- TUKYSA Combination Reduced Risk of Cancer
Progression in the Brain or Death by Two-Thirds, Doubled Response
Rate and Reduced Risk of Death by Nearly Half Compared to Standard
Therapy Alone -
- Published Simultaneously in the Journal of
Clinical Oncology and Presented in an Oral Session During the
Virtual Scientific Program of the 2020 ASCO Annual Meeting -
- First Anti-HER2 Oral Therapy in Combination
with Standard Medicines to Improve Overall and Progression-Free
Survival in Patients with Metastatic HER2-Positive Breast Cancer
With or Without Brain Metastases -
Seattle Genetics, Inc. today announced positive results from
exploratory analyses of intracranial efficacy, including survival,
in patients with HER2-positive metastatic breast cancer (MBC) who
had stable or active brain metastases in the HER2CLIMB pivotal
trial of TUKYSA™ (tucatinib). HER2CLIMB compared TUKYSA in
combination with trastuzumab and capecitabine to trastuzumab and
capecitabine alone in patients with unresectable, locally advanced
or metastatic HER2-positive breast cancer with or without brain
metastases. Of the patients enrolled in the trial, 48 percent had a
presence or history of brain metastases. Results demonstrated that
the addition of TUKYSA to trastuzumab and capecitabine in patients
with brain metastases delayed progression in the brain, doubled the
intracranial response rate (tumor shrinkage in the brain) and
reduced the overall risk of death by nearly half. The data were
consistent across patients who had either stable or active brain
metastases. Results were presented in an oral presentation in the
virtual scientific program of the 2020 American Society of Clinical
Oncology (ASCO) Annual Meeting and simultaneously published in the
Journal of Clinical Oncology.
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TUKYSA in combination with trastuzumab and capecitabine was
approved by the U.S. Food and Drug Administration (FDA) in April
2020 for adult patients with advanced unresectable or metastatic
HER2-positive breast cancer, including patients with brain
metastases, who have received one or more prior anti-HER2-based
regimens in the metastatic setting. Primary results from HER2CLIMB
were first presented at the San Antonio Breast Cancer Symposium in
December 2019 and published in the New England Journal of
Medicine.
“It is immensely gratifying to see for the first time, results
for patients with stable or active brain metastases who are not
typically included in clinical trials, especially when you consider
that nearly half of patients with HER2-positive metastatic breast
cancer experience disease progression to the brain,” said Nancy U.
Lin, M.D., director of the Metastatic Breast Cancer Program in the
Susan F. Smith Center for Women’s Cancers at Dana-Farber in Boston,
MA. “These additional analyses provide further evidence that TUKYSA
improves survival and delays cancer progression in the brain for
patients with HER2-positive metastatic breast cancer who have brain
metastases.”
“These additional analyses, together with the primary analysis
of HER2CLIMB, show TUKYSA is active for patients with and without
disease that has spread to the brain,” said Roger Dansey, M.D.,
Chief Medical Officer of Seattle Genetics. “We continue to be
encouraged by the remarkable clinical activity of TUKYSA in
combination with trastuzumab and capecitabine and look forward to
evaluating its potential in additional treatment settings and tumor
types through our ongoing clinical program.”
The new data that further examine TUKYSA’s effect in the brain
include exploratory analyses for central nervous system
progression-free survival (CNS-PFS), overall survival (OS),
intracranial objective response rate (ORR-IC) and duration of
response in HER2-positive metastatic breast cancer patients whose
disease had spread to the brain.
