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Journal of Clinical Oncology : Official... Feb 2021IMpower133 (ClinicalTrials.gov identifier: NCT02763579), a randomized, double-blind, phase I/III study, demonstrated that adding atezolizumab (anti-programmed... (Randomized Controlled Trial)
Randomized Controlled Trial
Updated Overall Survival and PD-L1 Subgroup Analysis of Patients With Extensive-Stage Small-Cell Lung Cancer Treated With Atezolizumab, Carboplatin, and Etoposide (IMpower133).
PURPOSE
IMpower133 (ClinicalTrials.gov identifier: NCT02763579), a randomized, double-blind, phase I/III study, demonstrated that adding atezolizumab (anti-programmed death-ligand 1 [PD-L1]) to carboplatin plus etoposide (CP/ET) for first-line (1L) treatment of extensive-stage small-cell lung cancer (ES-SCLC) resulted in significant improvement in overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET. Updated OS, disease progression patterns, safety, and exploratory biomarkers (PD-L1, blood-based tumor mutational burden [bTMB]) are reported.
PATIENTS AND METHODS
Patients with untreated ES-SCLC were randomly assigned 1:1 to receive four 21-day cycles of CP (area under the curve 5 mg per mL/min intravenously [IV], day 1) plus ET (100 mg/m IV, days 1-3) with atezolizumab (1,200 mg IV, day 1) or placebo, and then maintenance atezolizumab or placebo until unacceptable toxicity, disease progression, or loss of clinical benefit. Tumor specimens were collected; PD-L1 testing was not required for enrollment. The two primary end points, investigator-assessed PFS and OS, were statistically significant at the interim analysis. Updated OS and PFS and exploratory biomarker analyses were conducted.
RESULTS
Patients received atezolizumab plus CP/ET (n = 201) or placebo plus CP/ET (n = 202). At the updated analysis, median follow-up for OS was 22.9 months; 302 deaths had occurred. Median OS was 12.3 and 10.3 months with atezolizumab plus CP/ET and placebo plus CP/ET, respectively (hazard ratio, 0.76; 95% CI, 0.60 to 0.95; descriptive = .0154). At 18 months, 34.0% and 21.0% of patients were alive in atezolizumab plus CP/ET and placebo plus CP/ET arms, respectively. Patients derived benefit from the addition of atezolizumab, regardless of PD-L1 immunohistochemistry or bTMB status.
CONCLUSION
Adding atezolizumab to CP/ET as 1L treatment for ES-SCLC continued to demonstrate improved OS and a tolerable safety profile at the updated analysis, confirming the regimen as a new standard of care. Exploratory analyses demonstrated treatment benefit independent of biomarker status.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Carboplatin; Disease Progression; Double-Blind Method; Etoposide; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Small Cell Lung Carcinoma; Survival Analysis
PubMed: 33439693
DOI: 10.1200/JCO.20.01055 -
CA: a Cancer Journal For Clinicians 2023Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens.... (Review)
Review
Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens. Although the majority of SCLCs exhibit neuroendocrine features, an important subset of tumors lacks these properties. Genomic profiling of SCLC reveals genetic instability, almost universal inactivation of the tumor suppressor genes TP53 and RB1, and a high mutation burden. Because of early metastasis, only a small fraction of patients are amenable to curative-intent lung resection, and these individuals require adjuvant platinum-etoposide chemotherapy. Therefore, the vast majority of patients are currently being treated with chemoradiation with or without immunotherapy. In patients with disease confined to the chest, standard therapy includes thoracic radiotherapy and concurrent platinum-etoposide chemotherapy. Patients with metastatic (extensive-stage) disease are treated with a combination of platinum-etoposide chemotherapy plus immunotherapy with an anti-programmed death-ligand 1 monoclonal antibody. Although SCLC is initially very responsive to platinum-based chemotherapy, these responses are transient because of the development of drug resistance. In recent years, the authors have witnessed an accelerating pace of biologic insights into the disease, leading to the redefinition of the SCLC classification scheme. This emerging knowledge of SCLC molecular subtypes has the potential to define unique therapeutic vulnerabilities. Synthesizing these new discoveries with the current knowledge of SCLC biology and clinical management may lead to unprecedented advances in SCLC patient care. Here, the authors present an overview of multimodal clinical approaches in SCLC, with a special focus on illuminating how recent advancements in SCLC research could accelerate clinical development.
