Lead NeoSphere Author Discusses Pertuzumab Update in HER2+ Breast Cancer

Luca Gianni, MD

The encouraging 5-year follow-up results investigating the triplet regimen of pertuzumab (Perjeta), trastuzumab (Herceptin), and docetaxel have solidified this neoadjuvant treatment option for patients with early-stage HER2-positive breast cancer, according to lead study author Luca Gianni, MD.

These latest findings of the multicenter, open-label phase II NeoSphere study, published in The Lancet Oncology,¹ demonstrated that the combination improved progression-free survival and disease-free survival over trastuzumab and chemotherapy alone. Additionally, the authors noted, the total pathological complete response (pCR) could be an early indicator of long-term outcomes for patients with the disease.

Pertuzumab was granted an accelerated approval by the FDA in September 2013, in combination with trastuzumab and chemotherapy, primarily based on the preliminary NeoSphere findings.

OncLive: Can you give an overview of the NeoSphere study and discuss the 5-year follow-up results?

In an interview with OncLive, Gianni, director of Medical Oncology, head, Project of Development of New Drugs and Innovative Therapies in Solid Tumors at the San Raffaele Scientific Institute, cofounder of The Michaelangelo Foundation in Milan, Italy, discusses the significance of these results and how the regimen is already impacting the landscape of HER2-positive breast cancer.Gianni: The study is a long story and, basically, it goes back to the very early preliminary data from a metastatic study on women who were progressing on trastuzumab and were dying from this disease. We were testing additional pertuzumab in these cases.

What was evident, at the time, was that the administration of pertuzumab with the other monoclonal antibody was giving us really interesting results, in terms of antitumor activity in the metastatic setting and a cost of very limited toxicity. The combination of the two was particularly good. At the time we, at The Michelangelo Foundation, proposed the possibility of testing it in the neoadjuvant setting.

What is the significance of these long-term findings?

This was clinically explored in NeoSphere as a test of this hypothesis and it has been an extremely lucky study with very promising results.This is a phase II study that was not designed to address the question of long-term efficacy. On the other hand, we knew that patients had to be followed. This is because, when we started the trial with pertuzumab in combination, we had limited experience on the long-term safety of this combination. Therefore, we wanted to make sure that we were not doing something that we would regret at a later time. However, results showed that there was no increased toxicity due to the exposure to pertuzumab.

No new toxicities were observed. In terms of safety, what should oncologists know when administering this type of combination to patients?

What unanswered questions remain with this combination?

What is the significance of the results? We did not reach statistical significance; however, we observed that while we use pertuzumab in combination with trastuzumab and docetaxel in the neoadjuvant setting, there is a carry-over effect that persists at the end of surgery and during the follow-up period. After surgery, all patients receive the same type of adjuvant chemotherapy plus trastuzumab. Whatever difference we measure, it is a difference that is linked to what we have done during the neoadjuvant fraction of this study.First, this combination was approved by the FDA more than 1 year and a half ago. In July 2015, it was also approved by the European Medicines Agency (EMA) in the neoadjuvant setting. Frankly, the feasibility of the treatment is very, very simple in this 3-drug combination of docetaxel, pertuzumab, and trastuzumab.The unanswered questions are several. As I said, this is a phase II study and it would have been nicer to have a larger number of patients to see if the pCR would have translated into a benefit in terms of long-term efficacy.

Here, we have a trend that is very indicative but is not formal proof. It goes in the same direction of other trials; if you get pCR with this neoadjuvant therapy, you can predict long-term benefit. Still, that is not formal proof.

The formal proof will most likely come from studies such as the adjuvant APHINITY trial, where we show that the same combination that we used in the neoadjuvant setting works in the adjuvant setting. That would be a closed circle that would set the stage for neoadjuvant therapy—to predict what happens in the adjuvant setting.

Additional questions include whether or not we should continue therapy in patients who achieve eradication of their disease with the neoadjuvant approach. There is a big question mark that will have to be addressed for NeoSphere, as well as other types of treatments for other conditions.

How have you already seen this regimen have an impact on the neoadjuvant treatment landscape of HER2-positive disease?

We have the conservative attitude that, even if we reach pCR and eradication of disease, we still continue with adjuvant treatment for our patients. However, there is a doubt of this; if we eradicate disease, perhaps we do not really need to continue the toxic therapy. This is something that we really have to address.The arrangement has been picked up very nicely in the United States. In Europe, it depends very much on the different countries. Just to give an idea, Europe is very complicated; in some countries, the EMA approval has been translated immediately into the possibility of using pertuzumab in the neoadjuvant setting, with a reimbursement by the government. In Europe, the government covers most of the costs. In Italy, however, this is not the case. The regulatory body decided that the evidence to support the use of pertuzumab from the NeoSphere study is not enough to justify its use for the time being.

Are there any other ongoing clinical trials in the neoadjuvant setting that you’re excited to see the results of?

Now, there is a debate on whether or not to approve the use. Overall, the reason that is under consideration due to recent evidence in several journals indicating that if you reach eradication of disease with an anti-HER2 drug included in NeoSphere, there is a very high likelihood that you have also boosted immunologic surveillance against the tumor. Therefore, the result is a confirmatory result.There is another study that was completed with the combination of pertuzumab and trastuzumab and that is the TRYPHAENA study. Results of that phase II study demonstrated that 6 cycles instead of 4 cycles of chemotherapy plus pertuzumab and trastuzumab was extremely active. Therefore, NeoSphere is not the only study that has shown other confirmatory evidence in support of the value of this combination with chemotherapy. This is a large, adjuvant setting study to be completed with a readout in 2017.

Finally, what are some of the biggest challenges that remain with this disease?

Every time this combination is used together, there are results that are extremely positive.We have had outstanding progress over the years in treating patients with HER2-positive disease. Yet, some patients still have relatively poor response.

The key approach that is emerging nowadays in HER2-positive disease is to consider different approaches in patients with not only HER2-positive disease, but with progesterone receptor— and estrogen receptor–positive disease, as well. This is because these tumors have different molecular features and sensitivity to drugs than tumors that are HER2-positive. That is the way to go in the near future—to relatively select more subgroups within the HER2-positive umbrella and try to make the best out of the potential treatments for these subgroups.

Gianni L, Pienkowski T, Im, YH, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. [published online before print May 11, 2016] The Lancet Oncol. doi: 10.1016/S1470-2045(16)00163-7.