The exploratory analyses demonstrated that patients with brain
metastases who received the TUKYSA combination versus trastuzumab
and capecitabine alone had:
- a 42 percent reduction in the risk of death
- a 68 percent reduction in the risk of CNS disease progression
(a delay in progression in the brain) or death
- a more than doubling of intracranial response rate (47 percent
vs. 20 percent) for patients who had active measurable intracranial
lesions at baseline
Endpoint
TUKYSA Arm (TUKYSA + trastuzumab +
capecitabine)
Control Arm (Placebo + trastuzumab +
capecitabine)
OS Benefit in All Patients with Brain
Metastases
N=198
N=93
Risk Reduction
42% (Hazard Ratio [HR]=0.58 [95%
Confidence Interval (CI): 0.40, 0.85]; p=0.005)
One-Year OS
70.1% (95% CI: 62.1, 76.7)
46.7% (95% CI: 33.9, 58.4)
Median OS
18.1 months (95% CI: 15.5, not
estimable)
12 months (95% CI: 11.2, 15.2)
CNS-PFS Benefit in All Patients with
Brain Metastases
N=198
N=93
Risk Reduction
68% (HR=0.32 [95% CI: 0.22, 0.48];
p<0.0001)
One-year CNS-PFS
40.2% (95% CI: 29.5, 50.6)
0%
Median CNS-PFS
9.9 months (95% CI: 8.0, 13.9)
4.2 months (95% CI: 3.6, 5.7)
Intracranial Objective Response Rate
(ORR-IC) in Patients with Active Brain Metastases and Measurable
Intracranial Lesions at Baseline
N=55
N=20
Complete Response (CR)
3 (5.5%)
1 (5.0%)
Partial Response (PR)
23 (41.8%)
3 (15.0%)
Stable Disease
24 (43.6%)
16 (80.0%)
Progressive Disease
2 (3.6%)
0
Not Available
3 (5.5%)
0
ORR-IC (CR+PR)
26 (47%) (95% CI: 34, 61)
4 (20%) (95% CI: 6, 44)
Duration of Response-IC
6.8 months (95% CI: 5.5, 16.4)
3 months (95% CI: 3.0, 10.3)
About HER2CLIMB
HER2CLIMB is a multinational randomized (2:1), double-blind,
placebo-controlled, active comparator, pivotal clinical trial
comparing TUKYSA 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 OS,
PFS per BICR in patients with brain metastases at baseline and
confirmed ORR.1
Results of Primary Analysis of HER2CLIMB
Endpoint TUKYSA Arm (TUKYSA + trastuzumab +
capecitabine)
Control Arm (Placebo + trastuzumab +
capecitabine)
PFS by BICR in the first 480 patients
46% reduction in risk of progression or
death (HR=0.54 [95% CI: 0.42, 0.71]; p<0.00001; N=480)
OS
34% reduction in risk of death (HR=0.66
[95% CI: 0.50, 0.87]; p=0.0048; N=612)
PFS* by BICR in patients with brain
metastases
52% reduction in risk of progression or
death (HR=0.48 [95% CI: 0.34, 0.69]; p<.0.00001; N=291)
One-Year PFS
25% (95% CI: 17, 34)
0%
Median PFS
7.6 months (95% CI: 6.2, 9.5)
5.4 months (95% CI: 4.1, 5.7)
*standard RECIST, includes brain and
body
In HER2CLIMB, serious adverse reactions occurred in 26 percent
of patients who received TUKYSA. Serious adverse reactions
occurring in 2 percent or more of patients who received TUKYSA were
diarrhea (4%), vomiting (2.5%), nausea, abdominal pain, and seizure
(2% each). The most common adverse reactions occurring in 20
percent or more of patients who received TUKYSA were diarrhea,
palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity,
vomiting, stomatitis, decreased appetite, abdominal pain, headache,
anemia, and rash. Adverse reactions leading to treatment
discontinuation occurred in 6 percent of patients who received
TUKYSA; adverse reactions leading to treatment discontinuation of
TUKYSA (in 1 percent or more of patients) were hepatotoxicity
(1.5%) and diarrhea (1%).1
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 growth of cancer cells. An estimated
279,100 new cases of breast cancer will be diagnosed in the U.S. in
2020.2 Between 15 and 20 percent of breast cancer cases are
HER2-positive.3 Historically, HER2-positive breast cancer tends to
be more aggressive and more likely to recur than HER2-negative
breast cancer.3,4,5 Up to 50 percent of metastatic HER2-positive
breast cancer patients develop brain metastases over time.
