An unusual durable response with palbociclib plus letrozole in hormone receptor positive metastatic breast cancer after multiple lines of therapy
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Palbociclib
Letrozole
Abstract Purpose: To determine (i) the relationship between candidate biomarkers of the antiproliferative (Ki67) response to letrozole and palbociclib alone and combined in ER+/HER2− breast cancer; and (ii) the pharmacodynamic effect of the agents on the biomarkers. Experimental Design: 307 postmenopausal women with ER+/HER2− primary breast cancer were randomly assigned to neoadjuvant treatment with letrozole for 14 weeks; letrozole for 2 weeks, then letrozole+palbociclib to 14 weeks; palbociclib for 2 weeks, then letrozole+palbociclib to 14 weeks; or letrozole+palbociclib for 14 weeks. Biopsies were taken at baseline, 2 and 14 weeks and surgery at varying times after stopping palbociclib. Immunohistochemical analyses were conducted for Ki67, c-PARP, ER, PgR, RB1, CCNE1, and CCND1. Results: Higher baselines ER and PgR were significantly associated with a greater chance of complete cell-cycle arrest (CCCA: Ki67 <2.7%) at 14 weeks and higher baseline Ki67, c-PARP, and CCNE1 with a lower chance. The interaction with treatment was significant only for c-PARP. CCND1 levels were decreased c.20% by letrozole at 2 and 14 weeks but showed a tendency to increase with palbociclib. CCNE1 levels fell 82% (median) in tumors showing CCCA but were unchanged in those with no CCCA. Only 2/9 tumors showed CCCA 3–9 days after stopping palbociclib. ESR1 mutations were found in 2/4 tumors for which surgery took place ≥6 months after starting treatment. Conclusions: High CCNE1 levels were confirmed as a biomarker of resistance to letrozole+palbociclib. Ki67 recovery within 3–9 days of discontinuing palbociclib indicates incomplete suppression of proliferation during the “off” week of its schedule.
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In the initial PALOMA-2 (NCT01740427) analysis with median follow-up of 23 months, palbociclib plus letrozole significantly prolonged progression-free survival (PFS) in women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC) [hazard ratio (HR) 0.58; P < 0.001]. Herein, we report results overall and by subgroups with extended follow-up. In this double-blind, phase 3 study, post-menopausal women with ER+/HER2− ABC who had not received prior systemic therapy for their advanced disease were randomized 2:1 to palbociclib-letrozole or placebo-letrozole. Endpoints include investigator-assessed PFS (primary), safety, and patient-reported outcomes (PROs). After a median follow-up of approximately 38 months, median PFS was 27.6 months for palbociclib–letrozole (n = 444) and 14.5 months for placebo-letrozole (n = 222) (HR 0.563; 1-sided P < 0.0001). All subgroups benefited from palbociclib treatment. The improvement of PFS with palbociclib-letrozole was maintained in the next 2 subsequent lines of therapy and delayed the use of chemotherapy (40.4 vs. 29.9 months for palbociclib–letrozole vs. placebo-letrozole). Safety data were consistent with the known profile. Patients' quality of life was maintained. With approximately 15 months of additional follow-up, palbociclib plus letrozole continued to demonstrate improved PFS compared with placebo plus letrozole in the overall population and across all patient subgroups, while the safety profile remained favorable and quality of life was maintained. These data confirm that palbociclib-letrozole should be considered the standard of care for first-line therapy in patients with ER+/HER2− ABC, including those with low disease burden or long disease-free interval. Sponsored by Pfizer; ClinicalTrials.gov: NCT01740427.
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Abstract The experimental CDK-inhibitor palbociclib, when combined with the aromatase inhibitor letrozole, significantly extended progression-free survival in women with HER2-/ER+ breast cancer compared with letrozole alone, according to the final results from a phase II clinical trial of the drug.
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Palbociclib is a first-in-class inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) that inhibits cell proliferation and DNA synthesis by preventing cell-cycle progression from G1 to S phase (1). In cell line models of ER-positive breast cancer, estrogen activates CDK4/6 via cyclin D1, resulting in hyperphosphorylation of retinoblastoma (Rb) gene product, which leads to entry of the cell cycle (2). Endocrine resistance has been shown to be depends on cyclin D1 and CDK4/6 in vitro. Based on the impressive progression-free survival (PFS) found in the phase 2 study PALOMA-1 (3), palbociclib was granted accelerated approval in 2015 by the Food and Drug Administration (FDA) for treatment of estrogen-receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC).
