In combination with trastuzumab + capecitabine
TUKYSA DELIVERED SUPERIOR SURVIVAL FOR PATIENTS WITH HER2+ MBC1
In patients treated with TUKYSA (tucatinib) + trastuzumab + capecitabine (TUKYSA arm) vs those treated with placebo + trastuzumab + capecitabine (control arm):
Progression-free survival
- Primary endpoint: Median PFS: 7.8 months (95% CI: 7.5-9.6) in the TUKYSA arm vs 5.6 months (95% CI: 4.2-7.1) in the control arm; HR = 0.54 (95% CI: 0.42-0.71); P <0.000011*
- Secondary endpoint: Median PFS in patients with brain metastases: 7.6 months (95% CI: 6.2-9.5) in the TUKYSA arm vs 5.4 months (95% CI: 4.1-5.7) in the control arm; HR = 0.48 (95% CI: 0.34-0.69); P <0.000011
- Exploratory analysis: Median PFS in patients without brain metastases: 9.6 months (95% CI: 7.6-12.4) in the TUKYSA arm vs 6.8 months (95% CI: 4.3-9.3) in the control arm; HR = 0.57 (95% CI: 0.41-0.80)2
*Data from the first 480 patients.1
CI = confidence interval; HR = hazard ratio; HER = human epidermal growth factor receptor; KM = Kaplan-Meier; MBC = metastatic breast cancer; PFS = progression-free survival.
Select Important Safety Information
- The labeling for TUKYSA contains warnings and precautions for diarrhea, hepatotoxicity, and embryo-fetal toxicity, some of which may be severe or fatal. Please see the full Prescribing Information for management and dose modification information specific to adverse reactions.
- The most common serious adverse reactions in ≥2% of patients who received TUKYSA in combination with trastuzumab and capecitabine were diarrhea, vomiting, nausea, abdominal pain, and seizure.
- The most common adverse reactions in ≥20% of patients who received TUKYSA in combination with trastuzumab and capecitabine were diarrhea, palmar-plantar erythrodysesthesia, nausea, hepatotoxicity, vomiting, stomatitis, decreased appetite, anemia, and rash.
Please see additional Important Safety Information below.
In combination with trastuzumab + capecitabine
TUKYSA achieved a median overall survival of more than 2 years at follow-up analysis3
OS in the total population (N=612)1,3
Consistent results were observed across select subgroups at follow-up analysis3,4
9.1-month difference in patients with brain metastases5
- Median OS: 21.6 months (95% CI: 18.1-28.5) in the TUKYSA arm vs 12.5 months (95% CI: 11.2-16.9) in the control arm; HR = 0.60 (95% CI: 0.44-0.81); exploratory analysis
4.7-month difference in patients with visceral disease6
- Median OS: 21.6 months (95% CI: 18.1-25.6) in the TUKYSA arm vs 16.9 months (95% CI: 12.3-19.4) in the control arm; HR = 0.70 (95% CI: 0.55-0.89); exploratory analysis
OS RESULTS WERE CONSISTENT ACROSS SELECT SUBGROUPS AT FOLLOW-UP ANALYSIS3,4
OS RESULTS WERE CONSISTENT ACROSS SELECT SUBGROUPS AT FOLLOW-UP ANALYSIS3,4
Follow-up analysis data cutoff: February 8, 2021.3
*These subgroups were not prespecified.
†Data from the patients in the United States and Canada were combined for this analysis.7
Please see Important Safety Information and the accompanying full Prescribing Information.
Results of the exploratory subgroup analyses shown above are descriptive but not conclusive, are not controlled for type 1 error, and should be interpreted with caution.
OS = overall survival.
Follow-up analysis data cutoff: February 8, 20213
Please see Important Safety Information and the accompanying full Prescribing Information.
