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Massimo Cristofanilli - One of the best experts on this subject based on the ideXlab platform.
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hematologic adverse events following Palbociclib dose reduction in patients with hormone receptor positive human epidermal growth factor receptor 2 negative advanced breast cancer pooled analysis from randomized phase 2 and 3 studies
Breast Cancer Research, 2020Co-Authors: Johannes Ettl, Norikazu Masuda, Massimo Cristofanilli, Marco Colleoni, Hope S Rugo, Patrick Schnell, Eustratios Bananis, Richard S FinnAbstract:Palbociclib improves outcomes for women with hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (HR+/HER2− ABC). Dose reductions are recommended for the management of hematologic toxicities. A previous pooled analysis from the PALOMA clinical trials showed that 36.9% of patients required dose reduction, predominantly during the first 6 months of treatment and with decreasing frequency during subsequent 28-day treatment cycles (C). Previous data have shown that Palbociclib dose reductions do not affect efficacy. This pooled, post hoc analysis evaluated the frequency of hematologic adverse events (AEs) before and after Palbociclib dose reduction in PALOMA-1, PALOMA-2, and PALOMA-3. This analysis evaluated the frequency of hematologic AEs 30 days before dose reduction and during each subsequent treatment from C1 to C6 among patients who required Palbociclib dose reduction. Data were pooled from 3 randomized studies. PALOMA-1 was a phase 2, open-label study of postmenopausal patients untreated for ABC receiving Palbociclib plus letrozole or letrozole alone. PALOMA-2 was a phase 3, double-blind study of postmenopausal patients untreated for ABC receiving Palbociclib plus letrozole or placebo plus letrozole. PALOMA-3 was a phase 3, double-blind study of pre/perimenopausal or postmenopausal patients, whose disease progressed on prior endocrine therapy, receiving Palbociclib plus fulvestrant or placebo plus fulvestrant. A total of 311 (35.5%) patients with HR+/HER2− ABC required a Palbociclib dose reduction (93.6% due to AEs) from 125 to 100 mg. Mean patient age was 59.9 years, and 46.9% of patients had visceral disease. Median time to dose reduction was 70 days. The majority of dose reductions occurred within 3 months of starting Palbociclib treatment. Incidences of all-grade and grades 3/4 hematologic AEs were lower following dose reduction. A decrease in frequency and severity of hematologic AEs, including febrile neutropenia, following Palbociclib dose reduction was observed, supporting the recommended use of dose reduction in AE management. These studies were sponsored by Pfizer. ClinicalTrials.gov: NCT00721409; registration date July 24, 2008. ClinicalTrials.gov: NCT01740427; registration date December 4, 2012. ClinicalTrials.gov: NCT01942135; registration date September 13, 2013.
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predictors of prolonged benefit from Palbociclib plus fulvestrant in women with endocrine resistant hormone receptor positive human epidermal growth factor receptor 2 negative metastatic breast cancer in paloma 3
European Journal of Cancer, 2018Co-Authors: Massimo Cristofanilli, Dennis J Slamon, Seockah Im, Norikazu Masuda, C Giorgetti, Angela Demichele, Nicholas C Turner, Shailendra Verma, Marco Colleoni, Kathy Puyana TheallAbstract:Abstract Background The addition of Palbociclib to fulvestrant improved clinical outcomes over placebo-fulvestrant in endocrine-pretreated metastatic breast cancer (MBC) patients in PALOMA-3. Here, we examined factors predictive of long-term benefit. Methods Premenopausal-peri/postmenopausal patients with endocrine-resistant, hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative MBC were randomised 2:1 to fulvestrant (500 mg) and either Palbociclib (125 mg/d; 3/1 schedule; n = 347) or placebo (n = 174). Baseline characteristics, mutation status and HR expression levels were compared in patients with and without prolonged benefit (treatment duration ≥18 months). Results By August 2016, 100 patients (29%) on Palbociclib-fulvestrant and 26 (15%) on placebo-fulvestrant demonstrated prolonged benefit, with long-term responders in both arms sharing common clinical characteristics. They usually had less disease burden at baseline versus those treated Conclusions This exploratory analysis demonstrates that some patients with endocrine-resistant MBC derive significant and prolonged benefit when treated with Palbociclib-fulvestrant, with fewer patients experiencing similar efficacy with placebo-fulvestrant. The current analysis did not identify specific molecular or clinical factors prognostic of long-term benefit with Palbociclib-fulvestrant ( ClinicalTrials.gov , NCT01942135 ).
