On December 8, 2021 Seagen Inc. (Nasdaq:SGEN) reported the presentation of new data from exploratory analyses from the pivotal HER2CLIMB trial showing that improvement in overall survival (OS) was maintained after an additional 15.6 months of follow-up when TUKYSA (tucatinib) was combined with trastuzumab and capecitabine in patients with HER2-positive metastatic breast cancer (MBC) who had stable or active brain metastases (Press release, Seagen, DEC 8, 2021, View Source [SID1234596603]). The data were featured today in a spotlight poster (Abstract #PD4-04) at the 2021 San Antonio Breast Cancer Symposium (SABCS).
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"The risk of breast cancer spreading to the brain is more pronounced for patients with aggressive subtypes of breast cancer, including HER2-positive breast cancer," 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 analyses provide a hopeful outcome for patients with HER2-positive metastatic breast cancer when cancer has spread to the brain as they show that the TUKYSA regimen not only helped patients live longer but also slowed disease progression in the brain."
"After more than two years of follow up, these exploratory analyses show the impact that TUKYSA can have on HER2-positive metastatic breast cancer patients and underscore its importance as a treatment option," said Roger D. Dansey, M.D., Chief Medical Officer of Seagen.
After a median follow-up of 29.6 months, the TUKYSA regimen improved OS for patients with brain metastases by 9.1 months compared to trastuzumab and capecitabine alone (21.6 months vs. 12.5 months) (HR: 0.60; [95% CI: 0.44, 0.81]). The benefit extended to patients with active or stable brain metastases.
Overall Survival
Brain
Metastases
Subgroup
Hazard Ratio
[95% CI]
Improvement in
Median OS
Median OS [95% CI]
TUKYSA + trastuzumab
+ capecitabine
trastuzumab +
capecitabine
Active + Stable (n=291)
0.60 [0.44, 0.81]
9.1 months
21.6 months [18.1, 28.5]
12.5 months [11.2, 16.9]
Active (n=174)
0.52 [0.36, 0.77]
9.6 months
21.4 months [18.1, 28.9]
11.8 months [10.3, 15.2]
Stable (n=117)
0.70 [0.42, 1.16]
5.2 months
21.6 months [15.3, 42.4]
16.4 months [10.6, 21.6]
TUKYSA treatment continued to show clinically meaningful benefit in progression-free survival in the central nervous system (CNS-PFS), representing a delay of cancer progression in the brain. The rates for intracranial objective response rate (ORR-IC) and duration of objective response (DOR-IC) were consistent with previous analyses.
Central Nervous System-Progression Free Survival
Brain Metastases
Subgroup
Hazard Ratio [95% CI]
Median CNS-PFS [95% CI]
TUKYSA + trastuzumab
+ capecitabine
trastuzumab +
capecitabine
Active + Stable (n=291)
0.39 [0.27, 0.56]
9.9 months [8.4, 11.7]
4.2 months [3.6, 5.7]
Active (n=174)
0.34 [0.22, 0.54]
9.6 months [7.6, 11.1]
4.0 months [2.9, 5.6]
Stable (n=117)
0.41 [CI: 0.19, 0.85]
13.9 months [9.7, 24.9]
5.6 months [CI: 3.0, -]
Please see Important Safety Information for TUKYSA below.
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 overall survival, PFS per BICR in patients with brain metastases at baseline and confirmed objective response rate. Safety data were evaluated throughout the study.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. Up to 50 percent of metastatic HER2-positive breast cancer patients develop brain metastases over time.2,3,4 In 2020, more than two million new cases of breast cancer were diagnosed worldwide.5 Between 15 and 20 percent of breast cancer cases are HER2-positive.6
About TUKYSA (tucatinib)
TUKYSA is an oral medicine that is a tyrosine kinase inhibitor of the HER2 protein. 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.
TUKYSA is approved in 36 countries. It was approved by the U.S. FDA in April 2020 and by the European Medicines Agency and the UK Medicines and Healthcare Products Regulatory Agency in February 2021. Merck, known as MSD outside the U.S. and Canada, has exclusive rights to commercialize TUKYSA in Asia, the Middle East and Latin America and other regions outside of the U.S., Canada and Europe.
U.S. Indication and Important Safety Information
TUKYSA is indicated in combination with trastuzumab and capecitabine for treatment of 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.
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, 6% 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 hepatotoxicity, 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.