Administration Of Palbociclib Research Articles

Palbociclib in real clinical practice: Results of a single-center observational study

Introduction. A breakthrough in the treatment of metastatic hormone-dependent (HR+) breast cancer was combination endocrine therapy with CDK4/6 inhibitors, which significantly prolonged the tumor response time to treatment and the median survival before progression. The effectiveness of combination endocrine therapy in real-life practice is of particular interest due to the wider population of patients with different somatic status and comorbidity, often not included in randomized trials.Aim. Analyze of palbociclib using for treating patients with HR+/HER2– advanced breast cancer (mBC) at the Republican Clinical Oncology Dispensary.Materials and methods. Data from 323 patients were analyzed. Our study examined the effectiveness of combination endocrine therapy with palbociclib in patients with metastatic HR+ HER2– breast cancer. Data on the clinicopathological characteristics of patients and disease progression during palbociclib administration were obtained by reviewing clinical data from patient records and radiological/pathological examination reports.Results. The median age of patients included in the study was 62 years. When assessing the antitumor response, a partial response was recorded in 54 patients (16.7%), stabilization in 212 patients (65.6%), and progression in 57 patients (17.8%). The median progression-free survival was 13 months. Grade 3 adverse events were noted in 23 patients: neutropenia in 21.7% of cases, hepatotoxicity in 47.8% of cases, cardiotoxicity in 17.4% of cases, and coagulopathy in 4.3%. No patient discontinued therapy due to adverse events. The best treatment results were achieved by patients who used the combination of palbociclib with an endocrine partner as the first line of treatment for advanced stage.Conclusion. This analysis of real-world data on the use of palbociclib in real-world clinical practice confirms the RCT data on the efficacy and safety of using CDK4/6 inhibitors for the treatment of patients with HR+ HER2- mBC.

Strategy to Improve the Oral Pharmacokinetics of Cyclin-Dependent Kinase 4/6 Inhibitors: Enhancing Permeability and CYP450 Inhibition by a Natural Bioenhancer

Palbociclib and ribociclib an orally bioavailable, potent cyclin-dependent kinase 4/6 inhibitors, with low oral bioavailability due to substrate specificity towards CYP3A and P-glycoprotein. Thus, current research aims to examine the effect of a bioenhancer (naringin), on oral pharmacokinetics of palbociclib and ribociclib. Naringin’s affinity for CYP3A4 and P-glycoprotein was studied using molecular docking; its impact on palbociclib/ribociclib CYP3A metabolism and P-glycoprotein-mediated efflux was examined using in vitro preclinical models; and its oral pharmacokinetics in rats were assessed following oral administration of palbociclib/ribociclib in presence of naringin (50 and 100 mg/kg). Naringin binds optimally to both proteins with the highest net binding energy of − 1477.23 and − 1607.47 kcal/mol, respectively. The microsomal intrinsic clearance of palbociclib and ribociclib was noticeably reduced by naringin (5–100 µM), by 3.0 and 2.46-folds, respectively. Similarly, naringin had considerable impact on the intestinal transport and efflux of both drugs. The pre-treatment with 100 mg/kg naringin increased significantly (p < 0.05) the oral exposure of palbociclib (2.0-fold) and ribociclib (1.95-fold). Naringin's concurrent administration of palbociclib and ribociclib increased their oral bioavailability due to its dual inhibitory effect on CYP3A4 and P-glycoprotein; thus, concurrent naringin administration may represent an innovative strategy for enhancing bioavailability of cyclin-dependent kinase inhibitors.Graphical

Association between CDK4/6 inhibitors and drug-related osteonecrosis of the jaw: A pharmacoepidemiological study using the FDA Adverse Events Reporting System.

The most common toxicities associated with cyclin-dependent kinase (CDK) 4/6 inhibitor therapy include decreased leukopenia and neutropenia due to the inhibition of CDK6 of leukocyte and neutrophil precursors in bone marrow. These hematological toxicities are more commonly observed with palbociclib administration than with abemaciclib administration, which is approximately 13 times more selective against CDK4 than CDK6. Thus, even though both successfully inhibit CDK4/6, the side effects of palbociclib and abemaciclib differ due to differences in selectivity. Recent reports have suggested an association between palbociclib and medication-related osteonecrosis of the jaw; however, reports on this association are inconsistent. This study investigated the potential association of palbociclib and abemaciclib with MRONJ using the FAERS. Signals of "Osteonecrosis of jaw" were detected only in females using palbociclib (cROR025: 2.08). Other signals detected included stomatitis-related adverse events with abemaciclib and intraoral soft tissue damage and infection with palbociclib. As previous exploratory studies have reported MRONJ signals for bisphosphonates and denosumab, we calculated the aROR for palbociclib-induced osteonecrosis of the jaw using concomitant bisphosphonates and denosumab as covariates. A signal was detected even after adjusting for sex, age, and concomitant medications as covariates (aROR0025: 5.74). A proper understanding of the differences in CDK selectivity is necessary for the appropriate use of CDK4/6 inhibitors. To the best of our knowledge, this is the first report on CDK4/6 inhibitors and drug-related osteonecrosis of the jaw. We believe that these results will offer new insights into adverse events related to the use of CDK4/6 inhibitors, and may aid in the proper use of CDK4/6 inhibitors.