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clinical considerations of the role of Palbociclib in the management of advanced breast cancer patients with and without visceral metastases
Annals of Oncology, 2018Co-Authors: Nicholas C Turner, Angela Demichele, Marco Colleoni, Richard S Finn, V Dieras, Johannes Ettl, M Martin, S L Moulder, O Lipatov, Massimo CristofanilliAbstract:Abstract Background This report assesses the efficacy and safety of Palbociclib plus endocrine therapy (ET) in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) with or without visceral metastases. Patients and methods Pre- and postmenopausal women with disease progression following prior ET (PALOMA-3; N = 521) and postmenopausal women untreated for ABC (PALOMA-2; N = 666) were randomized 2 : 1 to ET (fulvestrant or letrozole, respectively) plus Palbociclib or placebo. Progression-free survival (PFS), safety, and patient-reported quality of life (QoL) were evaluated by prior treatment and visceral involvement. Results Visceral metastases incidence was higher in patients with prior resistance to ET (58.3%, PALOMA-3) than in patients naive to ET in the ABC setting (48.6%, PALOMA-2). In patients with prior resistance to ET and visceral metastases, median PFS (mPFS) was 9.2 months with Palbociclib plus fulvestrant versus 3.4 months with placebo plus fulvestrant [hazard ratio (HR), 0.47; 95% confidence interval (CI), 0.35–0.61], and objective response rate (ORR) was 28.0% versus 6.7%, respectively. In patients with nonvisceral metastases, mPFS was 16.6 versus 7.3 months, HR 0.53; 95% CI 0.36–0.77. In patients with visceral disease and naive to ET in the advanced disease setting, mPFS was 19.3 months with Palbociclib plus letrozole versus 12.9 months with placebo plus letrozole (HR 0.63; 95% CI 0.47–0.85); ORR was 55.1% versus 40.0%; in patients with nonvisceral disease, mPFS was not reached with Palbociclib plus letrozole versus 16.8 months with placebo plus letrozole (HR 0.50; 95% CI 0.36–0.70). In patients with prior resistance to ET with visceral metastases, Palbociclib plus fulvestrant significantly delayed deterioration of QoL versus placebo plus fulvestrant, whereas patient-reported QoL was maintained with Palbociclib plus letrozole in patients naive to endocrine-based therapy for ABC. Conclusions Palbociclib plus ET prolonged mPFS in patients with visceral metastases, increased ORRs, and in patients previously treated for ABC, delayed QoL deterioration, presenting a standard treatment option among patients with visceral metastases amenable to endocrine-based therapy. Clinical trial registration NCT01942135, NCT01740427
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A pilot study of Palbociclib in patients with HER2-positive breast cancer with brain metastasis.
Journal of Clinical Oncology, 2017Co-Authors: Cesar A. Santa-maria, Priya Kumthekar, Alfred W. Rademaker, Leeaht Gross, Sarika Jain, Lisa Flaum, William J. Gradishar, Massimo CristofanilliAbstract:TPS1110Background: HER2+ breast cancers have the propensity to metastasize to the CNS. Most systemic therapy does not cross the blood-brain barrier (BBB) effectively, limiting treatment options. Palbociclib is a small molecule inhibitor of cyclin dependent kinases (CDK) 4 and 6, which has been studied in hormone positive breast cancers and found to have significant anti-tumor activity. Preclinical models demonstrate HER2+ tumors require cyclin D1 and CDK4 for progression and maintenance, and Palbociclib has been found to have single agent activity in transgenic HER2+ models. Preclinical studies have also found that Palbociclib crosses the BBB and exerts anti-cancer effects; indeed, clinical trials investigating its activity in primary brain tumors are ongoing. The summary of these data provide rationale for investigation of Palbociclib in patients with HER2+ breast cancer and brain metastasis. Methods: A single arm study of Palbociclib in patients with metastatic HER2+ breast cancer with brain metastasis ...
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Palbociclib in combination with fulvestrant in women with hormone receptor positive her2 negative advanced metastatic breast cancer detailed safety analysis from a multicenter randomized placebo controlled phase iii study paloma 3
Oncologist, 2016Co-Authors: Sunil Verma, Hiroji Iwata, Massimo Cristofanilli, Angela Demichele, Marco Colleoni, N Harbeck, Patrick Schnell, Cynthia Huang Bartlett, Sherene Loi, Ke ZhangAbstract:Background. Palbociclib enhances endocrine therapy and improves clinical outcomes in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Because this is anew target, it is clinically important to understand Palbociclib's safety profile to effectively manage toxicity and optimize clinical benefit. Materials and Methods. Patients with endocrine-resistant, HR-positive/HER2-negative MBC (n = 521) were randomly assigned 2:1 to receive fulvestrant (500 mg intramuscular injection) with or without goserelin with oral Palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments at baseline and day 1 of each cycle included blood counts on day 15 for the first 2 cycles. Hematologic toxicity was assessed by using laboratory data. Results. A total of 517 patients were treated (Palbociclib, n = 345; placebo, n = 172); median follow-up was 8.9 months. With Palbociclib, neutropenia was the most common grade 3 (55%) and 4 (10%) adverse event; median times to onset and duration of grade >= 3 episodes were 16 and 7 days, respectively. Asian ethnicity and below-median neutrophil counts at baseline were significantly associated with an increased chance of developing grade 3-4 neutropenia with Palbociclib. Dose modifications for grade 3-4 neutropenia had no adverse effect on progression-free survival. In the Palbociclib arm, febrile neutropenia occurred in 3 (<1%) patients. The percentage of grade 1-2 infections was higher than in the placebo arm. Grade 1 stomatitis occurred in 8% of patients. Conclusion. Palbociclib plus fulvestrant treatment was well-tolerated, and the primary toxicity of asymptomatic neutropenia was effectively managed by dose modification without apparent loss of efficacy.
Richard S Finn - One of the best experts on this subject based on the ideXlab platform.
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Impact of Dose Reduction on Efficacy: Implications of Exposure-Response Analysis of Palbociclib.
