medwireNews: Women with treatment-naïve invasive breast cancer, positive for both human epidermal growth factor receptor 2 (HER2) and oestrogen receptor (ER) might benefit from a neoadjuvant combination of palbociclib, fulvestrant, trastuzumab and pertuzumab, phase II findings suggest.
The NA-PHER2 investigators hypothesized that convergence of HER2 and ER signals on the retinoblastoma protein (RB1) means that combining palbociclib against RB1, fulvestrant against ER, and trastuzumab plus pertuzumab against HER2 might have a synergistic effect.
As reported in The Lancet Oncology, the team recruited 35 patients with unilateral invasive, HER2/ER-positive breast cancer to undergo six 3-week cycles of trastuzumab 8 mg/kg loading dose and 6 mg/kg thereafter plus pertuzumab 840 mg loading dose and 420 mg thereafter. This regimen was given alongside oral palbociclib 125 mg/day for 21 days in a 4-week cycle and fulvestrant 500 mg every 4 weeks for 5 cycles.
The co-primary endpoint of change in Ki67 expression from baseline was significant after 2 weeks of treatment in the 25 patients assessed, from a geometric average of 31.9 to 4.3, and the average value remained significantly lower at 12.1 at the time of surgery, 16 weeks after treatment initiation.
The other primary endpoint of change in apoptosis between baseline and time of surgery also reached significance, from a geometric average of 1.2 to 0.4, say Luca Gianni, from San Raffaele Scientific Institute in Milan, Italy, and co-authors.
The secondary endpoint of a RECIST objective response before surgery was shown in 97% of the 30 assessed patients, half of whom had a complete clinical response. Indeed, 27% of patients achieved a pathological complete response in both the breast and axillary nodes.
None of the 35 patients experienced grade 4 or serious adverse events. Diarrhoea and neutropenia were the most common side effects at any grade (74 and 69%, respectively), and at grade 3 (14 and 29%).
“Change in Ki67 and apoptosis were the primary endpoints in NA-PHER2, so the observed encouraging antitumour activity can only be viewed as a strong signal that the chemotherapy-free regimen should be further investigated to better assess its merits in both early and metastatic HER2-positive and ER-positive breast cancer”, the investigators conclude.
The authors of an accompanying comment caution that “until now, the relation (if any) between biological modification and treatment efficacy has not been established”, but describe the NA-PHER2 regimen as showing “an encouraging signal of activity” and say the complete eradication of tumour cells in over a quarter of patients is “impressive.”
“The NA-PHER2 study reflects what might be the future: optimum study design combining extensive biological assessment, limited population accrual, early exposure in a neoadjuvant setting, and original endpoints based on tumour biological changes as indicators of early activity”, comment Xavier Pivot, from Paul Strauss Cancer Center in Strasbourg, France, and David Cox, from INSERM U1052 in Lyon, France.
“On the other hand, such modern designs need prudence with respect to the effect of the clinical trial on cure status, and vigilance addressing access to standard well-established strategies for cure”, they add.
Gianni L, Bisagni G, Colleoni M, et al. Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study. Lancet Oncol; Advance online publication 8 January 2018. DOI: http://dx.doi.org/10.1016/S1470-2045(18)30001-9
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