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

Click here to see KM curves.

*Data from the first 480 patients.1

CI = confidence interval; HR = hazard ratio; HER = human epidermal growth factor receptor; MBC = metastatic breast cancer; PFS = progression-free survival.

Select Important Safety Information

  • The Prescribing Information for TUKYSA contains warnings and precautions for diarrhea, hepatotoxicity, and embryo-fetal toxicity, some of which may be severe.
  • The most common serious adverse reactions in ≥2% of patients who received TUKYSA were diarrhea, vomiting, nausea, abdominal pain, and seizure.
  • The most commonly reported 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.

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

TUKYSA (tucatinib): Kaplan-Meier estimates of overall survival (OS) in HER2CLIMB trial
Results of this prespecified exploratory analysis are descriptive but not conclusive, are not controlled for type 1 error, and should be interpreted with caution. Data cutoff for follow-up analysis was February 8, 2021.3

Consistent results were observed across select subgroups at follow-up analysis3,4

FOLLOW-UP ANALYSIS

9.1-month improvement 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 improvement in patients with visceral disease3

  • 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
Review safety data for 2-year follow-up

OS RESULTS WERE CONSISTENT ACROSS SELECT SUBGROUPS AT FOLLOW-UP ANALYSIS3,4

Results of this exploratory subgroup analysis are descriptive but not conclusive, are not controlled for type 1 error, and should be interpreted with caution.

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.

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.

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 provided CNS activity in patients with brain metastases5-7

Delayed CNS-PFS in patients with brain metastases5

CNS-PFS in patients with brain metastases (N = 291)5*†

TUKYSA (tucatinib): Kaplan-Meier estimates of CNS-PFS in patients with brain metastases

EXPLORATORY ANALYSIS
HR = 0.39 (95% Cl: 0.27-0.56)

NUMBER OF EVENTS
TUKYSA arm: 94/198
Control arm: 48/93

*CNS-PFS was defined as the time from randomization to disease progression in the brain by investigator assessment or death. Progression in the brain was evaluated by applying RECIST, version 1.1, to assess brain lesions in isolation from other organs.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. The results are estimates (not exact numbers). Due to a high rate of censoring patients owing to extra-CNS progression or death, results should be interpreted with caution. Data cutoff for follow-up analysis was February 8, 2021.5

Increased intracranial response in patients with brain metastases5,6

ORR-IC in patients with measurable brain metastases (N = 75)5,6ठ(exploratory analysis)

Bar chart: Intracranial Overall Response Rate (ORR-IC) in patients with measurable brain metastases
2.5% stat graphic
Intracranial response was assessed by investigators according to RECIST, version 1.1, in patients with measurable CNS lesions at baseline.5,6

§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

TUKYSA reduced the risk of developing new brain lesions or death by nearly half in all patients7

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)

TUKYSA (tucatinib): Kaplan-Meier estimates of time from randomization to new brain lesion development
EXPLORATORY ANALYSIS
HR = 0.52(95% CI: 0.33-0.82)

NUMBER OF EVENTS
TUKYSA arm: 52/410
Control arm: 33/202

INCIDENCE OF NEW BRAIN LESIONS
TUKYSA arm: 6.1%(25/410)
Control arm: 9.4%(19/202)

INCIDENCE OF DEATH
TUKYSA arm: 6.6%(27/410)
Control arm: 6.9%(14/202)
Results of this exploratory analysis are descriptive but not conclusive, and they are not controlled for type 1 error. Due to a high rate of censoring of patients owing to extra-CNS progression or death, results should be interpreted with caution.

NE = non estimable

Select Important Safety Information

  • The Prescribing Information for TUKYSA contains warnings and precautions for diarrhea, hepatotoxicity, and embryo-fetal toxicity, some of which may be severe.
  • The most common serious adverse reactions in ≥2% of patients who received TUKYSA were diarrhea, vomiting, nausea, abdominal pain, and seizure.
  • The most commonly reported 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.

Please click here for Important Safety Information.


