Paul Cottu, MD
As neoadjuvant treatment of women with high-risk luminal breast cancer, the combination of letrozole and palbociclib (Ibrance) did not reduce the residual cancer burden or improve the rates of breast-conserving surgery, in the phase II UNICANCER-
NeoPAL study presented at the 2017 European Society for Medical Oncology (ESMO) Congress.1
“The letrozole plus palbociclib combination did not reach the ambitious goal of more than 20% rate of residual cancer burden of 0–I,” said Paul Cottu, MD, of the Institut Curie in Paris.
The primary endpoint was the locally assessed rate of residual cancer burden, which is a standardized method of assessing breast and nodal pathologic response after neoadjuvant chemotherapy. Very few patients with luminal breast cancer achieve residual cancer burden class 0 (pathologic complete response) or I (minimal residual disease) after neoadjuvant chemotherapy, which are outcomes that translate into good long-term prognosis.
The protocol stipulated the trial should be stopped for futility if five or fewer local residual cancer burden 0–I events were observed in the first 30 patients receiving letrozole and palbociclib, an inhibitor of cyclin--dependent kinase 4/6 (CDK4/6).
Why Letrozole Plus Palbociclib?
In women with luminal breast cancer who are not candidates for breast-conserving surgery, neoadjuvant chemotherapy is an option, though it results in low rates of pathologic complete response. Neoadjuvant endocrine therapy provides similar clinical response and has a more favorable tolerability profile than chemotherapy. The combination of letrozole and palbociclib also appears to be synergistic, creating “powerful” antiproliferative activity in advanced luminal breast cancer and significantly improving response rates and progression-free survival over letrozole alone, he explained.
These findings formed the basis of the UNICANCER-NeoPAL study, conducted in France and Belgium, which evaluated letrozole/palbociclib as neoadjuvant treatment of patients with stage II/III estrogen receptor–positive, HER2-negative breast cancer. The study’s 106 patients had high-risk luminal A or luminal B tumors, as determined by the PAM50 test, and lymph node involvement. They were randomized to six courses of third-generation chemotherapy using FEC100 (fluorouracil, epirubicin, cyclophosphamide) for three cycles and docetaxel 100 mg/m2 for three cycles, vs 19 weeks of letrozole (2.5 mg/d) plus palbociclib (125 mg/d) for four cycles. Surgery was performed at week 20.
Investigators assessed the value of assessing Ki67 levels and preoperative endocrine prognostic index scores. Studies have shown that a low posttreatment Ki67 value and preoperative endocrine prognostic index score (which integrates residual disease and Ki67) can reliably predict long-term outcomes in luminal disease.
No Better Than Chemotherapy
Clinical response and rates of breast-conserving surgery were no better with letrozole/palbociclib than with chemotherapy, Dr. Cottu reported. At the interim analysis of 60 patients, residual cancer burden 0–I was observed in only 1 patient (3.3%) in the letrozole/palbociclib arm and in 3 patients (10.0%) in the chemotherapy arm; study enrollment, therefore, was discontinued. At the final analysis, local residual cancer burden 0–I rates were twice as high with chemotherapy: 15.7% vs 7.7%.
“The final residual cancer burden 0 (pathologic complete response) and residual cancer burden III rates were strikingly similar between the arms,” Dr. Cottu noted. Clinical responses were observed in 74.5% of the letrozole/palbociclib arm and in 76.0% of the chemotherapy arm, and breast-conserving surgery was possible in 69.2% vs 68.6%, respectively.
Letrozole/palbociclib did, however, have an impact on Ki67 and preoperative endocrine prognostic index score, producing a final Ki67 value that was significantly lower than that achieved with chemotherapy. The baseline geometric means were similar, 24.1% and 27.7%, respectively, but final geometric means were 1.17% and 3.7% (P = .0418).
“We saw encouraging preoperative endocrine prognostic index score results with palbociclib,” he said. Preoperative endocrine prognostic index 0—which equates to a low pathologic stage and favorable biomarker profile at surgery and is associated with a very low risk for relapse—was observed in 17.3% of the experimental arm compared with 8% of the chemotherapy arm. Preoperative endocrine prognostic index 4+, the least favorable, was seen in 26.9% and 56.0%, respectively. “The results were consistent with the antiproliferative effect of the palbociclib/endocrine combination,” he commented.
Patients found letrozole/palbociclib more tolerable than chemotherapy, with 2 serious adverse events in this arm compared with 17 with chemotherapy (P < .001).
Future analyses will include 3-year event-free survival and late side effects. “A key issue is whether long-term outcomes are endangered without chemotherapy,” he said. Patients receiving palbociclib were offered adjuvant chemotherapy, but 70% rejected it.
Dr. Cottu acknowledged the primary objective of the study was “ambitious,” but lessons were learned: pathologic complete response rates by either approach are extremely low in patients with prospectively, genomically defined, high-risk luminal tumors, and palbociclib in combination with letrozole yields clinical efficacy that is similar to neoadjuvant chemotherapy but is better tolerated.
“Patients, if given the choice, would refuse chemotherapy,” he said, emphasizing the need for larger studies of CDK4/6 inhibitors as a replacement strategy in this patient population and setting. ■
DISCLOSURE: Dr. Cottu has received consulting fees and travel expenses from Pfizer, Roche, and Novartis.
Nadia Harbeck, MD, PhD
Invited discussant Nadia Harbeck, MD, PhD, Head of the Breast Center of the University of Munich (LMU), Germany, said the UNICANCER-NeoPAL trial points toward the future of endocrine therapy in early breast cancer—using cyclin-dependent kinase 4/6 (CDK4/6) inhibitors ...!-->!-->