bims-cyhorp 2021-10-24 papers

bims-cyhorp

Biomed News

on Cyclin-dependent kinases in hormone receptor positive breast cancer

Issue of 2021‒10‒24
twelve papers selected by
Piotr Okupski

A deep dive into CDK4/6 inhibitors: Evaluating real world toxicities and treatment paradigms in the elderly population.
Overall survival in patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer treated with a cyclin-dependent kinase 4/6 inhibitor plus fulvestrant: a US Food and Drug Administration pooled analysis.
Effects of the moderate CYP3A4 inhibitor erythromycin on the pharmacokinetics of palbociclib: a randomized cross-over trial in patients with breast cancer.
Japanese subgroup analysis of the phase 3 MONARCH 3 study of abemaciclib as initial therapy for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer.
Anti-cancer efficacy including Rb-deficient tumors and VHL-independent HIF1α proteasomal destabilization by dual targeting of CDK1 or CDK4/6 and HSP90.
Clinical efficacy of palbociclib-based therapy in women with HR+/HER2- metastatic breast cancer in the real-world setting for Chinese women: a comparison with the IRIS study.
Selective CDK4/6 inhibition of novel 1,2,3-triazole tethered acridinedione derivatives induces G1/S cell cycle transition arrest via Rb phosphorylation blockade in breast cancer models.
Real-World Data of Palbociclib in Combination With Endocrine Therapy for the Treatment of Metastatic Breast Cancer in Men.
[A Case of Advanced Late Recurrence of Hormone Receptor Positive Breast Cancer Successfully Treated with Abemaciclib and Anastrozole].
[Successful Treatment of Estrogen Receptor Positive, HER2 Negative Breast Cancer with Life-Threatening Multiple Bone Metastases Using the Combination of Fulvestrant and Palbociclib-A Case Report].
Pharmacokinetic/Pharmacodynamic Model of Neutropenia in Real-Life Palbociclib-Treated Patients.
Adjuvant Abemaciclib Combined With Endocrine Therapy for High-Risk Early Breast Cancer: Updated Efficacy and Ki-67 Analysis From the monarchE Study.

J Oncol Pharm Pract. 2021 Oct 19. 10781552211050106

A deep dive into CDK4/6 inhibitors: Evaluating real world toxicities and treatment paradigms in the elderly population.

Coral Olazagasti, Chung-Shien Lee, Angel Liu, Dimitre Stefanov, Kit Cheng.

  BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors have become part of the standard of care in the treatment of hormone receptor positive, Her2Neu negative metastatic breast cancer. There is concern regarding the efficacy and potential increased cyclin-dependent kinase 4/6 inhibitors toxicity in the geriatric population in the community compared to the clinical trial population.METHODS: We evaluated patients treated with cyclin-dependent kinase 4/6 inhibitors from 2015 to 2019 and stratified according to age ≥70 and <70 years. Complete blood count from the first two cycles was recorded. Rates of hematologic toxicities, dose interruptions and reductions, progression-free survival, and overall survival were compared between both groups. We sought to assess the hematologic toxicities between the age groups and the relationship between previous chemotherapy exposure, bone metastasis and starting cyclin-dependent kinase 4/6 inhibitors dose with progression-free survival and overall survival.
RESULTS: A total of 202 patients were included, 73 were ≥70 years and 129 were <70 years of age. There was no association between age group and grade of neutropenia or thrombocytopenia. There was a profound association between progression-free survival and overall survival and starting dose, where patients with recommended starting dose had higher progression-free survival and overall survival than those with a reduced dose (p = 0.0003 and p = 0.04).
CONCLUSIONS: Our study showed similar progression-free survival and overall survival between age groups without significant differences in neutropenia or thrombocytopenia toxicity. Nevertheless, we found an association between starting dose and progression-free survival and overall survival that has not been previously reported. Given the good tolerability across age groups and the improvement in progression-free survival and overall survival, patients should be treated at the cyclin-dependent kinase 4/6 inhibitors recommended dose and monitored appropriately.

Keywords:  CDK4/6 inhibitors; adverse events; hematologic toxicities; metastatic breast cancer

DOI:  https://doi.org/10.1177/10781552211050106
Lancet Oncol. 2021 Oct 14. pii: S1470-2045(21)00472-1. [Epub ahead of print]

Overall survival in patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer treated with a cyclin-dependent kinase 4/6 inhibitor plus fulvestrant: a US Food and Drug Administration pooled analysis.

