Chau Dang, MD

As exciting as fam-trastuzumab deruxtecan is, there’s a toxicity that we have to be aware of: interstitial lung disease, or pneumonitis. In the initial studies, when we weren’t fully aware of this potential toxicity, the incidence rates of all-grade ILDs [interstitial lung diseases]/pneumonitis was about 15%. Unfortunately, we had several deaths. But with the awareness of this toxicity, the rates have come down significantly. In the DESTINY-Breast03 study, the incidence rates were about 10% for all-grade ILD/pneumonitis, and no patients died, which is wonderful. To mitigate this toxicity, we have to be aware and on the lookout. We know a patient may be experiencing pulmonary toxicities by being aware of what the patient is reporting, such as shortness of breath, cough, or a fever. Be on the lookout and quickly get imaging, such as a CT scan of the chest. If there’s any sign of interstitial disease, the drug must be stopped, and we must get our pulmonary colleagues involved to help us manage our patients. Often times, that involves initiating steroids. Being aware is very important. There are guidelines in place for us to follow and monitor our patients.

As far as the TKIs [tyrosine kinase inhibitors], such as tucatinib and neratinib, diarrhea is a toxicity that we’re on the lookout for, and we’re very familiar with managing diarrhea. We’ve learned how to manage diarrhea with neratinib when it was approved first in using a regimen that’s been published by the CONTROL study, using loperamide as our antidiarrheal agent. There are other agents that we can use if optimal loperamide isn’t effective enough. If neratinib is used, there’s that escalation schema that we’ve used to basically manage the diarrhea for patients who are starting out neratinib.

Cardiotoxicity was a big issue 20 years ago. When trastuzumab was approved in 1988, it was a surprise that there was this issue with heart failure, probably because we were unaware and we were giving anthracycline. We had to learn how to do echo monitoring. ILDs are the new surprise. The question that comes up is, how do you monitor for ILD? Do you do PFTs [pulmonary function tests] serially to see if there’s a change in their result to advise on what to do with the drug? It’s an unanswerable question, but it’s a common question.

How do you monitor? You really don’t. You have to be on the lookout, know what can happen, and listen to the patient to see if they have any symptoms of concern, like shortness of breath, cough, fever.

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A key opinion leader in oncology shares expert perspectives on safety considerations when treating patients with T-DXd in the second-line setting for HER2+ mBC. 

Case 2: Safety Considerations in the Use of T-DXd for HER2+ mBC

 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 

-positive disease, based on updated guidelines?

 It’s unfortunate that she has metastatic breast cancer, but thank goodness we have many options for patients with metastatic 

+ 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.

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. 

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

 We use IV [intravenous] trastuzumab-pertuzumab during the chemotherapy phase because the patient already has a needle inserted, and it’s easy to continue delivering IV trastuzumab-pertuzumab after the chemotherapy to avoid another needle stick. We’ve typically used the fixed-dose combination of subcutaneous trastuzumab-pertuzumab after the patient is done with chemotherapy, when patients are to complete the rest of the metastatic HER2 [human epidermal growth factor receptor 2] treatment, especially those who have a pathologic complete response [pCR] rate after neoadjuvant therapy treatment and continue on with trastuzumab-pertuzumab. It saves chair time to have the subcutaneous formulation, but the subcutaneous formulation can be delivered during chemotherapy too.

There are 2 data sets. One is the FeDeriCa study. This is a study that randomized patients who have clinical stage II/III 

-positive breast cancer to IV formulation of trastuzumab-pertuzumab chemotherapy, or the fixed-dose combination of subcutaneous trastuzumab-pertuzumab in chemotherapy. The primary end point was to look for the noninferiority of the cycle 7 pertuzumab trough concentration. When comparing the subcutaneous formulation against IV formulation, it was found to have met its primary end point. Initially, it also showed that the pCR rates were the same, whether patients had the subcutaneous formulation or the IV formulation. That’s 1 study.

The second study was the PHranceSCa study, which was designed to assess patient preference for fixed-dose combination in comparison with IV formulation of trastuzumab-pertuzumab, and the majority of patients preferred the fixed-dose subcutaneous formulation of trastuzumab-pertuzumab and there were no new safety signals.

In the beginning of spring 2020, we had no idea what the significance of the COVID-19 pandemic was going to have on our patients with an immunocompromised status, so many of us made the decision to give the taxane phase of treatment. If patients were offered an anthracycline-taxane combination with NA [neoadjuvant] HER2 therapy, we’d opt to give the taxane phase first because there’s less myelosuppression during that phase, so we’d flip the sequence. We’d give the taxane phase first with antibody therapy, followed by anthracycline, but little did we know that the pandemic continued beyond several months. That was 1 slight change. The other 1 was that we started to adopt using the subcutaneous formulation of trastuzumab-pertuzumab when it was approved in June 2020, for ease of delivery and to minimize the time the patient was in the clinic. It did slightly change our practice without compromising efficacy.

