Metastatic HER Positive Breast Cancer to the Brain

• While HER2+ breast cancer makes up 15% to 20% of all breast cancer cases:
  • A higher proportion of HER2+ breast cancer patients develop brain metastases than other breast cancer subtypes:
    • With some studies indicating that up to 50% of patients with HER2+ breast cancer will develop brain metastases over the course of their disease
• Most metastases within the central nervous system (CNS):
  • Are intraparenchymal with a small percentage (5% to 14%) of patients have leptomeningeal metastases:
    • Although these metastatic sites are not mutually exclusive
• Patients with brain metastases have worse outcomes than those without brain metastases:
  • 30.2 months vs 38.3 months
• Patients with leptomeningeal metastases:
  • Have the worst outcomes with medial survival at 3.5 to 4 months
• Dual treatment of brain metastases:
  • Is recommended with the involvement of local therapies including radiation (like stereotactic radiosurgery, whole brain radiation) and / or surgical resection as well as systemic therapy
  • Historically, there has been a limited role for systemic therapy in brain metastases; however, studies like the CLEOPATRA trial:
    • Demonstrate that better systemic control of breast cancer leads to delayed development of CNS metastases
  • In the CLEOPATRA trial:
    • Patients who received Docetaxel / Herceptin/ Pertuzumab (THP):
      • Had improved progression free survival (PFS; 18.7 months THP vs 12.4 months TH)) as well as improved overall survival (OS; 57.1 months THP vs. 40.8 months TH)
    • While patients with brain metastases were excluded from the initial trial, a subsequent analysis showed that patients who received THP and developed brain metastases had improved progression free survival and overall survival than those patients who only received TH
• Second line therapy:
  • T-DM1 was approved for second line therapy based on the EMILIA trial:
    • Of which patients had prior treatment with trastuzumab plus a taxane (but no Pertuzumab)
  • The ongoing KAMILLA trial is evaluating the effect of T-DM1 in patients who have progressed on THP and investigators are including an exploratory CNS subgroup of which approximately 400 patients of the 2000 patient trial have active brain metastases
  • Recently published data suggests that T-DM1 does have activity in CNS disease with a brain metastasis overall response rate (ORR) of 21%, clinical benefit rate (CBR) of 43% and PFS of 5.5 months.
• Tucatinib / Herceptin / capecitabine (THX) was evaluated in the HER2CLIMB trial:
  • In which patients with active brain metastases were included
  • Patients with brain metastases who received THX had a longer 1 year CNS-PFS (40.2% vs 0% in the Herceptin/capecitabine (HX) arm) and a longer 1 year CNS-OS (70.1% THX vs 46.7% HX)
  • Even more exciting was that patients with active brain metastases, which was defined as untreated brain metastases or treated and progressing with brain metastases:
    • Also had an improved 1 year CNS-PFS (35.0% THX vs 0% HX) and a longer 1 year CNS-OS (71.7% THX vs 41.1% HX)
• The DESTINY trial:
  • Reported an impressive ORR of 60.9% in heavily pretreated patients (median 6 prior therapies)
  • A PFS of 16.4 months and the median OS is yet to be reached
  • In the trial, median time to response is 1.6 months so if patients are going to respond, they respond quickly
  • The DESTINY trial included patients with treated, stable of asymptomatic brain metastases
  • While the CNS subgroup analysis was small (24 patients in total, 17 patients with measurable brain metastases at baseline), similar ORR and PFS to the general population suggesting trastuzumab deruxtecan has activity in the CNS

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