Tiffany A. Traina, MD, medical oncologist, vice chair, Oncology Care, Department of Medicine, section head, Triple Negative Breast Cancer Clinical Research Program, Memorial Sloan Kettering Cancer Center, discusses the implications of the phase 3 EMERALD trial (NCT03778931) in advanced estrogen receptor (ER)–positive, HER2-negative breast cancer.

EMERALD compared standard-of-care endocrine therapy with elacestrant, which is now the first oral selective ER degrader (SERD) to demonstrate efficacy in patients with ER-positive, HER2-negative disease who previously received CDK4/6 inhibition in a phase 3 trial, Traina says.Data presented at the 2021 San Antonio Breast Cancer Symposium by Aditya Bardia, MD, MPH, of Massachusetts General Hospital, showed the SERD achieved a median progression-free survival of 2.79 months vs 1.91 months with standard endocrine therapy in the intent-to-treat population (HR, 0.697; 95% CI, 0.552-0.880; 

Along with a manageable safety profile, elacestrant elicited responses in patients who had prior exposure to fulvestrant (Faslodex), Traina continues. Elacestrant could expand options for this patient population as an additional line of endocrine therapy, Traina concludes.

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Tiffany A. Traina, MD, discusses the implications of the phase 3 EMERALD trial in advanced estrogen receptor–positive, HER2-negative breast cancer.

Dr. Traina on the Effects of Elacestrant in ER+, HER2- Breast Cancer

Tiffany A. Traina, MD, medical oncologist, vice chair, Oncology Care, Department of Medicine, section head, Triple Negative Breast Cancer Clinical Research Program, Memorial Sloan Kettering Cancer Center, discusses the implications of the phase 3 DESTINY-Breast03 trial (NCT03529110) in HER2-positive breast cancer.

The 1:1 randomized trial examined the safety and efficacy of the antibody-drug conjugate, fam-trastuzumab deruxtecan-nxki (Enhertu), vs ado-trastuzumab emtansine (Kaycyla; T-DM1) in the second line and later in patients with HER2-positive metastatic breast cancer, Traina explains. Results demonstrated trastuzumab deruxtecan elicited significantly higher overall response rates (ORRs) compared with T-DM1, Traina adds. Trastuzumab deruxtecan achieved an ORR of 79.7%.

Additionally, the median progression free survival (PFS) was not reached for patients in the trastuzumab deruxtecan group, and the median PFS was 6.8 months for the T-DM1 group, Traina continues. Notably, overall survival data remains immature, but the follow-up presentations are anticipated, Traina concludes

Tiffany A. Traina, MD, discusses the implications of the phase 3 DESTINY-Breast03 trial in HER2-positive breast cancer.


Dr. Traina on Results of the DESTINY-Breast03 Trial in HER2+ Breast Cancer

 Dr Müller, because we have the data from the HER2CLIMB trial, what’s the new treatment algorithm for HER2 [human epidermal growth factor receptor 2]–metastatic breast cancer?

Returning to these regimens, quality of life despite survival is important. I want to address your experience and your feelings on the adverse effects of these regimens. Dr Traina, can you explain the different adverse effects of these regimens, your management, and your experience?

You raise an excellent point. Getting the disease under control helps our patients feel their best, but they’re on therapy for a long time, and we want to ensure that the toxicities are manageable and not impacting their health-related quality of life. Trastuzumab and pertuzumab as a combination is well tolerated. We often see pertuzumab with a GI [gastrointestinal] toxicity; that is, diarrhea or nausea that the backbone chemotherapy or taxane [paclitaxel] can contribute to. In general the trastuzumab-pertuzumab combination, incrementally, is well tolerated, but the chemotherapy adverse effects are what we’re managing with that triplet. With capecitabine and TKI [tyrosine kinase inhibitors] combinations, there’s a pill burden to manage and toxicity related to that. There is also the GI toxicity around managing diarrhea and nausea, which is more significant than with the pertuzumab. Concern around hand-foot syndrome, rash, GI toxicity, LFT [liver function test] abnormalities, and the financial burden of an oral regimen has a different structure in the United States in terms of reimbursement for patients. They may have a higher out-of-pocket cost for a full oral regimen compared with an intravenous regimen.

Moving on to newer drugs—trastuzumab deruxtecan, for example—this ADC [antibody-drug conjugate] has asthenia and fatigue associated with it. A significant adverse event that we’re aware of is interstitial lung disease or pneumonitis. In the DESTINY-Breast01 trial, that occurred about 15% to 16% of the time of all grades, but there were grade 5 fatal events related to pneumonitis, about 2% to 3%. That is significant and gives us pause. In subsequent protocols, there were strict guidelines around managing, observing, and monitoring pneumonitis. In my practice, we’re monitoring with high-resolution CT scans that we use to evaluate for response to therapy. There’s a low threshold to whole drug, even with ground-glass opacities. If anyone is symptomatic, we are not only holding drug but intervening with corticosteroid and involving our pulmonologist to support these patients. It’s a different adverse event that we need to be aware of and intervene accordingly. We discussed TDM-1 [trastuzumab emtansine], which is well tolerated, but there are often LFT abnormalities, monitoring for thrombocytopenia, and dose adjustments around thrombocytopenia.

 I completely agree. We experience the same adverse effects that you’ve described. Additionally, there’s ILD [interstitial lung disease], which is potentially a fatal complication. It’s important to increase awareness, and oncologists must recognize it clearly to start appropriate treatment with steroids to avoid a fatal outcome. In the DESTINY-Breast03 trial, we achieved this end point because there were no patients who died from ILD. In the real world we should be careful. We must recognize the symptoms to start an appropriate treatment as soon as possible.

