Evolving Strategies in Sequencing for HER2+ MBC Therapy

Victoria Stern, MA


May 24, 2021

The landscape for therapies targeting HER2-positive metastatic breast cancer (MBC) has evolved rapidly in the past few years. In a 12-month window, the US Food and Drug Administration approved four agents targeting human epidermal growth factor 2 (HER2)–positive metastatic MBC, starting with trastuzumab deruxtecan in December 2019, followed by neratinib and tucatinib a few months later, and margetuximab last December.

Although first-line therapy for the majority of patients continues to be the CLEOPATRA regimen — the monoclonal antibodies trastuzumab and pertuzumab plus a taxane, such as docetaxel or paclitaxel — the influx of agents approved in the metastatic setting has opened up new avenues for second-line therapy and beyond.

"We have been really fortunate to see a number of highly effective new therapies approved for HER2-positive MBC in the past year, and this has given us even more options to offer our patients," remarked Rita Nanda, MD, director of the Breast Oncology Program and associate professor of medicine at University of Chicago Medicine.

What considerations do experts weigh when sequencing HER2-positive MBC?

For Kelly McCann, MD, PhD, the order largely depends on balancing two factors: regimens that will provide the best efficacy in terms of patient survival and quality of life. "In the metastatic setting, I know I'm going to end up using all of the available medications one after the other, so the order that allows patients to continue living their best life for as long as possible is essential," commented McCann, a hematologist/oncologist in the Department of Medicine at the David Geffen School of Medicine, University of California, Los Angeles.

A New Second-Line Option?

Before the wave of drug approvals for metastatic HER2-positive disease last year, oncologists routinely looked to trastuzumab emtansine (T-DM1) as second-line therapy.

But tucatinib may also now be considered in the second-line setting, after results from the HER2CLIMB trial. The decision between tucatinib and T-DM1 largely comes down to the presence or absence of brain metastases.

"T-DM1 is well-tolerated, so it's still my go-to in the second-line setting unless my patient has a brain metastasis, in which case I opt for tucatinib," McCann noted, adding that the HER2-specific oral tyrosine kinase inhibitor (TKI) not only crosses the blood-brain barrier but is also effective in patients with untreated brain metastases.

In HER2CLIMB, tucatinib exhibited strong efficacy in patients with advanced HER2-positive disease, including those with previously treated or untreated brain metastases. The randomized controlled trial, which paired tucatinib with trastuzumab and capecitabine, showed median progression-free survival of 7.8 months in 410 patients with HER2-positive MBC compared with 5.6 months in the 202 patients receiving the placebo regimen. The tucatinib cohort showed an overall survival advantage compared with the placebo group (21.9 vs 17.4 months).

Perhaps the most notable finding occurred in patients with brain or central nervous system (CNS) involvement, which develops in as many as half of patients with HER-positive MBC and is associated with shorter survival. In the HER2CLIMB trial, median progression-free survival was 7.6 months in patients with brain metastases compared with 5.4 months in the placebo group.

A follow-up exploratory analysis, which focused on 291 patients with brain metastases, found that adding tucatinib reduced the risk for intracranial progression by two thirds and death by almost half. In patients with active brain metastases, median progression-free survival reached 9.5 months vs 4.1 months in the placebo group. Those with stable metastases also benefited from tucatinib, with median progression-free survival of 13.9 vs 5.6 months in the placebo group.

On the basis of the results, the authors concluded that this randomized trial was the first to demonstrate improvements in both CNS progression–free survival and overall survival in patients with HER2-positive MBC and brain metastases.

Evolving Options in the Third-Line Setting and After

For third-line therapy and beyond, oncologists have an array of newer agents to choose from alongside longer-standing options — which include trastuzumab plus lapatinib, trastuzumab or lapatinib plus capecitabine, as well as T-DM1, if not given as second-line therapy.

