Results of the UNICANCER-NeoPAL study presented at ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain did not show improved residual cancer burden (RCB) or breast conserving surgery (BCS) rates with a combination of letrozole and palbociclib over third generation chemotherapy as neoadjuvant treatment of women with luminal breast cancer (LBC).
The combination of palbociclib and letrozole has demonstrated clinical benefit in postmenopausal women with oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer, which has resulted in the granting of accelerated approval for treatment in this setting by the US Food and Drug Administration.
Historically, limited benefit has been demonstrated with neoadjuvant chemotherapy in patients with LBC leadingPaul Cottu, Medical Oncology, Institut Curie, Paris, France and a research team to investigate a regimen of letrozole plus palbociclib as neoadjuvant treatment in LBC in a randomised parallel phase II study.
The trial enroled postmenopausal women with stage II or III ER-positive, HER2-negative breast cancer who were not candidates for BCS. All patients were required to have either a PAM50 luminal B or luminal A profile with proven lymph node involvement. Of 184 screened women, 106 patients with stage II-IIIA, PAM50-ascertained LBC underwent parallel 1:1 randomisation to six courses of third generation chemotherapy comprised of FEC100 for 3 cycles plus docetaxel 100 for 3 cycles or to 19 weeks of letrozole at 2.5 mg/day plus palbociclib at 125 mg/day for four, three-week cycles. Surgery was performed at week 20.
The primary endpoint was the locally assessed rate of RCB and secondary endpoints included safety, response rate, positive and negative predictive values of PAM50 risk of recurrence (ROR)-defined status, centrally reviewed RCB, and BCS rates.
Seventy-three percent of patients were categorised T1-2, 27% were T3, 26.5% of patients were node positive, and 89% of women had luminal B tumours. The median ROR score was 68 (range 22 to 93).
The protocol planned that the trial should be stopped for futility if ≤5 local RCB 0-I events (16.7%) were observed in the first 30 patients in the letrozole/palbociclib arm.
Similar clinical response and breast conserving surgery rates observed with letrozole/palbociclib and chemotherapy
At the interim analysis, RCB 0-I was observed in one patient in the letrozole/palbociclib arm and inclusions were stopped.
At the final analysis, local RCB 0, I, II, and III was observed in 3.8%, 3.8%, 52%, and 40.4% of patients receiving letrozole/palbociclib compared to 5.9%, 9.8%, 37.3%, 47.1% in patients on chemotherapy, respectively. Central and local RCB assessment results were identical.
The ROR score was not predictive of RCB 0/I.
The rates with neoadjuvant letrozole/palbociclib and chemotherapy were similar; the clinical objective response rates were 74.5% versus 76%, and the BCS rates were 69.2% versus 68.6%, respectively.
The final median Ki67 value was significantly lower in the letrozole/palbociclib arm; Ki67 was 3% (range 1 to 40) versus 8% (range 2 to 15) respectively (p = 0.017).
Letrozole/palbociclib demonstrated better tolerability with two serious adverse events occurring in the letrozole/palbociclib arm compared to 17 with chemotherapy (p < 0.001).
Although neoadjuvant letrozole/palbociclib provided a slightly lower pCR/RCB 0-I rate than chemotherapy, the clinical response and BCS rates were similar in both arms.
However, letrozole/palbociclib had a much better safety profile.
The investigators are continuing to perform extensive analyses of these data.
Commenting on the results of the study, Nadia Harbeck of the Breast Center, Department of Obstetrics and Gynecology, University of Munich (LMU), Munich, Germany said that it is a first head to head comparison of endocrine-based (CDK4/6 inhibitor, palbociclib) vs. chemotherapy. Similar trials are ongoing in metastatic breast cancer (e.g. PADMA). However, challenge remains to identify patients with luminal early breast cancer for whom an endocrine-based approach will improve outcome, either replacing chemotherapy in intermediate-risk or as an add-on in high-risk disease.
This trial was funded by Pfizer, Nanostring.
LBA9 – Cottu P, et al. Letrozole and palbociclib versus 3rd generation chemotherapy as neoadjuvant treatment of luminal breast cancer. Results of the UNICANCER-NeoPAL study.