PAL, a cyclin-dependent kinase (CDK) 4 and 6 inhibitor, demonstrated synergy with hormonal blockade in endocrine therapy (tx)–naive and endocrine-resistant ER+ breast cancer models. Sensitive cell lines had elevated levels of retinoblastoma (Rb) and CCND1 (cyclin D1) and decreased levels of CDKN2A (p16) by gene expression. PALOMA-2 demonstrated a significant improvement in median progression-free survival (mPFS) with PAL + L vs P + L (24.8 vs 14.5 mo; hazard ratio [HR], 0.58; P < 0.001) in postmenopausal ER + /HER2– ABC patients (pts) not given prior systemic tx for their advanced disease. Overall survival follow-up for this study remains active. Based on preclinical observations, we performed biomarker analyses to identify potential markers of clinical response.
666 pts were randomized 2:1 to receive PAL + L or P + L. The primary endpoint was investigator-assessed PFS. Tumor tissues from the original diagnostic or metastatic specimen were required from all pts. We performed a central blinded analysis using immunohistochemistry (H-score ≥1 defined positivity) for ER, Rb, p16, cyclin D1, and Ki-67 (proliferative indices based on 15%, 20%, and 40% cutpoints).
568 pts (85%) had tumor tissue available and 566 samples were evaluable for ER. Central review confirmed 89% as ER + ; ER median [interquartile range] H-scores: PAL + L, 120 [45-170]; P + L, 110 [38-158]). By H-scores, PFS improvement with PAL + L was observed in all ER quartiles, Rb+ pts (>90% of intent-to-treat population; 24.2 vs 13.7 mo; HR, 0.53; P < 0.0001), and p16+ pts (85%; 24.8 vs 13.8 mo; HR, 0.52; P < 0.0001). A trend was noted toward a PAL + L benefit for the p16- pts (n = 59); Rb- pts (n = 29) were too few to draw conclusions. In cyclin D1+ pts' tumor samples (97%), the benefit did not vary with H-score. Ki-67 index values did not reveal a pt group with better or worse PFS with PAL + L.
ER+ pts benefit from the addition of a CDK 4/6 inhibitor. Biomarker analyses on cell cycle–related genes did not reveal additional markers with sensitivity to PAL + L beyond ER+.
Clinical trial identification
Legal entity responsible for the study
R. Finn: Consultant: Pfizer, Merck, Bayer, Novartis, Bristol Myers Squibb. Y. Jiang: Employee and stock ownership: Pfizer, Inc. H. Rugo: Dr. Rugo does not receive funding personally. Funding is provided to her institution for the conduct of clinical trials sponsored by Pfizer. S.L. Moulder: Genentech; Oncothyreon; Pfizer Research Funding Institution. S-A. Im: AstraZeneca Grant Self AstraZeneca, Novartis, Roche Advisory role Self. V. Dieras: Roche, Pfizer, Novartis Consultant/Advisory Role Self Roche, Pfizer, Novartis Speakers' Bureau Self. M. Martin: Amgen; Novartis Honoraria Self Celgene; Novartis; Pfizer; Roche Pharma AG Consultant/Advisory Role Self Novartis Research Funding Self. A.A. Joy: Pfizer Advisory Board Self. M. Toi: Pfizer Research funding Self (department). E. Gauthier: Employee and stockholder: Pfizer, Inc. D.R. Lu: Pfizer Employee and stockholder. C.H. Bartlett: Pfizer Employee and stockholder Self. D. Slamon: Pfizer Stock Ownership; Travel Accommodations or Expenses Self BioMarin Leadership; Stock Ownership; Travel Accommodations or Expenses Self . All other authors have declared no conflicts of interest.