Protective effects of palbociclib on colitis-associated colorectal cancer.

Chronic or recurrent inflammatory injury to the intestinal mucosa is closely related to inflammation-related colorectal cancer (CRC). This study aimed to examine the protective effects of palbociclib, a stimulator of interferon genes (STING) antagonist, on colitis-related colorectal carcinogenesis. Bioinformatic analyses, including Gene Ontology (GO) enrichment, gene set enrichment analysis (GSEA), and network analysis, were conducted. Male C57BL/6 mice were administered azoxymethane (AOM) and dextran sulfate sodium (DSS), followed by treatment with palbociclib for 6 weeks. The general conditions of mice were observed and recorded. The colon histopathology was assessed based on hematoxylin and eosin (H&E) staining results. Relative messenger RNA (mRNA) expression levels of interferon b1 (Ifnb1), interleukin 6 (Il6), and interleukin 1b (Il1b) in colon were estimated based on quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) analysis. The STING signaling pathway was significantly upregulated in stages III and IV of CRC in The Cancer Genome Atlas (TCGA)-CRC cohort. After treatment with AOM/DSS, the weight of mice decreased significantly, whereas administration of palbociclib partially reversed this trend. The mouse colon treated with AOM/DSS showed significant pathological damages, disorderly epithelial cell structure, atypical hyperplasia, and infiltration of several inflammatory cell types; however, the colon damage was remarkably reduced upon treatment with palbociclib. It was also found that palbociclib almost abolished the increase in the downstream effectors of STING-mediated transcription in the colon tissue treated with AOM/DSS, as evidenced by the transcription levels of Ifnb1, Il6, and Il1b. These findings indicate that the STING pathway is closely associated with CRC. Palbociclib significantly alleviates tumor development in AOM/DSS-induced colitis-associated CRC.

Optimal Treatment of Hormone Receptor-positive Advanced Breast Cancer Patients With Palbociclib.

Palbociclib was the first cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor approved worldwide. Currently, CDK4/6 inhibitors are strongly recommended for endocrine therapy in the first or second line with hormone receptor-positive advanced breast cancer. It is expected the use of CDK4/6 inhibitor will further increase. Therefore, the aim was to investigate and better understand the use of palbociclib. We retrospectively analyzed the data of patients with advanced breast cancer who were treated with palbociclib in three hospitals between 2018 and 2022. Clinical data were obtained from the patients' medical electronic records. A total of 143 patients were enrolled. The median age was 66 years (range=33-89), and the majority (90.9%) were postmenopausal patients. In total, median time-to-treatment discontinuation (TTD) (95% confidence interval, CI) was 7 (6-10) months. Median TTD (95% CI) was 13 (7-20) months for the first or second line, and significantly prolonged compared to TTD for the third or later lines with palbociclib (p<0.0001). The importance of front-line use was indicated. Multivariate analyses showed that no visceral metastasis or first or second line therapy influenced the longer TTD. Between patients above or below 70 years of age, older age did not negatively affect TTD, though there were significantly more cases of dose reduction or withdrawal in patients over 70 years old. The variation of adverse events (AEs) among hospitals was very large (9.0%, 31.3%, 4.5%). We found that understanding of AE management was important. This study showed that dose reduction or withdrawal of palbociclib had no harmful effects in Japanese patients. Efficacy was also high in older patients. It is important to manage palbociclib administration more safely and appropriately. A combination of dose reduction and withdrawal is key to this therapeutic strategy.

243P Concomitant administration of palbociclib and proton pump inhibitors affects clinical outcomes in metastatic breast cancer patients

