Tumor Biomarker Analysis from the Phase 3 PALOMA-2 Trial

Palbociclib, a cyclin-dependent kinase (CDK) 4 and 6 inhibitor, has shown a synergistic effect with hormonal blockade in both endocrine therapy–naive and endocrine-resistant estrogen receptor–positive (ER+) breast cancer models in preclinical studies. Sensitive cell lines had elevated levels of retinoblastoma (Rb) and CCND1 (cyclin D1) and decreased levels of CDKN2A (p16) by gene expression. The PALOMA-2 trial was a double-blind, placebo-controlled study that demonstrated a significant improvement in median progression-free survival (PFS) with palbociclib plus letrozole compared with placebo plus letrozole (24.8 vs 14.5 months; hazard ratio [HR], 0.58; P <0.001) in postmenopausal ER+/human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer patients who had not received prior systemic therapy for their advanced disease. While overall survival follow-up for PALOMA-2 remains active, a biomarker analysis to identify potential markers of clinical response was reported here.

In PALOMA-2, 666 patients were randomized 2:1 to receive palbociclib plus letrozole or placebo plus letrozole. The primary end point was investigator-assessed PFS. Tumor samples from the original diagnostic or metastatic specimen were required from all patients. All samples underwent a central blinded analysis using immunohistochemistry (H-score ≥1 defined positivity) for ER, Rb, p16, cyclin D1, and Ki-67. An H-score ≥1 defined positivity for each marker, and for Ki-67, proliferative indices were based on 15%, 20%, and 40% cut-off points.

For this analysis, 568 (85%) patients had tumor tissue available, and ER evaluation was possible for 566 samples. Central review confirmed 89% as ER+; the ER median (interquartile range) H-score for patients receiving palbociclib plus letrozole was 120 (45-170), and for those receiving placebo plus letrozole was 110 (38-158). By H-scores, PFS improvement with palbociclib plus letrozole was observed in all ER quartiles. In Rb+ patients, who constituted >90% of the intent-to-treat (ITT) population, median PFS was 24.2 versus 13.7 months (HR, 0.53; P <0.0001) in patients receiving palbociclib plus letrozole versus placebo plus letrozole, respectively. Similarly, in p16+ patients, who constituted 85% of the ITT population, median PFS was 24.8 versus 13.8 months (HR, 0.52; P <0.0001) in patients receiving palbociclib plus letrozole versus placebo plus letrozole, respectively. Although sample sizes were too few to draw conclusions for other biomarkers explored, “these exploratory analyses did not identify a subgroup of ER+ patients who did not benefit from the addition of palbociclib to letrozole,” said Dr Richard Finn of Los Angeles, CA, who was affiliated with this study. He added that “Ki-67 index values did not further stratify patients.”

PALOMA-2 had already shown that patients with ER+ breast cancer benefit from the addition of a CDK 4/6 inhibitor to their treatment. This follow-up biomarker analysis on cell cycle–related genes did not reveal additional markers with sensitivity to palbociclib plus letrozole beyond ER+, although further analyses using other methodologies are ongoing.

Finn R, et al. ESMO 2016. Abstract LBA15.