Selecting Third-Line Therapy to Treat HER2+ De Novo Metastatic Breast Cancer

Reshma L. Mahtani, DO:So here in the third-line setting, there are several options for treatment with no clear standard. Recently, options have really expanded in this setting. The availability of trastuzumab deruxtecan [DS-8201] was approved in December 2019. This is an antibody-drug conjugate, with the payload being a topoisomerase inhibitor. It’s approved for patients who have received 2 or more prior anti-HER2 therapies in the metastatic setting. The agent was studied in a heavily pretreated population and showed an extremely high response rate—much higher than we would expect in that setting. A very important safety issue with this drug is highlighted in a boxed warning, which is interstitial lung disease. Fatal cases have been reported. So it’s important to monitor patients for cough, dyspnea, fever, or worsening respiratory symptoms.

Another option in the third-line setting that’s particularly attractive for this patient is neratinib and capecitabine. Recall that the patient had a taxane, trastuzumab, and pertuzumab in the first-line setting. Her second-line treatment was with trastuzumab emtansine. In the third-line setting, she progressed both systemically and in the CNS [central nervous system]. Brain metastases are particularly problematic for patients with HER2+ breast cancer. Some series indicate that as many as half of patients with HER2+ metastatic breast cancer will go on to develop brain metastases. At this point in time, I would say that neratinib with capecitabine is a good option.

We know that neratinib, which is an irreversible pan-HER tyrosine kinase inhibitor, has CNS activity and was actually included in combination with chemotherapy in the CNS guidelines by the NCCN [National Comprehensive Cancer Network] as an option for patients with brain metastases. And more recently, in February 2020, the FDA approved neratinib in combination with capecitabine for patients who have HER2+ metastatic breast cancer who have received 2 or more prior anti—HER2-based treatments in the metastatic setting. This approval was based on the phase 3 NALA trial in which patients were randomized to receive neratinib plus capecitabine or lapatinib plus capecitabine. There was a 24% reduction in the risk of disease progression or death associated with the use of neratinib plus capecitabine compared to lapatinib plus capecitabine.

Finally, another option that’s not yet approved but will hopefully be approved soon is tucatinib, capecitabine, and trastuzumab. This regimen is based on the HER2CLIMB study, which evaluated tucatinib—an investigational oral tyrosine kinase inhibitor—versus placebo, added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer, including those with brain metastases. What was unique about the HER2CLIMB study was that it included patients with previously untreated disease, treated and stable disease, and treated disease with progressing brain metastases.

Tucatinib is an oral tyrosine kinase inhibitor that’s highly selective for the kinase domain of HER2, with minimal inhibition of EGFR. This may substantially alter the toxicity profile to be more favorable. It substantially extended survival outcomes in the HER2CLIMB study. In addition, these outcomes were approved even in patients with brain metastases. So this will be an important addition to our third-line treatment options for patients when approved.

Transcript edited for clarity.

Case: A 59-Year-Old Woman WithHER2+ De Novo Metastatic Breast Cancer

Initial presentation

• A 59-year-old, postmenopausal woman presented to her PCP for an annual physical exam, she was referred to undergo screening mammography; she reported back and hip pain along with occasional headaches
• PMHx: diabetes, medically controlled
• OB/GYNHx: nulliparous
• FHx: no family history of cancer
• PE: obese, palpable left breast mass with axillary adenopathy

Clinical workup

• Labs: alkaline phosphatase 230 IU/L (normal range 20-140 IU/L); otherwise WNL
• Breast imaging revealed a 2.1 cm irregular appearing mass in the left breast with suspicious axillary adenopathy
• Ultrasound-guided core biopsy of the left breast mass and axillary node confirmed high-grade infiltrative ductal carcinoma; ER-, PR-,HER2,3+ by IHC
• Brain MRI was negative
• PET/CT and bone scan revealed multiple lesions in the spine and pelvis; and several pulmonary nodules; pulmonary nodule biopsy revealed invasive ductal carcinoma; ER-,HER2+
• ECOG PS 1

Treatment and Follow-Up

• She was started on paclitaxel + trastuzumab + pertuzumab and completed 6 months of chemotherapy at which point paclitaxel was discontinued due to worsening neuropathy; trastuzumab and pertuzumab were continued
• Follow-up imaging at 3 months showed no FDG activity in the bones or lungs; bone pain resolved
  • Denosumab was started to reduce skeletal related events
• Further follow-up imaging showed stable disease until 18 months when she developed worsening cough; imaging showed progressive bone disease and multiple new pulmonary nodules
  • Trastuzumab emtansine (T-DM1) was started
• Follow-up imaging showed response to treatment which lasted for ~ 9 months
  • She developed headaches, and increasing bone pain
• Brain MRI at that time showed 3 lesions, all < 2-cm; she was treated with SRS (stereotactic radio surgery)
  • Bone scan showed progressive bone metastases
• Initiated neratinib 240 mg (6 tablets) PO QD + capecitabine
  • She was started on prophylactic loperamide