In combination with trastuzumab + capecitabine

TUKYSA DELIVERED RAPID AND CONFIRMED TUMOR RESPONSE1,4

Achieved disease control for the majority of patients2,4,7

Best tumor response for patients with or without brain metastases in the TUKYSA arm
Waterfall plot: Disease control rate in patients with or without brain metastases

~2x greater confirmed ORR1 

  • 40.6% (95% CI: 35.3-46.0; CR = 0.9%; PR = 39.7%) in the TUKYSA arm vs 22.8% (95% CI: 16.7-29.8; CR = 1.2%; PR = 21.6%) in the control arm; P = 0.00008; secondary endpoint1

6 week median time to response8 

Results of this exploratory analysis are descriptive only and are not contained in the approved product labeling.

  • 92% disease control rate in the TUKYSA arm (320 patients evaluated: CR, n = 3; PR, n = 135; SD, n = 155)2*
  • 85% disease control rate in the control arm (163 patients evaluated: CR, n = 2; PR, n = 37; SD, n = 100)2*
  • Note that not every bar on the waterfall plot below the horizontal zero line represents a confirmed objective response
  • The interpretation and clinical relevance of a best overall response of SD are not clear, and it is not possible to determine if SD is a result of natural disease progression or treatment

Results of this exploratory analysis are descriptive but not conclusive, are not controlled for type 1 error, and should be interpreted with caution.

An OS benefit was observed 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)

Results of this exploratory subgroup analysis are descriptive but not conclusive, are not controlled for type 1 error, and should be interpreted with caution.

*Disease control rate is the percentage of patients with an evaluable scan post-baseline assessment who achieved a best response of CR, PR, or SD.
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 1.1 criteria as neither sufficient shrinkage to qualify as a PR (ie, a <30% decrease), nor sufficient increase to qualify as PD (ie, a <20% increase).2,4,9

CR = complete response; PD = progressive disease; PR = partial response; 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†
TUKYSA (tucatinib): Kaplan-Meier estimates of progression free survival (PFS) from the HER2CLIMB trial

At 12 months, ~3x as many patients were progression-free10‡

TUKYSA ARM

33%

(33.1%; 95% Cl: 26.6-39.7)

VS

CONTROL ARM

12%

12.3%; 95% Cl: 6.0-20.9)

‡Results of this exploratory landmark analysis are descriptive but not conclusive, are not controlled for type 1 error, and should be interpreted with caution. The rates shown are estimates at this time point.
*Time from randomization to documented disease progression, as assessed by blinded independent central review, or death from any cause.10

Data from the first 480 patients.1
Reduced risk of disease progression or death by 52% in patients with brain metastases1,10§
TUKYSA (tucatinib): Kaplan-Meier estimates of progression free survival (PFS) in patients with brain metastases from the HER2CLIMB trial

At 12 months, 1 in 4 patients with brain metastases were progression-free10||

TUKYSA ARM

25%

24.9%; 95% Cl: 16.5-34.3)

VS

CONTROL ARM

0%

‡Results of this exploratory landmark analysis are descriptive but not conclusive, are not controlled for type 1 error, and should be interpreted with caution. The rates shown are estimates at this time point.

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.10

§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 metastases
TUKYSA (tucatinib): Kaplan-Meier estimates of progression free survival (PFS) in patients without brain metastases
EXPLORATORY ANALYSIS
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.
*Time from randomization to documented disease progression, as assessed by blinded independent central review, or death from any cause.10
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Next: Review the safety profile

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 and 0.5% with Grade 4. 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.

    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 TUKYSA dose reductions in 8% of patients and TUKYSA discontinuation 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 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 at least 1 week after the last dose.

Adverse Reactions

Serious adverse reactions occurred in 26% of patients who received TUKYSA; those occurring 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; 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/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.

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.

References
1. TUKYSA [Prescribing Information]. Bothell, WA: Seagen Inc. April 2020. 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]. 3. 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. 4. Data on file. Seagen Inc. 5. 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. 6. 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. 7. Bachelot T, Lin NU, Murthy RK, et al. Impact of tucatinib on progression-free survival in patients with HER2+ metastatic breast cancer and stable or active brain metastases. Poster presented at: European Society for Medical Oncology Virtual Congress; September 19-21, 2020. 8. 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 9. 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. 10. 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.