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.
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ABSTRACT: Immune recognition and elimination of malignant cells require a series of steps orchestrated by the innate and the adaptive arms of the immune system. The majority of tumors have evolved mechanisms that allow for successful evasion of these immune responses. Recognition of these evasive processes led to development of immunotherapeutic antibodies targeting the co-stimulatory and co-inhibitory receptors on T cells, with the goal of enhancement of T cell activation or reversal of tumor-induced T cell inhibition. Several of these agents, such as antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1) have already demonstrated significant promise in clinical trials. Clinical benefit of these antibodies as single agents, however, has been limited to a subset of patients and has not been observed in all tumor types. These limitations call for development of rational combination strategies aiming to extend therapeutic benefit to a broader range of patients. These include: 1) modalities that enhance antigen presentation, such as radiation, cryotherapy, chemotherapy, targeted agents, vaccines, toll-like receptor (TLR) agonists, type I interferon, and oncolytic viruses; 2) additional agents aiming to reverse T cell dysfunction, such as other immune checkpoint inhibitors; and 3) agents targeting other immune inhibitory mechanisms, such as inhibitors of indoleamine dioxygenase (IDO), regulatory T cells, and myeloid-derived suppressor cells (MDSC). It is becoming increasingly evident that the efficacy of specific combinations will likely not be universal and that the choice of a treatment modality may need to be tailored to fit the needs of each individual patient.Pharmacology & Therapeutics. 01/2015;
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ABSTRACT: BackgroundNHS-IL2 (selectikine, EMD 521873, MSB0010445) consists of human NHS76 (antibody specific for necrotic DNA) fused to genetically modified human interleukin 2 (IL-2) and selectively activates the high-affinity IL-2 receptor. Based on an evolving investigational concept to prime the tumor microenvironment with ionizing radiation prior to initiating immunotherapy, 2 related studies were conducted and are reported here. The first, a preclinical study, tests the systemic effect of the immunocytokine NHS-IL2 and radiotherapy in a lung carcinoma animal model; the second, a phase Ib trial in patients with metastatic non-small cell lung carcinoma (NSCLC), was designed to determine the safety and tolerability of NHS-IL2 in combination with radiotherapy directly following first-line palliative chemotherapyMethods Tumor-bearing C57Bl/6 mice were treated with NHS-IL2 alone (5 mg/kg; days 7¿9), fractionated radiotherapy (3.6 Gy; days 0¿4) plus cisplatin (4 mg/kg; day 0), or the triple combination. Metastatic NSCLC patients who achieved disease control with first-line palliative chemotherapy were enrolled in the phase Ib trial. Patients received local irradiation (5x 4 Gy) of a single pulmonary nodule. Dose-escalated NHS-IL2 was administered as 1-h intravenous infusion on 3 consecutive days every 3 weeksResultsNHS-IL2 plus radiotherapy induced immune response activation and complete tumor growth regressions in 80%¿100% of mice. In patients with metastatic NSCLC treated with NHS-IL2 (3, 3, and 7 patients in the 0.15-mg/kg, 0.30-mg/kg, and 0.45-mg/kg cohorts, respectively), maximum tolerated dose was not reached. Most frequently reported adverse events were fatigue, anorexia, and rash. Transient increases in leukocyte subsets were observed. In 3 patients, thyroid gland dysfunction occurred. No objective responses were reported; long-term survival was observed in 2 patients, including 1 patient with long-term tumor controlConclusions Combining NHS-IL2 with radiotherapy achieved synergistic antitumor activity in preclinical studies, supporting the use in lung cancer patients. This combination was well tolerated and 2 of 13 patients achieved long-term survival.Trial registrationClinicalTrials.gov NCT00879866.Journal of translational medicine. 01/2015; 13(1):32.
- Atemwegs- und Lungenkrankheiten 01/2014; 40(01):22-25.