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are usually combined with fulvestrant or aromatase inhibitors for the treatment of patients with metastatic breast cancer (mBC). Drug-drug interactions may affect absorption by different mechanims, for instance, modification of digestive pH. Proton pump inhibitors (PPIs) are known to reduce the oral bioavailability of some anticancer drugs. Palbociclib is a weak base with pH-dependent solubility, therefore variations in gastric pH could affect its absorption. The objective of this study was to evaluate the interaction between PPIs and palbociclib by analizing progression-free survival (PFS) in patients with mBC. This is a retrospective study approved by the local Ethics Committee. Patients had received palbociclib between January 2016 and December 2021. The following variables were collected: age, menopausal status, performance status, hormonal treatment (fulvestrant or aromatase inhibitors), visceral or non-visceral disease, first-line vs second-line treatment, ki67, and concomitant use of PPIs. PFS was defined as the time from starting treatment to progression of the disease. Survival was estimated with the Kaplan-Meier method, whereas Cox Regression models were used to estimate hazard ratios and the chi-square test for categorical variables. A total of 169 patients were enrolled in the study: 80 received a PPI and 86 did not, without significant differences in clinical characteristics in both groups. The median PFS was 17.3 months (95% CI: 13.83-20.76), 36 months in first-line and 13 months in second and subsequent lines. Patients taking PPIs had a shorter median PFS (14.30 versus 42.6 months, p<0.001; HR 4.18: 95% CI 2.57-6.80; p<0.0001). Median PFS was 44 vs. 14 months in first-line ans 17 vs 9 months in second or subsequent lines. The line of treatment (first vs second or beyond) and ki67 had a significant influence on DFS, whereas the remaining clinical variables did not. Patients with mBC treated with hormonal therapy plus palbociclib had poor PFS when receving a concomitant PPI. Although further studies are needed in the field, caution is recommended with the long-term use of PPIs in this population.

On-treatment derived neutrophil-to-lymphocyte ratio and survival with palbociclib and endocrine treatment: analysis of a multicenter retrospective cohort and the PALOMA-2/3 study with immune correlates

BackgroundCyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have been established as a standard treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC); however, predictive biomarkers with translational relevance have not yet been elucidated.MethodsData from postmenopausal women who received the CDK4/6 inhibitor palbociclib and letrozole for HR-positive, HER2-negative ABC from tertiary referral centers were analyzed (N = 221; exploratory cohort). Pre- and on-treatment neutrophil-to-lymphocyte ratio (NLR) and derived NLR (dNLR; neutrophil/[leukocyte-neutrophil]) were correlated with survival outcomes. Data from the PALOMA-2 (NCT01740427) and PALOMA-3 studies (NCT01942135) involving patients treated with endocrine treatment with or without palbociclib were also analyzed (validation cohort). Prospectively enrolled patients (N = 20) were subjected to immunophenotyping with circulating immune cells to explore the biological implications of immune cell dynamics.ResultsIn the exploratory cohort, palbociclib administration significantly reduced leukocyte, neutrophil, and lymphocyte counts on day 1 of cycle 2. Although the baseline dNLR was not significantly associated with progression-free survival (PFS), higher on-treatment dNLRs were associated with worse PFS (hazard ratio = 3.337, P < 0.001). In the PALOMA-2 validation cohort, higher on-treatment dNLRs were associated with inferior PFS in patients treated with palbociclib and letrozole (hazard ratio = 1.498, P = 0.009), and reduction in the dNLR after treatment was predictive of a survival benefit (hazard ratio = 1.555, P = 0.026). On-treatment dNLRs were also predictive of PFS following palbociclib and fulvestrant treatment in the PALOMA-3 validation cohort. Using flow cytometry analysis, we found that the CDK4/6 inhibitor prevented T cell exhaustion and diminished myeloid-derived suppressor cell frequency.ConclusionsOn-treatment dNLR significantly predicted PFS in patients with HR-positive, HER2-negative ABC receiving palbociclib and endocrine treatment. Additionally, we observed putative systemic immune responses elicited by palbociclib, suggesting immunologic changes upon CDK4/6 inhibitor treatment.

Real clinical practice patterns of palbociclib usage in Russian Federation

Introduction. Current treatment of metastatic luminal Her2-negative breast cancer includes combination of endocrine therapy (ET) with CDK4/6 inhibitors. This type of therapy demonstrated impressive efficacy over mono ET in early lines of treatment in phase III randomized clinical trials. Treatment patterns in real clinical practice (RCP) are of great interest. We represent the first available local data for all CDK 4/6 inhibitors in RCP in Russian Federation in accordance with the number of patients (pts).Aim. Analysis of the patterns of palbociclib administration in RCP.Materials and methods. One hundred and 5 pts from 12 regions of Russian Federation were included in this analysis and received palbociclib in combination with ET from 2017 to 2020. Median age was 57 years (29-75), 31/105 (29.5%) of pts were &lt; 50. De novo metastatic disease was observed in 16 (15.2%) pts, 89 pts progressed after radical treatment. Visceral metastases (mts) at palbociclib initiation had 61/105 (58.1%) of pts.Results. Only 22/105 (21%) of pts received palbociclib as 1st line treatment of metastatic disease. The majority of pts was treated with palbociclib in 2nd and 3rd lines (28.5% and 30.5% respectively). In 26/105 (24.8%) pts palbociclib was combined with aromatase inhibitors, in other cases - with fulvestrant. Median follow-up time was 6.5 (1.1-31.9) months, median progression free survival - 6.0 (1.0-28.0) months. Most common adverse events (AE) were leukopenia, neutropenia and thrombocytopenia. Only in 3 cases palbociclib was completely stopped due to toxicity.Conclusions. Our data indicates that there is a need to move palbociclib initiation in first two lines of treatment to get maximal improvement in survival and to increase its usage in young women.

