Treatment Decisions Shifting in HER2+ Breast Cancer

Partner | Cancer Centers | <b>Sarah Cannon Research Institute</b>

Erika P. Hamilton, MD, discusses research presented at the 2019 San Antonio Breast Cancer Symposium and how the data are impacting the treatment of patients with HER2-positive breast cancer.

Erika P. Hamilton, MD

Research presented at the 2019 San Antonio Breast Cancer Symposium (SABCS) had a significant effect on the standard of care for patients with HER2-positive metastatic breast cancer, explained Erika P. Hamilton, MD.

“The metastatic setting is really evolving right now. We have traditionally thought of a taxane in combination with trastuzumab (Herceptin) and pertuzumab (Perjeta) as our first-line regimen and ado-trastuzumab emtansine (T-DM1; Kadcyla) as our second-line regimen,” said Hamilton. “The third-line [setting] was pretty open. A lot of times, it was a capecitabine (Xeloda) combination or a novel chemotherapy agent in combination with trastuzumab again. Now, things are changing a little bit.”

The phase III HER2CLIMB trial (NCT02614794) found that adding tucatinib to trastuzumab and capecitabine reduced the risk of death by 34% compared with trastuzumab and capecitabine alone in heavily pretreated patients with unresectable locally advanced or metastatic HER2-positive breast cancer. The median overall survival (OS) was 21.9 months (95% CI, 18.3-31.0) in the tucatinib arm versus 17.4 months (95% CI, 13.6-19.9) in the trastuzumab/capecitabine-alone arm (HR, 0.66; 95% CI, 0.50-0.88; P = .0048).1

The HER2CLIMB results led Seattle Genetics, the manufacturer of tucatinib, to submit a new drug application to the FDA in December 2019. The indication would be 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.

Secondly, the phase II DESTINY-Breast01 study (NCT03248492) examined the efficacy of fam-trastuzumab deruxtecan-nxki (Enhertu; DS-8201) in patients with previously treated HER2-positive breast cancer. Data showed that the confirmed objective response rate (ORR) with trastuzumab deruxtecan was 60.3% and the median duration of response (DOR) was 14.8 months.2 In December 2019, the FDA granted an accelerated approval to trastuzumab deruxtecan 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, based on the DESTINY-Breast01 findings.

In an interview during the 2020 OncLive State of the Science Summit on Breast Cancer, Hamilton, director of the Breast Cancer and Gynecologic Cancer Research Program at Sarah Cannon Research Institute, discussed research presented at the 2019 SABCS and how the data are affecting the treatment of patients with HER2-positive breast cancer.

OncLive: What trials results at the 2019 SABCS were you most excited about in the HER2-positive metastatic setting?

Hamilton: The HER2CLIMB trial was a phase II trial, but it was very large because they expanded the patient population knowing that they wanted a secondary end point of brain metastases. Patients received capecitabine and trastuzumab plus or minus tucatinib, which is a novel oral TKI. [Tucatinib] is special because it blocks just HER2 and doesn't block HER1 or EGFR like other drugs, including neratinib (Nerlynx) and lapatinib (Tykerb). These [drugs] often lead to adverse events, such as rash and diarrhea, but tucatinib does not.

[The HER2CLIMB trial] had several primary endpoints, including progression-free survival (PFS) in the all-comer population as well as ORR, OS, and PFS in patients with brain metastases. All these end points were met. One statistic that really stood out for me from the trial was the 1-year PFS rates, which were 25% for the tucatinib arm and 0% for capecitabine/trastuzumab alone.

This trial is special because they not only included the typical HER2-positive [population with] brain metastasis population that is allowed on clinical trials—who are patients who have brain metastases that are treated but stable—but they also allowed 2 different populations. [The trial included] patients with asymptomatic, untreated brain metastases and patients who had treated brain metastases that were progressive. It was a high-risk [population with] brain metastases, and the results were wildly positive.

