Case 2: Second-line Treatment Selection for Metastatic HER2+ BC


Emphasizing the variety of options available in the second-line setting, Chau T. Dang, MD, remarks on the case of a patient with HER2+ mBC and highlights key factors affecting therapeutic decision-making.


Moderator: The next case is a 63-year-old woman who presented after a 3.2-cm mass was found in her left breast upon routine mammography. Core needle biopsy showed IDC [invasive ductal carcinoma], which was ER [estrogen receptor] and PR [progesterone receptor] negative, and HER2 [human epidermal growth factor receptor 2] was 3+ by IHC [immunohistochemistry]. A CTCAP [CT chest-abdomen-pelvis] showed 2 liver lesions, with the largest being 2.5 cm.

Liver biopsy confirmed metastatic breast cancer with the same immunostains, and MRI of the brain was negative for metastases. She received THP [docetaxel, trastuzumab, pertuzumab] for 6 cycles, followed by HP [trastuzumab, pertuzumab]. Three months later, CTCAP showed that the patient had a partial response in her breast mass and complete response in the liver lesions. Sixteen months later, a repeat CTCAP showed progressive disease with recurrence of 1 liver lesion that was 1.5 cm. Dr Dang, could you briefly review the treatment options that you consider for recurrent metastatic HER-positive disease, based on updated guidelines?

Chau T. Dang, MD: It’s unfortunate that she has metastatic breast cancer, but thank goodness we have many options for patients with metastatic HER2+ breast cancer. She receives our frontline option, which is a taxane-trastuzumab-pertuzumab regimen based on the CLEOPATRA study, where the median progression-free survival is about 18 months. She had this optimal regimen for about 16 months before progression, and now the discussion is, what’s her best second-line therapy?

For many years, T-DM1 [trastuzumab emtansine] was the second-line option based on the EMILIA study, showing the improvement in progression-free survival over the control arm. However, recently, the DESTINY-Breast03 study demonstrated the significant progression-free survival gain when comparing fam-trastuzumab deruxtecan against T-DM1 [trastuzumab emtansine] for patients being treated in the second line and beyond. This is an impressive drug with results that are astonishing. The median PFS [progression-free survival] for fam-trastuzumab deruxtecan has not been reached, but for T-DM1 [trastuzumab emtansine], it’s bordering on 7 months. Fam-trastuzumab deruxtecan is the preferred second-line option today.

There are other options in the third line and beyond, and we have tucatinib capecitabine trastuzumab showing superiority against the non-tucatinib arm in the HER2CLIMB study. We have the NALA study, which has demonstrated neratinib-capecitabine better than lapatinib-capecitabine, and also the SOPHIA trial, which showed that margetuximab with chemotherapy was slightly better than trastuzumab and chemotherapy. These are recent drugs that have been approved over the last few years. There are many options, and there are others behind these treatments that I’ve just discussed. Thank goodness our patients have many therapies available to them. Many are living long, which is wonderful to see.

Unfortunately, many of these patients will also experience brain metastases. It’s been reported that 30% to 50% of patients will experience or suffer from brain metastases. Although their extracranial disease sites are controlled, they are noted to have progression in the brain. This is an area of unmet need, and we’re working hard to find drugs that cross the blood-brain barrier. It’s exciting to see that this is reported with tucatinib in the HER2CLIMB study, and there are some data to support neratinib as well as lapatinib. We’re looking forward to emerging data from other trials as well.

We have to look at the patient factors: previous exposure, what the patient had, what line of therapy, and comorbid status. In this patient, she’s relatively healthy, she’s had THP [docetaxel, trastuzumab, pertuzumab], and she’s had no issues, so the preferred second-line option for her should be fam-trastuzumab deruxtecan. She doesn’t have any brain metastases, but if she was found to have active brain metastases, then the preferred option is tucatinib with capecitabine trastuzumab, which has an endorsement to show that there’s activity of tucatinib in the brain as well as outside the brain. If she has active brain metastases, that would be the preferred option.

This patient is going onto her second-line therapy, and she has no brain metastases, so she should be given fam-trastuzumab deruxtecan. Thank goodness that so far, we don’t have the median PFS reported out. Based on the investigator assessment, it’s about 2 years, which is impressive. If we think about this study, half the patients were being treated in the second line and half in the third line. Still, the median PFS by the investigator assessment is about 2 years, which is impressive. If we think back to the CLEOPATRA study, where patients were being treated in the first line, the median PFS was not 2 years; it was 18 months. I’m not trying to do a trial comparison, but I’m trying to make a point of how impressive this drug is. The patient’s prognosis is going to be improved if she gets the better option earlier on, and if she progresses on fam-trastuzumab deruxtecan, she has other options afterward. Her prognosis should be excellent. From what we know from the CLEOPATRA study, the overall survival is still bordering on 5 years. We aim to improve on this overall survival with the availability of all these drugs and emergence of new drugs.

Transcript edited for clarity.

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