Long-term patient-reported outcomes from monarchE: Abemaciclib plus endocrine therapy as adjuvant therapy for HR+, HER2-, node-positive, high-risk, early breast cancer.

Background: In monarchE, abemaciclib demonstrated a sustained benefit in invasive disease-free survival and a tolerable safety profile at 42-months median follow-up. With no expected disease-related symptoms, therapies in the adjuvant setting should preserve quality of life (QoL). With all patients off abemaciclib, we report updated patient-reported outcomes (PROs) for the full 2-year treatment period and follow-up.

Adjuvant Abemaciclib Plus Endocrine Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative, High-Risk Early Breast Cancer: Results From a Preplanned monarchE Overall Survival Interim Analysis, Including 5-Year Efficacy Outcomes.

JCO Two years of adjuvant abemaciclib combined with endocrine therapy (ET) resulted in a significant improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) that persisted beyond the 2-year treatment period in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer (EBC). Here, we report 5-year efficacy results from a prespecified overall survival (OS) interim analysis. In the intent-to-treat population, with a median follow-up of 54 months, the benefit of abemaciclib was sustained with hazard ratios of 0.

Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial.

Background: Adjuvant abemaciclib plus endocrine therapy previously showed a significant improvement in invasive disease-free survival and distant relapse-free survival in hormone receptor-positive, human epidermal growth factor receptor 2 (HER2; also known as ERBB2)-negative, node-positive, high-risk, early breast cancer. Here, we report updated results from an interim analysis to assess overall survival as well as invasive disease-free survival and distant relapse-free survival with additional follow-up.

Methods: In monarchE, an open-label, randomised, phase 3 trial, adult patients (aged ≥18 years) who had hormone receptor-positive, HER2-negative, node-positive, early breast cancer at a high risk of recurrence with an Eastern Cooperative Oncology Group performance status of 0 or 1 were recruited from 603 sites including hospitals and academic and community centres in 38 countries.

Safety and efficacy of abemaciclib plus endocrine therapy in older patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: an age-specific subgroup analysis of MONARCH 2 and 3 trials.

Purpose: Abemaciclib in combination with endocrine therapy (ET) has demonstrated significant efficacy benefits in HR+ , HER2- advanced breast cancer patients in the Phase 3 studies MONARCH 2 (fulvestrant as ET) and MONARCH 3 (letrozole or anastrozole as ET). Here, we report age-specific safety and efficacy outcomes.

Methods: Exploratory analyses of MONARCH 2 and 3 were performed for 3 age groups (<65, 65-74, and ≥75 years).

Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE).

Purpose: Many patients with HR+, HER2- early breast cancer (EBC) will not experience recurrence or have distant recurrence with currently available standard therapies. However, up to 30% of patients with high-risk clinical and/or pathologic features may experience distant recurrence, many in the first few years. Superior treatment options are needed to prevent early recurrence and development of metastases for this group of patients.

Safety outcomes in advanced non-small-cell lung cancer patients treated with first-line platinum-based regimens in the United States.

Background: We analyzed the treatment patterns and safety outcomes of the most common first-line platinum-based regimens initiated on or after non-small cell lung cancer (NSCLC) diagnosis in a real-world setting.

Methods: Based on a United States oncology electronic medical record (EMR) database, patients treated with first-line platinum-based regimens after advanced NSCLC diagnosis from September 2008 to November 2014 were analyzed. Baseline characteristics and selected adverse events during treatment [incidence proportions and incidence rates (IRs)] were described by regimen.

Healthcare resource utilization and associated cost analysis of the PROCLAIM study in patients with stage III non-small-cell lung cancer.

To analyze patient-reported swallowing difficulties, healthcare resource utilization and associated costs during the PROCLAIM study. Patients with stage III non-squamous non-small cell lung cancer received pemetrexed-cisplatin (PemCis) combined with concurrent thoracic radiotherapy followed by consolidation pemetrexed, or concurrent chemoradiotherapy with etoposide-cisplatin (EtoCis) followed by standard consolidation chemotherapy. Patient - reported swallowing function was measured using diaries.

Radiation Therapy Quality Assurance (RTQA) of Concurrent Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer in the PROCLAIM Phase 3 Trial.

Purpose: Chemoradiation therapy trials of different tumors, including lung cancer, have shown a correlation between protocol deviations and adverse outcomes. Radiation therapy quality assurance (RTQA) was mandated for all patients treated in the PROCLAIM trial evaluating 2 different chemoradiation therapy regimens. The RTQA results were evaluated from the PROCLAIM study, and the impact of irradiation deviations on efficacy outcomes was investigated.

The Impact of Staging by Positron-Emission Tomography on Overall Survival and Progression-Free Survival in Patients With Locally Advanced NSCLC.

Introduction: We investigated the potential impact of stage migration because of positron-emission tomography (PET) scan staging on survival in the locally advanced (stage IIIA/B) NSCLC setting.

