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HER2-Positive Metastatic Breast Cancer: Current Status and Promising Agents

Adam M. Brufsky, MD, PhD
Released: April 13, 2020

Future Directions for TKIs in HER2-Positive MBC

Phase II Study: Tucatinib Plus Trastuzumab/Capecitabine in HER2-Positive MBC With Leptomeningeal Metastases

Tucatinib is also being investigated for the treatment of MBC with leptomeningeal disease. This is very difficult to treat in the HER2-positive setting. Various agents, including intrathecal trastuzumab,[32] have been tested with little success and there is no standard of care in this disease setting.

Now, a phase II study is underway evaluating the combination of tucatinib and trastuzumab/capecitabine in patients with HER2-positive MBC and leptomeningeal metastases (planned N = 30).[33] Patients can have an Eastern Cooperative Oncology Group performance status of 0-3 with no previous tucatinib. Following treatment with the triplet, MRI scans are obtained of the brain and spine every 2 cycles (ie, every 6 weeks). The primary endpoint is OS, with secondary endpoints including safety, PFS, and responses in the CNS.

plasmaMATCH Cohort B: Neratinib in HER2-Mutated MBC

Approximately 3% of breast cancers have HER2 mutations, which can occur in patients who are ER positive or who have triple-negative disease.[34]

The ongoing plasmaMATCH trial is a very important and much-needed proof-of-concept trial designed to assess the clinical utility of analyzing circulating tumor cell DNA (ctDNA) to identify targetable mutations and inform therapy decisions in patients with MBC.[35] This trial enrolled close to 1000 patients with locally recurrent breast cancer or MBC and measurable disease who had relapsed within 12 months of adjuvant chemotherapy or had progressive disease following previous treatment for advanced disease. Participants were permitted to have received up to 2 previous chemotherapy regimens and had to have an actionable mutation as detected by ctDNA testing.

In cohort B of plasmaMATCH, reported at SABCS 2019,[36] 21 patients with MBC or locally recurrent breast cancer and mutated HER2 were treated with neratinib and, if ER positive, fulvestrant. The investigators reported an ORR of 25%, a clinical benefit rate of 45%, and a median PFS of approximately 5 months; these are promising results in such heavily pretreated patients. For the 17 patients whose disease was also hormone receptor positive, which was the majority, the response rate was 23.5%. As expected, the most common grade ≥ 3 AE was diarrhea, affecting 20% of patients. Grade 3/4 hypertension was also a concern, affecting 15%.

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Seattle Genetics

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