Topics: Humans; Small Cell Lung Carcinoma; Lung Neoplasms; Etoposide; Combined Modality Therapy; Antineoplastic Combined Chemotherapy Protocols; Biological Products
PubMed: 37329269
DOI: 10.3322/caac.21785 -
Journal of Clinical Oncology : Official... Jul 2020Pembrolizumab monotherapy has shown antitumor activity in patients with small-cell lung cancer (SCLC). The randomized, double-blind, phase III KEYNOTE-604 study compared... (Randomized Controlled Trial)
Randomized Controlled Trial
Pembrolizumab or Placebo Plus Etoposide and Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer: Randomized, Double-Blind, Phase III KEYNOTE-604 Study.
PURPOSE
Pembrolizumab monotherapy has shown antitumor activity in patients with small-cell lung cancer (SCLC). The randomized, double-blind, phase III KEYNOTE-604 study compared pembrolizumab plus etoposide and platinum (EP) with placebo plus EP for patients with previously untreated extensive-stage (ES) SCLC.
METHODS
Eligible patients were randomly assigned 1:1 to pembrolizumab 200 mg once every 3 weeks or saline placebo for up to 35 cycles plus 4 cycles of EP. Primary end points were progression-free survival (PFS; RECIST version 1.1, blinded central review) and overall survival (OS) in the intention-to-treat population. Objective response rate (ORR) and duration of response were secondary end points. Prespecified efficacy boundaries were one-sided = .0048 for PFS and .0128 for OS.
RESULTS
Of the 453 participants, 228 were randomly assigned to pembrolizumab plus EP and 225 to placebo plus EP. Pembrolizumab plus EP significantly improved PFS (hazard ratio [HR], 0.75; 95% CI, 0.61 to 0.91; = .0023). Twelve-month PFS estimates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP. Although pembrolizumab plus EP prolonged OS, the significance threshold was not met (HR, 0.80; 95% CI, 0.64 to 0.98; = .0164). Twenty-four-month OS estimates were 22.5% and 11.2%, respectively. ORR was 70.6% in the pembrolizumab plus EP group and 61.8% in the placebo plus EP group; the estimated proportion of responders remaining in response at 12 months was 19.3% and 3.3%, respectively. In the pembrolizumab plus EP and placebo plus EP groups, respectively, any-cause adverse events were grade 3-4 in 76.7% and 74.9%, grade 5 in 6.3% and 5.4%, and led to discontinuation of any drug in 14.8% and 6.3%.
CONCLUSION
Pembrolizumab plus EP significantly improved PFS compared with placebo plus EP as first-line therapy for patients with ES-SCLC. No unexpected toxicities were seen with pembrolizumab plus EP. These data support the benefit of pembrolizumab in ES-SCLC.
Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Etoposide; Female; Humans; Lung Neoplasms; Male; Neoplasm Staging; Platinum; Small Cell Lung Carcinoma; Survival Analysis
PubMed: 32468956
DOI: 10.1200/JCO.20.00793 -
British Journal of Cancer Jul 2007We compared the efficacy and the safety of a carboplatin plus etoposide regimen (CE) vs split doses of cisplatin plus etoposide (SPE) in elderly or poor-risk patients... (Comparative Study)
Comparative Study Randomized Controlled Trial
Randomised phase III trial of carboplatin plus etoposide vs split doses of cisplatin plus etoposide in elderly or poor-risk patients with extensive disease small-cell lung cancer: JCOG 9702.