Another trial was DESTINY-Breast01, which looked at fam-trastuzumab deruxtecan-nxki in heavily pretreated patients who had a median of 6 prior [treatments] in the metastatic setting. Despite this, the PFS on the study was ≥16 months, and the DOR for those [patients] getting benefit was >14 months. These are probably the most impressive results we have seen in the HER2-positive arena. This drug, although not revealed in the trial, is also interesting because it has activity in the HER2-low population. Trials are coming that will look at this specific population. I suspect it's going to redefine what we consider to be HER2-positive disease moving forward. Some of these patients whom we have traditionally considered to have HER2-negative tumors are going to have actionable results now because of this drug.

Given these data, what are your expectations for the future of HER2-positive metastatic breast cancer?

We are increasingly using pertuzumab in the neoadjuvant space. We're increasingly using T-DM1 now in the adjuvant space, as per the KATHERINE trial, for those patients who have not had a pathologic complete response. It's important that we have new agents in the HER2-positive arena because we know that these women who truly have HER2-driven tumors can live a long time, and therefore, we need good therapies for them. [Additionally], up to 50% of women with HER2-positive breast cancer will have brain metastases; that is where a drug like tucatinib becomes important.

What other drugs are in the pipeline for metastatic HER2-positive breast cancer?

In addition to the drugs that we saw in the HER2CLIMB and DESTINY-Breast01 trials, new drugs are coming. There are multiple, new antibody-drug conjugates by a variety of companies and new TKIs. There is also a new antibody, margetuximab. We have a lot of new agents [moving along].

What is the state of treatment for patients with early-stage HER2-positive breast cancer?

Things are becoming clearer for early HER2-positive disease. We're firmly understanding that it's important to give neoadjuvant chemotherapy for these women, not only because of the KATHERINE data but because it allows us to see a response. We have approvals of pertuzumab and neratinib in the adjuvant setting. Of course, KATHERINE really won the award here [with T-DM1].

KATHERINE didn't focus on what women received in the neoadjuvant setting or what the cancer was like then; rather, they defined their high-risk population based on the fact that those women did not have a pathologic complete response (pCR) to whatever they received in the neoadjuvant setting. Doing that was a smart idea because they were then able to pick out a truly high-risk population and show that benefit of over 11% in disease-free survival—allowing us to ask the question “Who truly is high risk and needs more therapy versus who doesn't?” It's very important for us to catch these women before they go to surgery and offer them neoadjuvant therapy, as a way to classify their risk and decide what additional treatment they may need.

Are other criteria used to decide risk status?

Other traditional criteria are being used as well, including size, lymph node status, etc. However, the label for T-DM1 in the adjuvant setting from KATHERINE doesn't mention any of those other criteria. It's [based on] the fact that you didn't have a pCR to neoadjuvant therapy. It gives us a little bit of flexibility for women who may not be as high risk, and perhaps don't need the docetaxel, carboplatin, trastuzumab, and pertuzumab regimen.

What emerging agents are being explored in early-stage HER2-positive breast cancer?

There are not a ton of new agents in the early-stage setting. From all these trials, I am impressed with how well women with HER2-positive disease [respond to treatment]. There's an interesting statistic now that half of the women with metastatic HER2-positive disease have de novo metastatic disease. That doesn't mean that de novo disease is becoming more common. Really, that means the women [we can] give neoadjuvant therapy to do very well and tend to not relapse. It's going to be hard to beat that in the early-stage setting.

One thing that we might see become more common are more trials with immunotherapy. Now that we've had [success] in the triple-negative breast cancer arena, we've had a few small trials that have combined immunotherapy with HER2-directed agents; there is no reason to think that that wouldn't work. That is a combination that I would be excited to look at.

References

  1. Murthy RK, 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 December 11, 2019]. N Eng J Med. doi: 10.1056/NEJMoa1914609
  2. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies [news release]. Silver Spring, MD: FDA; December 20, 2019. https://bit.ly/2tzcabv. Accessed December 20, 2019.