Safety Of Palbociclib In Patients Research Articles

Abstract OT1-14-01: Efficiency and safety of palbociclib in patients with locally advanced or metastatic breast cancer: a muti-center real world study

Abstract Endocrine therapy is the main treatment for premenopausal women with HR+/HER2- breast cancer. Palbociclib is an oral CDK4/6 inhibitor which preclinical evidence that ER+ and HER2-amplified breast cancer cell lines are most sensitive to CDK4/6 inhibition of proliferation and is used in vitro in combination with endocrine therapy showed better tumor suppressive effect. To evaluate the efficacy and safety of palbociclib in patients with locally advanced or metastatic breast cancer, we enrolled females with hormone receptor-positive breast cancer who treat with Palbociclib from July 2018 to March 2022. The study has so far included 267 patients in 4 centers. 32.83% patients were treated in first-line, 31.32% and 38.85% patients in second and third lines. 30.34% patients had hepatic metastasis. 35.47% patients were sensitive to previous endocrine therapy; 18.23% patients had primary resistance to endocrine therapy, while 46.31% patients had secondary resistance to endocrine therapy. The median PFS was 12.67 months (95% CI 11.51-13.92), and Median overall survival (OS) was not reached. Among all patients, the overall response rate (ORR) was 25.84%, and the disease control rate (DCR) was 78.62%. The main adverse events related to treatment were neutropenia (91.38%), white blood cell decreased (90.09%), anemia (43.78%), and thrombocytopenia (37.93%). The most common grade 3/4 adverse event was neutropenia (55.61%). 11.99% of patients had dose reductions. More patients still needed for further analyze. Citation Format: Yongmei Yin, Xiang huang, Wei Li, Xinyu Wu, Yijia Hua, Chunxiao Sun. Efficiency and safety of palbociclib in patients with locally advanced or metastatic breast cancer: a muti-center real world study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-14-01.

A Phase 2 Study of Palbociclib for Recurrent or Refractory Advanced Thymic Epithelial Tumors (KCSG LU17-21)

Thymic epithelial tumors (TETs) are rare but are the most common tumors of the anterior mediastinum. Platinum-based combination chemotherapy is the standard of care for such tumors and is associated with a 50% to 90% objective response rate (ORR) in metastatic disease. Nevertheless, there is no standard chemotherapeutic option after failure of platinum-based combination chemotherapy. Genetic alterations associated with the cell cycle, including pRB, p16INK4A, and cyclin D1, are most often observed in TETs. On the basis of these results, we conducted a phase 2 trial to evaluate the efficacy and safety of palbociclib in patients with recurrent or refractory advanced TETs. This is a phase 2, multicenter, open-label, single-arm study of palbociclib monotherapy in patients with recurrent or metastatic advanced TETs who failed one or more cytotoxic chemotherapies. The patients received 125 mg of oral palbociclib daily for 21 days, followed by a 7-day break. The primary end point was progression-free survival (PFS). The secondary end points were ORR, duration of response, overall survival, and safety. Between August 2017 and October 2019, a total of 48 patients were enrolled. The median number of previous chemotherapies was one (range: one to four), and 21 (43.7%) of 48 patients received thymectomy. By the WHO classification, the patients were type A (n= 1), type B1 (n= 2), type B2 (n= 8), type B3 (n= 13), thymic carcinoma (n= 23), and unknown (n= 1). With a median follow-up of 14.5 months (range: 0.8-38.2), the median number of cycles of palbociclib monotherapy was 10 (range: 1-40). The ORR was 12.5% (four partial responses in thymoma and two partial responses in thymic carcinoma). The PFS at 6 months was 60.2%, and the median PFS was 11.0 months (95% confidence interval: 4.6-17.4). The median overall survival was 26.4 months (95% confidence interval: 17.4-35.4). The most common treatment-related adverse events of any grade were neutropenia (62.5%), anemia (37.5%), and thrombocytopenia (29.1%), and the most common grade 3/4 treatment-related hematologic adverse event was neutropenia (41.7%). Neutropenia above grade 3 was reversible, and there were no cases with neutropenic fever. Palbociclib monotherapy was well tolerated and had encouraging efficacy in patients with TETs who failed platinum-based combination chemotherapy.