We compared the efficacy and the safety of a carboplatin plus etoposide regimen (CE) vs split doses of cisplatin plus etoposide (SPE) in elderly or poor-risk patients with extensive disease small-cell lung cancer (ED-SCLC). Eligibility criteria included: untreated ED-SCLC; age >/=70 and performance status 0-2, or age <70 and PS 3. The CE arm received carboplatin area under the curve of five intravenously (IV) on day 1 and etoposide 80 mg m(-2) IV on days 1-3. The SPE arm received cisplatin 25 mg m(-2) IV on days 1-3 and etoposide 80 mg m(-2) IV on days 1-3. Both regimens were given with granulocyte colony-stimulating factor support in a 21-28 day cycle for four courses. A total of 220 patients were randomised. Median age was 74 years and 74% had a PS of 0 or 1. Major grade 3-4 toxicities were (%CE/%SPE): leucopenia 54/51, neutropenia 95/90, thrombocytopenia 56/16, infection 7/6. There was no significant difference (CE/SPE) in the response rate (73/73%) and overall survival (median 10.6/9.9 mo; P=0.54). Palliation scores were very similar between the arms. Although the SPE regimen is still considered to be the standard treatment in elderly or poor-risk patients with ED-SCLC, the CE regimen can be an alternative for this population considering the risk-benefit balance.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Small Cell; Cisplatin; Etoposide; Female; Humans; Lung Neoplasms; Male; Middle Aged; Treatment Outcome
PubMed: 17579629
DOI: 10.1038/sj.bjc.6603810 -
Targeted Oncology Nov 2021Durvalumab (IMFINZI), a fully human monoclonal antibody against programmed cell death-ligand 1 (PD-L1), is approved for use in combination with etoposide and either... (Review)
Review
Durvalumab (IMFINZI), a fully human monoclonal antibody against programmed cell death-ligand 1 (PD-L1), is approved for use in combination with etoposide and either carboplatin or cisplatin for the first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC). In the pivotal phase III CASPIAN trial in previously untreated adults with ES-SCLC, the addition of durvalumab to chemotherapy for up to 4 cycles followed by maintenance durvalumab was associated with a significantly longer overall survival and a favourable hazard ratio for progression-free survival compared with chemotherapy alone for up to 6 cycles. A higher proportion of patients in the durvalumab plus chemotherapy group had an objective response compared with the chemotherapy alone group. The efficacy of durvalumab was also sustained with longer follow-up. Durvalumab in combination with etoposide and either carboplatin or cisplatin had a manageable tolerability profile in patients with ES-SCLC. Given the available evidence, durvalumab in combination with etoposide and either carboplatin or cisplatin represents a valuable treatment option for the first-line treatment of patients with ES-SCLC, and is an accepted standard of care option in this setting.
Topics: Adult; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Etoposide; Humans; Lung Neoplasms; Small Cell Lung Carcinoma
PubMed: 34731446
DOI: 10.1007/s11523-021-00843-0 -
Blood Jun 2022
Topics: Antineoplastic Combined Chemotherapy Protocols; Etoposide; Hodgkin Disease; Humans; Neoplasm Recurrence, Local; Nivolumab; Salvage Therapy
PubMed: 35737409
DOI: 10.1182/blood.2022016274 -
BMJ Clinical Evidence Jun 2009People with Hodgkin's lymphoma usually present with a lump in the neck or upper chest, but a quarter of people also have fever, sweating, weight loss, fatigue, and itch.... (Review)
Review
INTRODUCTION
People with Hodgkin's lymphoma usually present with a lump in the neck or upper chest, but a quarter of people also have fever, sweating, weight loss, fatigue, and itch. Almost all people with localised disease can be cured, and, even among people with relapsed advanced disease, almost 80% survive event free for 4 years or more.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of: single-regimen chemotherapy treatments; combined chemotherapy and radiotherapy treatments compared with radiotherapy alone; and combined chemotherapy and radiotherapy treatments compared with the same chemotherapy agent alone, for first presentation stage I or II non-bulky disease? What are the effects of: specific combined chemotherapy and radiotherapy treatments versus each other; or different radiotherapy treatment strategies in stage I or II non-bulky disease? What are the effects of: single-regimen chemotherapy treatments; dose-intensified chemotherapy treatments; or combined chemotherapy plus radiotherapy treatments compared with chemotherapy alone, for first presentation stage II (bulky) disease, III, or IV disease? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 40 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: ABVD (with or without radiotherapy); ABVPP plus radiotherapy; ChlVPP-EVA; COPP-ABVD plus radiotherapy; CVPP plus radiotherapy; EBVP plus radiotherapy; escalating-dose BEACOPP; extended-field radiotherapy; increased-dose regimens; involved-field radiotherapy; MOPP (with or without radiotherapy); MOPP-ABV plus radiotherapy; and VBM plus radiotherapy.
Topics: Etoposide; Hodgkin Disease; Humans
PubMed: 21726488
DOI: No ID Found -
Annals of Palliative Medicine Dec 2021Currently, there is no consensus on the standard of care for patients with recurrent glioma. This study investigated the efficacy of combined carboplatin and etoposide...
BACKGROUND
Currently, there is no consensus on the standard of care for patients with recurrent glioma. This study investigated the efficacy of combined carboplatin and etoposide (CE) treatment in recurrent glioma.
METHODS
A retrospective analysis was performed on adult patients with recurrent glioma who received combination chemotherapy consisting of CE from September 2017 to November 2020 at the Beijing Shijitan Hospital, Capital Medical University, Beijing. The response rate (RR), defined as the complete response (CR) + partial response (PR), and the disease control rate (DCR), defined as CR + PR + stable disease (SD), were analyzed by Chi-square or Fisher's exact test according to different clinical characteristics. Time to progression (TTP) was estimated using Kaplan-Meier plots and the log-rank test was used to compare differences.