Targeted oncology, 2020Co-Authors: Jenny Zheng, Richard S Finn, Chandrasekar Durairaj, Véronique Diéras, Diane D. WangAbstract:Palbociclib is indicated for hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer (ABC). Exposure-response analyses were conducted to evaluate efficacy in Asian versus non-Asian patients and in patients with versus without dose reduction in PALOMA-2. PALOMA-2 compared Palbociclib plus letrozole versus placebo plus letrozole in patients with ABC. Population pharmacokinetic analysis provided apparent Palbociclib clearance (CL/F) for each patient. The time-varying exposure metric, Cavg,t, was calculated using average dose intensity and CL/F at the time of each progression-free survival (PFS) event. A Cox proportional model characterized PFS and Palbociclib Cavg,t relationships. Significant prognostic factors for PFS were identified by univariate analysis, which were subsequently included in multivariate analyses, in addition to the Cavg,t effect on PFS. PFS profiles in Asian/non-Asian patients and patients with/without dose reduction were simulated and compared using observed Palbociclib exposures and established exposure-response relationships. Patients (n = 421) received Palbociclib plus letrozole (Asian = 64, non-Asian = 357; no dose reduction = 272, dose reduction = 149). Based on univariate analyses, significant prognostic factors were Ki67 score, age, and baseline aspartate aminotransferase (BAST), tumor size, alkaline phosphatase, and albumin levels. In multivariate analysis, only Ki67 and BAST remained significant. Palbociclib exposure did not significantly affect PFS in either univariate (P = 0.12) or multivariate (P = 0.44) analyses. This analysis suggests that Palbociclib exposure has no impact on PFS when the dose reduction algorithm from Palbociclib clinical trials is used. There is no difference in efficacy between Asians and non-Asians, despite the higher level of dose reductions in Asians. NCT01740427.
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overall survival results from the randomized phase 2 study of Palbociclib in combination with letrozole versus letrozole alone for first line treatment of er her2 advanced breast cancer paloma 1 trio 18
Breast Cancer Research and Treatment, 2020Co-Authors: Richard S Finn, Katalin Boér, Igor Bondarenko, Ravindranath Patel, Tamas Pinter, Marcus Schmidt, Yaroslav Shparyk, Anu Thummala, Nataliia Voitko, Eustratios BananisAbstract:Palbociclib is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, approved in combination with endocrine therapy for the treatment of women and men with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer (HR+/HER2− ABC). In the phase 2, open-label, PALOMA-1 trial, Palbociclib plus letrozole significantly prolonged progression-free survival (PFS) versus letrozole alone (hazard ratio, 0.488; 95% CI 0.319‒0.748; P = 0.0004; median PFS, 20.2 vs 10.2 months, respectively) in postmenopausal women with estrogen receptor–positive (ER+)/HER2− ABC. Here, we present the final overall survival (OS) and updated safety results. Postmenopausal women with ER+/HER2− ABC were randomized 1:1 to receive either Palbociclib (125 mg/day, 3/1 schedule) plus letrozole (2.5 mg/day, continuous) or letrozole alone (2.5 mg/day, continuous). The primary endpoint was investigator-assessed PFS; secondary endpoints included OS and safety. A total of 165 patients were randomized. At the data cutoff date of December 30, 2016 (median duration of follow-up, 64.7 months), the stratified hazard ratio for OS was 0.897 (95% CI 0.623–1.294; P = 0.281); median OS in the Palbociclib plus letrozole and letrozole alone arms was 37.5 and 34.5 months, respectively. The median time from randomization to first subsequent chemotherapy use was longer with Palbociclib plus letrozole than letrozole alone (26.7 and 17.7 months, respectively). The most frequently reported adverse event in the Palbociclib plus letrozole arm was neutropenia (any grade, 75%; grade 3 or 4, 59%). Palbociclib plus letrozole treatment led to a numerical but not statistically significant improvement in median OS. Pfizer Inc (NCT00721409)
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hematologic adverse events following Palbociclib dose reduction in patients with hormone receptor positive human epidermal growth factor receptor 2 negative advanced breast cancer pooled analysis from randomized phase 2 and 3 studies
Breast Cancer Research, 2020Co-Authors: Johannes Ettl, Norikazu Masuda, Massimo Cristofanilli, Marco Colleoni, Hope S Rugo, Patrick Schnell, Eustratios Bananis, Richard S FinnAbstract:Palbociclib improves outcomes for women with hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (HR+/HER2− ABC). Dose reductions are recommended for the management of hematologic toxicities. A previous pooled analysis from the PALOMA clinical trials showed that 36.9% of patients required dose reduction, predominantly during the first 6 months of treatment and with decreasing frequency during subsequent 28-day treatment cycles (C). Previous data have shown that Palbociclib dose reductions do not affect efficacy. This pooled, post hoc analysis evaluated the frequency of hematologic adverse events (AEs) before and after Palbociclib dose reduction in PALOMA-1, PALOMA-2, and PALOMA-3. This analysis evaluated the frequency of hematologic AEs 30 days before dose reduction and during each subsequent treatment from C1 to C6 among patients who required Palbociclib dose reduction. Data were pooled from 3 randomized studies. PALOMA-1 was a phase 2, open-label study of postmenopausal patients untreated for ABC receiving Palbociclib plus letrozole or letrozole alone. PALOMA-2 was a phase 3, double-blind study of postmenopausal patients untreated for ABC receiving Palbociclib plus letrozole or placebo plus letrozole. PALOMA-3 was a phase 3, double-blind study of pre/perimenopausal or postmenopausal patients, whose disease progressed on prior endocrine therapy, receiving Palbociclib plus fulvestrant or placebo plus fulvestrant. A total of 311 (35.5%) patients with HR+/HER2− ABC required a Palbociclib dose reduction (93.6% due to AEs) from 125 to 100 mg. Mean patient age was 59.9 years, and 46.9% of patients had visceral disease. Median time to dose reduction was 70 days. The majority of dose reductions occurred within 3 months of starting Palbociclib treatment. Incidences of all-grade and grades 3/4 hematologic AEs were lower following dose reduction. A decrease in frequency and severity of hematologic AEs, including febrile neutropenia, following Palbociclib dose reduction was observed, supporting the recommended use of dose reduction in AE management. These studies were sponsored by Pfizer. ClinicalTrials.gov: NCT00721409; registration date July 24, 2008. ClinicalTrials.gov: NCT01740427; registration date December 4, 2012. ClinicalTrials.gov: NCT01942135; registration date September 13, 2013.