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Abstract Estrogen receptor-positive (HR+) breast cancer is the most common form of breast cancer that is accountable for the majority of breast cancer mortality. Currently, the cyclin dependent kinase inhibitor palbociclib in combination with endocrine therapy represents the new standard first and second line therapy for patients with metastatic HR+ breast cancer. While palbociclib has been shown to significantly improved progression free survival in combination with aromatase inhibitor (AI) and fulvestrant, resistance will inevitably occur in patients with metastatic breast cancer. However, the mechanisms of resistance to the combination of palbociclib and AI remain largely unknown. It is also unclear whether resistance mechanisms would be the same if palbociclib was given as first line treatment in combination with letrozole vs. if palbociclib was given as second line treatment after letrozole resistance had already occurred. To address this, previously well established and well characterizied letrozole-sensitive MCF7Ca cells and letrozole-resistant LTLTCa cells were subjected to continuous, long term treatment with increasing doses of letrozole and palbociclib until resistance to both drugs was achieved (MCF7Calet+palb and LTLTCapalb, respectively). Preliminary MTT cell viability assays indicate palbociclib IC50s of 750 nM in MCF7Ca and LTLTCa cells vs. 21 uM in palbociclib and letrozole-resistant cells. First line and second line palbociclib resistance correlated with changes in morphology, protein expression, and cancer stem cell characteristics. Under phase contrast microscopy, first line and second line palbociclib-resistant MCF7Ca and LTLTCa cells were larger in size, more irregular in shape, and tended not to grow in epithelial cell-like groups compared to palbociclib-sensitive MCF7Ca and letrozole cells, with second-line palbociclib resistant cells exhibiting these characteristics the most. Western blot showed that ER protein expression in ER+/HER2- MCF7Ca cells decreased with first line palbociclib and letrozole resistance, and that both ER and HER2 protein expression were decreased with second line palbociclib resistance in ERlow/HER2+ LTLTCa cells. Lastly, mammosphere assays demonstrated increasing percentage of cancer stem cells with letrozole resistance alone (4 per 1000 cells plated MCF7Ca vs. 58 per 1000 planted LTLTCa) and with palbociclib and palbociclib resistance (317 per 1000 cells plated MCF7Ca and 202 per 1000 cells plated LTLTCa cells). Overall, these results indicate that 1) resistance to palbociclib, whether as first line or second line treatment has significant effects on breast cancer cells that may be relevant to patient diagnosis and treatment. Citation Format: Armina A. Kazi, Antony Sare, Saranya Chumsri, Angela Brodie. Mechanisms of resistance to palbociclib and aromatase inhibitors in hormone receptor positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2053. doi:10.1158/1538-7445.AM2017-2053
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A phase 2 study showed that progression-free survival was longer with palbociclib plus letrozole than with letrozole alone in the initial treatment of postmenopausal women with estrogen-receptor (ER)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer. We performed a phase 3 study that was designed to confirm and expand the efficacy and safety data for palbociclib plus letrozole for this indication.
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Palbociclib, the first available cyclin-dependent kinase 4/6 inhibitor, plus endocrine therapy is approved for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC). This study compared real-world effectiveness of palbociclib plus letrozole versus letrozole in older patients with MBC in US clinical practice.This retrospective analysis included patients from the Flatiron Health longitudinal database. Overall, 796 women with HR+/HER2- MBC aged ≥65 years starting palbociclib plus letrozole or letrozole as first-line therapy between February 2015 and September 2018 were included. Patients were evaluated from treatment start until December 2018, death, or last visit, whichever came first. Real-world progression-free survival (rwPFS), overall survival (OS), and real-world best tumor responses (rwBTR) were endpoints. Stabilized inverse probability treatment weighting (sIPTW) balanced patient characteristics.After sIPTW, 450 patients treated with palbociclib plus letrozole and 335 treated with letrozole were included; median age was 74.0 years. Median rwPFS was 22.2 (95% CI, 20.0-30.4) months for palbociclib plus letrozole versus 15.8 (12.9-18.9) months for letrozole (hazard ratio, 0.59 [0.47-0.74]; P<0.001). Median OS was not reached for palbociclib plus letrozole versus 43.4 months (30.0-not estimable) with letrozole (hazard ratio, 0.55 [0.42-0.72]; P<0.001). No interactions between age groups (65-74 and ≥75 years) and treatment groups were observed for rwPFS or OS. Rate of rwBTR was significantly higher for palbociclib plus letrozole (52.4%) versus letrozole (22.1%; odds ratio, 2.0 [1.4-2.7]; P<0.001).This analysis demonstrates the effectiveness of palbociclib combination therapy as standard-of-care for older patients with HR+/HER2- MBC in the first-line setting.
