HER2CLIMB: A GLOBAL, RANDOMIZED, DOUBLE-BLIND, CONTROLLED TRIAL1

Pivotal trial design1,2

Adults with locally advanced unresectable or metastatic HER2+ breast cancer who had received prior trastuzumab, pertuzumab, and T-DM1 separately or in combination, in the neoadjuvant, adjuvant, or metastatic setting were eligible to enroll.

HER2CLIMB trial design: 612 patients were randomized (2:1) into the TUKYSA arm (n = 410; received TUKYSA + trastuzumab + capecitabine) or control arm (n = 202; received placebo + trastuzumab + capecitabine) HER2CLIMB trial design: 612 patients were randomized (2:1) into the TUKYSA arm (n = 410; received TUKYSA + trastuzumab + capecitabine) or control arm (n = 202; received placebo + trastuzumab + capecitabine)

PRIMARY ENDPOINT*

  • PFS (n = 480)

KEY SECONDARY ENDPOINTS

  • OS (N = 612)
  • PFS in patients with brain metastases (n = 291)
  • Confirmed ORR in patients with measurable disease at baseline (n = 511)
  • Dosing, repeated every 21 days: TUKYSA, 300 mg orally, twice daily, or placebo, twice daily; trastuzumab, 6 mg/kg intravenously, once every 21 days with an initial dose of 8 mg/kg (subcutaneous dosing was also allowed); capecitabine, 1000 mg/m2 orally, twice daily, on Days 1-14
  • PFS (primary endpoint) was assessed in the first 480 randomized patients; secondary endpoints were assessed in the total population
  • Patients were stratified according to whether brain metastases were present (yes or no), ECOG performance status score (0 or 1), and geographic region (United States and Canada, or rest of world)

*Target enrollment for HER2CLIMB was increased twice to ensure there was adequate statistical power to assess the primary endpoint and, subsequently, a key secondary endpoint.3

†Evaluated in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1, by means of blinded independent central review (BICR).2

ECOG = Eastern Cooperative Oncology Group; HER = human epidermal growth factor receptor; PFS = progression-free survival; ORR = objective response rate; OS = overall survival; T-DM1 = ado-trastuzumab emtansine.

HER2CLIMB included the largest cohort of patients with brain metastases studied in a registrational trial for HER2+ MBC‡1,2

48%

patients with brain metastases

52%

patients without brain metastases

52%

patients without brain metastases

48%

patients with brain metastases

60%

active

40%

stable

23%

untreated
progressing

37%

treated
progressing
The first and only randomized
trial to study these patients

Patients with brain metastases who did not require immediate local therapy were also permitted to enroll.‡2

‡All patients received a brain MRI at baseline. Patients with brain metastases, including those with progressing or untreated lesions, were eligible provided they were neurologically stable and did not require immediate radiation or surgery. The trial excluded patients with leptomeningeal disease.1,2

MBC = metastatic breast cancer; MRI = magnetic resonance imaging.

Select Safety Information

  • 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 hepatoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
Please click here for Important Safety Information.

ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal.

HER2CLIMB studied a broad population of patients with HER2+ MBC2,4

TUKYSA + trastuzumab + capecitabine (n = 410)
Placebo + trastuzumab + capecitabine (n =202)
Median age, years
55.0
54.0
Age <65 years, n (%)
328 (80.0)
168 (83.2)
Age ≥65 years, n (%)
82 (20.0)
34 (16.8)
PRIOR THERAPIES, n (%)
Trastuzumab
410 (100)
202 (100)
Pertuzumab
409 (99.8)
201 (99.5)
T-DM1
410 (100)
202 (100)
STAGE IV AT INITIAL DIAGNOSIS, n (%)
143 (34.9)
77 (38.1)
LOCATION OF METASTASES, n (%)
Visceral§
304 (74.1)
151 (74.8)
Bone
223 (54.4)
111 (55.0)
Brain
198 (48.3)
93 (46.0)
HORMONE RECEPTOR STATUS, n (%)
ER and/or PR positive
243 (59.3)
127 (62.9)
ER and PR negative
161 (39.3)
75 (37.1)
Other
6 (1.5)
0
ECOG PERFORMANCE STATUS, n (%)
0
204 (49.8)
94 (46.5)
1
206 (50.2)
108 (53.5)
RACE, n (%)
Asian
18 (4.4)
5 (2.5)
Black​/​African American
41 (10.0)
14 (6.9)
White
287 (70.0)
157 (77.7)
Unknown​/​other
64 (15.6)
26 (12.9)
REGION OF WORLD, n (%)
US and Canada
246 (60.0)
123 (60.9)
Rest of world
164 (40.0)
79 (39.1)

§Visceral disease was defined as tumors at all locations within the body except for those in bone, brain, breast, chest wall, lymph nodes, neck, skin, and subcutaneous tissue. Tumors located in the pleura and peritoneum were also classified as visceral disease.

ER = estrogen receptor; PR = progesterone receptor.

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 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 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: Seattle Genetics, 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;382:597-609.
  • 3. Murthy RK, Loi S, Okines A, et al. Supplemental appendix for: Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382:597-609.
  • 4. Data on file. Seattle Genetics, Inc. 2020.