Methods: In PROCLAIM, 598 patients with stage IIIA/B nonsquamous NSCLC (intent-to-treat population) were randomized to either pemetrexed plus cisplatin and concurrent thoracic radiotherapy for 3 cycles followed by 4 cycles of pemetrexed consolidation or etoposide plus cisplatin and concurrent thoracic radiotherapy for 2 cycles followed by a consolidation platinum-based doublet regimen for up to 2 cycles. Baseline PET scan (PET Yes versus No) was one of the stratification factors.

Evaluation of changes in renal function in PARAMOUNT: a phase III study of maintenance pemetrexed plus best supportive care versus placebo plus best supportive care after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer.

Objectives: To assess the effect of long-term pemetrexed maintenance therapy on patients' renal function.

Methods: In the PARAMOUNT phase III trial (NCT 00789373), pemetrexed was compared with placebo as maintenance treatment in advanced nonsquamous non-small-cell lung cancer patients who completed 4 cycles of pemetrexed plus cisplatin induction therapy. To evaluate changes in renal function during pemetrexed continuation maintenance treatment, we retrospectively analyzed changes in serum creatinine (sCr), treatment-emergent adverse events, dose delays and treatment discontinuations associated with impaired renal function.

Safety Analyses of Pemetrexed-cisplatin and Pemetrexed Maintenance Therapies in Patients With Advanced Non-squamous NSCLC: Retrospective Analyses From 2 Phase III Studies.

Background: In a phase III study, maintenance pemetrexed showed superior survival over placebo (PARAMOUNT) for patients with advanced non-squamous non-small cell lung cancer (NSCLC) who completed 4 cycles of pemetrexed plus cisplatin (PC) induction therapy, with low incidence of treatment-emergent adverse events (TEAEs) generally associated with pemetrexed. Prior analyses did not account for toxicities carried over from induction; thus, the current analysis was developed to understand toxicities that may be attributed to pemetrexed maintenance versus PC induction, and how treatment duration affects toxicity.

Patients And Methods: Selected clinically relevant TEAEs were explored in 2 analyses: assessing induction versus maintenance treatment in PARAMOUNT, and comparing PC from PARAMOUNT with toxicity data from a previous phase III study that established the role of PC in front-line therapy of non-squamous NSCLC (JMDB trial).

Meta-analysis of pemetrexed plus carboplatin doublet safety profile in first-line non-squamous non-small cell lung cancer studies.

Objectives: This meta-analysis compared safety profiles (selected drug-related treatment-emergent adverse events [TEAEs]) of first-line pemetrexed plus carboplatin (PCb) area under the concentration-time curve 5 mg/min•mL (PCb5) or 6 mg/min•mL (PCb6), two widely used regimens in clinical practice for advanced non-squamous non-small cell lung cancer.

Methods: All patients received pemetrexed 500 mg/m every 21 days with either of two carboplatin doses for up to 4-6 cycles. Safety profiles of PCb doses were compared using three statistical analysis methods: frequency table analysis (FTA), generalized linear mixed effect model (GLMM), and the propensity score method.

Safety profiles of non-small cell lung cancer patients treated with pemetrexed plus carboplatin: a real-world retrospective, observational, cohort study.

Objective: Pemetrexed plus carboplatin (PCb) is a frequently used first-line treatment in advanced non-small cell lung cancer (NSCLC). This study examined the characteristics and safety profile of a NSCLC population treated with PCb area under the concentration-time curve 5 (PCb5) or 6 mg/mL•min (PCb6) under real-world conditions.

Research Design And Methods: A retrospective, observational, cohort study was conducted, utilizing data from the IMS Oncology US clinic-based, longitudinal, patient-level electronic medical records (EMR), including patients with NSCLC on PCb5 or PCb6 regimens initiated concomitantly on or after the diagnosis of lung cancer during 2004-2014.

Meta-analysis examining impact of age on overall survival with pemetrexed for the treatment of advanced non-squamous non-small cell lung cancer.

Objective: In clinical practice, elderly patients are often undertreated relative to younger patients. This meta-analysis was designed to determine whether older patients with non-squamous non-small cell lung cancer (NSCLC) could derive an overall survival (OS) benefit from pemetrexed treatment comparable to that experienced by younger patients in the first-line, second-line, or maintenance settings.

Methods: Data from 2671 patients with non-squamous NSCLC participating in four pemetrexed phase III studies were included in a meta-analysis using a random-effects model.

PROCLAIM: Randomized Phase III Trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus Thoracic Radiation Therapy Followed by Consolidation Chemotherapy in Locally Advanced Nonsquamous Non-Small-Cell Lung Cancer.

Purpose: The phase III PROCLAIM study evaluated overall survival (OS) of concurrent pemetrexed-cisplatin and thoracic radiation therapy (TRT) followed by consolidation pemetrexed, versus etoposide-cisplatin and TRT followed by nonpemetrexed doublet consolidation therapy.

