Three-year survival rates were similarly high among postmenopausal women with high-risk early luminal breast cancer who were treated with either the neoadjuvant combination of letrozole and palbociclib (Ibrance) or standard neoadjuvant chemotherapy in the phase 2 NeoPAL study.
Progression-free survival (PFS) was a respective 86.7% and 87.2%, with a hazard ratio (HR) of 1.01 (P = .98) comparing the endocrine therapy and cyclin-dependent kinase (CDK) 4/6 inhibitor combination versus FEC/taxane chemotherapy.
There were also no differences between the two treatment arms in terms of invasive disease-free survival (iDFS, HR = 0.83, P = .71) or breast cancer–specific survival (BCSS), although the latter was an exploratory endpoint alongside overall survival (OS).
“The lack of difference is impressive,” said Hope S. Rugo, MD, FASCO, who commented independently on the study’s findings after their presentation at the European Society for Medical Oncology: Breast Cancer virtual meeting.
“Overall survival in patients who received chemotherapy appears to be better, but the very small numbers here make interpretation of this difference impossible,” observed Dr. Rugo, professor of medicine at the University of California San Francisco’s Helen Diller Family Comprehensive Cancer Center.
“Unfortunately, this study is underpowered for definitive conclusions,” acknowledged study investigator Suzette Delaloge, MD, associate professor of medical oncology at Institut Gustave Roussy in Villejuif, France.
However, “it shows that the nonchemotherapy, preoperative letrozole/palbociclib approach deserves further exploration and could be an option for a chemotherapy-free regimen in some specific cases.”
Primary data already reported
The NeoPAL study was an open-label, randomized study conducted in 27 centers throughout France that compared the preoperative use of letrozole plus palbociclib to neoadjuvant chemotherapy in 106 postmenopausal patients with either luminal A or B node-positive disease.
Patients were considered for inclusion in the trial if they had been newly diagnosed with estrogen receptor (ER)-positive, HER2-negative stage I-III breast cancer and were not candidates for breast conservation. Genetic testing was used to confirm that only those with luminal B, or luminal A and who were node positive were recruited.
Neoadjuvant treatment consisted of either letrozole (2.5 mg/day) and palbociclib (125 mg daily for 3 weeks out of 4 weeks) for 19 weeks or three 21-day cycles of 5-fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2), followed by three 21-day cycles of docetaxel (100 mg/m2).
The primary endpoint was the pathological complete response (pCR), defined as a residual cancer burden (RCB) of 0 to 1. Results, which have already been reported, showed equivalent, but perhaps disappointingly low, pathological responses in both the letrozole/palbociclib and chemotherapy arms (3.8% and 5.9%, respectively).
There were, however, identical clinical responses (at around 75%) and “encouraging biomarker responses in the Prosigna-defined high risk luminal breast cancer population,” Dr. Delaloge said.
The NeoPAL findings were on par with those of the CORALLEEN study, Dr. Delaloge suggested. That trial, as Dr. Rugo has also pointed out, was conducted in 106 patients with luminal B early breast cancer and used a combination of letrozole and the CDK 4/6 inhibitor ribociclib (Kisquali).
Future studies needed
NeoPAL “is a small study with relatively short follow-up even for hormone receptor-positive, high-risk disease,” Dr. Rugo observed. However, she qualified “this short follow-up can be very meaningful in high-risk disease.” as shown by other CDK 4/6 inhibitor trials.
Dr. Rugo also noted: “Short-term biologic endpoints are clearly more informative following and during neoadjuvant endocrine therapy than pCR and this trial, as well as the data from previous studies, indicates that this is the case.”
Further, Dr. Rugo said: “Antiproliferative response is enhanced with CDK 4/6 inhibitors, but this doesn’t seem to translate into a difference in pCR. The lack of impact on longer term, outcome to date, provides support for ongoing trials.”
Two such trials are already underway. The 200-patient CARABELA trial started recruitment in March last year and is comparing endocrine therapy with letrozole plus the CDK 4/6 inhibitor abemaciclib (Verzenio) to standard chemotherapy in patients with hormone receptor–positive, high-risk Ki67 disease.
Then there is the ADAPTcycle trial, a large open-label, phase 3 trial that is randomizing patients based on Ki67 and recurrence score after a short preoperative induction with endocrine therapy to postoperative chemotherapy or to 2 years of endocrine therapy plus ribociclib, with both arms receiving a standard course of 5 years of endocrine therapy.
“These two studies have provided interesting information that will help us design studies in the future,” said Dr. Rugo.
Not only that, but they will also help “investigate the subgroups of patients that benefit the most from CDK 4/6 inhibitors and better study neoadjuvant endocrine therapy which is an important option for patients that can be evaluated in terms of its efficacy by short term measures of antiproliferative response.”
NeoPAL was sponsored by UNICANCER with funding from Pfizer and NanoString Technologies. Dr. Delaloge disclosed receiving research grants or funding via her institution from Pfizer, AstraZeneca, Roche, Merck, Sanofi, Lilly, Novartis, BMS, Orion, Daiichi, Puma, and Pierre Fabre. Dr. Rugo reported receipt of grants via her institution to perform clinical trials from Pfizer and multiple other companies. She disclosed receiving honoraria from PUMA, Samsung, and Mylan.