Ipilimumab in Combination With Paclitaxel and Carboplatin As First-Line Treatment in Stage IIIB/IV Non-Small-Cell Lung Cancer: Results From a Randomized, Double-Blind, Multicenter Phase II Study
ABSTRACT Ipilimumab, which is an anti-cytotoxic T-cell lymphocyte-4 monoclonal antibody, showed a survival benefit in melanoma with adverse events (AEs) managed by protocol-defined guidelines. A phase II study in lung cancer assessed the activity of ipilimumab plus paclitaxel and carboplatin.
Patients (N = 204) with chemotherapy-naive non-small-cell lung cancer (NSCLC) were randomly assigned 1:1:1 to receive paclitaxel (175 mg/m(2)) and carboplatin (area under the curve, 6) with either placebo (control) or ipilimumab in one of the following two regimens: concurrent ipilimumab (four doses of ipilimumab plus paclitaxel and carboplatin followed by two doses of placebo plus paclitaxel and carboplatin) or phased ipilimumab (two doses of placebo plus paclitaxel and carboplatin followed by four doses of ipilimumab plus paclitaxel and carboplatin).Treatment was administered intravenously every 3 weeks for ≤ 18 weeks (induction). Eligible patients continued ipilimumab or placebo every 12 weeks as maintenance therapy. Response was assessed by using immune-related response criteria and modified WHO criteria. The primary end point was immune-related progression-free survival (irPFS). Other end points were progression-free survival (PFS), best overall response rate (BORR), immune-related BORR (irBORR), overall survival (OS), and safety.
The study met its primary end point of improved irPFS for phased ipilimumab versus the control (hazard ratio [HR], 0.72; P = .05), but not for concurrent ipilimumab (HR, 0.81; P = .13). Phased ipilimumab also improved PFS according to modified WHO criteria (HR, 0.69; P = .02). Phased ipilimumab, concurrent ipilimumab, and control treatments were associated with a median irPFS of 5.7, 5.5, and 4.6 months, respectively, a median PFS of 5.1, 4.1, and 4.2 months, respectively, an irBORR of 32%, 21% and 18%, respectively, a BORR of 32%, 21% and 14%, respectively, and a median OS of 12.2, 9.7, and 8.3 months. Overall rates of grade 3 and 4 immune-related AEs were 15%, 20%, and 6% for phased ipilimumab, concurrent ipilimumab, and the control, respectively. Two patients (concurrent, one patient; control, one patient) died from treatment-related toxicity.
Phased ipilimumab plus paclitaxel and carboplatin improved irPFS and PFS, which supports additional investigation of ipilimumab in NSCLC.
- SourceAvailable from: Robert Leone
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- "In two large initial phase III trials, the anti-CTLA-4 monoclonal antibody ipilimumab significantly prolonged survival and produced durable responses in patients with advanced melanoma  . CTLA-4 blockade has also been shown to be active in patients with renal cell carcinoma and in patients with NSCLC  . Clinical studies of anti-PD-1 mAbs have also shown improvement in overall survival with durable responses in a variety of heavily pre-treated tumor types, including melanoma, NSCLC, and renal cell carcinoma . "
ABSTRACT: The last several years have witnessed exciting progress in the development of immunotherapy for the treatment of cancer. This has been due in great part to the development of so-called checkpoint blockade. That is, antibodies that block inhibitory receptors such as CTLA-4 and PD-1 and thus unleash antigen-specific immune responses against tumors. It is clear that tumors evade the immune response by usurping pathways that play a role in negatively regulating normal immune responses. In this regard, adenosine in the immune microenvironment leading to the activation of the A2a receptor has been shown to represent one such negative feedback loop. Indeed, the tumor microenvironment has relatively high concentrations of adenosine. To this end, blocking A2a receptor activation has the potential to markedly enhance anti-tumor immunity in mouse models. This review will present data demonstrating the ability of A2a receptor blockade to enhance tumor vaccines, checkpoint blockade and adoptive T cell therapy. Also, as several recent studies have demonstrated that under certain conditions A2a receptor blockade can enhance tumor progression, we will also explore the complexities of adenosine signaling in the immune response. Despite important nuances to the A2a receptor pathway that require further elucidation, studies to date strongly support the development of A2a receptor antagonists (some of which have already been tested in phase 3 clinical trials for Parkinson disease) as novel modalities in the immunotherapy armamentarium.Computational and Structural Biotechnology Journal 04/2015; 30. DOI:10.1016/j.csbj.2015.03.008
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- "Of note, unlike with the phased regimen, efficacy improvements were not seen with a concurrent ipilimumab plus chemotherapy regimen as compared with the chemotherapy plus placebo control group. The investigators speculated that exposure to chemotherapy prior to ipilimumab may have led to enhanced activation of T cells, similar to that seen in preclinical models (Lynch et al., 2012; Reck et al., 2013). As further studies are "
ABSTRACT: The approval of the immune checkpoint inhibitor ipilimumab for the treatment of advanced melanoma in 2011 spearheaded the development of other anticancer therapies with immune mechanisms of action, including other immune checkpoint inhibitors. Instead of acting directly on the tumor, these therapies work to "remove the brakes" on the immune system to restore antitumor immune responses. In addition to ipilimumab, which targets the cytotoxic T lymphocyte-associated antigen 4 pathway, several new drugs that target the programmed death-1 pathway are in phase III trials across tumor types, including melanoma, lung cancer, and renal cell carcinoma. In keeping with their unique mechanism of action, these immune checkpoint inhibitors have shown both conventional and unconventional response patterns, including initial apparent tumor progression followed by regression, and adverse events (AEs) that are likely immune-related. Advanced practitioners (APs) treating patients receiving immuno-oncology agents are in a key position to educate patients about expectations with these therapies and to screen patients for AEs and initiate appropriate and timely interventions. This review summarizes current immune checkpoint inhibitor data and provides patient management strategies for APs to optimize patient outcomes with these novel therapies.11/2014; 5(6):418-31.
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- "This study is based on the results of the phase III study comparing the standard therapy of carboplatin and paclitaxel versus concomitant administration of ipilimumab in patients with metastatic squamous cell NSCLC who have never received chemotherapy1. In subtype analysis of this study, patients with squamous cell carcinoma, who received concomitant administration of ipilimumab, showed the primary benefit. "
ABSTRACT: Lung cancer is the leading cause of cancer-related mortality worldwide, and more than 80% of cases are of non-small cell lung cancer. Although chemotherapy and molecularly targeted therapy may provide some benefit, there is a need for newer therapies for the treatment of patients with advanced NSCLC. Immunotherapy aims to augment the recognition of cancer as foreign, to stimulate immune responsiveness, and to relieve the inhibition of the immune response that allows tolerance to tumor survival and growth. Two immunotherapeutic approaches showing promise in NSCLC are immune checkpoint inhibition and cancer vaccination. Although currently immunotherapy does not have an established role in the treatment of NSCLC, these patients should be enrolled in formal clinical trials.Tuberculosis and Respiratory Diseases 09/2014; 77(3):111-5. DOI:10.4046/trd.2014.77.3.111