Jennifer J Gao, Joyce Cheng, Tatiana M Prowell, Erik Bloomquist, Shenghui Tang, Suparna B Wedam, Melanie Royce, Danielle Krol, Christy Osgood, Gwynn Ison, Rajeshwari Sridhara, Richard Pazdur, Julia A Beaver, Laleh Amiri-Kordestani.

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are oral targeted agents approved for use in combination with endocrine therapy as first-line or second-line treatment of patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer. We previously reported the pooled analyses of progression-free survival in patients in specific clinicopathological subgroups, all of whom received consistent benefit from the addition of a CDKI to hormonal therapy. Here, we report the pooled overall survival results in patients treated with a CDKI and fulvestrant.METHODS: In this exploratory analysis, we pooled individual patient data from three phase 3 randomised trials of CDKI or placebo in combination with fulvestrant in patients with breast cancer submitted to the US Food and Drug Administration and approved before Aug 1, 2020, in support of marketing applications. All analysed patients were aged at least 18 years, had an Eastern Cooperative Oncology Group performance status of 0-1, had hormone receptor-positive, HER2-negative advanced or metastatic breast cancer, and received at least one dose of CDKI or placebo in combination with fulvestrant. The median overall survival was estimated using Kaplan-Meier methods, and hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression models. Patients were analysed collectively, by number of previous lines of systemic endocrine therapy in any disease setting (first-line or endocrine naive vs second-line and later), and in various clinicopathological subgroups of interest. The estimated median overall survival was not reported by group when the pooled population included patients treated across lines of therapy because of potential patient heterogeneity. All results presented are considered exploratory and hypothesis generating.
FINDINGS: Across the three pooled trials, 1960 patients were randomly assigned between Oct 7, 2013, and June 10, 2016 (12 patients were not treated and 1296 [66%] patients were randomly assigned to CDKI and 652 [33%] to placebo). In all treated patients (n=1948), the estimated HR for overall survival was 0·77 (95% CI 0·68-0·88), with a median follow-up of 43·7 months (IQR 37·8-47·7) and deaths in 935 (48%) of the 1948 patients. The difference in estimated median overall survival was 7·1 months, favouring CDKIs. In patients who received CDKIs or placebo in combination with fulvestrant as first-line systemic endocrine therapy (two trials; n=396), the estimated HR for overall survival was 0·74 (95% CI 0·52-1·07), with a median follow-up of 39·4 months (IQR 37·0-42·2). 123 (31%) of these patients died. The difference in estimated median overall survival could not be calculated because median overall survival was not estimable (95% CI 50·9-not estimable) in the CDKI group and was 45·7 months (95% CI 41·7-not estimable) in the placebo group. In patients who received CDKIs or placebo in combination with fulvestrant as second-line or later systemic endocrine therapy (three trials; n=1552), the estimated HR for overall survival was 0·77 (95% CI 0·67-0·89), with a median follow-up of 45·1 months (95% CI 39·2-48·5). 812 (52%) of these patients died. The difference in estimated median overall survival was 7·0 months, favouring CDKIs.
INTERPRETATION: The addition of CDKIs to fulvestrant resulted in a consistent overall survival benefit in all pooled patients and within most clinicopathological subgroups of interest. These findings support the existing standard of care of CDKIs plus fulvestrant for the treatment of patients with hormone receptor-positive, HER2-negative, advanced breast cancer.
FUNDING: None.

DOI: https://doi.org/10.1016/S1470-2045(21)00472-1
Clin Pharmacol Ther. 2021 Oct 21.

Effects of the moderate CYP3A4 inhibitor erythromycin on the pharmacokinetics of palbociclib: a randomized cross-over trial in patients with breast cancer.