S3709 A Novel Way to Administer Chemotherapy Medication in a Patient With Esophageal Stenosis Secondary to Metastatic Breast Cancer

Introduction: Breast cancer can present as cervical lymph node enlargement causing dysphagia due to esophageal compression. We present a case of esophageal stenosis requiring placement of gastrostomy for administration of Palbociclib, which cannot be crushed or split. Case Description/Methods: 64 year-old female with history of breast cancer treated with lumpectomy and adjuvant radiation therapy, 7 years ago presented with dysphagia and weight loss. Upper endoscopy (Fig. 1) showed extrinsic stenosis at cricopharyngeus 6 mm (diameter) × 2 cm (length). CT scan showed posterior triangle right cervical lymph nodes measuring 16 mm × 16 mm and a 20 mm × 23 mm mass along the right posterior para-tracheal/para-esophageal distribution. Endobronchial ultrasound guided biopsy was obtained. Pathology (Fig. 2 and 3) showed degenerated clusters of (GATA-3 positive) malignant cells suggestive of metastatic breast cancer. PET/CT confirmed irregular soft tissue mass near the right tracheoesophageal groove with intense FDG uptake. There was regional metastatic lymphadenopathy in the right neck at the level IIA and IIIA regions. Oncology recommended radiation treatment. Due to dysphagia and weight loss, a 20 French PEG tube was placed using an ultraslim upper endoscope. Repeat PET/CT showed partial response and patient was recommended 125 mg Palbociclib tablet daily. The pill cannot be crushed or split and is oval, measuring 16.2 mm × 8.6 mm. Repeat upper endoscopy was performed, gastrostomy was dilated to 30 French, and a 30 French gastrostomy tube was placed. Due to the pill’s dimensions, it could not flush down the 30 French tube. Patient was instructed to remove the peg tube daily by suctioning saline from the retention balloon, place Palbociclib directly into the stomach via the gastrostomy, replace gastrostomy tube, and inflate the retention balloon with saline. Nine months later patient had resolution of dysphagia. She was not using her PEG tube and the CT scan showed no residual disease (Figure 1). Discussion: We present a case of metastatic cancer causing esophageal stenosis, requiring treatment with a chemotherapy pill that cannot be crushed, split, or flushed down the largest (30 French diameter) available gastrostomy tube. Removing the gastrostomy tube, administering the pill directly into the stomach via gastrostomy, and replacing the tube, patient could self-administer the medication. We present a novel technique of medication administration when substitution of form, route of administration, and medication are not possible.Figure 1.: EGD showing extrinsic stenosis at cricopharyngeus.Figure 2.: Pathology with H&E stain showing presence of malignant cells.Figure 3.: Pathology with GATA-3 immunostain positive metastatic breast cancer cells.

Combination of palbociclib with adjuvant endocrine therapy for treatment of hormone receptor‑positive and human epidermal growth factor receptor 2‑negative metastatic breast cancer: An experience at two cancer centers in Saudi Arabia

The addition of palbociclib (a cyclin-dependent kinase 4/6 inhibitor) to endocrine therapy (ET) has been shown to significantly improve progression-free survival (PFS) and overall survival (OS) among patients with hormone receptor-positive (HR+) advanced breast cancer. The current study presents the local experience of using palbociclib at two cancer centers in Saudi Arabia. Electronic data of patients with metastatic HR+ and human epidermal growth factor receptor 2-negative breast cancer who progressed after prior ET and received at least one cycle of palbociclib plus ET, were retrospectively reviewed. A total of 97 patients were identified, and their data were included in the analysis. The median age of the patients was 55 years. Patients were heavily pretreated in the metastatic setting (55% received systemic chemotherapy and 49% received two or more lines of prior ET). In total, 29 (30%) and 50 (52%) patients achieved an objective response and clinical benefit, respectively. The median follow-up time was 31.0 months [95% confidence interval (CI), 16.9-44.9] and the median PFS time was 16.3 months (95% CI, 11.4-21.2), with 58% of patients remaining progression-free at 12 months. Upon multivariate regression analysis, liver involvement was the only significant independent variable that predicted a greater risk of progression or death (hazard ratio, 2.32; 95% CI, 1.22-4.40; P=0.010). The median OS time was 19.6 months (95% CI, 18.1-20.9), with 12- and 24-month OS rates of 75 and 30%, respectively. Overall, real-world data showed that administration of palbociclib in combination with ET in patients with advanced HR+ breast cancer achieved a favorable outcome that was comparable to that reported in clinical trials.

