In an Italian phase II study reported in The Lancet Oncology, Gianni et al found that neoadjuvant therapy with the RB1 inhibitor palbociclib (Ibrance), estrogen receptor (ER) inhibitor fulvestrant (Faslodex), and human epidermal growth factor receptor 2 (HER2) inhibitors trastuzumab (Herceptin) and pertuzumab (Perjeta) reduced Ki67 expression in patients with HER2-positive, ER-positive breast cancer.
In the study, 30 evaluable patients with previously untreated disease from 7 sites in Italy were treated every 3 weeks with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and pertuzumab (840 mg loading dose and then 420 mg) for six cycles plus palbociclib (125 mg once a day for 21 days in 4-week cycles) and fulvestrant (500 mg) every 4 weeks for five cycles.
The coprimary endpoints were change from baseline in Ki67 expression at 2 weeks of treatment and at surgery at 16 weeks after treatment, and changes in apoptosis (number of apoptotic bodies in sample) from baseline to surgery.
Changes in Ki67 Expression
Geometric mean Ki67 expression scores (standard deviation) were 31.9 (15.7) at baseline, 4.3 (15.0) at week 2 (n = 25, P < .0001), and 12.1 (20.0) at surgery (n = 22, P = .013). Geometric mean apoptosis scores were 1.2 (0.3) at baseline and 0.4 (0.4) at surgery (P = .019). Clinical objective response immediately before surgery was observed in 29 patients (97%). At surgery, pathologic complete response in breast and axillary lymph nodes was observed in 8 patients (27%).
No grade 4 or serious adverse events were observed among 35 patients receiving the regimen. The most common grade 3 adverse events were neutropenia (29%); diarrhea (14%); and stomatitis, increased ALT, and hypersensitivity reactions (3% each). No deaths occurred on study.
The investigators concluded, “The combination of palbociclib, fulvestrant, trastuzumab, and pertuzumab had a significant effect on the expression of Ki67 at 2 weeks and at surgery. Triple targeting of ER, HER2, and RB1 in HER2-positive and ER-positive breast cancer could be an effective chemotherapy-free treatment strategy. Further clinical testing and additional molecular characterisation is necessary, not only in hormone receptor-positive tumours but also in tumours without HER2 amplification.”
The study was funded by Pfizer and Roche.
Luca Gianni, MD, of San Raffaele Scientific Institute, Milan, is the corresponding author for The Lancet Oncology article.
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