How Three Clinical Trials Have Shaped the HER2+ Breast Cancer Treatment Landscape

Historically, human epidermal growth factor receptor 2 (HER2)-positive breast cancer has had a poor prognosis. But thanks to a handful of studies examining the targeting of therapy for this cancer subtype, researchers have made “a lot of progress in HER2 disease” in recent years, according to Dr. Natalie Marshall, assistant professor of medicine and medical director of the UC Berkeley Outpatient Center at the UCSF Comprehensive Cancer Center.

At CURE®’s Educated Patient Women’s Cancers Summit, Marshall held a session on three trials in particular, each focused on a different aspect of HER2-positive breast cancer, and examined how each one enhanced the treatment landscape and improved outcomes in their own way.

How the KATHERINE Trial Impacted Clinical Practice

Prior to the KATHERINE trial, researchers found that patients with residual disease after neoadjuvant chemotherapy, or treatment is given to shrink a tumor prior to surgery, and an anti-HER2 therapy had a worse prognosis than if they had a complete response. As Marshall explained, “That kind of makes sense if you think about it, because the tumor was obviously very sensitive to the treatment if it went completely away prior to surgery when they were getting that therapy.”

Because of these poorer outcomes, the KATHERINE study was designed to compare Herceptin (trastuzumab) alone to the antibody-drug conjugate T-DM1 (trastuzumab emtansine) in patients with HER2-positive breast cancer who had residual cancer following preoperative therapy, with the hypothesis that T-DM1 would be superior.

In the trial, 1,486 patients were randomized 1:1 to receive either Herceptin alone, which was the standard of care at the time, or T-DM1 for 14 cycles as adjuvant therapy. The primary endpoint was death or invasive disease.

Ultimately, patients in the T-DM1 arm had an 11% better outcome than patients who received Herceptin alone. “Among patients who had residual invasive disease after completion of neoadjuvant therapy, with a trastuzumab-containing regimen, the risk of recurrence of invasive breast cancer or death was 50% lower in those that got the TDM one treatment versus trastuzumab alone,” Marshall explained, noting that benefits were also seen regardless of tumor size, lymph node involvement, or breast cancer subgroup type.

The key point with this trial, Marshall noted, was that adjuvant T-DM1 should be offered in place of Herceptin or Herceptin plus Perjeta (pertuzumab) for patients with residual invasive disease after neoadjuvant chemotherapy and anti HER2 therapy.

DESTINY-Breast 01 Study Results’ Application to Care

With the DESTINY-Breast 01 trial, researchers set out to identify a meaningful palliative treatment for metastatic HERs-overexpressing/amplified breast cancer in the third line or higher setting. In this phase 2 trial, all 184 patients received DS-8201 (trastuzumab deruxtecan), of which 112 responded to therapy for a median of 14.8 months, with progression free survival of 16.4 months.

“What's really important about this is that many of the patients in this trial were really heavily pretreated,” Marshall explained, noting that this made the overall response rate of 61.4% even more impressive.

While some significant toxicities occurred, nausea being the most common, Marshall also noted that interstitial lung disease was a serious side effect, contributing to four deaths in the trial.

“The key points of this study are that the toxicities of this therapy could be significant in people who may have already been heavily pretreated and had a lot of toxicity already,” Marshall said. “So some people are arguing that we should maybe try to use it in an earlier line of therapy rather than waiting till people are sick.”

What the HER2CLIMB Study Means for Brain Metastases

When talking about patients with HER2-positive disease, Marshall said, “A large percentage of those patients will at some point, develop brain involvement. Their disease in their body might be under control, but then they'll have disease in the brain.”

The standard of care for these patients is radiation, mostly because the majority of treatments do not cross the blood-brain barrier. As such, later lines of palliative treatment for metastatic HER2-positive breast cancer may not work as well as those used in earlier settings.

In the HER2CLIMB study, researchers set out to examine Tukysa (tucatinib), an oral HER2 tyrosine kinase inhibitor that blocks HER2 in breast cancer cells, as a meaningful part of combination palliative treatment in patients with metastatic HER2-positive breast cancer, some of which had brain involvement.

A total of 612 patients were randomized 2:1 to a treatment group who received a combination of trastuzumab and capecitabine plus Tukysa, or a group that received the combination and a placebo in place of the HER2 blocker.

At one year, progression free survival was 33% in patients who received the HER2 blocker and 12.3% in the placebo group, with overall survival also reported as better over a two-year period: 44.9% in the treatment arm compared to 26.6% in the placebo group.

Most notably, progression free survival in patients with brain metastases at one year was 25%, versus 0% in the placebo group. “This is really important and practice changing, because for third line treatment, this is a very good option that's well tolerated, and also has the advantage of also treating the central nervous system. This can actually be used for patients with brain metastases, who might have progressed on therapy with radiation already or had stereotactic radiation,” Marshall explained. “So, this is another really important option to treat a problem that we have, which is the control of brain involvement with people with HER2-positive cancer.”

In conclusion, Marshall notes that “we still have a long way to go, we've made a lot of progress in HER2 disease. And these are three things that are clinically useful right now in the clinic for patients with HER2-positive cancer.”