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Palbociclib plus letrozole as first line therapy in estrogen receptor positive human epidermal growth factor receptor 2 negative advanced breast cancer with extended follow up
Breast Cancer Research and Treatment, 2019Co-Authors: Hope S Rugo, Shrividya Iyer, Richard S Finn, V Dieras, Johannes Ettl, Oleg N Lipatov, N Harbeck, Aurelio Castrellon, D R Lu, A MoriAbstract: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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clinical considerations of the role of Palbociclib in the management of advanced breast cancer patients with and without visceral metastases
Annals of Oncology, 2018Co-Authors: Nicholas C Turner, Angela Demichele, Marco Colleoni, Richard S Finn, V Dieras, Johannes Ettl, M Martin, S L Moulder, O Lipatov, Massimo CristofanilliAbstract:Abstract Background This report assesses the efficacy and safety of Palbociclib plus endocrine therapy (ET) in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) with or without visceral metastases. Patients and methods Pre- and postmenopausal women with disease progression following prior ET (PALOMA-3; N = 521) and postmenopausal women untreated for ABC (PALOMA-2; N = 666) were randomized 2 : 1 to ET (fulvestrant or letrozole, respectively) plus Palbociclib or placebo. Progression-free survival (PFS), safety, and patient-reported quality of life (QoL) were evaluated by prior treatment and visceral involvement. Results Visceral metastases incidence was higher in patients with prior resistance to ET (58.3%, PALOMA-3) than in patients naive to ET in the ABC setting (48.6%, PALOMA-2). In patients with prior resistance to ET and visceral metastases, median PFS (mPFS) was 9.2 months with Palbociclib plus fulvestrant versus 3.4 months with placebo plus fulvestrant [hazard ratio (HR), 0.47; 95% confidence interval (CI), 0.35–0.61], and objective response rate (ORR) was 28.0% versus 6.7%, respectively. In patients with nonvisceral metastases, mPFS was 16.6 versus 7.3 months, HR 0.53; 95% CI 0.36–0.77. In patients with visceral disease and naive to ET in the advanced disease setting, mPFS was 19.3 months with Palbociclib plus letrozole versus 12.9 months with placebo plus letrozole (HR 0.63; 95% CI 0.47–0.85); ORR was 55.1% versus 40.0%; in patients with nonvisceral disease, mPFS was not reached with Palbociclib plus letrozole versus 16.8 months with placebo plus letrozole (HR 0.50; 95% CI 0.36–0.70). In patients with prior resistance to ET with visceral metastases, Palbociclib plus fulvestrant significantly delayed deterioration of QoL versus placebo plus fulvestrant, whereas patient-reported QoL was maintained with Palbociclib plus letrozole in patients naive to endocrine-based therapy for ABC. Conclusions Palbociclib plus ET prolonged mPFS in patients with visceral metastases, increased ORRs, and in patients previously treated for ABC, delayed QoL deterioration, presenting a standard treatment option among patients with visceral metastases amenable to endocrine-based therapy. Clinical trial registration NCT01942135, NCT01740427
Angela Demichele - One of the best experts on this subject based on the ideXlab platform.
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a phase ii feasibility study of Palbociclib in combination with adjuvant endocrine therapy for hormone receptor positive invasive breast carcinoma
Annals of Oncology, 2019Co-Authors: Erica L Mayer, Rinath Jeselsohn, Angela Demichele, Hope S Rugo, Kathy D Miller, Adrienne G Waks, Steven E Come, Therese M Mulvey, Beth Overmoyer, H GuoAbstract:Abstract Background The CDK4/6 inhibitor Palbociclib prolongs progression-free survival in hormone receptor-positive/HER2-negative (HR+/HER2−) metastatic breast cancer when combined with endocrine therapy. This phase II trial was designed to determine the feasibility of adjuvant Palbociclib and endocrine therapy for early breast cancer. Patients and methods Eligible patients with HR+/HER2− stage II–III breast cancer received 2 years of Palbociclib at 125 mg daily, 3 weeks on/1 week off, with endocrine therapy. The primary end point was discontinuation from Palbociclib due to toxicity, non-adherence, or events related to tolerability. A discontinuation rate of 48% or higher would indicate the treatment duration of 2 years was not feasible, and was evaluated under a binomial test using a one-sided α = 0.025. Results Overall, 162 patients initiated Palbociclib; over half had stage III disease (52%) and most received prior chemotherapy (80%). A total of 102 patients (63%) completed 2 years of Palbociclib; 50 patients discontinued early for protocol-related reasons (31%, 95% CI 24% to 39%, P = 0.001), and 10 discontinued due to protocol-unrelated reasons. The cumulative incidence of protocol-related discontinuation was 21% (95% CI 14% to 27%) at 12 months from start of treatment. Rates of Palbociclib-related toxicity were congruent with the metastatic experience, and there were no cases of febrile neutropenia. Ninety-one patients (56%) required at least one dose reduction. Conclusion Adjuvant Palbociclib is feasible in early breast cancer, with a high proportion of patients able to complete 2 years of therapy. The safety profile in the adjuvant setting mirrors that observed in metastatic disease, with approximately half of the patients requiring dose-modification. As extended duration adjuvant Palbociclib appears feasible and tolerable for most patients, randomized phase III trials are evaluating clinical benefit in this population. Clinicaltrials.gov registration NCT02040857.
