December 9, 2016 (Poster P4-21-01).
3. ASCO Cancer.Net, Treatment of Metastatic HER2-Positive Breast
Cancer. Accessed July 2018.
4. Metro, et al., Clinical outcome of patients with brain
metastases from HER2-positive breast cancer treated with lapatinib
and capecitabine. Annals of Oncology, vol. 212, no. 3, pp. 625-630,
2011.
5. Ramakrishna N., et al., Journal of Clinical Oncology 32, no.
19 (July 2014) 2100-2108.
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version on businesswire.com: https://www.businesswire.com/news/home/20180711005198/en/
Seattle Genetics, Inc.Media:Monique Greer,
425-527-4641mgreer@seagen.comorInvestors:Peggy Pinkston,
425-527-4160ppinkston@seagen.com
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