Lead Researcher Talks Phase III APHINITY Trial Results for Pertuzumab in HER2+ Breast Cancer

Adding pertuzumab to standard postoperative trastuzumab therapy in patients with HER2-positive early breast cancer improved the rate of recurrence overall, but had a greater benefit for individuals with higher-risk disease, according to results from the phase III APHINITY trial.

Gunter von Minckwitz, MD, PhD

Adding pertuzumab (Perjeta) to standard postoperative trastuzumab (Herceptin) therapy in patients with HER2-positive early breast cancer improved the rate of recurrence overall, but had a greater benefit for individuals with higher-risk disease, according to results from the phase III APHINITY trial.

The APHINITY trial, which was presented at the 2017 ASCO Annual Meeting, included 4805 patients who were randomized to receive adjuvant chemotherapy for 18 weeks and 1 year of either pertuzumab plus trastuzumab (n = 2400) or trastuzumab plus placebo (n = 2405). The primary efficacy endpoint was invasive disease-free survival. No new safety signals were identified with the pertuzumab combination versus the placebo arm.

In an interview withTargeted Oncologyat ASCO, lead study investigator Gunter von Minckwitz, MD, PhD, president of the German Breast Group in Neu-Isenburg, Germany, discussed the APHINITY results and their implication for the use of pertuzumab in patients with HER2-positive breast cancer.

TARGETED ONCOLOGY:Please provide an overview of the APHINITY trial.

von Minckwitz:We know that pertuzumab has a distinct mechanism compared to trastuzumab. It inhibits the heterodimerization of the HER2, HER3, and other HER receptors. We know from metastatic disease, that when pertuzumab is added to docetaxel and trastuzumab, it can prolong PFS and overall survival. We have also seen data in the neoadjuvant setting that has demonstrated that the complete response rate can be almost doubled when pertuzumab is added to docetaxel and trastuzumab.

We know that a significant proportion of patients with HER2-positive breast cancer relapse in the long-term, which was our motivation to conduct the APHINITY study.

This study randomized 4805 patients with confirmed HER2-positive breast cancer. They were treated with either chemotherapy, trastuzumab, and placebo or chemotherapy, trastuzumab, and pertuzumab. The antibody treatment was for a total of 1 year and the radiotherapy or endocrine treatment was started after adjuvant chemotherapy. We allowed a couple of different chemotherapy regimens, either a sequence of an anthracycline followed by a taxane or an anthracycline-free regimen with a TCH regimen.

TARGETED ONCOLOGY:What were the significant findings from this study?

von Minckwitz:The APHINITY study met its primary objective. We demonstrated that the frequency of invasive disease-free events could be reduced by 19% and saw a significant P value of .045. The treatment effect was dominant in patients with a higher risk, such as node-positive patients where the benefit was 1.8% which was significant. The hormone receptor (HR)-negative patients saw a benefit of 1.6%, which was not particularly significant.

The number of patients treated to avoid 1 disease event was around 100 with 50 to 60 patients in the node-positive and the HR-negative population. These were the potential groups of patients where we could consider the use of pertuzumab beyond what is already established in the neoadjuvant setting.

There have been safety analyses looking specifically at the impact on the cardiac toxicity. Overall, cardiac toxicity was very low, only 17 and 8 events in the 2 arms, respectively. There was no statistically significant difference and about half of these patients recovered on later follow-up.

The main clinically relevant side-effect of grade 3 or higher was diarrhea. It was almost around 10% in the pertuzumab arm and a little bit less then 4% in the placebo arm. This was confined to the chemotherapy period and was more pronounced with the TCH regimen compared to the sequential anthracycline taxane regimens.

TARGETED ONCOLOGY:Were the side-effects manageable?

von Minckwitz:These higher rates of diarrhea occurred and it’s a very annoying for patients so physicians must be very careful with this. However, it is a period of up to 24 weeks where this occurs and it may not be clinically meaningful compared to the effect that we have observed.

TARGETED ONCOLOGY:Are there any next steps or additional analyses that you would like to see done?

von Minckwitz:We have collected a large amount of biomaterial in the trial and we are now investigating biomarkers that are specific candidate markers, such as PI3-kinase mutations, where there are signals that these might be markers that will help to better select those patients that will have the best benefit from pertuzumab.

Are there any other challenges with pertuzumab that you would like to see answered? One question is do we need a full year of treatment or should we continue after surgery to complete this year? Should we stop it or not give it to those patients that didn’t achieve pathologic complete response (pCR) because they seem to be resistant? Should it be continued in those patients with a pCR because they are sensitive but have a good prognosis? These are some questions, which are being addressed currently in subsequent studies but might be very difficult to answer as they would require a large study.

TARGETED ONCOLOGY:What are some of the most important things from this study that you would like community physicians to take away?

von Minckwitz:We can be more confident now with the use of pertuzumab in the neoadjuvant setting. We have a very homogenous picture of how pertuzumab works in breast cancer. We came to this very much based on a risk assessment. In the adjuvant setting it’s important to concentrate on those patients with a higher risk of relapse since this furthers the chances of survival for these patients.


von Minckwitz G, Procter MJ, De Azambuja, et al. APHINITY trial (BIG 4-11): A randomized comparison of chemotherapy (C) plus trastuzumab (T) plus placebo (Pla) versus chemotherapy plus trastuzumab (T) plus pertuzumab (P) as adjuvant therapy in patients (pts) with HER2-positive early breast cancer (EBC).J Clin Oncol.2017;35 (suppl; abstr LBA500).