Dr Lin on the Efficacy of T-DXd in HER2+ Advanced Breast Cancer With CNS Metastases

Nancy U. Lin, MD, associate chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, director, Metastatic Breast Cancer Program, director, Program for Patients with Breast Cancer Brain Metastases, Dana-Farber Cancer Institute; professor, medicine, Harvard Medical School, discusses findings from the phase 3 DESTINY-Breast12 trial (NCT04739761) investigating fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in patients with HER2-positive advanced or metastatic breast cancer with or without brain metastases.

Dr Lin reports consultant/advisory/steering committee participation with Artera, AstraZeneca, Bluepoint Medicines, Daiichi Sankyo, Eisai, Janssen, Olema Pharmaceuticals, Seagen, and Stemline Therapeutics; travel support from Olema Pharmaceuticals; institutional research support from AstraZeneca, Genentech, Olema Pharmaceuticals, Pfizer, Seagen, and Zion Pharmaceuticals; and royalties from book chapters from UpToDate.

Videos

Nancy U. Lin, MD, discusses the DESTINY-Breast12 trial of T-DXd in patients with HER2-positive metastatic breast cancer with or without brain metastases.

Nancy U. Lin, MD, associate chief, Division of Breast Oncology, Dana-Farber Cancer Institute, Susan F. Smith Center for Women’s Cancers, director, Metastatic Breast Cancer Program, Program for Patients with Breast Cancer Brain Metastases, senior physician, associate professor of medicine, Harvard Medical School, discusses selecting between systemic vs local therapy for patients with HER2-positive breast cancer displaying central nervous system (CNS) metastases.

For years, radiation therapy has been the established standard of care for the majority of patients with brain metastases, Lin begins. However, the selection of treatment approaches involving systemic therapies and radiation therapy continues to evolve as the role of systemic therapy is further elucidated, Lin states.

The decision to defer radiation therapy in favor of initial systemic therapy in patients with breast cancer brain metastases is complex, and requires consideration of several patient and disease characteristics. Surgical resection is commonly offered to patients who have very symptomatic or large lesions, Lin states. It is also considered in situations where there is a diagnostic dilemma, she adds.

There are now several effective systemic options for patients with HER2-positive breast cancer brain metastases, Lin continues. These agents have displayed decent CNS response rates and reasonable progression-free survival rates.

The HER2CLIMB regimen of tucatinib (Tukysa) plus trastuzumab (Herceptin) and capecitabine (Xeloda) is one particularly attractive treatment option, Lin details. The phase 2 HER2CLIMB (NCT02614794) trial was one of the first to demonstrate the potential for this systemic therapy to substantially improve survival outcomes vs whole brain radiation therapy for patients with both treated and stable, as well as active brain metastases, Lin says.

Howerver, as patients live longer, there are concerns about late toxicities associated with radiation therapy, Lin notes. Therefore, the efficacy of these agents raises the question of whether radiation-sparing approaches can be utilized more in clinical practice, she states.

In general, whole brain radiation therapy should be deferred as long as is reasonable for patients with HER2-positive disease, Lin advises. Those who have never received a prior tucatinib-based regimen or fam-trastuzumab deruxtecan-nxki (Enhertu) should be offered those regimens prior to radiation, as the resulting response rates may be high enough to further prolong time without radiation, she concludes.

Nancy U. Lin, MD, discusses selecting between systemic vs local therapy for patients with HER2-positive breast cancer displaying central nervous system metastases.


Dr Lin on the Selection of Systemic Therapy in HER2+ Breast Cancer With Brain Metastases

Nancy U. Lin, MD, associate chief, Division of Breast Oncology, Dana-Farber Cancer Institute, Susan F. Smith Center for Women’s Cancers, director, Metastatic Breast Cancer Program, director, Program for Patients with Breast Cancer Brain Metastases, senior physician, associate professor of medicine, Harvard Medical School, discusses the advantage of the oral selective estrogen receptor degrader(SERD), elacestrant, in 

The phase 3 EMERALD trial (NCT03778931) is investigating the efficacy of elacestrant vs standard-of-care endocrine therapy in patients whose breast cancer has advanced on no less than 1 endocrine therapy. An updated analysis of the phase 3 trial was presented at the 2022 ASCO Annual Meeting.

The potential advantage of elacestrant over medications such as fulvestrant is the dosing, as fulvestrant is limited by dosing issues, Lin says. Overall, the EMERALD trial was a positive. However, the activity of the drug in 

-mutated breast cancers was not entirely clear, Lin explains. Recently, a subset analysis showed that in patients with 

-mutated breast cancers, there was a substantial progression-free survival benefit with the agent, Lin says.

These results further support the potential role of elacestrant in endocrine-resistant breast cancer, Lin concludes.

Nancy U. Lin, MD, discusses the advantage of the oral selective estrogen receptor degrader, elacestrant, in ESR1-mutated breast cancers.