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predictors of prolonged benefit from Palbociclib plus fulvestrant in women with endocrine resistant hormone receptor positive human epidermal growth factor receptor 2 negative metastatic breast cancer in paloma 3
European Journal of Cancer, 2018Co-Authors: Massimo Cristofanilli, Dennis J Slamon, Seockah Im, Norikazu Masuda, C Giorgetti, Angela Demichele, Nicholas C Turner, Shailendra Verma, Marco Colleoni, Kathy Puyana TheallAbstract:Abstract Background The addition of Palbociclib to fulvestrant improved clinical outcomes over placebo-fulvestrant in endocrine-pretreated metastatic breast cancer (MBC) patients in PALOMA-3. Here, we examined factors predictive of long-term benefit. Methods Premenopausal-peri/postmenopausal patients with endocrine-resistant, hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative MBC were randomised 2:1 to fulvestrant (500 mg) and either Palbociclib (125 mg/d; 3/1 schedule; n = 347) or placebo (n = 174). Baseline characteristics, mutation status and HR expression levels were compared in patients with and without prolonged benefit (treatment duration ≥18 months). Results By August 2016, 100 patients (29%) on Palbociclib-fulvestrant and 26 (15%) on placebo-fulvestrant demonstrated prolonged benefit, with long-term responders in both arms sharing common clinical characteristics. They usually had less disease burden at baseline versus those treated Conclusions This exploratory analysis demonstrates that some patients with endocrine-resistant MBC derive significant and prolonged benefit when treated with Palbociclib-fulvestrant, with fewer patients experiencing similar efficacy with placebo-fulvestrant. The current analysis did not identify specific molecular or clinical factors prognostic of long-term benefit with Palbociclib-fulvestrant ( ClinicalTrials.gov , NCT01942135 ).
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clinical considerations of the role of Palbociclib in the management of advanced breast cancer patients with and without visceral metastases
Annals of Oncology, 2018Co-Authors: Nicholas C Turner, Angela Demichele, Marco Colleoni, Richard S Finn, V Dieras, Johannes Ettl, M Martin, S L Moulder, O Lipatov, Massimo CristofanilliAbstract:Abstract Background This report assesses the efficacy and safety of Palbociclib plus endocrine therapy (ET) in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) with or without visceral metastases. Patients and methods Pre- and postmenopausal women with disease progression following prior ET (PALOMA-3; N = 521) and postmenopausal women untreated for ABC (PALOMA-2; N = 666) were randomized 2 : 1 to ET (fulvestrant or letrozole, respectively) plus Palbociclib or placebo. Progression-free survival (PFS), safety, and patient-reported quality of life (QoL) were evaluated by prior treatment and visceral involvement. Results Visceral metastases incidence was higher in patients with prior resistance to ET (58.3%, PALOMA-3) than in patients naive to ET in the ABC setting (48.6%, PALOMA-2). In patients with prior resistance to ET and visceral metastases, median PFS (mPFS) was 9.2 months with Palbociclib plus fulvestrant versus 3.4 months with placebo plus fulvestrant [hazard ratio (HR), 0.47; 95% confidence interval (CI), 0.35–0.61], and objective response rate (ORR) was 28.0% versus 6.7%, respectively. In patients with nonvisceral metastases, mPFS was 16.6 versus 7.3 months, HR 0.53; 95% CI 0.36–0.77. In patients with visceral disease and naive to ET in the advanced disease setting, mPFS was 19.3 months with Palbociclib plus letrozole versus 12.9 months with placebo plus letrozole (HR 0.63; 95% CI 0.47–0.85); ORR was 55.1% versus 40.0%; in patients with nonvisceral disease, mPFS was not reached with Palbociclib plus letrozole versus 16.8 months with placebo plus letrozole (HR 0.50; 95% CI 0.36–0.70). In patients with prior resistance to ET with visceral metastases, Palbociclib plus fulvestrant significantly delayed deterioration of QoL versus placebo plus fulvestrant, whereas patient-reported QoL was maintained with Palbociclib plus letrozole in patients naive to endocrine-based therapy for ABC. Conclusions Palbociclib plus ET prolonged mPFS in patients with visceral metastases, increased ORRs, and in patients previously treated for ABC, delayed QoL deterioration, presenting a standard treatment option among patients with visceral metastases amenable to endocrine-based therapy. Clinical trial registration NCT01942135, NCT01740427
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characterization of neutropenia in advanced cancer patients following Palbociclib treatment using a population pharmacokinetic pharmacodynamic modeling and simulation approach
The Journal of Clinical Pharmacology, 2017Co-Authors: Wan Sun, Angela Demichele, Richard S Finn, Peter J Odwyer, Ana Ruizgarcia, Geoffrey I Shapiro, Gary K Schwartz, Diane WangAbstract:Neutropenia is the most commonly reported hematologic toxicity following treatment with Palbociclib, a cyclin-dependent kinase 4/6 inhibitor approved for metastatic breast cancer. Using data from 185 advanced cancer patients receiving Palbociclib in 3 clinical trials, a pharmacokinetic-pharmacodynamic model was developed to describe the time course of absolute neutrophil count (ANC) and quantify the exposure-response relationship for neutropenia. These analyses help in understanding neutropenia associated with Palbociclib and its comparison with chemotherapy-induced neutropenia. In the model, Palbociclib plasma concentration was related to its antiproliferative effect on precursor cells through drug-related parameters (ie, maximum estimated drug effect and concentration corresponding to 50% of the maximum effect), and neutrophil physiology was mimicked through system-related parameters (ie, mean transit time, baseline ANC, and feedback parameter). Sex and baseline albumin level were significant covariates for baseline ANC. It was demonstrated by different model evaluation approaches (eg, prediction-corrected visual predictive check and standardized visual predictive check) that the final model adequately described longitudinal ANC with good predictive capability. The established model suggested that higher Palbociclib exposure was associated with lower longitudinal neutrophil counts. The ANC nadir was reached approximately 21 days after Palbociclib treatment initiation. Consistent with their mechanisms of action, neutropenia associated with Palbociclib (cytostatic) was rapidly reversible and noncumulative, with a notably weaker antiproliferative effect on precursor cells relative to chemotherapies (cytotoxic). This pharmacokinetic-pharmacodynamic model aids in predicting neutropenia and optimizing dosing for future Palbociclib trials with different dosing regimen combinations.