For both IV formulation and subcutaneous formulation, it’s been diarrhea, with grade 3 event of less than 10%, so it’s very similar for both. We’ve learned how to manage diarrhea well with supportive medications. As far as the subcutaneous formulation goes, patients report more injection-site discomfort. It’s very predictable that patients will have diarrhea, so we educate our patients to be aware of diarrhea, hydrate, and have a loperamide at home and ready to take 2 loperamide tablets if they experienced an event and to have more as needed. Hydrate, and if they have more than grade 1 diarrhea, we ask them to report to us so we can coach them on how to further enhance their antidiarrheal regimens to basically control it. Certainly, trastuzumab-pertuzumab is relatively easy to give, with fewer diarrhea events than we’ve seen with tyrosine kinase inhibitors.

An expert in breast cancer considers the role of intravenous and fixed-dose subcutaneous formulations of trastuzumab/pertuzumab as studied in the FeDeriCa and PHranceSCa clinical trials. 

Case 1: Subcutaneous vs Intravenous Trastuzumab/Pertuzumab

 In clinic today, a 47-year-old woman who has 1 child presented with a palpable mass in the right breast. Mammography and ultrasound showed a right lower outer quadrant 2.3-cm mass. A breast MRI showed a 2.4-cm right outer quadrant plus a 0.5-cm mass at the 12 o’clock position and a large area of nonmass-like enhancement extending between those 2 areas, with a total area of 4 cm by 5 cm; 3 regional lymph nodes appeared enlarged. A biopsy of the 2.4-cm mass showed invasive ductal carcinoma, that is ER [estrogen receptor] and PR [progesterone receptor] negative, HER2 [human epidermal growth factor receptor 2]3+ by IHC [immunohistochemistry], FISH [fluorescence in situ hybridization] amplified with a ratio of 3.7 copy number 6, and Ki-67 of 42%. A biopsy of the axillary region showed metastatic breast cancer in the lymph node, and biopsy of the 12 o’clock area also showed invasive ductal carcinoma with the same immunostains as above. The stage was CT2N1M0 grade 3 and stage IIB.

 This is a young patient with high-risk disease based on her burden biology, so the risk of recurrence is based on the tumor burden. She does have a sizable tumor that is a T2, and she has nodal involvement. This is a high-risk biology tumor that is hormone receptor negative and 

-positive. Certainly, this patient deserves to have systemic neoadjuvant treatment.

+ breast cancer, and we typically give neoadjuvant treatment for patients with clinical stage II/III 

+ breast cancer. As we all know, the FDA approved the usage of dual-antibody therapy with trastuzumab and pertuzumab in combination with chemotherapy for patients with clinical stage II/III 

+ breast cancer. This approval was in 2013. This was based on the NeoSphere and TRYPHAENA study, and since that study, trastuzumab-pertuzumab has had its final approval with the data from the APHINITY adjuvant study. This patient should have neoadjuvant trastuzumab-pertuzumab–based treatment with chemotherapy to downstage her breast and axillae. Across several key trials since the publication of NeoSphere and TRYPHAENA, the pathologic complete response [pCR] rate is about 60%, so we expect that she should have a pCR rate of about 60%. This means that at the time of surgery, likely we’ll see pathologic complete response more so than non-pCR. If she does have a pCR, then she’ll complete out her adjuvant therapy with trastuzumab-pertuzumab–based treatment because she has lymph node–positive disease at baseline. If she has non-pCR, we’d typically give her T-DM1 [trastuzumab emtansine] for 14 cycles based on the KATHERINE study.

If she had surgery up front without the opportunity to have neoadjuvant treatment, and she was found to be node positive, then we’d give her a dual-antibody therapy with trastuzumab and pertuzumab with chemotherapy based on the APHINITY study. The APHINITY study randomized almost 5000 patients to chemotherapy with trastuzumab and pertuzumab vs chemotherapy with trastuzumab and showed that dual-antibody therapy led to significant improvement in invasive disease-free survival, especially in patients with node-positive breast cancer. Even if she was to have surgery first and was found to be node positive at the time of surgery, she would still have an opportunity to have the most optimal therapy today, which is dual-antibody trastuzumab-pertuzumab.

This is a young patient, with stage II, node-positive, hormone receptor–negative, HER2+ breast cancer. Many decades ago, it would have been a difficult disease to treat. But with the advent of modern treatments with pertuzumab-trastuzumab and even T-DM1 [trastuzumab emtansine], she should do very well. She’ll have a high pCR rate after neoadjuvant trastuzumab-pertuzumab treatment, but she also has an opportunity to have T-DM1 [trastuzumab emtansine] in the adjuvant setting if she has non-pCR. Her outcomes should be excellent, and she should have the most optimal therapy to improve her outcomes.

Chau T. Dang, MD, considers the case of a patient with early-stage HER2+ BC and discusses risk assessment and factors to consider when selecting between neoadjuvant and adjuvant treatment. 

Case 1: Risk Assessment and Treatment Selection in Early-stage HER2+ BC 

Chau Dang, MD, medical oncologist, chief, West Harrison Medical Oncology Service, Memorial Sloan Kettering Cancer Center, discusses the future of HER2+ breast cancer treatment.

Chau Dang, MD | Authors

Articles

Case 2: Safety Considerations in the Use of T-DXd for HER2+ mBC

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

Case 1: Subcutaneous vs Intravenous Trastuzumab/Pertuzumab

Case 1: Risk Assessment and Treatment Selection in Early-stage HER2+ BC

The Future of HER2+ Breast Cancer Treatment