Mark D. Pegram, MD
In 2013, pertuzumab (Perjeta) in combination with trastuzumab (Herceptin) and chemotherapy became the first neoadjuvant regimen formally approved by the FDA for the treatment of patients with breast cancer. The accelerated approval, based on the phase II NeoSphere trial, offered an exciting treatment option for patients with HER2-positive locally advanced or early-stage disease. Results from the confirmatory phase III APHINITY trial are now eagerly awaited.
Pertuzumab has also shown impressive outcomes in patients with metastatic HER2-positive disease. Adding pertuzumab to trastuzumab and chemotherapy improved median overall survival (OS) by almost 16 months over trastuzumab and docetaxel alone, according to long-term follow-up from the phase III CLEOPATRA study.
In an interview with OncLive
, Mark D. Pegram, MD, associate director of clinical research and director of the Breast Cancer Program at Stanford Cancer Institute, discusses what the available data suggest is the optimal use of pertuzumab for the management of HER2-positive breast cancer.OncLive: Please discuss completed and ongoing research involving neoadjuvant pertuzumab in HER2-positive early breast cancer.Dr Pegram:
I think the most progress that we have seen in HER2-positive early breast cancer in the neoadjuvant setting are the randomized trials involving the addition of pertuzumab to chemotherapy and trastuzumab. What has been observed in the NeoSphere trial is an increase in the fraction of patients who enjoy a pathologic complete response, which, based on several studies correlates with freedom from relapse. That is promising data, although it is not event-driven data. Based on recent FDA guidance, those types of data sets are sufficient for consideration of an accelerated approval designation, pending a larger randomized phase III trial in the adjuvant setting to confirm that the addition of pertuzumab will be impactful above and beyond chemotherapy and trastuzumab.
The APHINITY trial is ongoing and will do just that; it is the confirmatory phase III trial. The FDA granted an accelerated approval for pertuzumab in the neoadjuvant setting because proof of efficacy was demonstrated with the pathologic complete response endpoint. , Some additional safety work was done with a smaller phase II randomized trial of different chemotherapy combinations with pertuzumab and trastuzumab, which showed no cardiac safety concerns, . Because of that commitment, it went to a large randomized trial. That has really been a breakthrough. It is really practice changing, but we do need to wait for the follow-up phase III trial to really know for sure.
If that is a positive study, then I think pertuzumab in the early setting will have traction. If the APHINITY trial is negative, then I think the FDA will probably withdraw their accelerated approval designation for pertuzumab. Everyone is very anxious and excited to see the results of the phase III study when it becomes available. The good news is that the trial has already finished accruing and it is in follow-up stages, so we should expect the results in the next couples of years.What are the challenges associated with using neoadjuvant pertuzumab to treat patients with HER2-positive breast cancer?
One challenge is deciding if everyone needs neoadjuvant pertuzumab for the treatment of this disease. I think the answer to that is clearly, “no,” based on data published by the CALGB, which looked at smaller, stage I negative tumor sizes. A combination of weekly paclitaxel multiplied by 12, plus trastuzumab for one year in a group of patients with T1e to T1c size tumors afforded an astonishing 98.7% 3-year projected disease-free survival rate. Pertuzumab could not beat that kind of statistic in a randomized trial. I think for stage I disease, this combination of weekly paclitaxel and trastuzumab with no pertuzumab is arguably the most attractive in the adjuvant setting, and those subjects would not need to be considered for neoadjuvant therapy.
Another concern is safety. Pertuzumab adds a little bit in the aggregate safety data to the toxicity of chemotherapy and trastuzumab. It predominantly adds some GI toxicity, as well as about a 5% increase in the incidence in skin rash. Typically, both of those can be mitigated with some dose modification of the chemotherapy base.What is the best approach to sequencing pertuzumab and other treatments for advanced HER2-positive breast cancer?
The question of how to cycle through all the various HER2 targeting treatment strategies for advanced disease was complex. However, recent considerations have made it a little bit easier on the basis of a press release announcing the topline results from the pivotal phase III MARIANNE study.
MARIANNE involved over 1000 HER2-positive first-line metastatic patients who were to receive chemotherapy and trastuzumab in the control group, or T-DM1 and a placebo, or T-DM1 and pertuzumab.