Luca Gianni, MD
A 5-year follow-up of the phase II NeoSphere trial showed that patients with HER2-positive breast cancer receiving pertuzumab (Perjeta) plus trastuzumab (Herceptin) and docetaxel had better long-term outcomes than those who received trastuzumab and docetaxel alone, and those outcomes correlated with pathologic complete response (pCR) rates.
In September 2013, pertuzumab became the first drug ever approved based on pCR as a surrogate endpoint when the FDA authorized the anti-HER2 agent for use in combination with trastuzumab and chemotherapy as a neoadjuvant treatment for patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer at high risk for metastases or death. The approval was based on the primary analysis of the NeoSphere trial, in which the pCR in the pertuzumab triplet arm was 45.8% versus 29% with trastuzumab and docetaxel alone.
The updated findings correlated with the pCR data from the primary analysis. The 5-year progression-free survival (PFS) outcomes showed that the addition of pertuzumab reduced the risk of disease progression or death by 31% compared with trastuzumab and docetaxel alone (HR, 0.69; 95% CI, 0.34-1.40).
“We observed that when 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,” Luca Gianni, MD, director of Medical Oncology at the San Raffaele Scientific Institute in Milan, Italy, said in an interview with OncLive
The phase II NeoSphere trial evenly randomized 417 patients with newly diagnosed HER2-positive early-stage breast cancer to 1 of 4 treatment arms: trastuzumab plus docetaxel (n = 107, group A), pertuzumab and trastuzumab plus docetaxel (n = 107, group B), pertuzumab plus trastuzumab (n = 107, group C), or pertuzumab plus docetaxel (n = 96, group D).
In arms with pertuzumab, the agent was administered at a loading dose of 840 mg followed by 420 mg every 3 weeks. Trastuzumab was delivered at an 8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks, and docetaxel was administered at 75 mg/m2
, escalating, if tolerated, to 100 mg/m2
every 3 weeks. Treatment was delivered for 4 cycles.
Following surgery, patients received 3 cycles of FEC (fluorouracil 600 mg/m2
, epirubicin 90 mg/m2
, and cyclophosphamide 600 mg/m2
) every 3 weeks (patients in the pertuzumab/trastuzumab arm received 4 cycles of docetaxel before FEC), and 6 mg/kg of trastuzumab every 3 weeks to complete 1 full year of treatment.
The 5-year PFS rates were 81% (95% CI, 71-87) for group A, 86% (95% CI, 77-91) for group B, 73% (95% CI, 64-81) for group C, and 73% (95% CI, 63-81) for group D. PFS outcomes were not improved with pertuzumab plus trastuzumab versus trastuzumab plus docetaxel (HR, 1.25; 95% CI, 0.68-2.30) or with pertuzumab plus docetaxel versus pertuzumab plus trastuzumab and docetaxel (HR, 2.05; 95% CI, 1.07-3.93). The disease-free survival rates for arms A through D were 81% (95% CI, 72-88), 84% (95% CI, 72-91), 80% (95% CI, 70-86), and 75% (95% CI, 64-83), respectively.
Results from the previously reported primary analysis showed that patients who received pertuzumab and trastuzumab plus docetaxel experienced a significant improvement in pCR of 45.8% (95% CI, 36.1-55.7), compared with 29% (95% CI, 20.6-38.5), 24% (95% CI, 15.8-33.7), and 16.8% (95% CI, 10.3-25.3) for groups A, D, and C, respectively. The updated data demonstrated that across the entire population, the PFS rate was higher among patients who achieved total pCR versus those who did not: 85% versus 76% (HR, 0.54; 95% CI, 0.29-1.00).
Tolerability was similar across treatment groups and no new safety concerns emerged with the latest analysis. The most common grade ≥3 adverse events (AEs) with pertuzumab plus trastuzumab/docetaxel versus trastuzumab/docetaxel alone were neutropenia (55% vs 66%), febrile neutropenia (11% vs 9%), and leucopenia (6% vs 12%). Serious AEs were comparable across study arms at 19 to 22 incidents per group in 18% to 22% of patients.
The accelerated approval of neoadjuvant pertuzumab is contingent on outcomes from the phase III APHINITY trial. The study, which has enrolled more than 4800 patients with HER2-positive early stage breast cancer, is comparing pertuzumab, trastuzumab, and chemotherapy with trastuzumab and chemotherapy in the adjuvant setting.
Gianni L, Pienkowski T, Im Y-H, 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 May 11, 2016]. Lancet Oncol. http://dx.doi.org/10.1016/S1470-2045(16)00163-7.