Pertuzumab reduced risk of invasive disease in early-stage breast cancer: APHINITY results
Catherine Amey, Senior Medical Writer, Touch Medical Media, Goring-On-Thames, UK

Pertuzumab improved invasive disease-free survival (IDFS) in patients with human epidermal growth factor receptor 2 (HER2)-positive, early stage breast cancer when added to trastuzumab and chemotherapy.1 These findings, presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2017, were from the APHINITY study that randomly assigned 4805 patients, post-surgery, to standard adjuvant chemotherapy and trastuzumab plus either placebo (n=2405) or pertuzumab (n=2400). The 3-year rate of IDFS was 94.1% in the pertuzumab group and 93.2% for placebo. The data have also been published online in The New England Journal of Medicine.2

“Treatment effect was homogenous throughout all subgroups; however, the node-positive and hormone receptor–negative cohorts appeared to derive the most benefit at the current point of time,” said Gunter von Minckwitz, MD, PhD, of the German Breast Group Research Institute in Neuisenberg, Germany, “with a relative risk reduction of 23% and 24%, respectively, and a 3-year IDFS absolute increase of 1.8% and 1.6%, respectively.” The combination might be difficult to justify for all patients with early HER2-positive breast cancer, but a solid case can be made for selected patients with higher-risk disease, specialists said at the ASCO meeting.

"It's always an issue with adjuvant treatment that if you report the early results, you don't have the full view on the efficacy," commented Gunter von Minckwitz. "From a statistical point of view, we don't see a difference in efficacy in the node-positive versus node-negative patients or with regard to hormone-receptor status. But with the data we have right now, these results support the use more in the higher-risk patients: node positive and receptor negative."

Cardiac toxicity was low and not statistically significant. For the primary cardiac endpoint (heart failure or cardiac death) and secondary cardiac endpoint (asymptomatic or mildly symptomatic LVEF decline) rates were 0.7% versus 0.3% and 2.7% versus 2.8%, in the pertuzumab and placebo arms, respectively. Diarrhoea grade ≥3 was more frequent with pertuzumab compared with placebo (9.9% versus 3.7%, respectively).

Pertuzumab, a humanized monoclonal antibody, as complementary mechanisms of action to those of trastuzumab, blinding to different domains.3,4 Pertuzumab binds to the HER2 dimerization domain, inhibiting HER2 heterodimerization with other HER family members. By contrast, trastuzumab binds close to the transmembrane domain inhibiting dimerization.

In patients with HER2-positive metastatic breast cancer, pertuzumab added to trastuzumab and docetaxel has been demonstrated to prolong significantly both progression-free survival and overall survival.5,6 As a component of a neoadjuvant regimen, pertuzumab added to trastuzumab plus docetaxel was shown to increase significantly the pathological complete response rate.7,8

The next time-driven analysis for APHINITY will be 2.5 years, Dr von Minckwitz explained. In addition, ongoing studies are investigating whether, after 6 months of neoadjuvant pertuzumab treatment, patients will require further treatment post surgery (ClinicalTrials.gov numbers, NCT02131064 and NCT02132949).

REFERENCES


1. Von Minckwitz G, Procter MJ, De Azambuja E, 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):.
2. von Minckwitz G, Procter M, de Azambuja E, et al., Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer, N Engl J Med, 2017; DOI: 10.1056/NEJMoa1703643
3. Baselga J, Swain SM, Novel anticancer targets: revisiting ERBB2 and discovering ERBB3, Nat Rev Cancer, 2009;9:463-75.
4. Scheuer W, Friess T, Burtscher H, et al., Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models, Cancer Res, 2009;69:9330-6.
5. Baselga J, Cortes J, Kim SB, et al., Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer, N Engl J Med, 2012;366:109-19.
6. Swain SM, Baselga J, Kim SB, et al., Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer, N Engl J Med, 2015;372:724-34.
7. Gianni L, Pienkowski T, Im YH, et al., Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial, Lancet Oncol, 2012;13:25-32.
8. 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, Lancet Oncol, 2016;17:791-800.