Dutch Pharmacology Oncology Group (DPOG, www.dpog.nl)

  Palbociclib is an oral inhibitor of cyclin-dependent kinases 4 and 6 used in the treatment of locally advanced and metastatic breast cancer, and is extensively metabolized by CYP3A4. A pharmacokinetic/pharmacodynamic relationship between palbociclib exposure and neutropenia is well known. This study aimed to investigate the effects of the moderate CYP3A4 inhibitor erythromycin on the pharmacokinetics of palbociclib. We performed a randomized cross-over trial comparing the pharmacokinetics of palbociclib monotherapy 125 mg once daily (QD) with palbociclib 125 mg QD plus oral erythromycin 500 mg three times daily for seven days. Pharmacokinetic sampling was performed at steady-state for both dosing schedules. Eleven evaluable patients have been enrolled. For palbociclib monotherapy, geometric mean AUC0-24h , Cmax , and Cmin were 1.46*103 ng*h/mL (coefficient of variation (CV) 45.0%), 80.5 ng/mL (CV 48.5%), and 48.4 ng/mL (CV 38.8%), respectively, compared with 2.09*103 ng*h/mL (CV 49.3%, p=0.000977), 115 ng/mL (CV 53.7%, p=0.00562), and 70.7 ng/mL (CV 47.5%, p=0.000488) when palbociclib was administered concomitant with erythromycin. Geometric mean ratios (90% confidence intervals) of AUC0-24h , Cmax , and Cmin for palbociclib plus erythromycin versus palbociclib monotherapy were 1.43 (1.24-1.66), 1.43 (1.20-1.69), and 1.46 (1.30-1.63). Minor differences in adverse events were observed, and only one grade ≥ 3 toxicity was observed in this short period of time. To conclude, concomitant intake of palbociclib with the moderate CYP3A4 inhibitor erythromycin resulted in an increase in AUC0-24h and Cmax of both 43%. Therefore, a dose reduction of palbociclib to 75 mg QD is rational, when palbociclib and moderate CYP3A4 inhibitors are used concomitantly.

Keywords:  Palbociclib; breast cancer; cytochrome P450 3A4; drug-drug interaction; erythromycin

DOI:  https://doi.org/10.1002/cpt.2455
Breast Cancer. 2021 Oct 18.

Japanese subgroup analysis of the phase 3 MONARCH 3 study of abemaciclib as initial therapy for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer.

Masato Takahashi, Eriko Tokunaga, Joji Mori, Yoshinori Tanizawa, Jan-Stefan van der Walt, Tsutomu Kawaguchi, Matthew P Goetz, Masakazu Toi.

  BACKGROUND: This was a Japanese subpopulation analysis of MONARCH 3, a randomized, double-blind, placebo-controlled phase 3 study of abemaciclib plus nonsteroidal aromatase inhibitors (NSAIs) for initial therapy for advanced breast cancer (ABC).METHODS: Eligibility included postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative ABC who had no prior systemic therapy in the advanced disease setting. Patients (N = 493) were randomized 2:1 to receive abemaciclib or placebo (150 mg) plus either 1 mg anastrozole or 2.5 mg letrozole (physician's choice). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), pharmacokinetics (PK), safety, and health-related quality of life (HRQoL).
RESULTS: In Japan, 53 patients were randomized (abemaciclib, n = 38; placebo, n = 15). At final PFS analysis (November 3, 2017), median PFS was 29.1 and 14.9 months in the abemaciclib and placebo groups, respectively (hazard ratio 0.537; 95% confidence interval 0.224-1.289). ORR in measurable disease was 62.1 and 50.0% in the abemaciclib and placebo groups, respectively. The Japanese PK profile was comparable to that of the overall population. Consistent with prior studies, the most frequent adverse events reported were diarrhea (abemaciclib: any grade, 94.7%; grade ≥ 3, 10.5%; placebo: any grade, 46.7%; grade ≥ 3, 0%) and neutropenia (abemaciclib: any grade, 68.4%; grade ≥ 3, 21.1%; placebo: any grade, 0%). HRQoL outcomes were generally similar between treatments except for the diarrhea score, which favored placebo.
CONCLUSIONS: Consistent with findings in the overall population, abemaciclib plus NSAI was an effective initial treatment in the Japanese subpopulation, with a manageable safety profile.
CLINICAL TRIAL REGISTRATION: NCT02246621; U.S. National Library of Medicine: https://clinicaltrials.gov/ct2/show/NCT02246621 .