On-treatment derived neutrophil-to-lymphocyte ratio and response to palbociclib and letrozole: Analysis of a multicenter retrospective cohort and the PALOMA-2 study.

1066 Background: Relevant predictive biomarkers for cyclin dependent kinase 4 and 6 (CDK4/6) inhibitors have not been identified in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). We investigated whether dynamic changes in the peripheral immune cells can predict therapeutic response to CDK4/6 inhibitors in ABC with translational relevance. Methods: Postmenopausal women who received palbociclib and letrozole for HR-positive, HER2-negative ABC from tertiary referral centers were analyzed (n = 221; exploratory cohort). Pre- and on-treatment leucocyte, neutrophil, lymphocytes counts, neutrophil-to-lymphocyte ratio (NLR), and derived NLR (dNLR; neutrophil/[leucocyte-neutrophil]) were correlated with survival outcomes. Patients from the PALOMA-2 study (NCT01740427) treated with letrozole with or without palbociclib (n = 410 and 209, respectively) were analyzed for validation (validation cohort). Prospectively enrolled patients were subjected to immunophenotyping with flow cytometry to explore the immune cell dynamics after CDK4/6 inhibitor treatment. Results: In the exploratory cohort, palbociclib administration significantly reduced leucocyte, neutrophil, and lymphocyte counts on cycle 2 day 1. Not baseline, but on-treatment neutrophil and lymphocyte counts were associated with superior and inferior outcomes, providing predictive significance to on-treatment NLR and dNLR for progression-free survival (PFS; HR = 1.64 and 2.52; all P&lt; 0.001). In the validation cohort, higher on-treatment dNLR was associated with inferior PFS in patients treated with palbociclib and letrozole (HR = 1.50 and P= 0.009 with 1.04 cut-off), whereas not correlated with outcome in placebo and letrozole-administered patients. Exploratory analysis revealed that CDK4/6 inhibitor prevented T cell exhaustion and diminished relative frequencies of myeloid-derived suppressor cells, both of which trigger antitumor immunity. Conclusions: On-treatment dNLR significantly predicted treatment outcome in HR-positive, HER2-negative ABC treated with palbociclib and letrozole, allowing early prediction of treatment response with mechanistic insights. Clinical trial information: NCT01740427 .

Therapeutic evaluation of palbociclib and its compatibility with other chemotherapies for primary and recurrent nasopharyngeal carcinoma

BackgroundRecent genomic analyses revealed that druggable molecule targets were only detectable in approximately 6% of patients with nasopharyngeal carcinoma (NPC). However, a dependency on dysregulated CDK4/6–cyclinD1 pathway signaling is an essential event in the pathogenesis of NPC. In this study, we aimed to evaluate the therapeutic efficacy of a specific CDK4/6 inhibitor, palbociclib, and its compatibility with other chemotherapeutic drugs for the treatment of NPC by using newly established xenograft models and cell lines derived from primary, recurrent, and metastatic NPC.MethodsWe evaluated the efficacies of palbociclib monotherapy and concurrent treatment with palbociclib and cisplatin or suberanilohydroxamic acid (SAHA) in NPC cell lines and xenograft models. RNA sequencing was then used to profile the drug response–related pathways. Palbociclib-resistant NPC cell lines were established to determine the potential use of cisplatin as a second-line treatment after the development of palbociclib resistance. We further examined the efficacy of palbociclib treatment against cisplatin-resistant NPC cells.ResultsIn NPC cells, palbociclib monotherapy was confirmed to induce cell cycle arrest in the G1 phase in vitro. Palbociclib monotherapy also had significant inhibitory effects in all six tested NPC tumor models in vivo, as indicated by substantial reductions in the total tumor volumes and in Ki-67 proliferation marker expression. In NPC cells, concurrent palbociclib treatment mitigated the cytotoxic effect of cisplatin in vitro. Notably, concurrent treatment with palbociclib and SAHA synergistically promoted NPC cell death both in vitro and in vivo. This combination also further inhibited tumor growth by inducing autophagy-associated cell death. NPC cell lines with induced palbociclib or cisplatin resistance remained sensitive to treatment with cisplatin or palbociclib, respectively.ConclusionsOur study findings provide essential support for the use of palbociclib as an alternative therapy for NPC and increase awareness of the effective timing of palbociclib administration with other chemotherapeutic drugs. Our results provide a foundation for the design of first-in-human clinical trials of palbociclib regimens in patients with NPC.