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Palbociclib in combination with fulvestrant in women with hormone receptor positive her2 negative advanced metastatic breast cancer detailed safety analysis from a multicenter randomized placebo controlled phase iii study paloma 3
Oncologist, 2016Co-Authors: Sunil Verma, Hiroji Iwata, Massimo Cristofanilli, Angela Demichele, Marco Colleoni, N Harbeck, Patrick Schnell, Cynthia Huang Bartlett, Sherene Loi, Ke ZhangAbstract:Background. Palbociclib enhances endocrine therapy and improves clinical outcomes in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Because this is anew target, it is clinically important to understand Palbociclib's safety profile to effectively manage toxicity and optimize clinical benefit. Materials and Methods. Patients with endocrine-resistant, HR-positive/HER2-negative MBC (n = 521) were randomly assigned 2:1 to receive fulvestrant (500 mg intramuscular injection) with or without goserelin with oral Palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments at baseline and day 1 of each cycle included blood counts on day 15 for the first 2 cycles. Hematologic toxicity was assessed by using laboratory data. Results. A total of 517 patients were treated (Palbociclib, n = 345; placebo, n = 172); median follow-up was 8.9 months. With Palbociclib, neutropenia was the most common grade 3 (55%) and 4 (10%) adverse event; median times to onset and duration of grade >= 3 episodes were 16 and 7 days, respectively. Asian ethnicity and below-median neutrophil counts at baseline were significantly associated with an increased chance of developing grade 3-4 neutropenia with Palbociclib. Dose modifications for grade 3-4 neutropenia had no adverse effect on progression-free survival. In the Palbociclib arm, febrile neutropenia occurred in 3 (<1%) patients. The percentage of grade 1-2 infections was higher than in the placebo arm. Grade 1 stomatitis occurred in 8% of patients. Conclusion. Palbociclib plus fulvestrant treatment was well-tolerated, and the primary toxicity of asymptomatic neutropenia was effectively managed by dose modification without apparent loss of efficacy.
Hope S Rugo - One of the best experts on this subject based on the ideXlab platform.
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hematologic adverse events following Palbociclib dose reduction in patients with hormone receptor positive human epidermal growth factor receptor 2 negative advanced breast cancer pooled analysis from randomized phase 2 and 3 studies
Breast Cancer Research, 2020Co-Authors: Johannes Ettl, Norikazu Masuda, Massimo Cristofanilli, Marco Colleoni, Hope S Rugo, Patrick Schnell, Eustratios Bananis, Richard S FinnAbstract:Palbociclib improves outcomes for women with hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (HR+/HER2− ABC). Dose reductions are recommended for the management of hematologic toxicities. A previous pooled analysis from the PALOMA clinical trials showed that 36.9% of patients required dose reduction, predominantly during the first 6 months of treatment and with decreasing frequency during subsequent 28-day treatment cycles (C). Previous data have shown that Palbociclib dose reductions do not affect efficacy. This pooled, post hoc analysis evaluated the frequency of hematologic adverse events (AEs) before and after Palbociclib dose reduction in PALOMA-1, PALOMA-2, and PALOMA-3. This analysis evaluated the frequency of hematologic AEs 30 days before dose reduction and during each subsequent treatment from C1 to C6 among patients who required Palbociclib dose reduction. Data were pooled from 3 randomized studies. PALOMA-1 was a phase 2, open-label study of postmenopausal patients untreated for ABC receiving Palbociclib plus letrozole or letrozole alone. PALOMA-2 was a phase 3, double-blind study of postmenopausal patients untreated for ABC receiving Palbociclib plus letrozole or placebo plus letrozole. PALOMA-3 was a phase 3, double-blind study of pre/perimenopausal or postmenopausal patients, whose disease progressed on prior endocrine therapy, receiving Palbociclib plus fulvestrant or placebo plus fulvestrant. A total of 311 (35.5%) patients with HR+/HER2− ABC required a Palbociclib dose reduction (93.6% due to AEs) from 125 to 100 mg. Mean patient age was 59.9 years, and 46.9% of patients had visceral disease. Median time to dose reduction was 70 days. The majority of dose reductions occurred within 3 months of starting Palbociclib treatment. Incidences of all-grade and grades 3/4 hematologic AEs were lower following dose reduction. A decrease in frequency and severity of hematologic AEs, including febrile neutropenia, following Palbociclib dose reduction was observed, supporting the recommended use of dose reduction in AE management. These studies were sponsored by Pfizer. ClinicalTrials.gov: NCT00721409; registration date July 24, 2008. ClinicalTrials.gov: NCT01740427; registration date December 4, 2012. ClinicalTrials.gov: NCT01942135; registration date September 13, 2013.