Keywords:  Abemaciclib; Breast cancer; Cyclin-dependent kinase 4/6; Nonsteroidal aromatase inhibitor

DOI:  https://doi.org/10.1007/s12282-021-01295-0
Sci Rep. 2021 Oct 22. 11(1): 20871

Anti-cancer efficacy including Rb-deficient tumors and VHL-independent HIF1α proteasomal destabilization by dual targeting of CDK1 or CDK4/6 and HSP90.

Shuai Zhao, Lanlan Zhou, David T Dicker, Avital Lev, Shengliang Zhang, Eric Ross, Wafik S El-Deiry.

A prevalent characteristic of solid tumors is intra-tumoral hypoxia. Hypoxia-inducible factor 1α (HIF1α) predominantly mediates the adaptive response to O2 oscillation and is linked to multiple malignant hallmarks. Here we describe a strategy to robustly target HIF1α by dual inhibition of CDK(s) and heat shock protein 90 (HSP90). We show that CDK1 may contribute to HSP90-mediated HIF1α stabilization. CDK1 knockdown enhances the decrease of HIF1α by HSP90 inhibition. Dual inhibition of CDK1 and HSP90 significantly increases apoptosis and synergistically inhibits cancer cell viability. Similarly, targeting CDK4/6 using FDA-approved inhibitors in combination with HSP90 inhibition shows a class effect on HIF1α inhibition and cancer cell viability suppression not only in colorectal but also in various other cancer types, including Rb-deficient cancer cells. Dual inhibition of CDK4/6 and HSP90 suppresses tumor growth in vivo. In summary, combined targeting of CDK(s) (CDK1 or CDK4/6) and HSP90 remarkably inhibits the expression level of HIF1α and shows promising anti-cancer efficacy with therapeutic potential.

DOI: https://doi.org/10.1038/s41598-021-00150-8
Eur Rev Med Pharmacol Sci. 2021 Oct;pii: 26892. [Epub ahead of print]25(19): 6138-6148

Clinical efficacy of palbociclib-based therapy in women with HR+/HER2- metastatic breast cancer in the real-world setting for Chinese women: a comparison with the IRIS study.

C-F Shangguan, M Jiang, C Yang, G-Y Lou, Y-T Li, Q Qu.

OBJECTIVE: This retrospective study aimed to explore the clinical efficacy of palbociclib with endocrine therapy (ET) in women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer in real-world practice.PATIENTS AND METHODS: This retrospective study analyzed the medical records of patients to determine treatment outcomes. Progression-free survival (PFS) curves were generated using log-rank tests with the Kaplan-Meier method. Treatment outcomes in Chinese patients were compared with those in patients from the USA, Argentina, Canada, and Europe in the IRIS study.
RESULTS: In total, 69 patients were included in this study. The median PFS was 12.8 months (95% confidence interval: 10.1-15.5). A longer PFS was observed for patients with bone-only metastases, no liver metastases, no previous palliative chemotherapy, no previous palliative ET, and ET sensitivity. The overall response rate was 10.1%, and the clinical benefit rate was 78.3%. Nineteen patients (27.5%) received a reduced dose of palbociclib according to the decision of their physicians. Dose reduction did not affect the clinical efficacy of the combined treatment. Compared with those in the IRIS study, Chinese patients receiving palbociclib-based treatment were younger, and they had fewer bone-only metastases and more visceral and liver metastases. The clinical benefit rate and overall response rate for Chinese patients were lower than those observed for the patients in the IRIS study.
CONCLUSIONS: ET combined with palbociclib treatment was effective and well-tolerated in HR+/HER2- metastatic breast cancer patients in the real-world setting. Earlier use of palbociclib-ET was associated with more clinical benefits in HR+/HER2- metastatic breast cancer.

DOI: https://doi.org/10.26355/eurrev_202110_26892
Bioorg Chem. 2021 Nov;pii: S0045-2068(21)00754-9. [Epub ahead of print]116 105377

Selective CDK4/6 inhibition of novel 1,2,3-triazole tethered acridinedione derivatives induces G1/S cell cycle transition arrest via Rb phosphorylation blockade in breast cancer models.

E Praveenkumar, Nirmala Gurrapu, Prashanth Kumar Kolluri, Shivaraj, N J P Subhashini, Appaji Dokala.

