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
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.
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.
OncLive: Can you give an overview of the NeoSphere study and discuss the 5-year follow-up results?
: 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.
This was clinically explored in NeoSphere as a test of this hypothesis and it has been an extremely lucky study with very promising results.
What is the significance of these long-term findings?
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.
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.
No new toxicities were observed. In terms of safety, what should oncologists know when administering this type of combination to patients?
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.
What unanswered questions remain with this combination?
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.