 These drugs can potentially cause adverse events, but it’s important to be familiar with potential events to recognize and manage them. In this scenario it’s important to educate both patients and physicians. The toxicity may be reduced with our experience in using the drugs. The more we use the drug, the more we become confident and experts in managing them, even with the potential of adverse events.

There’s a learning curve from study to study, and supporting that curve has to be steep.

Recommendations for monitoring for and managing adverse events associated with newer therapies being sequenced into HER2+ metastatic breast cancer treatment algorithms.

Managing TRAEs Associated With Novel HER2+ MBC Therapies

Tiffany A. Traina, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the FDA approval of fam-trastuzumab deruxtecan-nxki (Enhertu; DS-8201) for patients with HER2-positive, locally advanced, or metastatic breast cancer who have been treated with trastuzumab (Herceptin) and pertuzumab (Perjeta) and have disease progression after ado-trastuzumab emtansine (T-DM1; Kadcyla).

This approval is based on an ongoing, dose escalation/expansion phase I study, preliminary data from which were presented at the 2017 ASCO Annual Meeting by Toshihiko Doi, MD, PhD, of Japan’s National Cancer Center Hospital East.

Dr. Traina on the FDA Approval of Trastuzumab Deruxtecan for HER2+ Breast Cancer

Tiffany A. Traina, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses patient conversations regarding extended adjuvant therapy with neratinib (Nerlynx) in early-stage HER2-positive breast cancer.

Once patients complete a year of adjuvant therapy with either a combination of trastuzumab (Herceptin) and pertuzumab (Perjeta), or ado-trastuzumab emtansine (T-DM1; Kadcyla), it is important that clinicians discuss the potential for extended adjuvant therapy, says Traina. Despite a year of adjuvant therapy, some patients remain at risk of recurrence. For that reason, Traina recommends to have these conversations with patients who have early-stage estrogen receptor-positive, HER2-positive breast cancer.

Neratinib is one agent that can be considered for use as extended adjuvant therapy based on data from the phase III ExteNET trial. Five-year follow-up data from the trial indicated an invasive disease-free survival rate of 90.2% with neratinib versus 87.7% with placebo. Although some patients may be hesitant to continue on another year of adjuvant therapy, the magnitude of benefit is compelling, says Traina. This, coupled with better diarrhea management strategies, should spur the pursuit of shared decision making regarding the use of neratinib, concludes Traina.

Dr. Traina on Conversations on Extended Adjuvant Therapy With Neratinib in HER2+ Breast Cancer

Tiffany A. Traina, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the prevalence of 

 mutations in triple-negative breast cancer (TNBC).

 mutations is difficult to fully understand because physicians are not clear what the ultimate denominator is. The data presented at the 2017 San Antonio Breast Cancer Symposium showed that there are patients who should undergo clinical genetic testing so they can be aware of their germline 

The data prior to the conference was related to the PARP inhibitor olaparib (Lynparza). Data from the OlympiAD study revealed single-agent olaparib oral therapy was superior to physicians' choice of chemotherapy. That arm included capecitabine, eribulin (Halaven), or vinorelbine. Olaparib had about a 40% improvement in median progression-free survival for women with germline 

 mutations with metastatic disease. The safety profile was very tolerable relative to cytotoxic chemotherapy.

Tiffany A. Traina, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the prevalence of BRCA mutations in triple-negative breast cancer (TNBC).

Dr. Traina on PARP Inhibition in BRCA-Mutated Breast Cancer

Tiffany A. Traina, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses neratinib (Nerlynx) in HER2-positive breast cancer.

In July 2017, the FDA approved neratinib for the extended adjuvant treatment of patients with early stage, HER2-positive breast cancer following postoperative trastuzumab (Herceptin). The approval followed a 12-4 recommendation from the Oncologic Drugs Advisory Committee, stemming from the results of the ExteNET trial.

Traina says that neratinib is in a unique position because so much has evolved in the treatment of patients with early stage HER2-positive disease in the past year. The use of pertuzumab (Perjeta) is more widespread with an approval for use in the neoadjuvant setting in combination with trastuzumab. Data from the APHINITY trial showed that 1 year of adjuvant trastuzumab and pertuzumab was associated with improved survival outcomes.

These data makes the integration of neratinib challenging, Traina explains. Early trials with neratinib did not include patients who had prior exposure to pertuzumab, making neratinib’s role in the sequencing of agents unclear.

Tiffany A. Traina, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses neratinib (Nerlynx) in HER2-positive breast cancer.
 

Dr. Traina Discusses Neratinib in HER2+ Breast Cancer

Tiffany A. Traina, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, on considerations for the treatment of patients with HER2-positive breast cancer.

With the FDA approval of neratinib (Nerlynx) in July of 2017, clinicians began to consider its role in the treatment paradigm of HER2-positive breast cancer. With the success of pertuzumab (Perjeta), and the established role of trastuzumab (Herceptin), some clinicians have found it difficult to decide where to place neratinib in the sequence of treatment for these patients.

Traina says that she favors using pertuzumab in patients with tumors larger that 2 cm in the setting of node negative or positive disease. She also incorporates neoadjuvant therapy with anthracycline taxane-based trastuzumab and pertuzumab, and then following surgery, administering trastuzumab and pertuzumab for a full year. For tumors that are smaller than 2 cm, Traina supports the idea of de-escalation. Neratinib, she says, is difficult to place, but it could be an option for patients that are extremely high risk after prior treatment.