  CDK4 & CDK6 are essential regulators of initial cell cycle phases and are always considered an exciting choice for anti-cancer therapy. In the present study, we presented the structure-based rational design & synthesis of a new class of 1,2,3-triazole tethered acridinedione derivatives (6a-l) as selective CDK4/6 inhibitors. Title molecules were prepared as a result of the rate-determining reaction between substituted derivatives of 1-Phenyl-1H-1,2,3-triazole-4-carbaldehydes and substituted dimedones, and the molecules were structurally characterized by IR, 1H,13C NMR, and MS spectral data. All molecules were screened for in-vitro cytotoxic potential against a group of human breast tumor cell lines of distinct origin with differential Rb expression status. Out of entire series of conjugated hexahydro acridinediones, 6g showed potent cytotoxic effect against MCF-7, BT-474, and SK-BR3 cell lines with IC50values 0.173 ± 0.037, 0.117 ± 0.025, and 0.136 ± 0.027 μM, respectively. Further, CDK inhibition assays revealed that the compounds 6g and 6h selectively inhibit CDK4/6 over other CDK-parter complexes of the family against the selected cell line group except for MDA-MB468 cells. Furthermore, apoptotic evaluation and cell cycle analysis determined that compound 6g successfully triggered apoptosis in all examined cell lines except MDA-MB468 through blocking G1/S cell cycle transformation. In addition, compound 6g showed the highest in-vitro selectivity towards CDK4/6 inhibition, even compared with Abemaciclib, and it was also proved for favourable in-vivo pharmacokinetic properties in male albino mice. Furthermore, molecule 6g showed promising tumor growth suppression with lower adverse effects in MCF-7 xenograft mice models, which could competently be considered as a novel chemotherapeutic candidate for a further comprehensive preclinical study involving breast cancer therapy.

Keywords:  Apoptosis; Breast cancer; CDK4/6; Hexahydroacridinediones; IC(50); Retinoblastoma protein (Rb)

DOI:  https://doi.org/10.1016/j.bioorg.2021.105377
Clin Pharmacol Ther. 2021 Oct 20.

Real-World Data of Palbociclib in Combination With Endocrine Therapy for the Treatment of Metastatic Breast Cancer in Men.

Albert L Kraus, Michelle Yu-Kite, Jack Mardekian, Matthew J Cotter, Sindy Kim, Jaclyn Decembrino, Tamara Snow, Kenneth R Carson, Jillian Motyl Rockland, Anala Gossai, Keith Wilner, Diane D Wang, Cynthia Huang Bartlett, Norihiko Oharu, Patrick Schnell, Todd VanArsdale, Dongrui R Lu, Jennifer M Tursi.

  This report examined the benefits and risks of palbociclib plus endocrine therapy (ET) in men with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Palbociclib was evaluated using 3 independent data sources: real-world data from pharmacy and medical claims, a de-identified real-world data source derived from electronic health records (EHRs), and a global safety database. From medical and pharmacy records, 1139 men with MBC were identified; in the first-line setting, median duration of treatment was longer with palbociclib plus ET (n=37; 8.5 months; 95% CI; 4.4-13.0) than ET alone (n=214; 4.3 months; 95% CI; 3.0-5.7) and specifically, was longer with palbociclib plus letrozole (n=26; 9.4 months; 95% CI; 4.4-14.0) than letrozole alone (n=63; 3.0 months; 95% CI; 1.8-4.8). In the EHR-derived database, 59 men received treatment for MBC; real-world response across all lines of therapy in the metastatic setting was reported in 4 of 12 patients (33.3%) in the palbociclib plus ET group, versus 1 of 8 (12.5%) patients in the ET group. Review of the global safety database did not identify any new safety signals in palbociclib-treated men. Real-world data indicated that men with MBC benefit from palbociclib plus ET, with a safety profile consistent with previous observations in women with MBC. Collective data on palbociclib in women and men in this report, including clinical trial data, real-world data, and a well-established risk/benefit profile, led to US approval of an expansion of the palbociclib indication to include men with MBC.

Keywords:  Cancers; Combination therapy; Men

DOI:  https://doi.org/10.1002/cpt.2454
Gan To Kagaku Ryoho. 2021 Oct;48(10): 1259-1263

[A Case of Advanced Late Recurrence of Hormone Receptor Positive Breast Cancer Successfully Treated with Abemaciclib and Anastrozole].