A Phase I/II Trial of CPX-351 + Palbociclib in Patients with Acute Myeloid Leukemia

A Phase I/II Trial of CPX-351 + Palbociclib in Patients with Acute Myeloid Leukemia

Concurrent use of palbociclib and radiation therapy: single-centre experience and review of the literature

Palbociclib in combination with endocrine therapy increases progression-free survival in patients with ER-positive, HER2-negative advanced breast cancer (BC). In this study, we retrospectively evaluated safety in the first patient treated with concurrent use of palbociclib and radiation therapy (RT) in the Curie Institute. Between April 2017 and August 2019, 30 women with metastatic BC received locoregional and/or symptomatic irradiation at a metastatic site concurrently with palbociclib. The most common acute toxicities were radiodermatitis and neutropenia. Palbociclib had to be discontinued during RT in three locally treated patients who developed grade 3 radiodermatitis and febrile neutropenia, grade 2 dysphagia and metastatic disease progression, respectively. After a follow-up of at least 6 months, none of the patients had late toxicity. Concomitant administration of palbociclib with RT was reasonably well tolerated in our series of 30 patients. More prospective data with longer follow-up are needed to confirm these results.

Tolerance of concurrent CDK inhibitor and radiation therapy in metastatic breast cancer patients.

e12598 Background: Palbociclib, a small-molecule inhibitor of cyclin-dependent kinases (CDK4 and CDK6), combined with letrozole increases progression-free survival among patients with previously untreated ER-positive, HER2 negative advanced breast cancer. The purpose of our study was to retrospectively evaluate the tolerance of the concomitant association of Palbociclib and radiation therapy (RT) at Curie Institute. Methods: Between April 2017 and August 2019, 30 women with ER-positive, HER2 negative metastatic breast cancer received locoregional (LR) and/or symptomatic irradiation at a metastatic site concurrently with Palbociclib at a daily dose of 125 mg, from d1 to d21 every 28 days. Palbociclib was always associated with endocrine therapy: letrozole (with or without an LHRH analogue) or fulvestrant. Thirty-five sites were irradiated: nine patients received post-operative locoregional RT, including the chest wall or breast and lymph node areas, and 26 sites of metastases were irradiated: 17 at the spine, 7 peripheral skeletal lesions, 1 brain lesion and 1 choroidal lesion. The dose prescribed for locoregional mammary radiotherapy was 50 Gy in 25 fractions and varied for the treatment of metastatic sites: 20 Gy in 5 fractions (n = 13), 30 Gy in 10 fractions (n = 10) and 8 Gy in 1 fraction (n = 2). The brain metastasis was stereotactically treated (1 fraction of 18 Gy). The primary endpoint was toxicity scored according to the common terminology criteria for NCI adverse events, version v5.0. Results: Mean number of days of Palbociclib during RT was 8.8 days (range, 1 to 24 days). The most common acute toxicities were dermatitis (12/35, including 2 grade 2) and neutropenia (12/35, including 9 grade 2). Palbociclib had to be stopped during the RT of two patients (2/30): one patient treated locoregionally (bilateral breast and lymph nodes irradiation) developed a grade 3 dermatitis and febrile neutropenia, another treated locoregionally developed grade 2 dysphagia. After a median follow-up since the end of RT of 17 months (6 – 31 months, SD 8), none of the patients have so far exhibited late toxicity. Conclusions: Concomitant administration of palbociclib with RT was reasonably well tolerated in our series of 30 patients. Given this experience, palbociclib should not be discontinued during radiation therapy. Nevertheless, our findings should be confirmed in prospective registration studies collecting larger number of patients.

Abstract P4-12-05: A retrospective study of 27 patients with ER-positive, HER2 negative metastatic breast cancer treated with concomitant palbociclib and radiation therapy