6,7,8
About TUKYSA (tucatinib)
TUKYSA is an oral, small molecule tyrosine kinase inhibitor
(TKI) of HER2, a protein that contributes to cancer cell growth.1,9
In vitro (in lab studies), TUKYSA inhibited phosphorylation of HER2
and HER3, resulting in inhibition of downstream MAPK and AKT
signaling and cell growth (proliferation), and showed anti-tumor
activity in HER2-expressing tumor cells. In vivo (in living
organisms), TUKYSA inhibited the growth of HER2-expressing tumors.
The combination of TUKYSA and the anti-HER2 antibody trastuzumab
showed increased anti-tumor activity in vitro and in vivo compared
to either medicine alone.1
Important Safety Information
Warnings and Precautions
- Diarrhea – TUKYSA can cause severe diarrhea including
dehydration, hypotension, acute kidney injury, and death. In
HER2CLIMB, 81% of patients who received TUKYSA experienced
diarrhea, including 12% with Grade 3 diarrhea and 0.5% with Grade 4
diarrhea. Both patients who developed Grade 4 diarrhea subsequently
died, with diarrhea as a contributor to death. The median time to
onset of the first episode of diarrhea was 12 days and the median
time to resolution was 8 days. Diarrhea led to dose reductions of
TUKYSA in 6% of patients and discontinuation of TUKYSA in 1% of
patients. Prophylactic use of antidiarrheal treatment was not
required on HER2CLIMB. If diarrhea occurs, administer antidiarrheal
treatment as clinically indicated. Perform diagnostic tests as
clinically indicated to exclude other causes of diarrhea. Based on
the severity of the diarrhea, interrupt dose, then dose reduce or
permanently discontinue TUKYSA.
- Hepatotoxicity – TUKYSA can cause severe hepatotoxicity.
In HER2CLIMB, 8% of patients who received TUKYSA had an ALT
increase >5 × ULN, 5% had an AST increase >5 × ULN, and 1.5%
had a bilirubin increase >3 × ULN (Grade ≥3). Hepatotoxicity led
to dose reduction of TUKYSA in 8% of patients and discontinuation
of TUKYSA in 1.5% of patients. Monitor ALT, AST, and bilirubin
prior to starting TUKYSA, every 3 weeks during treatment, and as
clinically indicated. Based on the severity of hepatoxicity,
interrupt dose, then dose reduce or permanently discontinue
TUKYSA.
- Embryo-Fetal Toxicity – TUKYSA can cause fetal harm.
Advise pregnant women and females of reproductive potential risk to
a fetus. Advise females of reproductive potential, and male
patients with female partners of reproductive potential, to use
effective contraception during TUKYSA treatment and for at least 1
week after the last dose.
Adverse Reactions
Serious adverse reactions occurred in 26% of patients who
received TUKYSA. Serious adverse reactions in ≥2% of patients who
received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea (2%),
abdominal pain (2%), and seizure (2%). Fatal adverse reactions
occurred in 2% of patients who received TUKYSA including sudden
death, sepsis, dehydration, and cardiogenic shock.
Adverse reactions led to treatment discontinuation in 6% of
patients who received TUKYSA; those occurring in ≥1% of patients
were hepatotoxicity (1.5%) and diarrhea (1%). Adverse reactions led
to dose reduction in 21% of patients who received TUKYSA; those
occurring in ≥2% of patients were hepatotoxicity (8%) and diarrhea
(6%).
The most common adverse reactions in patients who received
TUKYSA (≥20%) were diarrhea, palmar-plantar erythrodysesthesia,
nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased
appetite, abdominal pain, headache, anemia, and rash.
Lab Abnormalities
In HER2CLIMB, Grade ≥3 laboratory abnormalities reported in ≥5%
of patients who received TUKYSA were: decreased phosphate,
increased ALT, decreased potassium, and increased AST. The mean
increase in serum creatinine was 32% within the first 21 days of
treatment with TUKYSA. The serum creatinine increases persisted
throughout treatment and were reversible upon treatment completion.
Consider alternative markers of renal function if persistent
elevations in serum creatinine are observed.
Drug Interactions
- Strong CYP3A or Moderate CYP2C8 Inducers: Concomitant
use may decrease TUKYSA activity. Avoid concomitant use of
TUKYSA.
