Clinical Challenges: Proper Sequencing for Metastatic HER2-Positive Breast Cancer

With a plethora of therapeutic options for HER2-positive breast cancer, certain factors influence treatment recommendations for patients with metastatic disease. These include disease-free interval and response to prior therapy, extent and burden of disease, line of therapy, and performance status.

“When making decisions about treatment, I think about the impact of therapeutic options on overall survival [OS] and progression-free survival [PFS], and balance this with the tolerability of the treatment. I also review how well and how long the drug I’m recommending works compared to standard options,” explained Hope Rugo, MD, of the University of California San Francisco.

Frontline standard of care for patients with metastatic HER2-positive breast cancer remains a combination of trastuzumab [Herceptin], pertuzumab [Perjeta], and a taxane, regardless of hormone receptor status. Chemotherapy is discontinued after response, and trastuzumab and pertuzumab are continued as maintenance therapy.

For patients with hormone receptor-positive disease, endocrine therapy is added during maintenance treatment. If and when the cancer progresses on that regimen, the antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1, Kadcyla) had been the choice for second-line therapy. However, based on the head-to-head phase III DESTINY-Breast03 trial, another ADC, trastuzumab deruxtecan (T-DXd, Enhertu), has become the clear preferred choice.

An update of this trial at the 2022 San Antonio Breast Cancer Symposium (SABCS) continued to show that T-DXd was superior to T-DM1 for PFS, and led to significantly longer OS. “T-DXd resulted in a remarkable improvement in PFS, which was four times longer than that seen with T-DM1,” said Rugo. “T-DXd also showed a survival benefit overall and when compared to TDM1 at 24 months, 77% vs 70% of patients were alive who were treated with T-DXd vs T-DM1, respectively. Almost everyone who received T-DXd had shrinkage of disease. T-DM1 works well — just nowhere near as well as T-DXd.”

T-DXd appeared to be safe in the trial. The major toxicity is nausea, not low blood counts. The rates of any-grade interstitial lung disease (ILD)/pneumonitis were 15.2% in the T-DXd arm vs 3.1% in the T-DM1 arm, but the median treatment exposure was much longer in the T-DXd arm (18.2 months) compared with the T-DM1 arm (6.9 months).

“Originally, ILD was found in just over 10% of patients, and now is up to 15% with longer follow-up, but there was no mortality from ILD in this trial,” Rugo noted. “There is mortality in every other trial — but under 1%.”

Also reported at SABCS, an update of the phase III DESTINY Breast02 trial showed that T-DXd was superior to physician’s choice of capecitabine (Xeloda)-based regimens among patients with confirmed metastatic HER2-positive breast cancer previously treated with T-DM1. After a median follow-up of just under 2 years, the PFS was 17.8 months with T-DXd vs 6.9 months with physician’s choice. Median OS was 39.2 months versus 26.5 months in the T-DXd and physicians-choice arms, respectively.

“This is a good indicator that T-DXd is not only highly active in the second-line setting, but is also superior to conventional chemotherapy-based regimens,” said Rugo.

Another second- or third-line treatment option is the triplet combination of tucatinib (Tukysa), trastuzumab, and capecitabine. In the HER2CLIMB trial, patients with HER2-positive metastatic breast cancer, with and without active brain metastases, who were previously treated with trastuzumab, pertuzumab, and T-DM1 received either tucatinib or placebo in combination with trastuzumab and capecitabine. In these heavily pretreated patients, the tucatinib therapy resulted in significantly improved PFS and OS, including in patients with active brain metastases.

Rugo noted that the triplet regimen is often a preferred option for patients with progressing brain metastases. Several small single-arm studies have demonstrated that T-DXd may also be an effective therapy for patients with poorly controlled brain metastases.

For fourth-line therapy, patients may receive T-DM1 or margetuximab-cmkb (Margenza) plus chemotherapy, or tyrosine kinase inhibitors. “In the fourth line, I use lapatinib, which is a good drug if you know how to manage diarrhea, and most times we can. For the fifth line, I use neratinib [Nerlynx],” said Thomas Samuel, MD, of Cleveland Clinic Florida, Weston Hospital.

ADCs have demonstrated value in treating patients with all stages of HER2-positive breast cancer. T-DM1 and T-DXd benefit patients with metastatic disease, and T-DM1 improves overall survival for patients who harbor residual disease after neoadjuvant treatment for HER2-amplified cancer.

“Clearly this is an area ripe for additional development,” said Julie Fisher, MD, of Atrium Health Levine Cancer Institute in Charlotte, North Carolina. “Hopefully, we can continue to fine-tune this drug category, optimizing outcomes while minimizing toxicities.”

Samuel agreed: “In the old days, we gave sequential chemotherapy, one after another. Now we use the same antibody, trastuzumab, and change the conjugate. Drug companies are developing trastuzumab-based ADC-targeted therapies with fewer side effects than chemotherapy and better efficacy than antibody therapy alone.” Additional targeted agents are also needed to address HER2-resistant clones, he noted.

Some questions about sequencing remain unanswered. “We don’t know how well T-DM1 works after T-DXd,” said Rugo. “We need more data about the optimal sequence of all agents after T-DXd. We already think T-DXd may be a great agent for patients in the first-line setting, but we don’t have the answer yet – a number of clinical trials are ongoing.” Another question is the optimal therapy for patients with brain metastases, and if these new therapies could prevent the spread of breast cancer to the brain.

Sequencing may also play a role for preventive therapy. “We know tucatinib is great for CNS penetration,” Samuel noted. “Should we move it up to become part of the initial regimen?”

Rugo said the guidelines of the National Comprehensive Cancer Network have been responsive to new data, with rapid updates on drug sequencing, and already include T-DXd and tucatinib with level 1 evidence.

“We now have many effective therapies for metastatic HER2-positive disease,” she said. “ADCs and tyrosine kinase inhibitors have changed how we treat patients, and with significantly better outcomes for our patients. We are able to utilize new options, such as T-DXd after trastuzumab-based regimens.”

She added: “We plan to move these newer therapies to earlier settings with the hope of curing more patients with HER2-positive early-stage breast cancer. More effective therapies will also allow us to personalize therapy based on response, potentially optimizing intensity of therapy on an individual patient level.”