Abstract Background: Palbociclib, a small-molecule inhibitor of cyclin-dependent kinases (CDK4 and CDK6), combined with letrozole increases progression-free survival among patients with previously untreated ER-positive, HER2 negative advanced breast cancer. However, the data on the safety of the concomitant association between Palbociclib and radiation therapy are scarce. The purpose of our study was to retrospectively evaluate the tolerance of the first patients treated with this concomitant combination at Institut Curie. Materials and methods: Between April 2017 and July 2019, 27 women with ER-positive, HER2 negative metastatic breast cancer received locoregional and/or symptomatic irradiation at a metastatic site concomitantly with Palbociclib at a daily dose of 125 mg, from d1 to d21 every 28 days. Palbociclib was always associated with an endocrine treatment: Letrozole (17 patients /27, with or without an LHRH analogue) or Fulvestrant (10 patients /27). Median age at the time of diagnosis of metastases was 60 years (range, 35-85 years). Thirty-two sites were irradiated: 9 patients received post-operative locoregional radiation therapy, including the chest wall or breast and lymph node areas, and 23 sites of metastases were irradiated: 15 at the spine (3 cervical, 6 thoracic, 4 lumbar, 2 sacral), 2 pelvic lesions, 4 peripheral skeletal lesions, 1 brain lesion and 1 choroidal lesion (two patients received locoregional treatment and irradiation in one metastatic site and two patients were treated in two different metastatic sites). The dose prescribed for locoregional mammary radiotherapy was 50 Gy in 25 fractions and varied for the treatment of metastatic sites: 20 Gy in 5 fractions (n=14), 30 Gy in 10 fractions (n=7) and 8 Gy in 1 fraction (n=1). The brain metastasis was stereotactically treated (1 fraction of 18 Gy). The primary endpoint was toxicity scored according to the common terminology criteria for NCI adverse events, version v4.0. Results: Median follow-up was 22 months (range, 4 to 54). Mean number of days of Palbociclib during radiation therapy was 8.7 days (range, 1 to 23 days). Most common acute toxicities were radiodermatitis (12/27, including 1 grade 3, 2 grade 2 and 9 grade 1) and neutropenia (13/27, including 1 grade 4, 7 grade 3, 5 grade 2). Palbociclib had to be stopped during the radiation therapy of three patients (3/27): one patient treated locoregionally (bilateral breast and lymph nodes irradiation) developed a grade 3 radiodermatitis and febrile neutropenia, another treated locoregionally developed grade 2 dysphagia (loss of 4 kg in 1 month) and one patient treated for sacral metastases (20 Gy in 4 fractions) developed grade 3 proctitis. Of the 19/27 patients with a follow-up of more than 6 months none developed late toxicities. Conclusion: Concomitant administration of Palbociclib with radiation therapy was reasonably well tolerated in our series of 27 patients. Caution should be exercised when a large volume is irradiated, and when the dose per fraction is high. It remains unsure whether the interruption-causing side effects of Palbociclib was based on synergistic toxicity with radiation therapy. We suggest that our findings are to be confirmed in prospective registration studies collecting larger number of patients. Citation Format: Arnaud Beddok, Alexandre Arsene-Henry, Baptiste Porte, Kim Cao, Louis Bazire, Nathaniel Scher, Alain Labib, Ilan Darmon, Joëlle Otz, Mathieu Minsat, Hamid Mammar, François Clément Bidar, Alain Fourquet, Paul Cottu, Phlip Poortmans, Youlia Kirova. A retrospective study of 27 patients with ER-positive, HER2 negative metastatic breast cancer treated with concomitant palbociclib and radiation therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-12-05.

TMOD-20. COMBINING TARGETED INHIBITOR AND RADIOTHERAPY IN TREATING ANAPLASTIC MENINGIOMA

Abstract BACKGROUND Anaplastic meningiomas pose a serious health concern due to their propensity for recurrence and brain invasion. Five-year overall survival of patients with anaplastic meningiomas is less than 10%, similar to that of glioblastoma patients. Standard treatment of recurrent anaplastic meningioma is radiotherapy (RT), but radioresistance is common. New therapeutic strategies, used singularly or in combination with RT, are urgently needed. Since deletion of the gene encoding the p16 cell cycle checkpoint protein is common in anaplastic meningioma, we hypothesized that such tumors would be sensitive to Palbociclib, a cdk4/6 inhibitor, and that Palbociclib could enhance RT efficacy. METHODS CH157 anaplastic meningioma cells were used in vitro for investigating tumor cell proliferation response to RT and Palbociclib, either alone or in combination, and as indicated by MTT assay results. CH157 cells were also used to establish intracranial xenografts in mice treated with RT or Palbociclib. Accuracy of RT dose was verified with calibrated MOSFET\OSLD dosimeters. Mice were monitored for intracranial tumor growth and response to treatment, as indicated by bioluminescence imaging. Length of survival data was collected and analyzed by log-rank test. RESULTS At two days post RT, the in vitro anti-proliferative effect of 2, 6, and 10 Gy radiation was significantly enhanced with concurrent 1mM Palbociclib (p &lt; 0.001). Daily administration of Palbociclib (150 mg/kg) for 1 week significantly extended the survival of mice with intracranial CH157 xenografts (group mean value of 18.4 vs. 13.6 days with vehicle control, p &lt; 0.001). A single dose of 10 Gy RT was superior to 6 Gy administered 1x and 2Gy/day administered on 5 consecutive days (group mean values of 37.4 vs. 24.0 vs. 24.6, respectively: p &lt; 0.001). CONCLUSIONS These data support further investigation of RT + Palbociclib for treating p16-deficient anaplastic meningiomas.

