The new indication for pertuzumab (Perjeta) as part of a three-drug neoadjuvant regimen for patients with HER2-positive metastatic breast cancer marks the first time the FDA has authorized a therapy based on pathologic complete response.
Dietmar Berger, MD
South San Francisco, CA
The new indication for pertuzumab (Perjeta) as part of a three-drug neoadjuvant regimen for patients with HER2-positive metastatic breast cancer marks the first time the FDA has authorized a therapy based on pathologic complete response (pCR). The next step for the regimen is a phase III trial that is expected to generate additional efficacy and safety data in 2016.
The FDA approved pertuzumab in combination with trastuzumab (Herceptin) and docetaxel on September 30 under its accelerated drug development program based on the findings of several clinical trials, particularly the NeoSphere trial (Table 1).1 Specifically, the regimen is intended for women with HER2-positive, locally advanced, inflammatory, or early-stage tumors (>2 cm or node-positive). Pertuzumab initially was approved in June 2012 in certain HER2-positive metastatic breast cancer settings.
Now, the regimen will be evaluated in the APHINITY study, which has randomized approximately 4800 patients who have undergone surgery for HER2- positive primary breast cancer to trastuzumab plus chemotherapy with or without pertuzumab (Table 2).2 The primary endpoint is invasive disease-free survival.
In an interview with OncologyLive, Dietmar Berger, MD, vice president of Clinical Oncology at Genentech, which developed both pertuzumab and trastuzumab, discusses the reasons that this approval could be important to breast cancer patients, and how it might affect the FDA’s processes.
Endpoint/ Study Population
H + T
Ptz + H + T
Ptz + H
Ptz + T
N = 107
N = 107
N = 107
N = 96
pCR,a n (%) [95% CI]
23 (21.5%) [14.1- 30.5]
42 (39.3%) [30.0-49.2]
12 (11.2%) [5.9-18.8]
17 (17.7%) [10.7-26.8]
.0063 (vs H + T)
.0223 (vs H + T)
.0018 (vs Ptz + H + T)
H indicates trastuzumab; ITT, intent to treat; pCR, pathologic complete response; Ptz, pertuzumab; T, docetaxel.
apCR is defined as absence of invasive cancer in the breast and nodes.
OncologyLive: How will the new pertuzumab regimen fit into the treatment timeline, and what impact will this new option have on patients?
Berger: Patients receive a complete regimen in early breast cancer, which may consist of neoadjuvant treatment, surgery, adjuvant therapy, and perhaps radiotherapy and antihormonal therapy. We are improving that neoadjuvant component. We are helping patients achieve a higher rate of pCR, which we believe also has an impact on long-term outcomes such as disease- free survival or overall survival.
In addition, we can get a promising medicine like Perjeta to patients with early breast cancer faster. Classically, we had to do these studies in the adjuvant setting with a very long time to readout. If you think about classic comparisons, Herceptin took eight years from the metastatic approval to the early breast cancer approval. Now, we would be down to less than two years, and that is really good news for patients.
Patient Population (N= 4800)
Operable, HER2- positive primary breast cancer
Does a higher pCR rate translate into long-term benefits for patients?
The FDA conducted a meta-analysis to look at exactly that question. They looked at a total of 12 different studies in nearly 13,000 patients and compared pCR data with long-term outcome data.3 They came to the conclusion that there is a clear association between pCR and long-term outcome such as disease-free survival and overall survival. We cannot call it a validated surrogate endpoint at this time because in order to do that, you require a specific analysis of validation. The meta- analysis was unable to do that, which is why we are in the accelerated approval setting.
This regimen has the potential to be relatively expensive, since it contains three agents. Please comment on the cost versus the benefits.
This is a high-risk patient population, and it is very important that they have a meaningful increase in pCR and potentially a meaningful improvement in long-term outcome. There are other studies that demonstrate a dual blockade of HER2 in patients with HER2-positive breast cancer makes a clear difference. Perjeta is already approved in the metastatic breast cancer setting, and there we have seen a clear benefit in progression-free survival and overall survival, so we are very encouraged by this data and also by the pCR data indicating that these patients will have a clear benefit. We know there is cost associated with it, but we believe the patient benefit is very important.
Genentech does have a broad patient assistance program so we are doing what we can to help with the affordability of the medicine. We hope to get drugs to patients much earlier by utilizing this neoadjuvant pathway, which provides a clear benefit not only because they have access to effective drugs earlier, but also this is where you achieve long-term survivorship.
One combination that is generating considerable excitement is the addition of pertuzumab to T-DM1 (Kadcyla). Is the neoadjuvant approval of the Perjeta regimen a steppingstone to other therapeutic combinations?
We have to take one step at a time. We have very convincing data with Kadcyla at this point as single- agent therapy in the second-line metastatic breast cancer setting. That is where Kadcyla is approved. We are currently conducting studies with Kadcyla and Perjeta in the first-line breast cancer setting. We also have studies planned for Kadcyla and Perjeta in the early breast cancer setting, both in the neoadjuvant and adjuvant settings, and I know people are very excited about those studies. We are also very excited, but we need to see the data, and we should not forget the combination of Perjeta and Herceptin provides a very meaningful option to patients now.