MA04.03 A Phase II Study of Palbociclib for Recurrent or Refractory Advanced Thymic Epithelial Tumor (KCSG LU17-21)

Thymic epithelial tumors (TETs) are rare but the most common tumor of the anterior mediastinum. Platinum-based combination chemotherapy is standard of care which is associated with a 50%-90% overall response rate (ORR) in metastatic disease. However, there is no standard chemotherapeutic option after failure of platinum-based combination chemotherapy. Genetic alterations associated with cell cycle including pRB, p16INK4A, and cyclin D1 are commonly observed in TETs. Based on these results, we conducted a phase II trial to evaluate the efficacy and safety of palbociclib in patients with recurrent or refractory advanced TETs.

Efficacy and safety of palbociclib in patients with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer with preexisting conditions: A post hoc analysis of PALOMA-2

ObjectiveIn the PALOMA-2 trial, palbociclib in combination with letrozole prolonged progression-free survival (PFS) and exhibited an acceptable safety profile in patients with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ABC). This post hoc analysis of PALOMA-2 evaluated the efficacy and safety of palbociclib plus letrozole in patients with preexisting conditions grouped by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC).MethodsPostmenopausal patients without prior treatment for ABC were randomized 2:1 to receive palbociclib (125 mg/d on a 3 weeks on/1 week off schedule) plus letrozole (2.5 mg/d, continuous) or placebo plus letrozole. Patients were grouped by the following MedDRA SOC preexisting conditions: gastrointestinal, musculoskeletal, metabolic, and vascular/cardiac. Median PFS was estimated by the Kaplan-Meier method, and treatment emergent adverse events (AEs) were compared between treatment arms within each preexisting condition subgroup.ResultsAt baseline, 276 (41.4 %) patients had preexisting gastrointestinal disorders, 390 (58.6 %) had musculoskeletal disorders, 259 (38.9 %) had metabolic disorders, and 382 (57.4 %) had vascular/cardiac disorders. Baseline characteristics were similar between subgroups and between each arm within subgroups. Regardless of baseline preexisting condition, palbociclib plus letrozole prolonged PFS compared with placebo plus letrozole. Treatment-emergent AEs associated with palbociclib plus letrozole and dose modifications due to AEs were similar across preexisting condition subgroups.ConclusionThis post hoc analysis of PALOMA-2 demonstrated a favorable effect of palbociclib on PFS and a safety profile consistent with previous observations, regardless of underlying preexisting condition. Pfizer Inc (NCT01740427).

A phase II study of palbociclib for recurrent or refractory advanced thymic epithelial tumor (KCSG LU17-21).

8576 Background: Thymic epithelial tumors (TETs) are rare but the most common tumor of the anterior mediastinum. Platinum-based combination chemotherapy is standard of care which is associated with a 50%-90% overall response rate (ORR) in metastatic disease. However, there is no standard chemotherapeutic option after failure of platinum-based combination chemotherapy. Genetic alterations associated with cell cycle including pRB, p16INK4A, and cyclin D1 are commonly observed in TETs. Based on these results, we conducted a phase II trial to evaluate the efficacy and safety of palbociclib in patients with recurrent or refractory advanced TETs. Methods: This is a phase II multicenter, open-label, single arm study of palbociclib monotherapy in patients with recurrent or metastatic advanced TETs who failed one or more cytotoxic chemotherapy. Patients receive oral palbociclib 125mg daily for 21 days followed by a 7-day break. The primary endpoint was the progression-free survival (PFS) rate at 6 months (H0 = 30% vs H1 = 48%). Results: Between August 2017 and October 2019, 48 patients were enrolled. The median number of previous chemotherapy was 1 (range: 1-4) and 21 (43.7%) of 48 patients received thymectomy. By WHO classification, Type A (n = 1), Type B1 (n = 2), Type B2 (n = 8), Type B3 (n = 13), Type C (n = 23), and unknown (n = 1). With medial follow-up of 14.5 months (range 0.8-38.2), the median cycle of palbociclib was 10 (range 1-40). The PFS at 6 months was 60% and the median PFS was 11.0 months (95% CI: 4.6-17.4). Six of 48 patients (12.5%) achieved partial response. The median overall survival was 26.4 months (95% CI: 17.4-35.4). The most common adverse events of any grade included neutropenia (62.5%), anemia (37.5%) and thrombocytopenia (29.1%). Conclusions: Palbociblib monotherapy is well tolerable and encouraging efficacy in patients with TETs who failed platinum-based combination chemotherapy. Updated results will be presented. Clinical trial information: NCT03219554.

