SABCS Showcased Novel Agents in the HER2+ Breast Cancer Armamentarium

Katherine D. Crew, MD

On the heels of the 2019 San Antonio Breast Cancer Symposium (SABCS), Katherine D. Crew, MD, highlighted practice-changing novel agents entering the treatment paradigm in advanced HER2-positive breast cancer.

“Historically, HER2-positive disease has been a more aggressive form of breast cancer,” said Crew. “Recently, there has been an explosion of HER2-targeted therapies. We have 3 different classes of drugs being pursued. As a result, the median survival has significantly improved for patients with metastatic disease.”

Topline data from the phase II HER2CLIMB trial demonstrated a 34% reduction in the risk of disease progression or death with the addition of novel TKI tucatinib to trastuzumab (Herceptin) and capecitabine (Xeloda) for patients with unresectable locally advanced or metastatic HER2-positive breast cancer (HR, 0.66; 95% CI, 0.50-0.88; P = .0048).¹

Based on these findings, a new drug application was submitted to the FDA in December 2019 for tucatinib in combination with trastuzumab and capecitabine for the treatment of patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including patients with brain metastases, following ≥3 prior HER2-directed agents separately or in combination, in the neoadjuvant, adjuvant, or metastatic setting.

Additionally, fam-trastuzumab deruxtecan-nxki (Enhertu; DS-8201), showed an unprecedented 60.3% overall response rate (ORR), per independent central review, with a complete response (CR) rate of 4.3%, based on updated findings from the phase II DESTINY-Breast01 trial that were presented at the 2019 SABCS.2 In December 2019, the FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received ≥2 prior anti-HER2-based regimens in the metastatic setting.

In an interview during the 2020 OncLive^® State of the Science Summit™ on Breast Cancer, Crew, associate professor of medicine and epidemiology at the NewYork-Presbyterian/Columbia University Medical Center, discussed the results of HER2CLIMB and DESTINY-Breast01, as well as other impactful data in HER2-positive breast cancer that emerged from the 2019 SABCS.

OncLive: What were some of the key updates in HER2-positive breast cancer from the 2019 SABCS?

Crew: The most exciting plenary session featured 5 different trials in HER2-positive breast cancer. One was HER2CLIMB, which looked at tucatinib, a new TKI, in the third-line setting for heavily pretreated patients with metastatic disease.

HER2CLIMB was unique in that it included patients with untreated or progressive brain metastases. HER2-positive breast cancer has a propensity for [progressing] to the brain with up to 50% of patients developing disease in the central nervous system (CNS).

Results of the trial showed that when tucatinib was added to trastuzumab and capecitabine, progression-free survival (PFS) and overall survival (OS) were significantly improved. This has changed the third-line standard of care for patients with HER2-positive metastatic breast cancer.

Another exciting trial looked at the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki. This was a single-arm, phase II trial that showed an [impressive] ORR [with fam-trastuzumab deruxtecan-nxki] for heavily pretreated patients with HER2-positive metastatic disease. Fam-trastuzumab deruxtecan-nxki more than doubled the PFS that we would expect in such a population. Additionally, the response rate was higher than 60%, including [a high CR rate].

One caveat of that trial was that there were a few treatment-related deaths due to interstitial lung disease. If we are interested in pursuing this drug in earlier settings for HER2-positive disease, we need to monitor these symptoms and intervene with protocols, such as high-dose steroids to avoid this potentially serious adverse event.

What impact do the results of the NALA study have?

The NALA trial findings were presented at the 2019 ASCO Annual Meeting. It was a head-to-head comparison of neratinib (Nerlynx) and lapatinib (Tykerb) to capecitabine alone. The study showed that neratinib/capecitabine improved PFS; however, there were higher rates of grade 3 diarrhea with the neratinib arm. All of the TKIs have better central nervous system penetration and may be favored in patients who have brain metastases.

What other data emerged from the 2019 SABCS?

The SOPHIA trial looked at another monoclonal antibody called margetuximab, which was compared with trastuzumab in combination with investigator's choice of chemotherapy in the third-line metastatic setting for patients who had a least 1 to 3 lines of treatment in the metastatic setting. There were improvements in ORR and PFS, although they were relatively modest compared with other trials.

The second interim analysis presented at the 2019 SABCS did not show significant difference in OS with margetuximab compared with trastuzumab. The results were more modest compared to other novel HER2-targeted agents, but it is nice to see newer agents in our armamentarium that we can offer to patients as they are living longer.

Margetuximab is engineered to enhance [a patient's] immune response to [elicit] an antitumor effect. It was an exploratory analysis, but a subset of patients with the CD16A-F allele showed a trend toward OS improvement. It is possible that a subset of patients will benefit more from this drug.

What other agents are poised to enter this space?

There are so many drugs coming down the pike. Tucatinib and fam-trastuzumab deruxtecan-nxki look the most promising. Newer studies are pushing these agents into the first- and second-line settings now that patients are being exposed to pertuzumab (Perjeta), ado-trastuzumab emtansine (T-DM1; Kadcyla), and potentially neratinib in the adjuvant setting.

If we introduce these agents earlier in treatment, we have to be cognizant of long-term, treatment-related adverse events because these patients are living longer.

What unmet needs remain in advanced breast cancer?

A lot of advocates spoke out in favor of the HER2CLIMB data, particularly for patients with brain metastases. It was essentially the first randomized, controlled trial in the HER2-positive space that included patients with progressing brain metastases.

If we continue to exclude those patients, we won't know how to treat that aspect of the disease. Most of the drugs we currently give do not cross the blood-brain barrier, including the available monoclonal antibodies. If we are able to develop effective drugs that [penetrate] the CNS, we can get better at treating this comorbidity. Similarly, leptomeningeal disease is challenging to treat and generally, those patients have a poor prognosis.

References

1. Murthy R, Loi S, Okines A, et al. Tucatinib vs placebo, both combined with capecitabine and trastuzumab, for patients with pretreated HER2-positive metastatic breast cancer with and without brain metastases (HER2CLIMB) [published online ahead of print December 11, 2019]. N Eng J Med. doi: 10.1056/NEJMoa1914609.
2. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. [published online ahead of print December 11, 2019]. N Eng J Med. doi:10.1056/NEJMoa1914510.