In combination with trastuzumab + capecitabine
TUKYSA delivered CNS activity in patients with brain metastases at follow-up analysis5
Delayed CNS-PFS in patients with brain metastases5
CNS-PFS in patients with brain metastases (n = 291)5,8*†
EXPLORATORY ANALYSIS
HR = 0.39 (95% Cl: 0.27-0.56)
NUMBER OF EVENTS
TUKYSA arm: 94/198
Control arm: 48/93
†Results of this post-hoc, exploratory analysis are descriptive, but they are not conclusive, are not controlled for type 1 error, and should be interpreted with caution. The results are estimates (not exact numbers). Due to a high rate of censoring patients owing to extra-CNS progression, results should be interpreted with caution. Data cutoff for follow-up analysis was February 8, 2021.5
CNS = central nervous system; ORR = objective response rate.
Increased intracranial response rate in patients with brain metastases5
ORR-IC in patients with measurable brain metastases (n = 75)5,9ठ(exploratory analysis)
‡Intracranial response was assessed by investigators according to RECIST, version 1.1, in patients with measurable intracranial lesions at baseline.5
§Results of this post-hoc, exploratory analysis are descriptive, but they are not conclusive, are not controlled for type 1 error, and should be interpreted with caution. Data cutoff for follow-up analysis was February 8, 2021.5
CR = complete response; IC = intracranial; ORR = objective response rate; PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors.
TUKYSA reduced the risk of developing new brain lesions or death by nearly half in all patients5
Time from randomization to new brain lesion development as the first site of progression per investigator assessment or death in patients with or without brain metastases at baseline (N = 612)
HR = 0.55 (95% CI: 0.36-0.85)
NE = not estimable.
Select Important Safety Information
- The labeling for TUKYSA contains warnings and precautions for diarrhea, hepatotoxicity, and embryo-fetal toxicity, some of which may be severe or fatal. Please see the full Prescribing Information for management and dose modification information specific to adverse reactions.
- The most common serious adverse reactions in ≥2% of patients who received TUKYSA in combination with trastuzumab and capecitabine were diarrhea, vomiting, nausea, abdominal pain, and seizure.
- The most common adverse reactions in ≥20% of patients who received TUKYSA in combination with trastuzumab and capecitabine were diarrhea, palmar-plantar erythrodysesthesia, nausea, hepatotoxicity, vomiting, stomatitis, decreased appetite, anemia, and rash.
Please click here for Important Safety Information.
In combination with trastuzumab + capecitabine
TUKYSA delivered rapid and confirmed tumor response1,10
OS results in patients with stable disease as best overall response (n = 343)4 *
- Median OS: 21.8 months (95% CI: 18.1-NE) in the TUKYSA arm vs 15.2 months (95% CI:12.0-20.0) in the control arm; HR = 0.60 (95% CI: 0.41-0.88)
- Stable disease rates in HER2CLIMB2:
- 45.6% (155/340) in the TUKYSA arm
- 58.5% (100/171) in the control arm
Results of this exploratory subgroup analysis are descriptive but not conclusive, are not controlled for type 1 error, and should be interpreted with caution.
*Analysis included patients in the total population whose confirmed best overall response by BICR was classified as one of the following: SD or non-CR/non-PD. SD was defined using RECIST, version 1.1, as neither sufficient shrinkage to qualify as a PR (PR was defined as ≥30% decrease) nor sufficient increase to qualify as PD (PD was defined as ≥20% increase).2,4,11
BICR = blinded independent central review; PD = progressive disease; SD = stable disease.
