Managing brain metastases in advanced HER2-positive breast cancer: Where are we now?
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Managing brain metastases in advanced
HER2-positive breast cancer: Where are we now?
HER2, human epidermal growth factor receptor 2.
What can the recent data tell us about emerging
treatment options for patients with brain metastases?
Dr Sara A Hurvitz, MD
Associate Professor of Medicine,
University of California, Los Angeles (UCLA),
Jonsson Comprehensive Cancer Center,
Los Angeles, CA, USADisclaimer Unapproved products or unapproved uses of approved products may be discussed by the faculty; these situations may reflect the approval status in one or more jurisdictions. The presenting faculty have been advised by touchIME to ensure that they disclose any such references made to unlabelled or unapproved use. No endorsement by touchIME of any unapproved products or unapproved uses is either made or implied by mention of these products or uses in touchIME activities. touchIME accepts no responsibility for errors or omissions.
HER2CLIMB (phase II): Study design1,2
612 adult patients with advanced HER2-positive breast cancer:
• Previous treatment: trastuzumab, pertuzumab and T-DM1
• ECOG performance status: 0 or 1
• No previous treatment with capecitabine or HER2-targeted TKI
291/612 patients with brain metastases, including active and untreated
• Included untreated and larger than 2cm (with approval from medical monitor)
• Patients with leptomeningeal disease were excluded
2:1
Tucatinib (n=410) Placebo (n=202)
plus trastuzumab plus trastuzumab
and capecitabine and capecitabine
Efficacy and safety
ECOG, Eastern Cooperative Oncology Group; HER2, human epidermal growth factor receptor 2; T-DM1, trastuzumab emtansine; TKI, tyrosine kinase inhibitors.
1. Murthy RK, et al. N Engl J Med. 2020;382:597–609; 2. Lin NU, et al. J Clin Oncol. 2020; JCO2000775. doi: 10.1200/JCO.20.00775 [Epub ahead of print].HER2CLIMB: CNS-PFS and CNS-OS1
CNS-PFS at 1 year Median CNS-PFS
50 12
HR=0.32 68% lower risk of CNS
Median PFS (months)
40.2% 9.9
40 (95% CI, 0.22 to 0.48) 10
Probability (%)
pHER2CLIMB: Intracranial ORR and second progression1
5.5% 5.5% Intracranial response rate 5.0% ORR=20.0%
3.6%
ORR=47.3%
Complete response 15.0%
41.8% Partial response
43.6% Stable disease
Progressive disease 80.0%
Not evaluated
Tucatinib (n=55) Placebo (n=20)
(Median DoR = 6.8 months) (Median DoR = 3.0 months)
PFS to second progression or death
Median time from randomization to Median time from first CNS progression
second CNS progression or death to second progression or death
15.9 months 7.6 months
Tucatinib Tucatinib
(95% CI, 11.7-22.2) (95% CI, 3.9-11.3)
9.7 months 3.1 months
Placebo Placebo
(95% CI, 4.9-12.0) (95% CI, 1.2-4.1)
CNS, central nervous system; DoR, duration of response; ORR, objective response rate; PFS, progression-free survival.
1. Lin NU, et al. J Clin Oncol. 2020;JCO2000775. doi: 10.1200/JCO.20.00775 [Epub ahead of print].DESTINY-Breast01 (phase II): Study design & outcomes1
184 adult patients with unresectable or metastatic HER2-positive
breast cancer: Trastuzumab deruxtecan
• Previous treatment: T-DM1 5.4 mg per kg of body weight
• ECOG performance status: 0 or 1
• No untreated or symptomatic brain metastases Efficacy and safety of the
• No current, suspected or history of interstitial lung disease recommended dose
24/184 patients had treated and asymptomatic brain metastases
Confirmed response rates PFS
1.1% 6.0% ORR=60.9% Trastuzumab deruxtecan
1.6% showed a high level of
36.4% 16.4
n=184 clinical activity in patients
54.9% with HER2-positive
18.1 metastatic breast cancer who
n=24 had undergone extensive
Complete response Progressive disease
0 5 10 15 20
previous therapies
Partial response Not evaluated
Stable disease Median PFS (months)
ECOG, Eastern Cooperative Oncology Group; HER2, human epidermal growth factor receptor 2; PFS, progression-free survival; T-DM1, trastuzumab emtansine.
1. Modi S, et al. N Engl J Med. 2020;382:610–21.NALA, NEfERT-T and TBCRC 022: Study designs
NALA (phase III)1 NEfERT-T (phase III)2 TBCRC 022 (phase II)3
• HER2-positive breast cancer • HER2-positive inoperable, recurrent • HER2-positive breast cancer
• ECOG: 0 or 1 or metastatic breast cancer • ECOG: 0 to 2
• Two or more previous • No prior systemic therapy for • No prior neratinib
HER2-directed therapies metastatic disease and capecitabine
• N=621 • N=479 • N=49
Patients with asymptomatic or Patients with asymptomatic and All patients had measurable brain
stable brain metastases were definitively treated brain metastases metastases with brain progression
included were included after any prior CNS-directed therapy
Neratinib + capecitabine (n=307) Neratinib + paclitaxel (n=242) Neratinib + capecitabine
vs vs
Lapatinib + capecitabine (n=314) Trastuzumab + paclitaxel (n=237) • Lapatinib-naïve patients (n=37)
• Lapatinib-treated patients (n=12)
CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; HER2, human epidermal growth factor receptor 2.
1. Saura C, et al. J Clin Oncol. 2020;JCO2000147. doi: 10.1200/JCO.20.00147 [Epub ahead of print]; 2. Awada A, et al. JAMA Oncol. 2016;2:1557–64;
3. Freedman RA, et al. J Clin Oncol. 2019;37:1081–9.NALA, NEfERT-T and TBCRC 022: Outcomes
NALA (phase III)1 NEfERT-T (phase III)2 TBCRC 022 (phase II)3
Mean PFS Mean OS Median PFS
10 30 15 18
8.8 12.9 12.9
Duration (months)
Duration (months)
25 24.0 15.1
8 22.2 16
6.6 20 10
6 14 13.3
15
4 12
10 5
Months
2 5 10
0 0 0 8
Neratinib Lapatinib Neratinib Trastuzumab 6 5.5
4 3.1
22.8% 8.3% 2
0
29.2% 17.3% PFS OS
0% 10% 20% 30% 40% 0% 4% 8% 12% 16% 20% 24% Lapatinib-naïve
Incidence of CNS interventions Incidence of CNS recurrence Lapatinib-treated
CNS, central nervous system; PFS, progression-free survival; OS, overall survival.
1. Saura C, et al. J Clin Oncol. 2020;JCO2000147. doi: 10.1200/JCO.20.00147 [Epub ahead of print]; 2. Awada A, et al. JAMA Oncol. 2016;2:1557–64;
3. Freedman RA, et al. J Clin Oncol. 2019;37:1081–9.You can also read