RESULTS
A total of 55 patients were assessed and 47 patients were eligible to be enrolled in this study. There was 1 case of CR (2.1%), 3 patients with PR (6.4%), and 18 patients with SD (38.3%). The RR was 8.5% and the DCR was 46.8%. When the patients were stratified by World Health Organization (WHO) grade, the DCR was significantly higher in patients with grade 2 and 3 tumors (83.3% and 50%, respectively) compared to patients with grade 4 tumors (29.6%; P=0.039). For patients with grade 4 gliomas, the median TTP and median overall survival (OS) were 2 [95% confidence interval (CI): 0.988 to 3.012] and 7 (95% CI: 3.626 to 10.374) months, respectively. By comparison, the TTP and OS for patients with grade 2-3 gliomas were 4 (95% CI: 1.947 to 6.053) and 13 (95% CI: 0.000 to 26.47) months, respectively. The 6-month progression free survival (PFS) and 12-month OS were 11.1% and 16.3%, respectively, in patients with grade 4 glioma, compared to 37.9% and 48%, respectively, in patients with grade 2-3 gliomas.
CONCLUSIONS
CE regimen may be effective as a salvage treatment for recurrent glioma. Patients with anaplastic or low-grade glioma may benefit more from such therapy compared to patients with grade 4 tumors.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carboplatin; Etoposide; Glioma; Humans; Retrospective Studies; Treatment Outcome
PubMed: 35016422
DOI: 10.21037/apm-21-3382 -
BMB Reports Mar 2022Etoposide is a chemotherapeutic medication used to treat various types of cancer, including breast cancer. It is established that pulsed electromagnetic field (PEMF)...
Etoposide is a chemotherapeutic medication used to treat various types of cancer, including breast cancer. It is established that pulsed electromagnetic field (PEMF) therapy can enhance the effects of anti-cancer chemotherapeutic agents. In this study, we investigated whether PEMFs influence the anti-cancer effects of etoposide in MCF-7 cells and determined the signal pathways affected by PEMFs. We observed that co-treatment with etoposide and PEMFs led to a decrease in viable cells compared with cells solely treated with etoposide. PEMFs elevated the etoposide- induced PARP cleavage and caspase-7/9 activation and enhanced the etoposide-induced down-regulation of survivin and up-regulation of Bax. PEMF also increased the etoposideinduced activation of DNA damage-related molecules. In addition, the reactive oxygen species (ROS) level was slightly elevated during etoposide treatment and significantly increased during co-treatment with etoposide and PEMF. Moreover, treatment with ROS scavenger restored the PEMF-induced decrease in cell viability in etoposide-treated MCF-7 cells. These results combined indicate that PEMFs enhance etoposide-induced cell death by increasing ROS induction-DNA damage-caspase-dependent apoptosis. [BMB Reports 2022; 55(3): 148-153].
Topics: Apoptosis; Electromagnetic Fields; Etoposide; Humans; MCF-7 Cells; Reactive Oxygen Species
PubMed: 34674796
DOI: 10.5483/BMBRep.2022.55.3.119 -
Nature Communications Oct 2022Autophagy is a major contributor to anti-cancer therapy resistance. Many efforts have been made to understand and overcome autophagy-mediated therapy resistance, but...
Autophagy is a major contributor to anti-cancer therapy resistance. Many efforts have been made to understand and overcome autophagy-mediated therapy resistance, but these efforts have been unsuccessful in clinical applications. In this study, we establish an autophagy signature to estimate tumor autophagy status. We then classify approximately 10,000 tumor samples across 33 cancer types from The Cancer Genome Atlas into autophagy score-high and autophagy score-low groups. We characterize the associations between multi-dimensional molecular features and tumor autophagy, and further analyse the effects of autophagy status on drug response. In contrast to the conventional view that the induction of autophagy serves as a key resistance mechanism during cancer therapy, our analysis reveals that autophagy induction may also sensitize cancer cells to anti-cancer drugs. We further experimentally validate this phenomenon for several anti-cancer drugs in vitro and in vivo, and reveal that autophagy inducers potentially sensitizes tumor cells to etoposide through downregulating the expression level of DDIT4. Our study provides a comprehensive landscape of molecular alterations associated with tumor autophagy and highlights an opportunity to leverage multi-omics analysis to utilize multiple drug sensitivity induced by autophagy.
Topics: Humans; Etoposide; Autophagy; Antineoplastic Agents; Neoplasms
PubMed: 36289218
DOI: 10.1038/s41467-022-33946-x