A combination of palbociclib, a selective inhibitor of cyclin-dependent kinases (CDK) 4 and 6, and aromatase inhibitor letrozole demonstrated a statistically significant improvement in progression-free survival (PFS) in a phase II trial of first-line treatment for ER-positive, HER2-negative advanced breast cancer, according to Dr Richard Finn, an associate professor of medicine at the University of California, Los Angeles (UCLA). He presented the study results at AACR Annual Meeting 2014 (5-9 April, San Diego, USA).
Palbociclib (PD0332991) prevents DNA synthesis by blocking cell cycle progression. Preclinical studies identified that hormone receptor-positive breast cancer cells are dependent on CDK4/6 and that these cancers are sensitive to CDK4/6 inhibition. In particular, ER-positive breast cancer cell lines showed elevated expression of cyclin-D1, Rb and reduced p16 expression. Synergistic activity was observed in vitro when palbociclib was combined with tamoxifen.
After these preclinical observations, a phase I study was conducted. It showed that palbociclib and letrozole could be given safely in combination, with manageable side effects. That study also showed preliminary signs of efficacy. A recommended phase II dose of palbociclib was 125 mg once daily for three weeks followed by one week off plus letrozole 2.5 mg continuously once daily.
The PALOMA-1 trial was designed as a two-part study evaluating palbociclib and letrozole vs. letrozole alone in the first-line treatment for ER-positive, HER2-negative metastatic breast cancer. Part 1 enrolled post-menopausal patients, while part 2 enrolled patients with the same breast cancer subtype additionally screened for CCND1 amplification and/or loss of p16.
The primary endpoint was PFS as assessed by investigators. It was defined as the time from randomisation to objective progression or death. Secondary endpoints included objective response rate, overall survival, safety, and correlative biomarker studies.
In both parts, patients were randomised 1:1 to receive either palbociclib/letrozole or letrozole alone. It was foreseen that patients continue the treatment until disease progression, unacceptable toxicity, or consent withdrawal. The patients have been followed for tumour assessments every two months.
In this randomised, phase II study the investigators recruited 165 patients, 66 in part 1 and 99 patients in part 2. Baseline characteristics were balanced between two the treatment arms.
When the investigators evaluated patients from both parts of the study combined, they found that PFS was 20.2 months in patients who received palbociclib plus letrozole, while it was 10.2 months for those who received letrozole only (hazard ratio (HR)=0.488; p = 0.0004). The PFS results indicated a 51% reduction in the risk of disease progression with the addition of palbociclib to letrozole.
In part 1 of the study, PFS was 26.1 months for the combination of palbociclib plus letrozole vs. 5.7 months for letrozole alone (p < 0.0001). In part 2, PFS was 18.1 vs. 11 months, respectively (p = 0.0046). The risk for progression of the disease did not decrease in patients from part 2 whose tumours had the molecular targets specific for the drug. In particular, the risk decreased by 70% in those in part 1, compared with 49% for those in part 2.
Dr Finn said to AACR news that having an intact Rb pathway seems to be the most critical factor for palbociclib to be effective.
Best overall response was 43% for the combination treatment vs. 33% for letrozole alone. Clinical benefit rate (complete and partial response plus stable disease) was 81% vs. 58%, respectively.
The overall survival analysis with 61 events demonstrated a trend in favour of combined treatment vs. letrozole alone (37.5 months vs. 33.3 months, respectively), but this difference was not statistically different.
The most common adverse events in the combined arm were neutropenia, leukopenia, fatigue and anaemia.
Ongoing phase III studies
According to the study authors this phase II study proved the testing hypothesis that a combination of palbociclib and letrozole is better than letrozole alone in this patient subgroup. A phase III study of palbociclib in combination with letrozole in same metastatic breast cancer population is ongoing (PALOMA-2). A phase III study of its combination with fulvestrant (PALOMA-3) for metastatic breast cancers is also ongoing, as well as a combination with standard endocrine therapy (PENELOPE-B) for certain early-stage breast cancers.
The PALOMA-1 trial was funded by Pfizer. Dr Finn declares no conflicts of interest.
The abstract co-authors are from the Irish Cooperative Oncology Research Group, Dublin, Ireland; Orszagos Onkologiai Intezet, Budapest, Hungary; Onkologia, Szent Margit Korhaz, Budapest, Hungary; Dnipropetrovsk City Multiple-Discipline Clinical Hospital, Dnipropetrovsk, Ukraine; Donetsk City Oncology Dispensary, Donetsk, Ukraine; Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; Comprehensive Blood and Cancer Center, Bakersfield, USA; Petz Aladar Teaching Hospital Győr, Győr, Hungary; Department of Obstetrics and Gynecology, University Mainz, Mainz, Germany; Lviv State Oncologic Regional Treatment and Diagnostic Center, Lviv, Ukraine; Comprehensive Cancer Centers of Nevada, Henderson, USA; Kyiv City Clinical Oncology Center, Kyiv, Ukraine; and Pfizer Oncology, San Diego, USA.
The study was presented at 105th Annual Meeting of the American Association for Cancer Research (AACR). The theme for AACR Annual Meeting 2014, “Harnessing Breakthroughs – Targeting Cures,” reflects the fact that the translation of basic science into clinical advances for the benefit of cancer patients is occurring at an increasing pace and more seamlessly than ever before.
- Finn RS, Crown JP, Lang I, et al. Final results of a randomized Phase II study of PD 0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (PALOMA-1; TRIO-18). Abstract CT101, AACR Annual Meeting 2014. Page visited last time on 7 April 2014.
- AACR News: Palbociclib Shows Promising Results in Patients With Hormone Receptor-positive Metastatic Breast Cancer. Page visited last time on 7 April 2014.