Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial
TL;DR: The results of this phase 2 study suggest further investigation of ipilimumab in ED-SCLC, and highlight the need for further investigation into the anti-CTLA4 monoclonal antibody.
About: This article is published in Annals of Oncology.The article was published on 2013-01-01 and is currently open access. It has received 575 citations till now. The article focuses on the topics: Ipilimumab & Carboplatin.
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TL;DR: The immune system recognizes and is poised to eliminate cancer but is held in check by inhibitory receptors and ligands, so drugs interrupting immune checkpoints, such as anti-CTLA-4, anti-PD-1, and others in early development, can unleash anti-tumor immunity and mediate durable cancer regressions.
3,097 citations
Cites background from "Ipilimumab in combination with pacl..."
...…lung cancer (NSCLC) (n = 204) or extensive disease small-cell lung cancer (ED-SCLC) (n = 130) received standard chemotherapy alone or combined with ipilimumab during initial (‘‘concurrent’’) or later (‘‘phased’’) chemotherapy cycles in a phase III trial (Lynch et al., 2012; Reck et al., 2013)....
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TL;DR: This guide to cancer immunotherapy provides a comprehensive historical and biological perspective regarding the advent and clinical implementation of cancer immunotherapeutics, with an emphasis on the fundamental importance of T lymphocyte regulation.
Abstract: The T lymphocyte, especially its capacity for antigen-directed cytotoxicity, has become a central focus for engaging the immune system in the fight against cancer. Basic science discoveries elucidating the molecular and cellular biology of the T cell have led to new strategies in this fight, including checkpoint blockade, adoptive cellular therapy and cancer vaccinology. This area of immunological research has been highly active for the past 50 years and is now enjoying unprecedented bench-to-bedside clinical success. Here, we provide a comprehensive historical and biological perspective regarding the advent and clinical implementation of cancer immunotherapeutics, with an emphasis on the fundamental importance of T lymphocyte regulation. We highlight clinical trials that demonstrate therapeutic efficacy and toxicities associated with each class of drug. Finally, we summarize emerging therapies and emphasize the yet to be elucidated questions and future promise within the field of cancer immunotherapy.
1,695 citations
Queen's University1, European Organisation for Research and Treatment of Cancer2, Merck & Co.3, NewYork–Presbyterian Hospital4, Columbia University Medical Center5, Mayo Clinic6, Harvard University7, National Institutes of Health8, VU University Medical Center9, Memorial Sloan Kettering Cancer Center10, Ludwig Institute for Cancer Research11, Genentech12, Cornell University13, University Medical Center Groningen14
TL;DR: This guideline describes a standard approach to solid tumour measurements and definitions for objective change in tumour size for use in trials in which an immunotherapy is used and defines the minimum datapoints required from future trials to facilitate the compilation of a data warehouse to later validate iRECIST.
Abstract: Tumours respond differently to immunotherapies compared with chemotherapeutic drugs, raising questions about the assessment of changes in tumour burden-a mainstay of evaluation of cancer therapeutics that provides key information about objective response and disease progression. A consensus guideline-iRECIST-was developed by the RECIST working group for the use of modified Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) in cancer immunotherapy trials, to ensure consistent design and data collection, facilitate the ongoing collection of trial data, and ultimate validation of the guideline. This guideline describes a standard approach to solid tumour measurements and definitions for objective change in tumour size for use in trials in which an immunotherapy is used. Additionally, it defines the minimum datapoints required from future trials and those currently in development to facilitate the compilation of a data warehouse to use to later validate iRECIST. An unprecedented number of trials have been done, initiated, or are planned to test new immune modulators for cancer therapy using a variety of modified response criteria. This guideline will allow consistent conduct, interpretation, and analysis of trials of immunotherapies.
1,416 citations
TL;DR: The tremendous clinical success of checkpoint blockers illustrates the potential of reestablishing latent immunosurveillance for cancer therapy, and their in-depth comprehension will facilitate the design of novel combinatorial regimens with improved clinical efficacy.
1,094 citations
Cites background from "Ipilimumab in combination with pacl..."
...For instance, ipilimumab has been shown to improve the efficacy of carboplatin/paclitaxel-based chemotherapy in NSCLC and small cell lung carcinoma (Lynch et al., 2012; Reck et al., 2013)....
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TL;DR: Some of the main strategies in cancer immunotherapy (cancer vaccines, adoptive cellular immunotherapy, immune checkpoint blockade, and oncolytic viruses) are outlined and the progress in the synergistic design of immune-targeting combination therapies is discussed.
Abstract: These are exciting times for cancer immunotherapy. After many years of disappointing results, the tide has finally changed and immunotherapy has become a clinically validated treatment for many cancers. Immunotherapeutic strategies include cancer vaccines, oncolytic viruses, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies or recombinant proteins that either costimulate cells or block the so-called immune checkpoint pathways. The recent success of several immunotherapeutic regimes, such as monoclonal antibody blocking of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD1), has boosted the development of this treatment modality, with the consequence that new therapeutic targets and schemes which combine various immunological agents are now being described at a breathtaking pace. In this review, we outline some of the main strategies in cancer immunotherapy (cancer vaccines, adoptive cellular immunotherapy, immune checkpoint blockade, and oncolytic viruses) and discuss the progress in the synergistic design of immune-targeting combination therapies.