In combination with trastuzumab + capecitabine
TUKYSA delivered proven PFS* benefit in patients with and without brain metastases1,2
Reduced risk of disease progression or death by 46% in the primary endpoint population1†
At 12 months, an estimated 3x as many patients were progression-free7‡
TUKYSA ARM
33%
(33.1%; 95% Cl: 26.6-39.7)
VS
CONTROL ARM
12%
(12.3%; 95% Cl: 6.0-20.9)
*Time from randomization to documented disease progression, as assessed by blinded independent central review, or death from any cause.7
†Data from the first 480 patients.1
Reduced risk of disease progression or death by 52% in patients with brain metastases1,7§
At 12 months, an estimated 1 in 4 patients with brain metastases were progression-free7||
TUKYSA ARM
25%
(24.9%; 95% Cl: 16.5-34.3)
VS
CONTROL ARM
0%
Kaplan-Meier estimates of PFS in patients with brain metastases (secondary endpoint) from the HER2CLIMB trial
*Time from randomization to documented disease progression, as assessed by blinded independent central review, or death from any cause.12
§Analysis includes patients with history or presence of parenchymal brain metastases at baseline, including target and nontarget lesions. Analysis does not include patients with dural lesions only.1
Reduced risk of disease progression or death by 43% in patients without brain metastases2¶
HR = 0.57 (95% CI: 0.41-0.80)
NUMBER OF EVENTS
TUKYSA arm: 91/211
Control arm: 60/108
¶Results of this exploratory subgroup analysis are descriptive but not conclusive, are not controlled for type 1 error, and should be interpreted with caution.
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Important Safety Information
Warnings and Precautions
- Diarrhea: TUKYSA can cause severe diarrhea including dehydration, hypotension, acute kidney injury, and death. 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.
In HER2CLIMB, when TUKYSA was given in combination with trastuzumab and capecitabine, 81% of patients who received TUKYSA experienced diarrhea, including 0.5% with Grade 4 and 12% with Grade 3. Both patients who developed Grade 4 diarrhea subsequently died, with diarrhea as a contributor to death. 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 TUKYSA dose reductions in 6% of patients and TUKYSA discontinuation in 1% of patients. Prophylactic use of antidiarrheal treatment was not required on HER2CLIMB. - Hepatotoxicity: TUKYSA can cause severe hepatotoxicity. 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.
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 TUKYSA dose reductions in 8% of patients and TUKYSA discontinuation in 1.5% of patients. - Embryo-Fetal Toxicity: TUKYSA can cause fetal harm. Advise pregnant women and females of reproductive potential of the 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 1 week after the last dose.
Adverse Reactions
In HER2CLIMB, serious adverse reactions occurred in 26% of patients who received TUKYSA; the most common (in ≥2% of patients) 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; the most common (in ≥1% of patients) were hepatotoxicity (1.5%) and diarrhea (1%). Adverse reactions led to dose reduction in 21% of patients who received TUKYSA; the most common (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, hepatotoxicity, vomiting, stomatitis, decreased appetite, 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/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 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.
REF-7648_FINAL_01/23
Indication
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.
Please see full Prescribing Information.
1. TUKYSA [Prescribing Information]. Bothell, WA: Seagen Inc. January 2023. 2. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. Supplementary appendix. doi:10.1056/NEJMoa1914609 3. Curigliano G, Mueller V, Borges V, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. Ann Oncol. 2022;33(3):321-329. doi:10.1016/j.annonc.2021.12.005 4. Data on file. Seagen Inc. 5. Lin NU, Murthy RK, Abramson V, et al. Tucatinib vs placebo, both in combination with trastuzumab and capecitabine, for previously treated ERBB2 (HER2)-positive metastatic breast cancer in patients with brain metastases: updated exploratory analysis of the HER2CLIMB randomized clinical trial. JAMA Oncol. Published online December 1, 2022. doi:10.1001/jamaoncol.2022.5610 6. Curigliano G, Mueller V, Borges V, et al. Updated results of tucatinib vs placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB). Poster presented at: American Society of Clinical Oncology Annual Meeting; June 4-8, 2021. 7. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609 8. Lin NU, Murthy RK, Abramson V, et al. Updated results of tucatinib vs placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). Poster presented at: San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. 9. Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38(23):2610-2619. doi:10.1200/JCO.20.00775 10. Curigliano G, Murthy R, Loi S, et al. Tucatinib vs placebo added to trastuzumab and capecitabine in previously treated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB). Ann Oncol. 2020;31(suppl 2):S62-S63. doi:10.1016/j.annonc.2020.03.238 11. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. doi:10.1016/j.ejca.2008.10.026