- Strong or Moderate CYP2C8 Inhibitors: Concomitant use of
TUKYSA with a strong CYP2C8 inhibitor may increase the risk of
TUKYSA toxicity; avoid concomitant use. Increase monitoring for
TUKYSA toxicity with moderate CYP2C8 inhibitors.
- CYP3A Substrates: Concomitant use may increase the
toxicity associated with a CYP3A substrate. Avoid concomitant use
of TUKYSA where minimal concentration changes may lead to serious
or life-threatening toxicities. If concomitant use is unavoidable,
decrease the CYP3A substrate dosage.
- P-gp Substrates: Concomitant use may increase the
toxicity associated with a P-gp substrate. Consider reducing the
dosage of P-gp substrates where minimal concentration changes may
lead to serious or life-threatening toxicity.
Use in Specific Populations
- Lactation: Advise women not to breastfeed while taking
TUKYSA and for at least 1 week after the last dose.
- Renal Impairment: Use of TUKYSA in combination with
capecitabine and trastuzumab is not recommended in patients with
severe renal impairment (CLcr < 30 mL/min), because capecitabine
is contraindicated in patients with severe renal impairment.
- Hepatic Impairment: Reduce the dose of TUKYSA for
patients with severe (Child-Pugh C) hepatic impairment.
For more information, please see the full Prescribing
Information for TUKYSA here.
About Seattle Genetics
Seattle Genetics, Inc. is a global biotechnology company that
discovers, develops and commercializes transformative medicines
targeting cancer to make a meaningful difference in people’s lives.
The company is headquartered in the Seattle, Washington area, and
has offices in California, Switzerland and the European Union. For
more information on our robust pipeline, visit
www.seattlegenetics.com and follow @SeattleGenetics on Twitter.
Forward Looking Statements
Certain statements made in this press release are forward
looking, such as those, among others, relating to the therapeutic
potential of TUKYSA including its efficacy, safety and therapeutic
uses, including its use in combination with trastuzumab and
capecitabine to treat patients with HER2-positive metastatic breast
cancer with brain metastases who have received one or more previous
anti-HER2 therapies, and its potential use in additional treatment
settings and tumor types. 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 possibility that adverse events or safety signals may occur;
that utilization and adoption of TUKYSA by prescribing physicians
may be limited due to impacts related to the COVID-19 pandemic,
availability and extent of reimbursement or other factors; and that
adverse regulatory actions may occur. 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, 2020
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.
1 TUKYSA [package insert]. Bothell, WA: Seattle Genetics, Inc. 2
Cancer Facts & Figures 2020. American Cancer Society website.
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf.
Accessed May 28, 2020. 3 Loibli S, Gianni L. HER2-positive breast
cancer. Lancet. 2017; 389(10087): 2415-29. 4 Slamon D, Clark G,
Wong S, et al. Human breast cancer: correlation of relapse and
survival with amplification of the HER-2/neu oncogene. Science.
1987; 235(4785): 177-82. 5 Breast Cancer HER2 Status. American
Cancer Society website.
www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-her2-status.html.
Accessed May 28, 2020. 6 Freedman RA, Gelman RS, Anders CK, et al.
TBCRC 022: a phase II trial of neratinib and capecitabine for
patients with human epidermal growth factor receptor 2-positive
breast cancer and brain metastases. J Clin Oncol.
2019;37:1081-1089. 7 Olson EM, Najita JS, Sohl J, et al. Clinical
outcomes and treatment practice patterns of patients with
HER2-positive metastatic breast cancer in the post-trastuzumab era.
Breast. 2013;22:525-531. 8 Bendell JC, Domchek SM, Burstein HJ, et
al. Central nervous system metastases in women who receive
trastuzumab-based therapy for metastatic breast carcinoma. Cancer.
2003;97:2972-2977. 9 Anita Kulukian, Patrice Lee, Janelle Taylor,
et al. Preclinical Activity of HER2-Selective Tyrosine Kinase
Inhibitor Tucatinib as a Single Agent or in Combination with
Trastuzumab or Docetaxel in Solid Tumor Models. Mol Cancer Ther
2020;19:976-987.
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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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