Ramy Ibrahim

Ipilimumab plus dacarbazine for previously untreated metastatic melanoma

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 dose-limiting 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.).

Improved Endpoints for Cancer Immunotherapy Trials

Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan–Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation.

Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study

BACKGROUND This phase II study evaluated the safety and activity of ipilimumab, a fully human mAb that blocks cytotoxic T-lymphocyte antigen-4, in patients with advanced melanoma. PATIENTS AND METHODS Patients with previously treated, unresectable stage III/stage IV melanoma received 10 mg/kg ipilimumab every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. The primary end point was best overall response rate (BORR) using modified World Health Organization (WHO) criteria. We also carried out an exploratory analysis of proposed immune-related response criteria (irRC). RESULTS BORR was 5.8% with a disease control rate (DCR) of 27% (N = 155). One- and 2-year survival rates (95% confidence interval) were 47.2% (39.5% to 55.1%) and 32.8% (25.4% to 40.5%), respectively, with a median overall survival of 10.2 months (7.6-16.3). Of 43 patients with disease progression by modified WHO criteria, 12 had disease control by irRC (8% of all treated patients), resulting in a total DCR of 35%. Adverse events (AEs) were largely immune related, occurring mainly in the skin and gastrointestinal tract, with 19% grade 3 and 3.2% grade 4. Immune-related AEs were manageable and generally reversible with corticosteroids. CONCLUSION Ipilimumab demonstrated clinical activity with encouraging long-term survival in a previously treated advanced melanoma population.

Development of Ipilimumab: Contribution to a New Paradigm for Cancer Immunotherapy

Identification of cytotoxic T-lymphocyte antigen-4 (CTLA-4) as a key negative regulator of T-cell activity led to development of the fully human, monoclonal antibody ipilimumab to block CTLA-4 and potentiate antitumor T-cell responses. Animal studies first provided insight into the ability of an anti-CTLA-4 antibody to cause tumor regression, particularly in combination regimens. Early clinical studies defined ipilimumab pharmacokinetics and possibilities for combinability. Phase II trials of ipilimumab in advanced melanoma showed objective responses, but a greater number of patients had disease stabilization. In a phase III trial, ipilimumab was the first agent to demonstrate an improvement in overall survival in patients with previously treated, advanced melanoma. The adverse event profile associated with ipilimumab was primarily immune-related. Adverse events can be severe and life-threatening, but most were reversible using treatment guidelines. Ipilimumab monotherapy exhibits conventional and new patterns of activity in advanced melanoma, with a delayed separation of Kaplan-Meier survival curves. The observation of some new response patterns with ipilimumab, which are not captured by standard response criteria, led to novel criteria for the evaluation of immunotherapy in solid tumors. Overall, lessons from the development of ipilimumab contributed to a new clinical paradigm for cancer immunotherapy evolved by the Cancer Immunotherapy Consortium.

Direct Economic Burden of High-Risk and Metastatic Melanoma in the Elderly: Evidence from the SEER-Medicare Linked Database

BackgroundWhile the clinical implications of advanced melanoma have been extensively documented, little is known about the direct medical costs associated with the disease, particularly for elderly patients who carry the highest disease incidence and morbidity.ObjectiveTo document resource utilization and costs to the Medicare system for elderly patients with high-risk (stages IIB/C, IIIA/B, IIIC) or metastatic (stage IV) melanoma.MethodsData were taken from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database combining clinical information on incident cancer cases in the US between 1991 and 2002 with longitudinal (1991–2005) administrative Medicare claims. Subjects aged ≥65 years with at least one stage IIB or higher melanoma diagnosis were selected. An index date was identified corresponding to the first observed stage IIB or higher diagnosis. Subjects were then categorized into mutually exclusive index disease stages, based on the SEER-reported melanoma stage observed at the index date. All subsequent analyses were stratified according to the index disease stage. Subjects without a record of death were required to have at least 6 months of continuous Medicare Part A and Part B benefits coverage before and after their index date. Subjects who died <6 months after their index date were retained for analysis. Resource utilization and costs were evaluated for each patient from index date until death, benefits cessation or end of the database (31 December 2005). Cost data were inflated to 2007

Abstract CT230: Pediatric phase 1 trial of moxetumomab pasudotox: Activity in chemotherapy refractory acute lymphoblastic leukemia (ALL)

US and stratified by the care setting in which they were incurred: inpatient hospital, skilled nursing facility, emergency room, physician office, home healthcare, hospice and other ancillary.Results6470 subjects met all inclusion criteria. Index stage distribution was: IIB/C (38%), IIIA/B (46%), IIIC (1%) and IV (15%). Median follow-up was 56, 39, 16 and 6 months, respectively. Patients with stage IV disease had 3.1 hospital days per month, compared with 0.5, 0.6 and 1.1 days for stage IIB/C, IIIA/B and IIIC patients, respectively. Adjusted inpatient costs for stage IV subjects were

New Cancer Immunotherapy Agents in Development: a report from an associated program of the 31stAnnual Meeting of the Society for Immunotherapy of Cancer, 2016

US5565 per patient per month versus

Safety and disease response to MEDI-551, an anti-CD19 antibody, in chronic lymphocytic leukemia patients previously treated with rituximab

US1031,

Abstract LB-228: Pharmacokinetics of Tremelimumab, a fully human anti-CTLA-4 monoclonal antibody, in subjects with unresectable malignant mesothelioma

US1440 and

Abstract B80: A Phase II randomized, double-blind, placebo-controlled study of tremelimumab for second- and third-line treatment in patients with unresectable pleural or peritoneal mesothelioma.

US2275 for stage IIB/C, IIIA/B and IIIC patients, respectively (p < 0.0001). Adjusted total costs were