Expert Explains Evolution of De-Escalating Therapies in HER2+ Breast Cancer

Keerthi Gogineni, MD, MSHP

Several trials, such as APT and KRISTINE, have examined the effects of de-escalating treatment for patients with HER2-positive breast cancer in an effort to decrease toxicity without comprising efficacy, explained Keerthi Gogineni, MD, MSHP.

The single-arm APT study examined the effects of paclitaxel with trastuzumab (Herceptin) in patients with node-negative, HER2-positive breast cancer. Seven-year follow-up data showed a disease-free survival (DFS) rate of 93.3% and an overall survival (OS) rate of 95.0%.¹

In the KRISTINE trial, 444 patients with HER2-positive breast cancer were randomized to neoadjuvant ado-trastuzumab emtansine (T-DM1; Kadcyla) plus pertuzumab (Perjeta; n = 223) or docetaxel/carboplatin/trastuzumab plus pertuzumab (TCHP; n = 221) every 3 weeks for 6 cycles. In the 3-year follow-up, the event-free survival (EFS) rate was 85.3% in the T-DM1 plus pertuzumab group vs 94.2% with TCHP.² Additionally, the invasive disease-free survival (iDFS) rate was 93.0% versus 92.0% with T-DM1/pertuzumab and TCHP, respectively, suggesting that systemic chemotherapy may be unnecessary in some patients.

In an interview with OncLive, Gogineni, an assistant professor in the Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, discussed several trials in the breast cancer field, specifically looking at de-escalation therapies.

OncLive: Could you discuss the importance of personalizing treatment in early-stage HER2-positive disease?

Gogineni: We have a lot of options now to tailor curative therapy for early-stage HER2-positive breast cancer. There have been various attempts to de-escalate by minimizing the toxicity without compromising the efficacy of the chemotherapy backbone. There have been studies looking at ways we could potentially de-escalate the trastuzumab component by changing the duration of therapy.

Conversely, we also have ways that we can escalate therapy both in the setting of patients who we know have higher risk of recurrence, but also adapting escalation by looking at pathologic complete response (pCR) rates at the time of surgery to try to increase therapy for people who we know have resistant disease.

Are there any important trials evaluating de-escalation strategies you want to highlight?

Some key de-escalation strategies began in 2015 with a trial led by Sara Tolaney, MD, which was the APT trial. This protocol took women who had small HER2-positive breast cancer and essentially node-negative disease, and evaluated whether we could use a chemotherapy backbone that just consisted of paclitaxel and combine that with trastuzumab. There was an explicit decision in that trial not to include a control arm because the researchers thought it would be hard to randomize a control arm when we didn't have a standard of care for small HER2-positive cancer.

We're now 7 years later, and the follow-up is outstanding. There is a 95% OS rate. It's hard to imagine there would be a compared arm that could beat that. When we have a patient who has HER2-positive disease, has a smaller tumor, and is node-negative, this would be a perfectly adequate therapy to ensure they are at low risk of relapse.

There have been a couple of studies, including meta analyses, looking at the idea of using less trastuzumab. We've standardized trastuzumab to be a duration of 12 months. The question arose whether we can get away with less. There have been 2 trials, PERSEPHONE and HERA, that have looked at [different durations] of trastuzumab.

PERSEPHONE ended up meeting its noninferiority boundary. However, the major concern over de-escalating this part of therapy is the chemotherapy backbone that was used in these trials is no longer the chemotherapy backbone that we're using in a lot of patients. Is it safe to de-escalate both the chemotherapy and the duration of trastuzumab? For a patient who has some cardiac risk factors and you are looking to minimize toxicity, you may consider doing a 6-month regimen, but you have to think about what chemotherapy backbone that patient had.

Another trial looking at de-escalating therapy is the KRISTINE study, presented by Sara Hurvitz, MD, which looked at women who had larger HER2-positive tumors. In that space, a question arose whether we can use T-DM1 with pertuzumab rather than docetaxel/carboplatin/trastuzumab plus pertuzumab (TCHP), which we know is a more toxic regimen, to achieve the same survival benefits and have less toxicity.

There is clearly a decreased rate of grade 3 toxicity with the dual-targeting arm compared with TCHP. However, in the study, we saw that event-free survival seemed inferior in the T-DM1/ pertuzumab arm. It looked like it was mostly driven by early progressors. That story that came out of the 2019 ASCO Annual Meeting is really interesting in terms of trying to predict who is going to respond.

If you look at the group of patients who didn't progress before surgery, which was strongly HER2-positive and HER2-homogeneity patients, those patients did well [with TCHP]. In fact, when you look at the iDFS rates, their arms are virtually inseparable. This is going to present an option for de-escalation for these larger HER2-positive tumors, but we have to decide how we're going to look at HER2-heterogeneity and HER2 expression to make sure we're selecting the right population to de-escalate therapy for.

Are there ongoing trials that you would like to highlight?

One trial that we think will be presented later this year or early 2020 is the ATEMPT trial; this is taking the APT trial to the next level. It is the same population that was looked at in Dr Sara Tolaney's trial and includes small HER2-positive breast cancers that are node-negative. In this trial, they randomized patients to either receive APT regimen, which is 12 weekly doses, versus getting T-DM1. Can we entirely remove the chemotherapy backbone? That trial has fully enrolled so we're awaiting those results.

Could you expand on some of the escalation strategies?

Conversely, we have patients who need more therapy, so there are a few escalation strategies that have emerged. One of them is looking at women who received preoperative therapy and then had residual disease at the time of surgery.

KATHERINE was a landmark study that was presented at the 2018 San Antonio Breast Cancer Symposium. In that protocol, we saw that women who were randomized to receive adjuvant T-DM1 as opposed to the standard trastuzumab did much better in terms of disease-free survival. Therefore, we know now that a patient who has received preoperative therapy and hasn't had a complete response will do better if we give them T-DM1 in the adjuvant setting.

Another strategy that's being used, for high-risk patients who are node-positive and hormone-receptor negative, is to consider using adjuvant pertuzumab/trastuzumab as opposed to just trastuzumab alone. The benefits seen with a dual-targeting regimen in the adjuvant setting is statistically significant—modest—but it represents another way to escalate therapy if needed.

References

1. Tolaney SM, Guo H, Pernas S, et al. Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2—positive breast cancer. J Clin Oncol. 2019;37(suppl; abstr 511). doi: 10.1200/JCO.19.00066.
2. Hurvitz SA, Martin M, Jung KH, et al. Neoadjuvant trastuzumab emtansine and pertuzumab in human epidermal growth factor receptor 2—positive breast cancer: three-year outcomes from the phase III KRISTINE study. J Clin Oncol. 2019;37(suppl; abstr 500). doi: 10.1200/JCO.19.00882.