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Palbociclib with letrozole in postmenopausal women with er her2 advanced breast cancer hematologic safety analysis of the randomized paloma 2 trial
Oncologist, 2019Co-Authors: V Dieras, Johannes Ettl, N Harbeck, A Mori, Anil A Joy, Karen A Gelmon, Sunil Verma, Eric Gauthier, Patrick Schnell, Hope S RugoAbstract:Author(s): Dieras, Veronique; Harbeck, Nadia; Joy, Anil Abraham; Gelmon, Karen; Ettl, Johannes; Verma, Sunil; Lu, Dongrui R; Gauthier, Eric; Schnell, Patrick; Mori, Ave; Rugo, Hope S; Finn, Richard S | Abstract: BackgroundPALOMA-2 confirmed that first-line Palbociclib + letrozole improved progression-free survival (hazard ratio, 0.58; 95% confidence interval, 0.46-0.72) in postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). This analysis evaluated Palbociclib-associated hematologic adverse events (AEs) and provides insight on managing these AEs.Materials and methodsPostmenopausal women with ER+/HER2- ABC were randomly assigned 2:1 to letrozole (2.5 mg daily continuously) plus oral Palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments were performed at baseline, days 1 and 15 (first two cycles) and day 1 of subsequent cycles, and included white blood cell, platelet, and absolute neutrophil count (ANC).ResultsPALOMA-2 randomized 666 women to Palbociclib + letrozole (n = 444) or placebo + letrozole (n = 222). Neutropenia was the most common AE (95.3%) with Palbociclib (grade 3, 55.6%; grade 4, 11.5%) and was managed by dose modifications; progression-free survival was similar between patients who experienced grade ≥ 3 neutropenia versus those who did not. Median (range) time to onset of neutropenia with Palbociclib + letrozole was 15 (12-700) days (grade ≥ 3, 28.0 [12-854] days); median duration of each neutropenia episode grade ≥ 3 was 7.0 days. Asian ethnicity and low baseline ANC were associated with increased risk of grade 3/4 neutropenia with Palbociclib (p l .001).ConclusionPalbociclib + letrozole was generally well tolerated. Neutropenia, the most frequently reported AE in women with ER+/HER2- ABC, was mostly transient and manageable by dose modifications in patients who experienced grade ≥ 3 neutropenia, without appearing to compromise efficacy. (Pfizer; NCT01740427) IMPLICATIONS FOR PRACTICE: Palbociclib demonstrated an acceptable safety profile in PALOMA-2 in women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) receiving first-line Palbociclib + letrozole. Although hematologic adverse events (AEs) are typically expected with anticancer therapies and are often clinically significant, Palbociclib-related hematologic AEs, particularly neutropenia (most frequent AE), were transient/manageable by dose reduction, interruption, or cycle delay, which is in contrast to the more profound neutropenia associated with chemotherapy. Palbociclib dose adjustments decreased hematologic AE severity without appearing to compromise efficacy, supporting Palbociclib + letrozole as a first-line treatment for ER+/HER2- ABC.
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a phase ii feasibility study of Palbociclib in combination with adjuvant endocrine therapy for hormone receptor positive invasive breast carcinoma
Annals of Oncology, 2019Co-Authors: Erica L Mayer, Rinath Jeselsohn, Angela Demichele, Hope S Rugo, Kathy D Miller, Adrienne G Waks, Steven E Come, Therese M Mulvey, Beth Overmoyer, H GuoAbstract:Abstract Background The CDK4/6 inhibitor Palbociclib prolongs progression-free survival in hormone receptor-positive/HER2-negative (HR+/HER2−) metastatic breast cancer when combined with endocrine therapy. This phase II trial was designed to determine the feasibility of adjuvant Palbociclib and endocrine therapy for early breast cancer. Patients and methods Eligible patients with HR+/HER2− stage II–III breast cancer received 2 years of Palbociclib at 125 mg daily, 3 weeks on/1 week off, with endocrine therapy. The primary end point was discontinuation from Palbociclib due to toxicity, non-adherence, or events related to tolerability. A discontinuation rate of 48% or higher would indicate the treatment duration of 2 years was not feasible, and was evaluated under a binomial test using a one-sided α = 0.025. Results Overall, 162 patients initiated Palbociclib; over half had stage III disease (52%) and most received prior chemotherapy (80%). A total of 102 patients (63%) completed 2 years of Palbociclib; 50 patients discontinued early for protocol-related reasons (31%, 95% CI 24% to 39%, P = 0.001), and 10 discontinued due to protocol-unrelated reasons. The cumulative incidence of protocol-related discontinuation was 21% (95% CI 14% to 27%) at 12 months from start of treatment. Rates of Palbociclib-related toxicity were congruent with the metastatic experience, and there were no cases of febrile neutropenia. Ninety-one patients (56%) required at least one dose reduction. Conclusion Adjuvant Palbociclib is feasible in early breast cancer, with a high proportion of patients able to complete 2 years of therapy. The safety profile in the adjuvant setting mirrors that observed in metastatic disease, with approximately half of the patients requiring dose-modification. As extended duration adjuvant Palbociclib appears feasible and tolerable for most patients, randomized phase III trials are evaluating clinical benefit in this population. Clinicaltrials.gov registration NCT02040857.