Correction: Activity and Safety of Palbociclib in Patients with Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib: A Biomarker-driven Phase II Study.

Purpose: CDKN2A loss is frequent in GIST and associated with aggressive outcome. Palbociclib is a CDK4 inhibitor with preclinical anti-tumor efficacy in tumors with P16/CDKN2A loss. Methods: This is a multicenter single-arm phase 2 clinical trial assessing safety and efficacy of Palbociclib in patients (pts) with advanced GIST bearing CDKN2A gene loss. Adults with unresectable locally advanced or metastatic, refractory to previously treated with at least Imatinib and Sunitinib, measurable and documented progressive disease (PD) as per RECIST 1.1, and CDKN2A deletion centrally assessed were eligible. Pts received Palbociclib 125mg orally daily on a 21 days on / 7 days off dosing schedule, until PD or unacceptable toxicity. The primary endpoint was 4-month non-PD rate according to RECIST 1.1. Results: As of May 2017, 71 pts had been included in the study, and 29 pts (40.3%) met the molecular eligibility requirement. Twenty five pts (86.2%) had grade 1-2 adverse events (AE) and 12 pts (41.4%)grade 3-4 AE possibly related to the drug. The planned interim statistical analysis performed after central histological and radiological review showed that 19 (86.4%) out of the first 22 evaluable pts had PD at 4 months. CDKN2A status had no impact either on overall survival or outcome on previous standard lines of treatment. Translational analysis suggested up-regulation of CCNE1 or down-regulation of CDKN1A/P21 or LRRC3B as potential mechanisms of resistance. Conclusion: Palbociclib has no significant clinical activity as a single agent in P16/CDKN2A deleted GIST refractory to Imatinib and Sunitinib.

Phase II trial of palbociclib in recurrent RB-positive anaplastic oligodendroglioma: A Spanish group for research in neurooncology (GEINO) trial.