890 citations
References
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Harvard University1, Vanderbilt University2, Netherlands Cancer Institute3, University of Colorado Denver4, Institut Gustave Roussy5, University of Duisburg-Essen6, University of Mannheim7, University of Utah8, VU University Amsterdam9, Mount Sinai Hospital10, Washington University in St. Louis11, University Hospital Southampton NHS Foundation Trust12, University of Paris13, Technische Universität München14, Loyola University Chicago15, Memorial Sloan Kettering Cancer Center16, University of South Florida17, Medarex18, Bristol-Myers Squibb19
TL;DR: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma.
Abstract: Background An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab — which blocks cytotoxic T-lymphocyte–associated antigen 4 to potentiate an antitumor T-cell response — administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. Methods A total of 676 HLA-A*0201–positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. Results The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P = 0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P = 0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Conclusions Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)
13,081 citations
"Ipilimumab in combination with pacl..." refers background in this paper
...(AEs) occurring in ≥15% of patients included pruritus, rash and diarrhea, and most AEs were managed by the drugspecific treatment guidelines [19, 20]....
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...Two phase 3 studies have demonstrated ipilimumab as the first agent to significantly improve OS in patients with metastatic melanoma [19, 20]....
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TL;DR: Recommendations have been developed for standardized approaches to the recording of baseline data relating to the patient, the tumor, laboratory and radiologic data, the reporting of treatment, grading of acute and subacute toxicity, reporting of response, recurrence and disease‐free interval, and reporting results of therapy.
Abstract: On the initiative of the World Health Organization, two meetings on the Standardization of Reporting Results of Cancer Treatment have been held with representatives and members of several organizations. Recommendations have been developed for standardized approaches to the recording of baseline data relating to the patient, the tumor, laboratory and radiologic data, the reporting of treatment, grading of acute and subacute toxicity, reporting of response, recurrence and disease-free interval, and reporting results of therapy. These recommendations, already endorsed by a number of organizations, are proposed for international acceptance and use to make it possible for investigators to compare validly their results with those of others.
7,799 citations
"Ipilimumab in combination with pacl..." refers methods in this paper
...A blinded Independent Radiologic Review Committee assessed tumor response using both modified World Health Organization (WHO) criteria (mWHO) and newly proposed immune-related (ir) response criteria (irRC) [39, 40]....
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TL;DR: None of four chemotherapy regimens offered a significant advantage over the others in the treatment of advanced non-small-cell lung cancer.
Abstract: Background We conducted a randomized study to determine whether any of three chemotherapy regimens was superior to cisplatin and paclitaxel in patients with advanced non–small-cell lung cancer. Methods A total of 1207 patients with advanced non–small-cell lung cancer were randomly assigned to a reference regimen of cisplatin and paclitaxel or to one of three experimental regimens: cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel. Results The response rate for all 1155 eligible patients was 19 percent, with a median survival of 7.9 months (95 percent confidence interval, 7.3 to 8.5), a 1-year survival rate of 33 percent (95 percent confidence interval, 30 to 36 percent), and a 2-year survival rate of 11 percent (95 percent confidence interval, 8 to 12 percent). The response rate and survival did not differ significantly between patients assigned to receive cisplatin and paclitaxel and those assigned to receive any of the three experimental regimens. Treatment with cisplatin...
4,781 citations
"Ipilimumab in combination with pacl..." refers methods in this paper
...Paclitaxel/carboplatin was chosen as comparator in this study, because this combination is a common standard of care for non-small-cell lung cancer (NSCLC) patients, the larger of the two cohorts in this trial [32, 33], and also because the long-term efficacy of paclitaxel/carboplatin in ED-SCLC was comparable with that of cisplatin/etoposide, the commonly used chemotherapy combination in ED-SCLC [3, 34, 35]....
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4,095 citations
Institut Gustave Roussy1, University of South Florida2, University of Tübingen3, University of Paris4, Université catholique de Louvain5, Aix-Marseille University6, National Health Service7, University of Kiel8, McGill University9, University of Barcelona10, MedImmune11, Bristol-Myers Squibb12, Memorial Sloan Kettering Cancer Center13
TL;DR: Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dACarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma.
Abstract: A B S T R AC T Background Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma. Methods We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no doselimiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival. Results Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab–dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab–dacarbazine group. Conclusions Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.)
4,069 citations
"Ipilimumab in combination with pacl..." refers background or result in this paper
...Two phase 3 studies have demonstrated ipilimumab as the first agent to significantly improve OS in patients with metastatic melanoma [19, 20]....
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...(AEs) occurring in ≥15% of patients included pruritus, rash and diarrhea, and most AEs were managed by the drugspecific treatment guidelines [19, 20]....
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...Consistent with previous experience from other studies [20, 21], the most common irAEs involved skin (rash and pruritus) and gastrointestinal tract (diarrhea), and occurred more frequently in the ipilimumab-containing arms....
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