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Palbociclib plus letrozole as first line therapy in estrogen receptor positive human epidermal growth factor receptor 2 negative advanced breast cancer with extended follow up
Breast Cancer Research and Treatment, 2019Co-Authors: Hope S Rugo, Shrividya Iyer, Richard S Finn, V Dieras, Johannes Ettl, Oleg N Lipatov, N Harbeck, Aurelio Castrellon, D R Lu, A MoriAbstract: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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Palbociclib has no clinically relevant effect on the QTc interval in patients with advanced breast cancer.
Anti-cancer drugs, 2018Co-Authors: Chandrasekar Durairaj, Justin Hoffman, Richard S Finn, Johannes Ettl, Anil A Joy, Eric Gauthier, Ana Ruiz-garcia, Xin Huang, Hope S RugoAbstract:The aim of this study was to assess the potential effects of Palbociclib in combination with letrozole on QTc. PALOMA-2, a phase 3, randomized, double-blind, placebo-controlled trial, compared Palbociclib plus letrozole with placebo plus letrozole in postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The study included a QTc evaluation substudy carried out as a definitive QT interval prolongation assessment for Palbociclib. Time-matched triplicate ECGs were performed at 0, 2, 4, 6, and 8 h at baseline (Day 0) and on Cycle 1 Day 14. Additional ECGs were collected from all patients for safety monitoring. The QT interval was corrected for heart rate using Fridericia's correction (QTcF), Bazett's correction (QTcB), and a study-specific correction factor (QTcS). In total, 666 patients were randomized 2 : 1 to Palbociclib plus letrozole or placebo plus letrozole. Of these, 125 patients were enrolled in the QTc evaluation substudy. No patients in the Palbociclib plus letrozole arm of the substudy (N=77) had a maximum postbaseline QTcS or QTcF value of ≥ 480 ms, or a maximum increase from clock time-matched baseline for QTcS or QTcF values of ≥ 60 ms. The upper bounds of the one-sided 95% confidence interval for the mean change from time-matched baseline for QTcS, QTcF, and QTcB at all time points and at steady-state Cmax following repeated administration of 125 mg Palbociclib were less than 10 ms. Palbociclib, when administered with letrozole at the recommended therapeutic dosing regimen, did not prolong the QT interval to a clinically relevant extent.
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a novel tankyrase inhibitor msc2504877 enhances the effects of clinical cdk4 6 inhibitors
Scientific Reports, 2019Co-Authors: Malini Menon, Richard Elliott, Leandra Bowers, Nicolae Balan, Rumana Rafiq, Sara Costacabral, Felix Munkonge, Ines Trinidade, Roderick Porter, Andrew D CampbellAbstract:Inhibition of the PARP superfamily tankyrase enzymes suppresses Wnt/β-catenin signalling in tumour cells. Here, we describe here a novel, drug-like small molecule inhibitor of tankyrase MSC2504877 that inhibits the growth of APC mutant colorectal tumour cells. Parallel siRNA and drug sensitivity screens showed that the clinical CDK4/6 inhibitor Palbociclib, causes enhanced sensitivity to MSC2504877. This tankyrase inhibitor-CDK4/6 inhibitor combinatorial effect is not limited to Palbociclib and MSC2504877 and is elicited with other CDK4/6 inhibitors and toolbox tankyrase inhibitors. The addition of MSC2504877 to Palbociclib enhances G1 cell cycle arrest and cellular senescence in tumour cells. MSC2504877 exposure suppresses the upregulation of Cyclin D2 and Cyclin E2 caused by Palbociclib and enhances the suppression of phospho-Rb, providing a mechanistic explanation for these effects. The combination of MSC2504877 and Palbociclib was also effective in suppressing the cellular hyperproliferative phenotype seen in Apc defective intestinal stem cells in vivo. However, the presence of an oncogenic Kras p.G12D mutation in mice reversed the effects of the MSC2504877/Palbociclib combination, suggesting one molecular route that could lead to drug resistance.
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A novel tankyrase inhibitor, MSC2504877, enhances the effects of clinical CDK4/6 inhibitors.
Scientific reports, 2019Co-Authors: Malini Menon, Richard Elliott, Leandra Bowers, Nicolae Balan, Rumana Rafiq, Felix Munkonge, Ines Trinidade, Roderick Porter, Sara Costa-cabral, Andrew D CampbellAbstract:Inhibition of the PARP superfamily tankyrase enzymes suppresses Wnt/β-catenin signalling in tumour cells. Here, we describe here a novel, drug-like small molecule inhibitor of tankyrase MSC2504877 that inhibits the growth of APC mutant colorectal tumour cells. Parallel siRNA and drug sensitivity screens showed that the clinical CDK4/6 inhibitor Palbociclib, causes enhanced sensitivity to MSC2504877. This tankyrase inhibitor-CDK4/6 inhibitor combinatorial effect is not limited to Palbociclib and MSC2504877 and is elicited with other CDK4/6 inhibitors and toolbox tankyrase inhibitors. The addition of MSC2504877 to Palbociclib enhances G1 cell cycle arrest and cellular senescence in tumour cells. MSC2504877 exposure suppresses the upregulation of Cyclin D2 and Cyclin E2 caused by Palbociclib and enhances the suppression of phospho-Rb, providing a mechanistic explanation for these effects. The combination of MSC2504877 and Palbociclib was also effective in suppressing the cellular hyperproliferative phenotype seen in Apc defective intestinal stem cells in vivo. However, the presence of an oncogenic Kras p.G12D mutation in mice reversed the effects of the MSC2504877/Palbociclib combination, suggesting one molecular route that could lead to drug resistance.