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Determinants of response to CDK4/6 inhibitors in the real-world setting.

ABSTRACT: Despite widespread use and a known mechanism of action for CDK4/6 inhibitors in combination with endocrine therapy, features of disease evolution and determinants of therapeutic response in the real-world setting remain unclear. Here, a cohort of patients treated with standard-of-care combination regimens was utilized to explore features of disease and determinants of progression-free survival (PFS) and overall survival (OS). In this cohort of 280 patients, >90% of patients were treated with palbociclib in combination with either an aromatase inhibitor (AI) or fulvestrant (FUL). Most of these patients had modified Scarff-Bloom-Richardson (SBR) scores, and ER, HER2, and PR immunohistochemistry. Both the SBR score and lack of PR expression were associated with shorter PFS in patients treated with AI combinations and remained significant in multivariate analyses (HR = 3.86, p = 0.008). Gene expression analyses indicated substantial changes in cell cycle and estrogen receptor signaling during the course of treatment. Furthermore, gene expression-based subtyping indicated that predominant subtypes changed with treatment and progression. The luminal B, HER2, and basal subtypes exhibited shorter PFS in CDK4/6 inhibitor combinations when assessed in the pretreatment biopsies; however, they were not associated with OS. Using unbiased approaches, cell cycle-associated gene sets were strongly associated with shorter PFS in pretreatment biopsies irrespective of endocrine therapy. Estrogen receptor signaling gene sets were associated with longer PFS particularly in the AI-treated cohort. Together, these data suggest that there are distinct pathological and biological features of HR+/HER2- breast cancer associated with response to CDK4/6 inhibitors. Clinical trial registration number: NCT04526587.

SUBMITTER: Witkiewicz AK

PROVIDER: S-EPMC10499925 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Determinants of response to CDK4/6 inhibitors in the real-world setting.

Witkiewicz Agnieszka K AK Schultz Emily E Wang Jianxin J Hamilton Deanna D Levine Ellis E O'Connor Tracey T Knudsen Erik S ES

NPJ precision oncology 20230913 1

Despite widespread use and a known mechanism of action for CDK4/6 inhibitors in combination with endocrine therapy, features of disease evolution and determinants of therapeutic response in the real-world setting remain unclear. Here, a cohort of patients treated with standard-of-care combination regimens was utilized to explore features of disease and determinants of progression-free survival (PFS) and overall survival (OS). In this cohort of 280 patients, >90% of patients were treated with pal ...[more]

PMID: 37704753

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Project description:BackgroundRandomized controlled trials have shown inconsistent overall survival (OS) benefit among the three cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) as first-line (1L) treatment of patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC). Several real-world studies compared CDK4/6i effectiveness, with inconsistent findings. This study compared overall survival (OS) of patients with HR+/HER2- mBC receiving 1L palbociclib, ribociclib, or abemaciclib, in combination with an aromatase inhibitor (AI), in US clinical practice.Patients and methodsThis retrospective study used real-world data from the Flatiron Health electronic health record-derived deidentified longitudinal database. Patients with HR+/HER2- mBC aged ≥18 years at mBC diagnosis started 1L CDK4/6i therapy (index treatment) between February 2015 and November 2023, with a potential ≥6-month follow-up. OS was defined as months from start of index treatment to death. Stabilized inverse probability of treatment weighting (sIPTW; primary analysis) was used to balance baseline patient characteristics. Multivariable Cox proportional hazards model was carried out as a sensitivity analysis.ResultsOf 9146 eligible patients, 6831, 1279, and 1036 received palbociclib plus AI, ribociclib plus AI, or abemaciclib plus AI, respectively. After sIPTW, baseline characteristics were balanced between treatment groups. After sIPTW, no significant OS differences were found between treatment groups [ribociclib versus palbociclib: adjusted hazard ratio (aHR) 0.98, 95% confidence interval (CI) 0.87-1.10, P = 0.7531; abemaciclib versus palbociclib: aHR 0.95, 95% CI 0.84-1.08, P = 0.4292; abemaciclib versus ribociclib: aHR 0.97, 95% CI 0.82-1.14, P = 0.6956]. Sensitivity analysis including a subanalysis of patients who started index treatment in 2017 or later also showed no significant OS differences between treatment groups.ConclusionsThis large real-world study suggested that there were no significant OS differences between 1L ribociclib, abemaciclib, and palbociclib in combination with an AI for patients with HR+/HER2- mBC. These findings together with other factors such as safety and quality of life are helpful in the selection of CDK4/6i combination therapy for patients with HR+/HER2- mBC.

