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Neoadjuvant HER2+ Breast Cancer Options Need Refinement, Expert Says

Gina Columbus @ginacolumbusonc
Published: Wednesday, Jun 22, 2016

Lisa A. Carey, MD

Lisa A. Carey, MD

While recent findings from the I-SPY 2 trial have shown potential with the combination of ado-trastuzumab emtansine (T-DM1; Kadcyla) and pertuzumab (Perjeta) for patients with HER2-positive breast cancer, the neoadjuvant space still has a lot of work ahead, according to Lisa A. Carey, MD.

Results presented at the 2016 AACR Annual Meeting1 showed that, out of the 249 patients enrolled on the I-SPY 2 study, 54% of those who received T-DM1/pertuzumab experienced a pathological complete response (pCR) rate compared with 22% of those who received the combination of paclitaxel (Abraxane) plus trastuzumab (Herceptin).

This suggests that T-DM1 could increase overall survival (OS) in this patient population, but Carey adds more research with the regimen needs to be conducted.

“The I-SPY 2 paradigm is a really interesting one,” Cary explains. “They are really pushing the envelope on trying to help with developing drugs and regimens in the neoadjuvant setting. I do worry how often the assumptions are going to hold true. In this particular case, we will see.”

Moreover, findings of the KRISTINE trial,2 which were presented at the 2016 ASCO Annual Meeting, demonstrated that neoadjuvant treatment with docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) was associated with a higher pCR rate compared with T-DM1 plus pertuzumab in HER2-positive patients, at 55.7% and 44.4%, respectively.

In an interview with OncLive, who is the medical director of the University of North Carolina Breast Center and chief of Hematology/Oncology and physician-in-chief of the North Carolina Cancer Hospital, comments on the recent I-SPY 2 and KRISTINE findings, the I-SPY 2 program as a whole, and the work ahead in the neoadjuvant landscape of HER2-positive breast cancer.

OncLive: What are your thoughts on the I-SPY 2 trial of T-DM1/pertuzumab versus paclitaxel/trastuzumab in the neoadjuvant setting?

Carey: In this particular trial, the control arm received trastuzumab and paclitaxel for 12 weeks, then they got AC (doxorubicin and cyclophosphamide), and then they went to surgery. In the investigational arm, patients received T-DM1 and pertuzumab, so they switched out 2 drugs. There is a hidden chemotherapy kind of tucked inside T-DM1.

The estimates of the performance of the T-DM1 arm outperform the estimates of the control arm with a certain level of statistical certainty—99% based on what they had seen. Based on the early signals of this, it was much more likely that the T-DM1/pertuzumab arm would outperform. That’s what the authors reported.

In context, their control arm didn’t perform very well. The T-DM1 arm was estimated to be 52% and the control arm was at 22%. Those 2 differences may be true, but I’m not entirely sure why the control arm underperformed. I’m a little bit concerned that T-DM1 seems to underperform relative to what we would expect these days with a trastuzumab-containing regimen.

That said, this clearly is a positive trial. What they have is a difference that is based on their statistical assumptions—that T-DM1/pertuzumab would outperform paclitaxel/trastuzumab. I’m a little worried about the underperformance of the control arm, which only has 30 patients in it.

What did the KRISTINE study show in regard to T-DM1?

The KRISTINE study is a randomized neoadjuvant clinical trial comparing TCHP with T-DM1/pertuzumab in HER2-positive breast cancer—very similar to the I-SPY 2 trial. They received it for 6 cycles. In that setting, TCHP outperformed T-DM1/pertuzumab in pCR significantly more than 10%.

On the other hand, while the pCR rate was in favor of the TCHP arm, toxicity was in favor of the T-DM1/pertuzumab arm, with serious adverse events at approximately 5% [versus] almost 30% in the TCHP arm.

There is going to have to be some thoughtful consideration of how T-DM1 plus pertuzumab moves forward, given a pretty good-sized study that used TCHP where it was a significantly lower pCR rate.

Can you explain the purpose of the I-SPY 2 program?

Basically, it is a framework for trying to identify promising drugs or regimens but it is a very statistically complicated framework. Essentially, the trials are mostly made of up clinical subsets by estrogen receptor, progesterone receptor, and HER2 receptor [status]. Low MammaPrint-score luminal tumors are excluded, so some of the low biologically risk tumors are not selected.

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