- First HER2 Tyrosine Kinase Inhibitor in
Combination to Show Improved Progression-Free Survival and Overall
Survival in Patients with Metastatic HER2-Positive Breast Cancer
With or Without Brain Metastases -
- NDA and MAA On Track for Submission by First
Quarter of 2020 -
Seattle Genetics, Inc. (Nasdaq:SGEN) today announced positive
pivotal data from the HER2CLIMB trial evaluating tucatinib in
patients with HER2-positive metastatic breast cancer (MBC) were
presented at the 2019 San Antonio Breast Cancer Symposium (SABCS)
and simultaneously published in the New England Journal of Medicine
(NEJM). The HER2CLIMB trial compared tucatinib in combination with
trastuzumab and capecitabine to trastuzumab and capecitabine alone
in patients with unresectable locally advanced 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 lines in the metastatic setting. Forty-seven
percent of the patients enrolled in the trial had brain metastases
at the time of enrollment. HER2CLIMB is the first randomized
pivotal trial completed to enroll patients with metastatic
HER2-positive breast cancer who have untreated or previously
treated and progressing brain metastases. Tucatinib is an oral,
small molecule tyrosine kinase inhibitor (TKI) that is highly
selective for HER2.
“Following progression on trastuzumab, pertuzumab and T-DM1 in
the metastatic HER2-positive breast cancer setting, there is no
single standard of care regimen and clinical trial participation is
often strongly encouraged. There is a significant unmet medical
need for these patients, particularly those who develop brain
metastases,” said Rashmi Murthy, MD, MBE, Assistant Professor,
Department of Breast Medical Oncology, Division of Cancer Medicine,
The University of Texas MD Anderson Cancer Center. “The addition of
tucatinib to the commonly used combination of trastuzumab and
capecitabine improved overall survival, reducing the risk of death
by 34 percent compared to trastuzumab and capecitabine alone. The
results from HER2CLIMB demonstrate tucatinib has the potential to
become a new treatment option for patients who have been previously
treated with multiple anti-HER2 agents, including patients with and
without brain metastases.”
“Continued innovation to bring new therapies for the treatment
of metastatic HER2-positive breast cancer is urgently needed, and
we are encouraged by the impressive clinical activity demonstrated
with the addition of tucatinib to trastuzumab and capecitabine in
the HER2CLIMB trial,” said Roger Dansey, M.D., Chief Medical
Officer at Seattle Genetics. “Tucatinib demonstrated a
statistically significant and clinically meaningful benefit in
overall survival, progression-free survival and objective response
rate compared to the control arm. We plan to submit a New Drug
Application (NDA) to the U.S. Food and Drug Administration and a
Marketing Authorization Application (MAA) to the European Medicines
Agency by the first quarter of 2020, with the goal of bringing a
much-needed new medicine to patients.”
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. HER2CLIMB enrolled a total of 612 patients
to support the analyses of key secondary endpoints, including
overall survival (OS) as well as progression-free survival (PFS) in
patients with brain metastases at baseline.
Pivotal HER2CLIMB Trial Results
Efficacy:
- 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).
- Estimated PFS at one year was 33 percent (95% CI: 27, 40) in
the tucatinib arm, compared to 12 percent (95% CI: 6, 21) in the
trastuzumab and capecitabine arm (control arm).
- Median PFS was 7.8 months (95% CI: 7.5, 9.6) in the tucatinib
arm, compared to 5.6 months (95% CI: 4.2, 7.1) in the control
arm.
- The addition of tucatinib to trastuzumab and capecitabine
prolonged OS, a key secondary endpoint, reducing the risk of death
by 34 percent (HR=0.66 [95% CI: 0.50, 0.88]; p=0.0048), compared to
the control arm.
- Estimated OS at two years was 45 percent (95% CI: 37, 53) in
the tucatinib arm, compared to 27 percent (95% CI: 16, 39) in the
control arm.
- Median OS was 21.9 months (95% CI: 18.3, 31.0) in the tucatinib
arm, compared to 17.4 months (95% CI: 13.6, 19.9) in the control
arm.
- For patients with brain metastases at baseline, a key secondary
endpoint, the tucatinib arm also demonstrated superior PFS compared
to trastuzumab and capecitabine alone. Findings demonstrated that
the tucatinib regimen resulted in 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).
- The estimated PFS at one year was 25 percent (95% CI: 17, 34)
with the tucatinib regimen, compared to zero percent in the control
arm.
- Median PFS was 7.6 months (95% CI: 6.2, 9.5) in the tucatinib
arm, compared to 5.4 months (95% CI: 4.1, 5.7) in the control
arm.
- The confirmed objective response rate (ORR) in the patient
population with measurable disease at baseline (511/612) was 40.6
percent (95% CI: 35.3, 46.0) in the tucatinib arm, compared with
22.8 percent (95% CI: 16.7, 29.8) for trastuzumab and capecitabine
alone (p=0.0008).
Safety:
- 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 (80.9 vs. 53.3 percent),
palmar-plantar erythrodysaesthesia syndrome (PPE) (63.4 vs. 52.8
percent), nausea (58.4 vs. 43.7 percent), fatigue (45.0 vs. 43.1
percent) and vomiting (35.9 vs. 25.4 percent), which were primarily
low grade.
- 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 and 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:
- American Cancer Society, Cancer Facts and Figures
2018-2019.
- Loibl S, Gianni L (2017). HER2-positive breast cancer. The
Lancet 389(10087): 2415-29.
- 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.
- American Cancer Society (ACS) (2018). Breast cancer HER2
status. Accessed: December 10, 2018.
- Kennecke H, Yerushalmi R, Woods R, et al. (2010). Metastatic
Behavior of Breast Cancer Subtypes. Journal of Clinical Oncology
28(20): 3271-7.
- 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.
- Duchnowska R, Loibl S, Jassem J (2018). Tyrosine kinase
inhibitors for brain metastases in HER2-positive breast cancer.
Cancer Treatment Reviews 67: 71-7.
- 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.
- 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.
- 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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version on businesswire.com: https://www.businesswire.com/news/home/20191211005577/en/
Media: Monique Greer (425) 527-4641 mgreer@seagen.com
Investors: Peggy Pinkston (425) 527-4160
ppinkston@seagen.com
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