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Abstract Background and ObjectivesPalbociclib and Ribociclib are a cyclin-dependent kinase (CDK 4/6) oral molecular inhibitors may improve overall survival (OS), progression free survival (PFS) and quality of life (QoL) in metastatic breast cancer (MBC) patients. We aimed to cost utility analysis (CUA) of Palbociclib in comparison with other alternative regimens in the first line treatment of patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2–) MBC in Iran.MethodsCUA was performed using partitioned survival model (PSM) from Iranian healthcare system perspective. Comparative strategies were Palbociclib+letrozole, Ribociclib+letrozole and Letrozole mono-therapy. Model structured with 1-month cycle length and 15 years as time horizon. Clinical safety and efficacy of interventions and survival functions in terms of PFS and OS for Palbociclib+letrozole, and Ribociclib+Letrozole was obtained from the latest update of PALOMA-1, 2 and MONALEESA-2 study, respectively. Direct medical costs include the cost of drugs, visits, hospitalization, CT scan, bone x-rays, monitoring and testing, and the medications side effects were considered. In order to uncertainty evaluations, deterministic sensitivity analysis (DSA) and probabilistic sensitivity analysis (PSA) were performed. Excel 2016 and TreeAge 2020 were used in all stages of evaluation.ResultsBase case results showed that despite the lower effectiveness, Letrozole mono-therapy was the most cost-effective strategy and Palbociclib+letrozole and Ribociclib+letrozole were not cost effective. The incremental cost effectiveness ratio (ICER) of the Palbociclib+Letrozole and Ribociclib+Letrozole compared to Letrozole mono-therapy was estimated at $137,302 and $120,478 per quality adjusted life year (QALY), respectively, indicating a large interval from the target threshold ($4956). DSA showed that the results of the CUA were not significantly sensitive to changes in the values of uncertain variables. PSA also showed Palbociclib+letrozole and Ribociclib+letrozole did not have a chance to be cost effective based on changes in various parameters and simulations.Conclusionsalbociclib and Ribociclib showed significant efficacy in the addition to Letrozole based on the PFS but were not cost effective strategies in the first line treatment of MBC.
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PURPOSE CDK4/6 inhibitors are used to treat estrogen receptor (ER)–positive metastatic breast cancer (BC) in combination with endocrine therapy. PALLET is a phase II randomized trial that evaluated the effects of combination palbociclib plus letrozole as neoadjuvant therapy. PATIENTS AND METHODS Postmenopausal women with ER-positive primary BC and tumors greater than or equal to 2.0 cm were randomly assigned 3:2:2:2 to letrozole (2.5 mg/d) for 14 weeks (A); letrozole for 2 weeks, then palbociclib plus letrozole to 14 weeks (B); palbociclib for 2 weeks, then palbociclib plus letrozole to 14 weeks (C); or palbociclib plus letrozole for 14 weeks. Palbociclib 125 mg/d was administered orally on a 21-days-on, 7-days-off schedule. Core-cut biopsies were taken at baseline and 2 and 14 weeks. Coprimary end points for letrozole versus palbociclib plus letrozole groups (A v B + C + D) were change in Ki-67 (protein encoded by the MKI67 gene; immunohistochemistry) between baseline and 14 weeks and clinical response (ordinal and ultrasound) after 14 weeks. Complete cell-cycle arrest was defined as Ki-67 less than or equal to 2.7%. Apoptosis was characterized by cleaved poly (ADP-ribose) polymerase. RESULTS Three hundred seven patients were recruited. Clinical response was not significantly different between palbociclib plus letrozole and letrozole groups ( P = .20; complete response + partial response, 54.3% v 49.5%), and progressive disease was 3.2% versus 5.4%, respectively. Median log-fold change in Ki-67 was greater with palbociclib plus letrozole compared with letrozole (−4.1 v −2.2; P < .001) in the 190 evaluable patients (61.9%), corresponding to a geometric mean change of −97.4% versus −88.5%. More patients on palbociclib plus letrozole achieved complete cell-cycle arrest (90% v 59%; P < .001). Median log-fold change (suppression) of cleaved poly (ADP-ribose) polymerase was greater with palbociclib plus letrozole versus letrozole (−0.80 v −0.42; P < .001). More patients had grade 3 or greater toxicity on palbociclib plus letrozole (49.8% v 17.0%; P < .001) mainly because of asymptomatic neutropenia. CONCLUSION Adding palbociclib to letrozole significantly enhanced the suppression of malignant cell proliferation (Ki-67) in primary ER-positive BC, but did not increase the clinical response rate over 14 weeks, which was possibly related to a concurrent reduction in apoptosis.
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Ribociclib, palbociclib and abemaciclib are currently approved CDK4/6 inhibitors along with aromatase inhibitors as the first-line standard-of-care for patients with hormone receptor-positive, HER2-negative metastatic breast cancer.
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