Patients And Methods: Patients with stage IIIA/B unresectable nonsquamous non-small-cell lung cancer randomly received (1:1) pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2) intravenously every 3 weeks for three cycles plus concurrent TRT (60 to 66 Gy) followed by pemetrexed consolidation every 3 weeks for four cycles (arm A), or standard therapy with etoposide 50 mg/m(2) and cisplatin 50 mg/m(2) intravenously, every 4 weeks for two cycles plus concurrent TRT (60 to 66 Gy) followed by two cycles of consolidation platinum-based doublet chemotherapy (arm B). The primary objective was OS.

Long-term and low-grade safety results of a phase III study (PARAMOUNT): maintenance pemetrexed plus best supportive care versus placebo plus best supportive care immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer.

Introduction: In the PARAMOUNT ("A Phase 3, Double-Blind, Placebo-Controlled Study of Maintenance Pemetrexed plus Best Supportive Care vs. Best Supportive Care Immediately Following Induction Treatment with Pemetrexed Plus Cisplatin for Advanced Non-Squamous Non-Small-Cell Lung Cancer") trial, patients with advanced nonsquamous non-small-cell lung cancer (NS-NSCLC) benefited from pemetrexed maintenance therapy after induction therapy with pemetrexed and cisplatin by extending survival, delaying disease progression, and maintaining quality of life (QoL). However, low-grade 1 or 2 toxicities during long-term maintenance treatment may become burdensome and impact QoL.

Final efficacy and safety results of pemetrexed continuation maintenance therapy in the elderly from the PARAMOUNT phase III study.

Introduction: The PARAMOUNT Phase III trial showed that maintenance pemetrexed after pemetrexed plus cisplatin induction was well tolerated and effective for patients with advanced nonsquamous non-small-cell lung cancer. Approximately 17% of patients receiving maintenance therapy in this study were 70 years of age or older. Here we report efficacy and safety results from the PARAMOUNT study for elderly (≥70 years) and non-elderly (<70 years) patients.

Classical markers like ER and ki-67, but also survivin and pERK, could be involved in the pathological response to gemcitabine, adriamycin and paclitaxel (GAT) in locally advanced breast cancer patients: results from the GEICAM/2002-01 phase II study.

Introduction: The identification and validation of biomarkers of chemotherapy sensitivity is critical in order to individualise therapy in breast cancer. We evaluated pathological complete response (pCR) to GAT, and its correlation with tumour biomarkers before and after neoadjuvant chemotherapy.

Materials And Methods: Stage III (and stage II with T≥5 cm) breast cancer patients were included.

A phase II randomized study of cisplatin-pemetrexed plus either enzastaurin or placebo in chemonaive patients with advanced non-small cell lung cancer.

Objectives: Enzastaurin is a serine/threonine kinase inhibitor that targets protein kinase C and AKT pathways. Enzastaurin and pemetrexed demonstrated synergy in preclinical studies. This trial was designed to evaluate the safety and efficacy of first-line enzastaurin plus cisplatin-pemetrexed in advanced non-small cell lung cancer (NSCLC).

Cot/Tpl2 and PKCzeta cooperate in the regulation of the transcriptional activity of NFATc2 through the phosphorylation of its amino-terminal domain.

Nuclear factor of activated T cells (NFAT) plays a prominent role in gene transcription during the immune response. Growing evidence demonstrates the implication of inducible phosphorylation of the transactivation domain (TAD) of NFAT in transcriptional activation of genes. We have analyzed the regulation of NFATc2 activation by Cot/Tpl2 and protein kinase C zeta (PKCzeta) in T cells.

Differential regulation of p65 and c-Rel NF-kappaB transactivating activity by Cot, protein kinase C zeta and NIK protein kinases in CD3/CD28 activated T cells.

It has been shown that phosphorylation of p65/RelA and c-Rel plays a role in the regulation of transcriptional activity of NF-kappaB independent on IkappaB degradation. In this study, we show that anti CD3/CD28 activation induces the transactivation activity of both p65/RelA and c-Rel in T cells using Gal4 dependent assays. Moreover, protein kinase C (PKC)zeta, Cot kinase and NF-kappaB-inducing kinase (NIK) seem to be involved in those processes in a different manner.

Protein kinase Czeta phosphorylates nuclear factor of activated T cells and regulates its transactivating activity.

Although several isoforms of protein kinase C (PKC) have been implicated in T lymphocyte activation events, little is known about their mode of action. To address the role of PKCzeta in T cell activation, we have generated Jurkat T cell transfectants expressing either the wild type (J-PKCzeta) or "kinase-dead" mutant (J-PKCzeta(mut)) versions of this protein. Expression of PKCzeta but not PKCzeta(mut) increased transcriptional activation mediated by the NF-kappaB or nuclear factor of activated T cells (NFAT).