Later-Line Treatments for HER2-Positive Breast Cancer

Based on results from the DESTINY-Breast03 trial, trastuzumab deruxtecan (T-DXd; Enhertu) became the preferred, guideline-supported, second-line therapy for HER2-positive metastatic breast cancer, regardless of hormone receptor (HR) status, replacing trastuzumab emtansine (T-DM1; Kadcyla) as the default standard.

However, findings from DESTINY-Breast09 have led to a shift.

In that trial, first-line T-DXd combined with pertuzumab (Perjeta) significantly improved progression-free survival (PFS) in HER2-positive locally advanced or metastatic breast cancer, regardless of HR status, compared with the standard first-line treatment of trastuzumab (Herceptin) plus pertuzumab and a taxane (THP).

Thus, T-DXd has become a frontline option alongside THP, leading to the question of what comes next.

“There’s a lot of movement,” Erika Hamilton, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee, told MedPage Today. “I think the biggest question right now is whether everyone is going to receive trastuzumab deruxtecan in combination with pertuzumab up front, or whether some patients are still appropriate for taxane, trastuzumab, and pertuzumab.”

She noted that DESTINY-Breast09 did not account for maintenance regimens.

Recent studies demonstrated that integrating a HER2-targeted tyrosine kinase inhibitor (TKI) or CDK4/6 inhibitor can optimize antibody-based maintenance in this population.

Hamilton was the principal investigator of the phase III HER2CLIMB-05 trial, which showed that the addition of the TKI tucatinib (Tukysa) to first-line maintenance therapy with trastuzumab and pertuzumab significantly improved PFS (24.9 months vs 16.3 months for those who received placebo plus trastuzumab and pertuzumab, P<0.0001), with that PFS benefit observed regardless of HR status.

“We also have palbociclib [Ibrance] for the HR-positive subset [evaluated in the PATINA study],” Hamilton said, adding that these maintenance regimens are attractive to patients because they are able to discontinue chemotherapy.

“A lot of people are saying, ‘I don’t really want to use trastuzumab deruxtecan indefinitely,’ especially with it being such an active drug where somebody might be on this for years,” she said. “Plus, [there is] the advantage of being able to do something like THP where we do six to eight cycles of the taxane and drop that out, and then the patient’s just on maintenance antibodies.”

“That’s very tolerable for my patient — my patient gets to be cytotoxic free,” she pointed out, noting that in that instance she might use T-DXd as a second-line agent.

In cases of patients progressing after first-line treatment with the DESTINY-Breast09 regimen, there are options.

However, Mariana Chavez MacGregor, MD, of the University of Texas MD Anderson Cancer Center in Houston, told MedPage Today that the quandary is that the options “have not been evaluated formally after that first-line treatment.”

She said T-DM1, as well as the HER2CLIMB regimen of tucatinib, trastuzumab, and capecitabine, are still “reasonable” options.

HER2CLIMB evaluated heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, and showed that adding tucatinib to trastuzumab and capecitabine resulted in better PFS and overall survival compared with the addition of placebo. The regimen is listed as a preferred second- or third-line option in National Comprehensive Cancer Network guidelines.

“But, again, this regimen was evaluated in a different setting,” Chavez MacGregor noted, so treatment choices are likely to be individualized, from the first line on.

“We’re taking into account patients’ condition, performance status, comorbidities, and, of course, preferences,” she said. “And we have to take into account the tolerance to side effects.”

For example, interstitial lung disease is a side effect of special interest associated with T-DXd.

Furthermore, the presence of brain metastases will likely favor treatment with the tucatinib-based HER2CLIMB regimen, Chavez MacGregor pointed out.

Beyond those second and third lines, she said a potential option is the anti-HER2 monoclonal antibody margetuximab (Margenza), which was approved in 2020 in combination with chemotherapy for the treatment of patients with HER2-positive metastatic breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease.

That approval was based on data from the phase III SOPHIA trial, which showed that patients had a 24% reduction in the risk of disease progression or death with margetuximab plus chemotherapy compared with trastuzumab plus chemotherapy (P=0.033).

In addition, Chavez MacGregor said breast cancer specialists would likely be looking at options including older TKIs, such as lapatinib (Tykerb) or neratinib (Nerlynx) with chemotherapy.

“The reality is that if a patient already was treated with tucatinib — which is a much more effective tyrosine kinase inhibitor — the chances of us using some of these other molecules are less,” she said.

“We will continue to try to target the HER2 pathway, and then combine the chemotherapy,” she added. “That would be kind of the more standard journey.”