Treatment effect of palbociclib plus endocrine therapy by prognostic and intrinsic subtype and biomarker analysis in patients with bone-only disease: a joint analysis of PALOMA-2 and PALOMA-3 clinical trials

Abstract

Purpose This analysis evaluated the relationship between treatment-free interval (TFI, in PALOMA-2)/disease-free interval (DFI, in PALOMA-3) and progression-free survival (PFS) and overall survival (OS, in PALOMA-3), treatment effect in patients with bone-only disease, and whether intrinsic subtype affects PFS in patients receiving palbociclib. Methods Data were from phase 3, randomized PALOMA-2 and PALOMA-3 clinical studies of hormone receptor‒positive/human epidermal growth factor receptor 2‒negative (HR+ /HER2−) advanced breast cancer (ABC) patients receiving endocrine therapy plus palbociclib or placebo. Subpopulation treatment effect pattern plot (STEPP) analysis evaluated the association between DFI and PFS and OS. PFS by luminal subtype and cyclin-dependent kinase (CDK) 4/6 or endocrine pathway gene expression levels were evaluated in patients with bone-only disease; median PFS and OS were estimated by the Kaplan–Meier method. Results Median durations of TFI were 37.1 and 30.9 months (PALOMA-2) and DFI were 49.2 and 52.0 months (PALOMA-3) in the palbociclib and placebo groups, respectively. Among the PALOMA-2 biomarker population (n = 454), 23% had bone-only disease; median PFS was longer with palbociclib versus placebo (31.3 vs 11.2 months; hazard ratio, 0.41; 95% CI 0.25‒0.69). The interaction effect of bone-only versus visceral disease subgroups on median PFS with palbociclib was not significant (P = 0.262). Among the PALOMA-3 biomarker population (n = 302), 27% had bone-only disease. STEPP analyses showed that palbociclib PFS benefit was not affected by DFI, and that palbociclib OS effect may be smaller in patients with short DFIs. Among patients who provided metastatic tumor tissues (n = 142), regardless of luminal A (hazard ratio, 0.23; 95% CI 0.11‒0.47; P = 0.0000158) or luminal B (hazard ratio, 0.26; 95% CI 0.12‒0.56; P = 0.000269) subtype, palbociclib improved PFS versus placebo. Conclusions These findings support palbociclib plus endocrine therapy as standard of care for HR+ /HER2− ABC patients, regardless of baseline TFI/DFI or intrinsic molecular subtype, including patients with bone-only disease. Trial registration Pfizer (clinicaltrials.gov:NCT01740427, NCT01942135).

Systematic Review of Molecular Biomarkers Predictive of Resistance to CDK4/6 Inhibition in Metastatic Breast Cancer

“… Potential resistance biomarkers from tumor analyses of primary tumor or metastases in patients with HR+ve mBC (n = 1,162; Molecular alterations associated with drug resistance [solid tumors: DNA, RNA, or protein]). Intrinsic and acquired resistance biomarkers from PALOMA2 (n = 454 palbociclib plus letrozole), 29 PALOMA3 (gene expression analyses n = 302 paired samples; palbociclib plus fulvestrant), 30 the study by Wander et al 22 (n = 58; paired samples CDK4/6i plus endocrine therapy), and the study by Li et al 21 for FAT1 loss (CDK4/6i plus endocrine therapy; n = 348). AURKA , aurora kinase A; CDK4/6, cyclin-dependent kinase 4 and 6; EGFR, epidermal growth factor receptor; ER, estrogen receptor; FAT1 , FAT atypical cadherin 1; FGFR2 , fibroblast growth factor receptor 2; HER2 , human epidermal growth factor receptor 2; IGFR1, insulin-like growth factor 1 receptor; MET, mesenchymal-epithelial transition factor; PLK, polo-like kinase; RAS, rat sarcoma virus; RB1 , Retinoblastoma 1 gene.…”

Updates on managing advanced breast cancer with palbociclib combination therapy

“…35,[39][40][41] Subpopulation treatment effect pattern plot (STEPP) analysis presented at the 2018 American Society of Clinical Oncology Annual Meeting showed that the treatment effect of the addition of palbociclib to endocrine therapy was not impacted by the length of the initial treatment-free interval (TFI; PALOMA-2) or disease-free interval (DFI; PALOMA-3). 43 The median TFI in PALOMA-2 was 37.1 months for palbociclib plus letrozole and 30.9 months for letrozole plus placebo, with approximately 56% of patients having a TFI of over 2 years. 43 The median DFI in PALOMA-3 was 49.2 months for palbociclib plus fulvestrant versus 52.0 months for fulvestrant plus placebo, with over 80% of patients having had a DFI more than 2 years.…”

“…43 The median TFI in PALOMA-2 was 37.1 months for palbociclib plus letrozole and 30.9 months for letrozole plus placebo, with approximately 56% of patients having a TFI of over 2 years. 43 The median DFI in PALOMA-3 was 49.2 months for palbociclib plus fulvestrant versus 52.0 months for fulvestrant plus placebo, with over 80% of patients having had a DFI more than 2 years. 43 In addition, patient subgroup analyses of PALOMA-2 showed patients with either a low disease burden or a demonstrated sensitivity to endocrine monotherapy derived substantial PFS benefit from the combination of palbociclib plus letrozole (i.e.…”

Targeted Therapy in HR+ HER2− Metastatic Breast Cancer: Current Clinical Trials and Their Implications for CDK4/6 Inhibitor Therapy and beyond Treatment Options

“…However, data suggest that some subgroups of patients have a higher benefit than others, mainly in the subgroups of postmenopausal women, patients with visceral metastasis, and patients with the progression of disease under endocrine therapy (second-line therapy) [ 29 ]. Regarding the intrinsic molecular subtypes of BC, PFS is marginally pronounced in the luminal A subtype compared to the luminal B subtype in the cohort of PALOMA-2 and -3 [ 30 ].…”