Kanji Minamoto, Toshio Ikeda, Kayoko Araki, Miki Hamada.

BACKGROUND: In step with the aging of the Japanese population, late recurrence of hormone receptor positive (HR+) breast cancer occurring especially beyond 20 years after the initial diagnosis has been recognized as not rare anymore, as it has been occurring at a constant rate lately. The administration of an aromatase inhibitor with a CDK4/6 inhibitor has become the gold standard in Japan for cases of recurring HR+ breast cancer without severe visceral metastasis.CASE: A 73- year-old woman was diagnosed by chance with late recurrence of HR+ breast cancer 21 years after undergoing radical resection followed by adjuvant anastrozole for 5 years for stage Ⅲb right breast cancer. Asymptomatic multiple bone metastases on her ribs and sternum with bilateral lung metastasis and malignant effusion all disappeared while she was on a year- long administration of anastrozole and an optimal dose of abemaciclib(100 mg bid). However, because of the Grade 3 digestive adverse event that occurred at approximately 1 year of treatment, she could only maintain the treatment for up to 13 months. After then, no recurrence has been detectable for 6 months so far.
CONCLUSION: CDK4/6 inhibitors, in combination with anastrozole, will play a pivotal role in the initial approach to elderly patients with HR+ late recurrence as a chemotherapy- free strategy.
Gan To Kagaku Ryoho. 2021 Oct;48(10): 1251-1254

[Successful Treatment of Estrogen Receptor Positive, HER2 Negative Breast Cancer with Life-Threatening Multiple Bone Metastases Using the Combination of Fulvestrant and Palbociclib-A Case Report].

Asuka Nakamura, Takashi Shigekawa, Hideki Asakawa, Keiichi Park, Noriyuki Baba.

Palbociclib, a CDK4/6 inhibitor, is found to be an effective therapeutic drug in the treatment of estrogen receptor positive (ER+)metastatic breast cancer. In this report, we describe a case of rapid progression of life-threatening multiple bone metastases of breast cancer treated with a combination of fulvestrant and palbociclib. The patient, a 58-year-old postmenopausal woman, was diagnosed with left breast cancer at the age of 43 years and underwent breast-conserving surgery. After the completion of postoperative adjuvant endocrine therapy and radiotherapy, the patient was placed on regular follow-up. Eleven years after the surgery, multiple bone metastases and multiple lymph node metastases occurred, and the patient was treated with letrozole as first-line therapy for recurrent breast cancer. Although she continued to receive this treatment for 2 years and 10 months, her general condition worsened due to the occurrence of new liver metastases and the rapid progression of existing metastatic lesions. Thus, she was sent to an emergency room. Marked hypercalcemia and a severe decrease in erythrocyte and platelet counts were observed, which could be the cause of her worsening general condition. Her performance status(PS)was 4, and palliative treatment was also considered. However, she received treatment for hypercalcemia and red blood cell transfusion; as a result, she recovered to the PS 2 where she could begin chemotherapy. Then, she began a treatment consisting of a combination of fulvestrant and palbociclib as a second-line treatment for the recurrence. The patient responded well to the treatment, and her general condition improved to PS 1. She has since maintained a good quality of life for 2 years and 11 months without serious adverse events. In conclusion, the combination of fulvestrant and palbociclib has a low risk of serious adverse events and is a worthwhile treatment for rapidly progressing, life-threatening multiple bone metastases of breast cancer.
Pharmaceutics. 2021 Oct 16. pii: 1708. [Epub ahead of print]13(10):

Pharmacokinetic/Pharmacodynamic Model of Neutropenia in Real-Life Palbociclib-Treated Patients.

Alexandre Le Marouille, Emma Petit, Courèche Kaderbhaï, Isabelle Desmoulins, Audrey Hennequin, Didier Mayeur, Jean-David Fumet, Sylvain Ladoire, Zoé Tharin, Siavoshe Ayati, Silvia Ilie, Bernard Royer, Antonin Schmitt.