According to McCann, the antibody-drug conjugate trastuzumab deruxtecan has been a particularly exciting addition to third-line treatment. In the phase 2 DESTINY-01 trial, more than 60% of a heavily pretreated population showed an objective response to trastuzumab deruxtecan, with a median response duration of almost 15 months and a median progression-free survival of 16.4 months. Longer-term follow-up results, presented in December at the 2020 San Antonio Breast Cancer Symposium, revealed progression-free survival of 19.4 months and preliminary median overall survival of 24.6 months.

Neratinib, the second TKI to bridge the blood-brain barrier in HER2-positive disease, was also approved for third-line use; however, Sayeh Lavasani, MD, MS, said she is more likely to consider this agent later in the sequence, potentially in the fourth-line setting and beyond, given the more robust outcomes observed in the HER2CLIMB tucatinib trial.

"Neratinib improved progression-free survival and time to intervention for CNS metastasis but, unlike tucatinib, did not demonstrate an overall survival benefit," remarked Lavasani, a medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.

More specifically, the phase 3 NALA trial, which randomly assigned patients to receive neratinib plus capecitabine or lapatinib plus capecitabine, reported progression-free survival of 8.8 months in the neratinib group compared with 6.6 months in the control arm but no significant gains in overall survival (hazard ratio, 0.88; P = .2098).

The fourth recently approved drug, margetuximab, has not yet made a significant mark on sequencing decisions for McCann.

"Margetuximab could have been a potential game changer, but clinical trial results were underwhelming," she said.

In the phase 3 randomized clinical SOPHIA trial, margetuximab plus chemotherapy prolonged median progression-free survival by just over 1 month compared with trastuzumab plus chemotherapy. Preliminary overall survival data showed a slight, but not significant, benefit in the margetuximab group (21.6 vs 19.8 months).

For Lavasani, the presence of brain metastases is the most important consideration when weighing sequencing options. "For some of my patients with HER2-positive MBC, it's ultimately disease progression in the brain that takes their life," she said.

Aside from CNS metastases, specific sequencing choices may vary on the basis of drug-related tolerance as well as patient preferences. "It is critical to get a patient's input in treatment selection," Nanda remarked. "Given the number of effective treatments for HER2-positive MBC and the lack of data to guide how to sequence these regimens, it is important to ask patients what their preferences are."

McCann agreed, noting that "a patient with HER2-positive MBC typically has a life expectancy measured in years, which is also why sequencing should be influenced by quality of life considerations."

Convenience, side-effect profile, and financial toxicity should factor into clinical decision-making, according to Nanda. Some patients may, for instance, prefer a combination of tucatinib, capecitabine, and trastuzumab over trastuzumab deruxtecan to avoid hair loss and the risk for interstitial lung disease, which has been reported in more than 13% of patients, whereas others may prefer trastuzumab deruxtecan to avoid the possibility of diarrhea.

Taxanes come with a high risk for infusion reactions — which occur in about 30% of patients — and can cause neuropathy as well as hair loss and severe gastrointestinal side effects. In first-line care, McCann typically stops the taxane at some point for toxicity reasons and continues with trastuzumab plus pertuzumab until disease progression.

Even with an array of new options for treating metastatic HER2-positive disease, ultimately drug resistance does occur, Lavasani cautioned. Several ongoing trials are exploring new combinations of existing drugs to see whether those variations move the needle on survival outcomes. The HER2CLIMB-04 trial, for instance, is pairing tucatinib with trastuzumab deruxtecan, whereas HER2CLIMB-02 is pairing tucatinib with T-DM1.

But given progress in drug development in just the past few years, Lisa A. Carey, MD, deputy director of Clinical Sciences at the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, sees a promising future for treating metastatic HER2-positive disease. "There is so much going on in the HER2-positive MBC therapeutics space that almost every 6 months, oncologists have to regroup and reevaluate treatment and sequencing, which is a great position to be in," Carey noted.

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