Dr. Lin on the Advantage of Elacestrant in ESR1-Mutated Breast Cancer

Nancy U. Lin, MD, associate professor of medicine at Harvard Medical School; associate chief of the Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers; director of the Metastatic Breast Cancer Program and senior physician at Dana-Farber Cancer Institute, discusses the challenges faced in the treatment of patients with HER2-positive breast cancer and brain metastases.

The natural history of HER2-positive metastatic breast cancer has changed over the past decade with the advent of anti-HER2 therapies, says Lin. Over time, it has been found that approximately half of patients who have HER2-positive metastatic disease will eventually develop cancer in the brain, according to Lin.

These patients can now survive much longer than they have historically. However, 1 course of radiation or 1 course of local treatment is often not enough, and patients can repeatedly experience central nervous system progression, explains Lin. It can be difficult to determine what the best treatment options are for these patients now that the disease has a longer natural history, concludes Lin.

Nancy U. Lin, MD, discusses the challenges faced in the treatment of patients with HER2-positive breast cancer and brain metastases.

Dr. Lin on Treatment Challenges in HER2+ Breast Cancer and Brain Metastases

Nancy U. Lin, MD, associate professor of medicine at Harvard Medical School; associate chief of the Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers; director of the Metastatic Breast Cancer Program and senior physician at Dana-Farber Cancer Institute, discusses the development of systemic therapies for the treatment of patients with metastatic HER2-positive breast cancer and brain metastases.

At least half of patients with HER2-positive metastatic breast cancer will develop brain metastases over the course of their disease, says Lin. However, there weren't any approved agents for the systemic treatment of patients with brain metastases until recently. 

Several trials evaluating HER2-directed TKIs such as lapatinib (Tykerb) and neratinib (Nerlynx) demonstrated objective responses in the central nervous system, explains Lin. However, the phase 2 HER2CLIMB study was the first randomized trial to demonstrate an overall survival benefit for patients with brain metastases.

Additionally, the study opened the discussion of including patients with brain metastases in future clinical trials, which is currently an unmet need in this space, concludes Lin.

Nancy U. Lin, MD, discusses the development of systemic therapies for the treatment of patients with metastatic HER2-positive breast cancer and brain metastases.

Dr. Lin on Developing Systemic Therapies for Patients with Brain Metastases in HER2+ Breast Cancer 

Nancy U. Lin, MD, associate professor of medicine at Harvard Medical School; associate chief of the Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers; director of the Metastatic Breast Cancer Program and senior physician at Dana-Farber Cancer Institute, discusses 

updated findings from the phase 2 HER2CLIMB study

 in patients with HER2-positive metastatic breast cancer with brain metastases.

In the trial, patients were randomized to receive either tucatinib (Tukysa) or placebo, in combination with trastuzumab (Herceptin) and capecitabine. Investigators looked at the overall population of patients with brain metastases but also provided additional granular details on how patients in the various brain metastases subgroups faired on the treatment, says Lin. Investigators examined how patients with newly diagnosed brain metastases did on the trial. They also shed light on how patients who had active or progressive brain metastases going into the trial did on the HER2CLIMB regimen.

In patients with brain metastases, the PFS rate by blinded independent central review at 1 year was 25.9% with the tucatinib combination versus 0% with the placebo combination, which led to a 52% reduction in the risk of progression or death in these patients. The median PFS in this patient population was 7.6 months in those treated with tucatinib and 5.4 months in those who received placebo.

Another interesting aspect of this research, which was unique to HER2CLIMB, is that patients who developed isolated central nervous system (CNS) progression, when they were on the randomized trial therapy, were not immediately taken off of protocol, says Liu. These patients were allowed to stay on the study, receive stereotactic radiation or localized CNS-directed therapy, and remain on the randomized blinded arm. Investigators also presented data comparing the 2 arms as far as how long patients were able to continue on their treatment until time of next progression, concludes Lin.

Nancy U. Lin, MD, discusses updated findings from the phase 2 HER2CLIMB study in patients with HER2-positive metastatic breast cancer with brain metastases.
 
 

Dr. Lin on Updated Findings of HER2CLIMB Study in HER2+ Breast Cancer Brain Mets

Nancy U. Lin, MD, associate professor of medicine, Harvard Medical School, associate chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, director, Metastatic Breast Cancer Program, and senior physician, Dana-Farber Cancer Institute, discusses central nervous system (CNS) activity with HER2-directed TKIs in HER2-positive breast cancer.

A previous study was conducted to examine the HER2-based TKI lapatinib (Tykerb) in combination with capecitabine in patients with HER2-positive breast cancer who have brain metastases, and results showed that the combination has CNS activity, says Lin. The study encouraged further research dedicated to determining whether other HER2 TKIs, such as neratinib (Nerlynx), also have CNS activity. This area of research is especially important because one of the key potential differentiating factors in developing new HER2-targeted TKIs is CNS activity, says Lin.

Several compounds are currently in later stages of development and data with those agents were reported at the 2019 San Antonio Breast Cancer Symposium. If a compound shows CNS activity, that becomes an important differentiating factor, concludes Lin.

Nancy U. Lin, MD, discusses central nervous system activity with HER2-directed TKIs in HER2-positive breast cancer.

Nancy U. Lin, MD

Articles