2038 Background: The pRB-dependent cell cycle checkpoint is altered in the vast majority of anaplastic oligodendrogliomas (AO), either by homozygous deletion or by hypermethylation of CDKN2A and/or CDKN2B, or by amplification and/or overexpression of CDK4. Palbociclib is an oral inhibitor of CDK4 and 6 that has already been shown to be highly active in breast cancer. Methods: We conducted a multicenter, open-label, phase II trial evaluating efficacy and safety of Palbociclib in patients with AO that progressed to radiotherapy and more than one chemotherapy regimen containing Temozolomide and/or Lomustine. Inclusion criteria included: histologically and molecularly confirmed grade III oligodendroglioma (WHO 2016 classification, IDH1/2 mutation and 1p/19 codeletion were mandatory), recurrence after radiotherapy and 1 or 2 chemotherapy regimens and conserved RB protein expression by immunohistochemistry (IHC). Patients were treated with Palbociclib 125 mg/daily 3 weeks on/1off. The primary objective of the study was progression-free survival at 6 months (6M-PFS). Results: Between October 2015 and September 2018, 34 patients were enrolled across ten hospitals. The study was stopped early secondary to lack of efficacy, with 74% of evaluable patients progressing within 6 months. Number of patients alive and free from progression at 6 months after the enrollment was 9 (26%) out of the first 34 patients, below the minimum number required (18 out of 40) to consider Palbociclib as an active drug in this population. With a median follow-up of 11.2 months, the median PFS was 3 months (95% CI: 2.5-3.5 months). Median overall survival (OS) was 23.1 months (95% CI: 17.2-25 months). There were no partial or complete responses and only 11 patients (32%) achieved stable disease as best response. Palbociclib was well tolerated with neutropenia (Grade 3 or 4: 40%) and thrombocytopenia (Grade 3 or 4: 15%) as the most common adverse effects (AEs). Both AEs had no significant impact since there were no episodes of febrile neutropenia or bleeding. Conclusions: Despite the good tolerance and drug exposure, Palbociclib monotherapy did not show favorable activity in recurrent AO. Clinical trial information: NCT02530320.

1481PD - Efficacy and safety of palbociclib in patients with advanced gastrointestinal stromal tumors refractory to imatinib and sunitinib

1481PD - Efficacy and safety of palbociclib in patients with advanced gastrointestinal stromal tumors refractory to imatinib and sunitinib

P09.59 Phase 2 trial of palbociclib in adult patients with recurrent Rb positive glioblastoma

AbstractAlterations in the CDK4/6 – RB signaling pathway are common causes of dysregulation of the cell cycle in many cancers, including glioblastoma. Palbociclib is an oral, highly selective, reversible inhibitor of CDK4/6, which leads to phosphorylation of RB and cell-cycle arrest. In a two-arm study, we evaluated the efficacy and safety of palbociclib in patients with recurrent glioblastoma. Notable eligibility criteria included confirmation of RB proficiency by IHC; ≤ 3 relapses; KPS ≥ 60; secondary glioblastomas were included; there were no limitation on prior treatments including bevacizumab. Patients were administered oral palbociclib 125 mg daily for 21 consecutive days followed by a 7 day break. Arm 1 planned for 15 patients to receive palbociclib for 7 days prior to indicated surgical resection for progression, followed by palbociclib. Arm 2 planned for 15 patients to receive palbociclib without additional resection. The primary objective was PFS-6, which was hypothesized to be 30% in this heavily pretreated population, and null hypothesis of 10%. Secondary objectives of toxicity, OS, and ORR. Exploratory results included biomarker assessment and pharmacodynamic effects for the surgical Arm 1 patients. A total of 22 patients were enrolled; 6 on Arm 1 and 16 on Arm 2. Median age for all arms was 47.5 years old (range 23 – 78 years old); 54% (12 patients) were male; and the median KPS was 90 (range 60 – 100). Palbociclib was started at first recurrence in 50% (11 patients – 3 in Arm 1 and 8 in Arm 2) of patients; at second recurrence in 36% (8 patients – 3 in Arm 1 and 5 in Arm 2); and at third recurrence in 14% (3 patients, all in Arm 2). Bevacizumab had previously been used in 77% (17 patients – 4 in Arm 1 and 13 in Arm 2) of cases. The trial was stopped early secondary to futility, with 95% (18 of 19) evaluable patients progressing within 6 months of intiating treatment. Four samples were available for immunohistochemistry for Rb and Ki67. There were no consistent changes in Rb expression or cell proliferation when compared to samples from diagnosis. Median progression free survival for all patients was 5.14 weeks (range 5 days – 142 weeks) and median overall survival was 15.4 weeks (range 2 – 274 weeks). Two patients (10%) had treatment related AEs that were grade ≥3. In this trial, palbociclib did not appear to have been an effective treatment for recurrent glioblastoma. However, this was a heavily pretreated patient population and targeting the CDK4/6 pathway may deserve further exploration.