A study of the renal hypofunction and accompanying adverse events in breast cancer patients treated with palbociclb

Abstract Background Palbociclb is an orally available selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) that is indicated for patients with hormone receptor-positive HER2-negative advanced or recurrent breast cancer with 3 weeks on/1 week off schedule. Previous report showed that elevated serum creatinine (Scr) was only 2.0% in frequency for all grade, without cases of grade 3 or more. Anecdotal episode of declined eGFR (implying elevated Scr) seems to be more frequent in daily clinical practice; however, the actual frequency of declined eGFR and its impact on severe toxicity has not been determined yet. Objective To investigate the frequency of declined eGFR in patients treated with palbociclib and to determine the association between declined eGFR and severe toxicity. Methods Consecutive patients treated with palbociclib at National Cancer Center Hospital East between December 1 2017 and May 31 2018 were retrospectively investigated. Patient characteristics, eGFR at cycle 1 day1 (C1D1) and C1D15, C2D1, C2D15, and C3D1 of palbociclib, grade 4 neutropenia, treatment discontinuation or interruption caused by toxicity were retrieved from medical records. The frequency of declined eGFR and its correlation with severe toxicity were analyzed. Results A total of 42 patients were included. Median age was 65 years (range 43-80), and 41 cases were female. Median eGFR at the start of palbociclib was 76 mL/min/1.73m2, which declined 12.5 in median (range 3.0-39.0) on C1D15. At C2D1, eGFR was recovered (change in median -3 mL/min/1.73m2; range -17.0 - +19.0). Declined eGFR was not correlated significantly with either grade 4 neutropenia or treatment discontinuation. Conclusions While eGFR was declined by median of 12.5 mL/min/1.73m2 with palbociclib administration on C1D15, eGFR recovered to the baseline by drug interruption. Declined eGFR was not correlated with severe toxicity such as grade 4 neutropenia or toxicities leading to treatment discontinuation.

Safety and Efficacy of Palbociclib (CDK4/6 inhibitor) and Radiotherapy in Metastatic Breast Cancer Patients: Initial Results of a Novel Combination

Palbociclib is a selective CDK4/6 inhibitor approved for metastatic ER+/HER2- breast cancer. Preclinical evidence suggests palbociclib can augment radiotherapy (RT) antitumor effect by 1) preventing cell cycle progression from G1 to the more radioresistant S phase and 2) inhibiting RT-induced DNA double-strand break repair. Despite this potential benefit, clinicians seldom use this combination due to fear that RT may exacerbate palbociclib toxicity, particularly hematologic. The aim of this study is to report the preliminary results of this novel combination in patients with metastatic breast cancer. Records of patients treated with palbociclib at our institution from 2015-2018 were retrospectively reviewed. Patients who received RT for symptomatic metastases concurrently or within 14 days of palbociclib were included. Local treatment effect was assessed by clinical exam and subsequent CT/MRI imaging. Toxicity was graded based on CTCAE v5.0. A total of 16 women (median age: 59.6 years) received palliative RT in close temporal proximity to palbociclib administration. Four patients received palbociclib prior to RT (25.0%), 5 (31.3%) concurrent, and 7 (43.8%) post-RT. The median interval from closest palbociclib use to RT was five (range 0-14) days. The following sites were irradiated in decreasing order of frequency: bone (15 axial skeleton [9-vertebra; 4-pelvis; 2-other]; 3-extremity), brain (4: 3-WBRT & 1-fSRS), and mediastinum (1). The most frequently used RT dose/fractionation by was 30 Gy in 10 fractions. The median follow-up time is 14.7 (range 1.7-38.2) months. Pain relief was achieved in all patients. No radiographic local failure was noted in the 13 patients with evaluable follow-up imaging. Leukopenia, neutropenia, and thrombocytopenia were seen in 4 (25.0%), 5 (31.3%), and 1 (6.3%) patients before RT. Following RT, 5 (31.3%), 1 (6.3%), and 3 (18.8%) patients were leukopenic, neutropenic, and thrombocytopenic, respectively. All but two (Grade 2) hematologic toxicities were Grade 1. No acute or late Grade 2+ cutaneous, neurological, or gastrointestinal toxicities were noted. Toxicity results did not differ based on disease site or palbociclib-RT temporal association. The use of RT in patients receiving palbociclib resulted in minimal Grade 2 and no Grade 3+ toxicities. This preliminary work suggests that symptomatic patients receiving palbociclib may be safely irradiated without discontinuation of systemic therapy. Further studies with larger cohorts are needed to confirm these results.

Reproductive and developmental toxicity assessment of palbociclib, a CDK4/6 inhibitor, in Sprague-Dawley rats and New Zealand White rabbits

Palbociclib is a selective inhibitor of the cyclin-dependent kinase (CDK) 4/6, approved for the treatment of breast cancer. We assessed the potential effects of oral administration of palbociclib on reproduction and development. There were no effects on female or male fertility indices; however, in the male there was seminiferous tubule degeneration in the testes and secondary findings in the epididymides, lower testicular and epididymal weights, sperm density and motility. Palbociclib was not teratogenic in rats or rabbits; however, in the presence of maternal toxicity (lower maternal body weight gain and food consumption), low fetal body weights were observed in rats and small forepaw phalanges were noted in rabbits. There were, however, no adverse effects on the F1 generation in a pre- and post-natal developmental toxicity study in the rat.