touchEXPERT OPINIONS Exploring the impact of recent data on the management of HER2- positive advanced breast cancer Disclaimer ∙ 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 Exploring the impact of recent data on the management of HER2-positive advanced breast cancer
Prof. Dr Sibylle Loibl
German Breast Group Neu-Isenburg, Germany Tucatinib, trastuzumab deruxtecan and neratinib in HER2-positive advanced breast cancer
Agent Indications FDA approval EMA approval status status Tucatinib In combination with trastuzumab and capecitabine: adult patients with Approved Accepted MAA on 31 advanced unresectable or metastatic HER2-positive breast cancer, April 20201 Jan 20202 including patients with brain metastases, who have received ≥1 prior anti-HER2-based regimens in the metastatic setting.
Trastuzumab Adult patients with unresectable or metastatic HER2-positive breast Approved Accepted MAA on 6 deruxtecan cancer who have received ≥2 prior anti-HER2-based regimens in the Dec 20193 July 20204 metastatic setting. Neratinib In combination with capecitabine: adult patients with advanced or Approved Feb metastatic HER2-positive breast cancer who have received ≥2 prior 20205 anti-HER2 based regimens in the metastatic setting.
EMA, European Medicines Agency; FDA, US Food and Drugs Administration; HER2, human epidermal growth factor receptor 2; MAA, marketing authorisation application. 1. Tucatinib Prescribing Information (PI). April 2020. 2. Press release. 31 January 2020. Available at: https://investor.seagen.com/press-releases/news-details/2020/EMA- Validates-Seattle-Genetics-Marketing-Authorization-Application-for-Tucatinib-for-Patients-with-Locally-Advanced-or-Metastatic-HER2-Positive-Breast-Cancer/default.aspx (accessed October 2020). 3. Trastuzumab deruxtecan PI. December 2019. 4. Press release 6 July 2020. Available at: www.daiichisankyo.com/media/press_release/ (accessed October 2020). 3. Neratinib PI. February 2020. PIs for all agents freely available at: www.accessdata.fda.gov/scripts/cder/daf/ (accessed October 2020). Treatment-emergent adverse events with tucatinib, trastuzumab deruxtecan and neratinib
Tucatinib Trastuzumab deruxtecan Neratinib HER2CLIMB1 DESTINY-Breast012 TBCRC 0223
Grade ≥3 occurring in >5% of Grade ≥3 occurring in >5% of Grade 3 (no events grade ≥4) patients in the tucatinib arm: patients in the tucatinib arm: occurring in >5% of patients:
• Diarrhoea (12.9%) • Decreased neutrophil count (20.7%) • Diarrhoea (29%) • PPE syndrome (13.1%) • Anaemia (8.7%) • Hypokalaemia (12%) • ALT increased (5.4%) • Nausea (7.6%) • Fatigue (10%) • Decreased white-cell count (6.5%) • Nausea (6%) • Decreased lymphocyte count (6.5%) • Fatigue (6.0%) • Interstitial lung disease • Overall: 13.6% • Grade 1/2: 10.9% • Grade 3/4: 0.5% • Grade 5: 2.2%
ALT, alanine aminotransferase; PPE, palmar-plantar erythrodysesthesia. 1. Murthy RK, et al. N Engl J Med. 2020;382:597–609. 2. Modi S, et al. N Engl J Med. 2020;382:610–21. 3. Freedman RA, et al. J Clin Oncol. 2019;37:1081–89. Patient- and disease-related characteristics influence choice of novel treatments HR and HER2 Previous Patient’s status therapies preference and toxicities
Disease- Available free therapies interval
Socio- economic Tumour /psycho- burden logical factors
Rapid disease/ Biological symptom age control
Meno- pausal PS status Patient (for ET) comor- ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; bidities PS, performance status. Cardoso F, et al. Ann Oncol. 2018;29:1634–57. Patient- and disease characteristics influence choice of novel treatments
Clinical trial data will help oncologists to identify candidate patients and determine how to optimize use of novel treatments in clinical practice
In HER2CLIMB, in the subset of HER2-positive women with active BM (n=174):1 Tucatinib • One-year estimated CNS-PFS was 35% in tucatinib-combination group vs 0% in the control-arm group • Median duration of CNS-PFS was 9.5 months and 4.1 months, respectively
In DESTINY-Breast01, in HER2-positive patients with treated and asymptomatic BM (n=24):2 Trastuzumab • Median duration of PFS was 18.1 months vs 16.4 months in the overall population deruxtecan
In TBCRC 022, in HER2-positive patients with BM:3 Neratinib • Median PFS was 5.5 and 3.1 months in lapatinib-naive and and lapatinib-treated patients, respectively • Median survival was 13.3 and 15.1 months, respectively
BM, brain metastases; CNS, central nervous system; HER2, human epidermal growth factor receptor 2; PFS, progression-free survival. 1. Lin NU, et al. J Clin Oncol. 2020;38:2610–19. 2. Modi S, et al. N Engl J Med. 2020;382:610–21. 3. Freedman RA, et al. J Clin Oncol. 2019;37:1081–89. Examples of ongoing clinical trials investigating novel therapies in HER2-positive breast cancer
Agent Ongoing trials
Tucatinib HER2CLIMB-02: Randomized, double-blind, phase III study of tucatinib or placebo in combination with T-DM1 for patients with unresectable locally-advanced or metastatic HER2-positive breast cancer1
Trastuzumab deruxtecan DESTINY-Breast-2: Phase III, multicentre, randomized, open-label, active-controlled study of trastuzumab deruxtecan vs standard of care (investigator's choice) in patients with unresectable and/or metastatic breast cancer previously treated with T-DM12 DESTINY-Breast-3: Phase III, multicentre, randomized, open-label, controlled trial of trastuzumab deruxtecan vs T-DM1 in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and taxane3 DESTINY-Breast-4: Phase III, multicentre, randomized, 2-arm, open-label study to compare the safety and efficacy of trastuzumab deruxtecan vs the physician's choice (2:1) in patients with HER2-low, unresectable and/or metastatic breast cancer4 Neratinib TBCRC 022: The phase II study is ongoing, including a cohort of patients receiving T-DM1 and neratinib5
HER2, human epidermal growth factor receptor 2; T-DM1, Trastuzumab emtansine. 1. NCT03975647. 2. NCT03523585. 3. NCT03529110. 4. NCT03734029. 5. NCT01494662. Clinical trials listed by their identifiers at: ClinicalTrials.gov (accessed October 2020).