- Designation Based on Positive Pivotal
HER2CLIMB Trial Evaluating Tucatinib in Locally Advanced or
Metastatic HER2-Positive Breast Cancer; Data were Presented at 2019
SABCS and Published in the New England Journal of Medicine -
- New Drug Application Submission to U.S. FDA
Expected by First Quarter of 2020 -
Seattle Genetics, Inc. (Nasdaq:SGEN) today announced that the
U.S. Food and Drug Administration (FDA) has granted Breakthrough
Therapy designation to tucatinib, in combination with trastuzumab
and capecitabine, for treatment of patients with locally advanced
unresectable or metastatic HER2-positive breast cancer, including
patients with brain metastases, who have been treated with
trastuzumab, pertuzumab, and T-DM1. The positive topline results of
the pivotal HER2CLIMB clinical trial were announced in October
2019, and additional data were presented at the 2019 San Antonio
Breast Cancer Symposium (SABCS) on December 11, 2019 and were
simultaneously published in the New England Journal of Medicine
(NEJM). Tucatinib is an oral, small molecule tyrosine kinase
inhibitor (TKI) that is highly selective for HER2.
The FDA’s Breakthrough Therapy process is intended to expedite
the development and review of promising drug candidates intended
for serious or life-threatening conditions. Designation is based
upon preliminary clinical evidence of the potential for substantial
improvement over existing therapies on one or more clinically
significant endpoints.
“The addition of tucatinib to the commonly used combination of
trastuzumab and capecitabine demonstrated superior activity
compared to trastuzumab and capecitabine alone in patients with
unresectable locally advanced or metastatic HER2-positive breast
cancer, including those with and without brain metastases,” said
Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics. “The
decision by the FDA to grant Breakthrough Therapy designation to
tucatinib recognizes the urgent need for new medicines that can
impact the lives of those with HER2-positive metastatic breast
cancer. We intend to submit a New Drug Application to the FDA and
an MAA to the EMA by the first quarter 2020, with the goal of
making tucatinib available to patients in this setting as soon as
possible.”
This Breakthrough Therapy designation was based on data from the
pivotal HER2CLIMB clinical trial, which compared tucatinib in
combination with trastuzumab and capecitabine to trastuzumab and
capecitabine alone in patients with locally advanced unresectable
or metastatic HER2-positive breast cancer. Patients had previously
received trastuzumab, pertuzumab and ado-trastuzumab emtansine
(T-DM1). Patients had received a median of four prior lines of
therapy overall and three in the metastatic setting. Forty-seven
percent of the patients enrolled in the trial had brain metastases
at the time of enrollment.
Data presented at SABCS and published in NEJM include the
primary endpoint of progression-free survival (PFS) as assessed by
blinded independent central review (BICR) in the first 480 patients
enrolled in the trial. The primary endpoint of PFS showed that the
addition of tucatinib was superior to trastuzumab and capecitabine
alone, with a 46 percent reduction in the risk of disease
progression or death (hazard ratio (HR)=0.54 (95% Confidence
Interval (CI): 0.42, 0.71); p<0.00001). The trial met the two
key secondary endpoints at interim analysis. The tucatinib arm
demonstrated an improvement in overall survival, with a 34 percent
reduction in the risk of death (HR=0.66 [95% CI: 0.50, 0.88];
p=0.0048), compared to the control arm. For patients with brain
metastases at baseline, the tucatinib arm also demonstrated
superior PFS, with a 52 percent reduction in the risk of disease
progression or death, compared to the control arm (HR=0.48 [95% CI:
0.34, 0.69]; p<0.00001).
Tucatinib in combination with trastuzumab and capecitabine was
generally well tolerated. The most common adverse events occurring
in more than 20 percent of patients in the tucatinib arm vs. the
control arm included diarrhea, palmar-plantar erythrodysaesthesia
syndrome (PPE), nausea, fatigue, and vomiting. Discontinuation of
tucatinib and placebo due to adverse events was 5.7 percent in the
tucatinib arm and 3.0 percent in the control arm. Greater than or
equal to Grade 3 diarrhea was seen in 12.9 percent of the patients
in the tucatinib arm vs. 8.6 percent in the control arm.
Antidiarrheal prophylaxis was not required per protocol.
Antidiarrheals were used in less than half of all cycles where
diarrhea was reported. In both treatment arms, when used, the
duration of antidiarrheal treatment was short (median of 3
days/cycle). Greater than or equal to Grade 3 aspartate
aminotransferase (AST) was seen in 4.5 percent of the patients in
the tucatinib arm vs. 0.5 percent in the control arm, and alanine
aminotransferase (ALT) elevation in 5.4 percent vs. 0.5 percent,
respectively. Discontinuations due to liver transaminase elevations
were infrequent in both arms (ALT: 1.0 vs. 0.5 percent; AST: 0.7
vs. 0.5 percent).