  Palbociclib is an oral CDK4/6 inhibitor indicated in HR+/HER2- advanced or metastatic breast cancer in combination with hormonotherapy. Its main toxicity is neutropenia. The aim of our study was to describe the kinetics of circulating neutrophils from real-life palbociclib-treated patients. A population pharmacokinetic (popPK) model was first constructed to describe palbociclib pharmacokinetic (PK). Individual PK parameters obtained were then used in the pharmacokinetic/pharmacodynamic (PK/PD) model to depict the relation between palbociclib concentrations and absolute neutrophil counts (ANC). The models were built with a population of 143 patients. Palbociclib samples were routinely collected during therapeutic drug monitoring, whereas ANC were retrospectively retrieved from the patient files. The optimal popPK model was a mono-compartmental model with a first-order absorption constant of 0.187 h-1 and an apparent clearance Cl/F of 57.09 L (32.8% of inter individuality variability (IIV)). The apparent volume of distribution (1580 L) and the lag-time (Tlag: 0.658 h) were fixed to values from the literature. An increase in creatinine clearance and a decrease in alkaline phosphatase led to an increase in palbociclib Cl/F. To describe ANC kinetics during treatment, Friberg's PK/PD model, with linear drug effect, was used. Parameters estimated were Base (2.92 G/L; 29.6% IIV), Slope (0.0011 L/µg; 28.8% IIV), Mean Transit Time (MTT; 5.29 days; 17.9% IIV) and γ (0.102). The only significant covariate was age on the initial ANC (Base), with lower ANC in younger patients. PK/PD model-based simulations show that the higher the estimated CressSS (trough concentration at steady state), the higher the risk of developing neutropenia. In order to present a risk lower than 20% to developing a grade 4 neutropenia, the patient should show an estimated CressSS lower than 100 µg/L.

Keywords:  neutropenia; palbociclib; pharmacokinetic/pharmacodynamic

DOI:  https://doi.org/10.3390/pharmaceutics13101708
Ann Oncol. 2021 Sep 29. pii: S0923-7534(21)04494-X. [Epub ahead of print]

Adjuvant Abemaciclib Combined With Endocrine Therapy for High-Risk Early Breast Cancer: Updated Efficacy and Ki-67 Analysis From the monarchE Study.

N Harbeck, P Rastogi, M Martin, S M Tolaney, Z M Shao, P A Fasching, C S Huang, G G Jaliffe, A Tryakin, M P Goetz, H S Rugo, E Senkus, L Testa, M Andersson, K Tamura, L Del Mastro, G G Steger, H Kreipe, R Hegg, J Sohn, V Guarneri, J Cortés, E Hamilton, V André, R Wei, S Barriga, S Sherwood, T Forrester, M Munoz, A Shahir, B San Antonio, S C Nabinger, M Toi, S R D Johnston, J O'Shaughnessy.

  BACKGROUND: Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in HR+, HER2-, node-positive, high risk early breast cancer (EBC) at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome (PO) analysis and an additional follow-up analysis (AFU1).PATIENTS AND METHODS: This global, phase 3, open-label trial, randomized (1:1) 5637 patients to adjuvant ET for ≥5 years +/- abemaciclib for 2 years. Cohort 1 enrolled patients with ≥4 positive axillary lymph nodes (ALN), or 1-3 positive ALN and either Grade 3 disease or tumor ≥5 cm. Cohort 2 enrolled patients with 1-3 positive ALN and centrally determined high Ki-67 index (≥20%). Primary endpoint was IDFS in the intent-to-treat population (Cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety.
RESULTS: At the PO analysis, with 19 months median follow-up time, abemaciclib + ET resulted in a 29% reduction in the risk of developing an IDFS event (HR=0.71, 95% CI: 0.58, 0.87; nominal p=0.0009). At the AFU1 analysis, with 27 months median follow-up and 90% of patients off-treatment, IDFS (HR=0.70, 95% CI=0.59, 0.82; nominal p<0.0001) and DRFS (HR=0.69, 95% CI=0.57, 0.83; nominal p<0.0001) benefit was maintained. The absolute improvement in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. While Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data was consistent with the known abemaciclib risk profile.
CONCLUSION: Abemaciclib+ET significantly improved IDFS in patients with HR+, HER-, node-positive, high risk EBC, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period.

Keywords:  CDK4/6; Ki-67; abemaciclib; adjuvant; early breast cancer

DOI:  https://doi.org/10.1016/j.annonc.2021.09.015