Neoadjuvant T-DM1/Pertuzumab Combo Boosts pCR in HER2+ Breast Cancer

Angela M. DeMichele, MD

Neoadjuvant ado-trastuzumab emtansine (T-DM1; Kadcyla) in combination with pertuzumab (Perjeta) improved pathologic complete response (pCR) compared with standard of care in patients with advanced HER2-positive breast cancer, according to recently reported data from the adaptively randomized I-SPY 2 trial.

Of the 249 patients with HER2-positive disease included in the I-SPY 2 trial, 54% of those who received T-DM1/pertuzumab experienced a pCR compared with 22% of those who received the combination of paclitaxel (Abraxane) plus trastuzumab (Herceptin).

These findings suggest that T-DM1 may ultimately increase survival in these patients, says lead study author Angela M. DeMichele, MD, professor of Medicine and Epidemiology at the University of Pennsylvania.

“The primary endpoint of the trial is pCR and this is important because, in HER2-positive breast cancer, pCR is a very good short-term surrogate for long-term outcomes,” says DeMichele, who presented the HER2-positive I-SPY 2 data at the 2016 AACR Annual Meeting. “Our ultimate goal is to prevent disease from recurring, but if a drug or drug combination can get patients to the point of pCR, then they stand a very good likelihood of never having their breast cancer come back.”

OncLive: What was the design of the I-SPY 2 trial?

In an interview with OncLive, DeMichele explains the significance of the I-SPY 2 data, the advantages of T-DM1 versus standard of care, and what is on the horizon for the use of T-DM1 in HER2-positive disease.DeMichele: I-SPY 2 is a phase II trial that aims to identify active new agents in breast cancer to take to phase III. It is adaptively randomized, which means that we can evaluate several drugs simultaneously; it also minimizes the number of patients we need to enroll to find effective agents.

What were the most significant findings in the HER2-positive arm?

In this particular arm of the trial, which was for HER2-positive patients, we tested 2 drugs; T-DM1 and pertuzumab against the standard paclitaxel plus trastuzumab. All patients went on to get doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan) and then go on to have surgery.What we found in the trial was that the combination of T-DM1/pertuzumab did a much better job of getting patients to pCR than the standard paclitaxel plus trastuzumab. In fact, there was a 30% increase in the likelihood of achieving a pCR.

It accomplished the increase in pCR along with another nice outcome—less toxicity. By dropping the paclitaxel and using 2 HER2-targeted agents, we were able to avoid some of the more bothersome side effects that patients experience.

For example, these patients usually experience neuropathy, which can be very debilitating and can even become permanent. There was really a negligible amount of neuropathy in the T-DM1/pertuzumab arm. Alopecia is another thing that is extremely common with paclitaxel, but is very rare with T-DM1 or pertuzumab. The combination of T-DM1 and pertuzumab has the potential to increase the quality of life for our patients, while giving them a more effective option for treatment.

We are excited about the findings of this cohort in the I-SPY 2 trial because it gives us another option for patients with HER2-positive breast cancer on which to build. While we improved the pCRs, we didn’t hit 100% and that is our goal. Our goal is to get every patient to a pCR. We know that a patient who gets to a pCR has a much better prognosis versus a patient who does not.

Now, we can start to build upon this with less toxicity, which will make it much easier to start to combine it with other drugs such as immunotherapies, or even other HER2-targeted agents. It was very gratifying for us to see a drug combination in which our patients are feeling very well, but are also getting very good outcomes.

What phase III trials investigating T-DM1 are you excited about?

Certainly, these findings need to be confirmed in a large phase III trial.There are 3 trials in particular that are examining the effects of T-DM1 in the neoadjuvant or adjuvant setting. There is the KRISTINE trial, which is looking at the impact of T-DM1 with or without pertuzumab against standard taxane and trastuzumab therapy in the neoadjuvant setting. That has completed accrual.

There is also the KATHERINE study, which is similarly designed for patients who have been through neoadjuvant therapy and then have residual disease. Those patients can then go on to potentially be randomized to receive T-DM1 or standard therapy.

In the adjuvant setting, there is the KAITLIN trial, which is a large phase III trial. Again, they are looking at the benefit of T-DM1 against standard trastuzumab.

What do you see on the horizon in HER2-positive breast cancer?

There is also the ATEMPT trial, which is looking at long-term use of T-DM1—1 year of therapy as added assurance in the adjuvant setting. We are very anxious to see the results of these trials. We are also anxious to see the results of the APHINITY trial, which compares the efficacy and safety of chemotherapy plus trastuzumab and placebo versus chemotherapy plus trastuzumab and pertuzumab in the adjuvant setting.Right now, we have so many great options for women with HER2-positive breast cancer. I think it is easy for us to continue to want to add new things all the time, but what we are starting to see now is that we can really get to a personalized approach, and find unique combinations with unique sets of side effects that are all effective.

We can then start to tailor our approach to that individual patient for who neuropathy may be a concern, or for who liver disease might be a concern, and we can start to pick and choose from among a variety of effective regimens based on what is best for the patient.

DeMichele AM, Moulder S, Buxton M, et al. Efficacy of T-DM1 + pertuzumab over standard therapy for HER2+ breast cancer: results from the I-SPY 2 trial. Presented at: AACR 2016 Annual Meeting, New Orleans; April 16-20, 2016. Abstract CT-042.