About HER2-Positive 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. An
estimated 271,270 new cases of invasive breast cancer will be
diagnosed in the U.S. in 2019.1 Between 15 and 20 percent of breast
cancer cases worldwide are HER2-positive.2 Historically,
HER2-positive breast cancer tends to be more aggressive and more
likely to recur than HER2-negative breast cancer.2, 3, 4 In
patients with metastatic breast cancer, the most common site of
first metastasis is in bone, followed by lung, brain, and liver.5,
6 Up to 50 percent of metastatic HER2-positive breast cancer
patients develop brain metastases over time.2, 7 Despite recent
treatment advances, there is still a significant need for new
therapies that can impact metastatic disease, especially brain
metastases. There are currently no approved therapies demonstrating
progression-free survival or overall survival benefit for the
treatment of patients with HER2-positive metastatic breast cancer
after progression on T-DM1.8, 9, 10
About HER2CLIMB
HER2CLIMB is a multinational randomized (2:1), double-blind,
placebo-controlled, active comparator, pivotal clinical trial
comparing tucatinib in combination with trastuzumab and
capecitabine compared with trastuzumab and capecitabine alone in
patients with locally advanced unresectable or metastatic
HER2-positive breast cancer who were previously treated with
trastuzumab, pertuzumab and T-DM1. The primary endpoint of the
trial was PFS per Response Evaluation Criteria in Solid Tumors
(RECIST) v1.1 as determined by blinded independent central review
(BICR) in the first 480 patients enrolled in the trial. HER2CLIMB
enrolled a total of 612 patients to support the analyses of key
secondary endpoints, including overall survival, PFS per BICR in
patients with brain metastases at baseline and confirmed objective
response rate. Safety data were evaluated throughout the study.
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 targeted 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, colorectal and gastric cancers. HER2
mediates cell growth, differentiation and survival. Tucatinib has
been granted orphan drug designation by the FDA for the treatment
of breast cancer patients with brain metastases.
In addition to HER2CLIMB, tucatinib is being evaluated in a
randomized, double-blind, placebo-controlled, multi-center phase 3
trial of tucatinib in combination with T-DM1 compared to T-DM1
alone, in patients with unresectable locally advanced or metastatic
HER2-positive breast cancer, including those with brain metastases,
who have had prior treatment with a taxane and trastuzumab. The
primary endpoint is progression-free survival per RECIST criteria.
Secondary endpoints include overall survival, objective response
rate and duration of response. The trial is being conducted in
North America and is expected to enroll approximately 460 patients.
More information about the phase 3 trial, including enrolling
centers, is available at www.clinicaltrials.gov.
Tucatinib is also being evaluated in a multi-center, open-label,
single-arm phase 2 clinical trial known as MOUNTAINEER, which is
evaluating tucatinib in combination with trastuzumab in patients
with HER2-positive, RAS wildtype metastatic or unresectable
colorectal cancer. The primary endpoint of the trial is objective
response rate by RECIST criteria. Progression-free survival,
duration of response, overall survival and safety and tolerability
of the combination regimen are secondary objectives. Results for 26
patients were evaluated in an analysis and presented at the
European Society for Medical Oncology (ESMO) 2019 Congress.
Enrollment is ongoing. More information about the MOUNTAINEER
trial, including enrolling centers, is available at
www.clinicaltrials.gov.
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 a late-stage pipeline including enfortumab vedotin for
metastatic urothelial cancer, currently being reviewed for approval
by the FDA, and tisotumab vedotin in clinical trials for metastatic
cervical cancer, which utilize our proprietary ADC technology. In
addition, tucatinib, a small molecule tyrosine kinase inhibitor, is
in late-stage development for HER2-positive metastatic breast
cancer and in clinical development for metastatic colorectal
cancer. We are also 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 the therapeutic
potential of tucatinib, including its possible efficacy, safety and
therapeutic uses; anticipated development activities including
ongoing and future clinical trials; and intended regulatory
actions, including the plan to submit an NDA to the FDA and a MAA
to the EMA by the first quarter of 2020. 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, the risk of adverse events or safety signals,
the possibility of disappointing results in ongoing or future
clinical trials despite earlier promising clinical results, the
possibility of delays in the submission of an NDA to the FDA and a
MAA to the EMA, the possibility that data from the HER2CLIMB trial
may not be sufficient to support approval of tucatinib, the
possibility of adverse regulatory action. 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 September 30,
2019 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, except as required by
law.
References:
1. American Cancer Society, Cancer Facts and Figures
2018-2019.
2. Loibl S, Gianni L (2017). HER2-positive breast cancer. The
Lancet 389(10087): 2415-29.
3. Slamon D, Clark G, Wong S, et al. (1987). Human breast
cancer: correlation of relapse and survival with amplification of
the HER-2/neu oncogene. Science 235(4785): 177-82.
4. American Cancer Society (ACS) (2018). Breast cancer HER2
status. Accessed: December 10, 2018.
5. Kennecke H, Yerushalmi R, Woods R, et al. (2010). Metastatic
Behavior of Breast Cancer Subtypes. Journal of Clinical Oncology
28(20): 3271-7.
6. Berman AT, Thukral AD, Hwang W-T, et al. (2013). Incidence
and Patterns of Distant Metastases for Patients With Early-Stage
Breast Cancer After Breast Conservation Treatment. Clinical Breast
Cancer 13(2): 88-94.
7. Duchnowska R, Loibl S, Jassem J (2018). Tyrosine kinase
inhibitors for brain metastases in HER2-positive breast cancer.
Cancer Treatment Reviews 67: 71-7.
8. Verma S, Miles D, Gianni L, et al. (2012). Trastuzumab
Emtansine for HER2-Positive Advanced Breast Cancer. New England
Journal of Medicine 367(19): 1783-91.
9. Geyer CE, Forster J, Lindquist D, et al. (2006). Lapatinib
plus Capecitabine for HER2-Positive Advanced Breast Cancer. New
England Journal of Medicine 355(26): 2733-43.
10. Blackwell KL, Burstein HJ, Storniolo AM, et al. (2012).
Overall Survival Benefit With Lapatinib in Combination With
Trastuzumab for Patients With Human Epidermal Growth Factor
Receptor 2–Positive Metastatic Breast Cancer: Final Results From
the EGF104900 Study. Journal of Clinical Oncology 30(21):
2585-92.
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Media: Monique Greer (425) 527-4641 mgreer@seagen.com Investors:
Peggy Pinkston (425) 527-4160 ppinkston@seagen.com
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