MADRID – For women with luminal breast cancer who are not initially candidates for breast-conserving surgery, neoadjuvant therapy with an aromatase inhibitor and a cyclin-dependent kinases 4/6 (CDK4/6) inhibitor offered a slightly higher residual cancer burden prior to surgery, but a significantly better safety profile than conventional chemotherapy with similar near-term safety outcomes, results of a phase 2 parallel group, noncomparative trial suggested.
Among 60 patients evaluable for response in an interim analysis of the UNICANCER NeoPAL trial, one patient (3.3%) treated with a combination of letrozole (Femara) and palbociclib (Ibrance) had a residual cancer burden (RCB) score of 0 (equivalent to a pathologic complete response; pCR), whereas three patients (10%) treated with FEC 100 chemotherapy (5-fluorouracil, epirubicin, and cyclophosphamide) had RCB 0 or I, reported Paul-Henri Cottu, MD, of the Institut Curie in Paris.
Dr. Paul-Henri Cottu
Following the interim analysis, the independent data monitoring committee for the NeoPAL trial recommended halting accrual; accrual was stopped in November 2016, after 106 patients had been randomized.
The IDMC also recommended that patients in the letrozole/palbociclib arm who did not have an RCB of 0 or I be offered adjuvant chemotherapy.
“Please note that 70% of those patients refused adjuvant chemotherapy,” Dr. Cottu said.
The investigators set out to test whether letrozole and palbociclib, which have been shown to have synergistic antiproliferative activity against advanced luminal breast cancer, could have similar benefits in the neoadjuvant setting.
They screened for women with luminal breast cancer who had newly diagnosed stage II or III breast cancer with biopsy-proven endocrine receptor–positive, human epidermal growth factor receptor 2–negative tumors, using the Prosigna test, based on the PAM50 gene signature assay. Women with node-positive luminal A or luminal B disease were enrolled and randomized to receive either letrozole 2.5 mg and palbociclib 125 mg daily for 3 out of every 4 weeks over 19 weeks, or three cycles of FEC 100, followed by three cycles of docetaxel 100 mg/m2 every 3 weeks, followed by surgery.
An interim analysis was planned after 30 patients were evaluable for RCB in the experimental arm, and, as prespecified, the trial was stopped for futility when fewer than five patients had an RCB of 0 or I.
The safety analysis, conducted with all 106 patients randomized, showed that letrozole/palbocilib was associated with more frequent grade 3 neutropenia (23% vs. 10% of patients with FEC), but less grade 4 neutropenia (1% vs. 11%, respectively), and no febrile neutropenia vs. 6% in the chemotherapy arm.
There were 2 serious adverse events with the AI/CDK-inhibitor combination vs. 17 with chemotherapy. Dose reductions or interruptions were less frequent with letrozole/palbociclib (10 and 16), and only two patients in the experimental arm required premature cessation of therapy vs. seven in the chemotherapy arm.
The final response analysis in 103 patients showed that the rate of RCB 0 or I was 7.7% with letrozole/palbociclib and 15.7% with chemotherapy. Respective rates of RCB II-III were 92.3% and 84.3%.
Clinical response rates were similar in each study arm, with approximately 30% complete responses and 44% partial responses.
In each arm, slightly less than one-third of patients underwent mastectomy, and a little more than two-thirds were able to have breast-conserving surgery after neoadjuvant therapy.
The patients will be followed out to at least 3 years to see whether those patients in the letrozole/palbociclib arm who turned down subsequent chemotherapy will have worse survival than patients who decided to undergo it, Dr. Cottu said.
Invited discussant Nadia Harbeck, MD, PhD, of the University of Munich called the NeoPAL trial “a very daring study.”
“This is not a practice-changing trial, but it’s a very, very interesting hypothesis-generating trial,” she said.
She said that the choice of RCB was probably not the best endpoint in a trial of endocrine-based therapy vs. chemotherapy.
“I think the challenge remains to identify those patients with luminal early breast cancer for whom an endocrine-based approach – not endocrine, but endocrine-based – will improve outcome, either replacing chemotherapy in the intermediate-risk setting or as an add-on in high-risk disease,” she said.
The study was funded by Pfizer and Nanostring. Dr. Cottu disclosed advisory board participation and travel support from Pfizer and others, and research support from Roche, Novartis, and AstraZeneca. Dr. Harbeck disclosed advising and consulting fees from Pfizer, Nanostring, and other companies.