Project description:PurposeCDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy are considered standard-of-care for first-line therapy of patients with hormone receptor positive, HER2 negative, advanced breast cancer (HR+/HER2- ABC). Superiority of combination therapy over endocrine monotherapy has been demonstrated in a multitude of randomized controlled trials (RCTs) in phase III and IV. However, RCTs reflect clinical reality only to a limited extent, as narrow inclusion criteria lead to a selected patient collective. Here, we present real-world data (RWD) on CDK4/6i treatment in patients with HR+/HER2- ABC at four certified German university breast cancer centers.MethodsPatients diagnosed with HR+/HER2- ABC who were treated in clinical routine with CDK4/6i between November 2016 and December 2020 at four certified German university breast cancer centers (Saarland University Medical Center, University Medical Center Charité Berlin, University Medical Center Bonn, and University Medical Center Hospital Schleswig-Holstein, Campus Kiel) were identified and enrolled in this retrospective study. Clinicopathological characteristics and clinical outcomes were recorded with particular emphasis on CDK4/6i therapy course [progression-free survival (PFS) following treatment initiation, toxicity, dose reduction, therapy discontinuation, prior and subsequent therapy line].ResultsData from n = 448 patients were evaluated. The mean patient age was 63 (±12) years. Of these patients, n = 165 (36.8%) were primarily metastasized, and n = 283 (63.2%) had secondary metastatic disease. N = 319 patients (71.3%) received palbociclib, n = 114 patients (25.4%) received ribociclib, and n = 15 patients (3.3%) received abemaciclib, respectively. Dose reduction was performed in n = 132 cases (29.5%). N = 57 patients (12.7%) discontinued the treatment with CDK4/6i due to side effects. N = 196 patients (43.8%) experienced disease progression under CDK4/6i treatment. The median PFS was 17 months. Presence of hepatic metastases and prior therapy lines were associated with shorter PFS, whereas estrogen positivity and dose reduction due to toxicity were positively associated with PFS. Presence of bone and lung metastases, progesterone positivity, Ki67 index, grading, BRCA1/2 and PIK3CA mutation status, adjuvant endocrine resistance, and age did not significantly impact on PFS.ConclusionOur RWD analysis on CDK4/6i treatment in Germany supports data from RCTs regarding both treatment efficacy and safety of CDK4/6i for treatment of patients with HR+/HER2- ABC. In comparison to data from the pivotal RCTs, median PFS was lower but within the expected range for RWD, which could result from inclusion of patients with more advanced diseases (i.e., higher therapy lines) to our dataset.

Project description:IntroductionQTc prolongation carries the risk of ventricular tachyarrhythmia (Torsades de Pointes) and sudden cardiac death. Psychotropic drugs can affect ventricular repolarization and thus prolong the QTc interval. The present study sought to investigate the risk factors (pharmacological and non-pharmacological) of severe QTc prolongation in gerontopsychiatric patients.MethodsElectrocardiograms of patients on a gerontopsychiatric ward were screened for QTc prolongation. Medication lists were examined utilizing the AzCERT classification. Potential drug interactions were identified with the electronic drug interaction program mediQ.ResultsThe overall prevalence of QTc prolongation was 13.6%, with 1.9% displaying severe QTc prolongation (≥ 500 ms). No statistically significant differences between patients with moderate and severe QTc prolongation were identified; however, patients with severe QTc prolongation tended to take more drugs (p = 0.063). 92.7% of patients with QTc prolongation took at least one AzCERT-listed drug, most frequently risperidone and pantoprazole. Risperidone and pantoprazole, along with pipamperone, were also most frequently involved in potential drug interactions. All patients displayed additional risk factors for QTc prolongation, particularly cardiac diseases.ConclusionIn addition to the use of potentially QTc-prolonging drugs, other risk factors, especially cardiac diseases, appear to be relevant for the development of QTc prolongation in gerontopsychiatric patients. Pantoprazole was frequently involved in potential drug interactions and should generally not be used for more than 8 weeks in geriatric populations. As clinical consequences of QTc prolongation were rare, potentially QTc-prolonging drugs should not be used overcautiously; their therapeutic benefit should be considered as well. It is paramount to perform diligent benefit-risk analyses prior to the initiation of potentially QTc-prolonging drugs and to closely monitor their clinical (side) effects.

Project description:Introduction: Hyperprogressive disease (HPD) is a state of accelerated tumor growth from cancer immunotherapy, associated with poor outcome. The reported incidence is 6% to 29% among studies using varying definitions of HPD, with no predictive biomarkers. Tumor infiltrating lymphocytes (TILs) are prognostic and predictive for immunotherapy benefit in various tumor types, but have only been tested for correlation with HPD in one study. Objectives: The objective of the study was to determine the prevalence of HPD in solid tumor patients treated with immune checkpoint inhibitor therapy in a real-world setting, and to assess clinicopathological features as potential biomarkers for HPD. Methods: We conducted a retrospective analysis of solid tumor patients treated with immune checkpoint inhibitors at a single institution. Imaging pre-immunotherapy and postimmunotherapy were assessed for HPD, and correlated against clinicopathological factors, including TILs and programmed death-ligand 1 (PD-L1) status through archival tumor assessment. HPD was defined per Matos et al as response evaluation criteria in solid tumors (RECIST) progressive disease, minimum increase in measurable lesions of 10 mm, plus increase of ≥40% in sum of target lesions compared with baseline and/or increase of ≥20% in sum of target lesions compared with baseline plus new lesions in at least 2 different organs. Results: HPD occurred in 11 of 87 patients (13%), and associated with inferior overall survival (median 5.5 months vs 18.3 months, P = .002). However, on multivariate analysis, only liver metastases (hazard ratio [HR] 4.66, 95% confidence interval [CI] 2.27-9.56, P < .001) and PD-L1 status (HR 0.53, 95% CI 0.30-0.95, P = .03) were significantly associated with survival. Presence of liver metastases correlated with occurence of HPD (P = .01). Age, sex, and monotherapy versus combination immunotherapy were not predictive for HPD. PD-L1 status and TILs were not associated with HPD. Conclusions: We found 13% HPD among solid tumor patients treated with immunotherapy, consistent with the range reported in prior series. Assessment for HPD is feasible outside of a clinical trials setting, using modified criteria that require comparison of 2 imaging studies. Liver metastases were associated with risk of HPD, while TILs and PD-L1 status were not predictive for HPD.

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Determinants of response to CDK4/6 inhibitors in the real-world setting.

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Determinants of response to CDK4/6 inhibitors in the real-world setting.

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