Long-term real-world experience with ipilimumab and non-ipilimumab therapies in advanced melanoma: the IMAGE study.

Funder: This work was supported by Bristol Myers Squibb (no grant number is applicable).BACKGROUND: Ipilimumab has shown long-term overall survival (OS) in patients with advanced melanoma in clinical trials, but robust real-world evidence is lacking. We present long-term outcomes from the IMAGE study (NCT01511913) in patients receiving ipilimumab and/or non-ipilimumab (any approved treatment other than ipilimumab) systemic therapies. METHODS: IMAGE was a multinational, prospective, observational study assessing adult patients with advanced melanoma treated with ipilimumab or non-ipilimumab systemic therapies between June 2012 and March 2015 with ≥3 years of follow-up. Adjusted OS curves based on multivariate Cox regression models included covariate effects. Safety and patient-reported outcomes were assessed. RESULTS: Among 1356 patients, 1094 (81%) received ipilimumab and 262 (19%) received non-ipilimumab index therapy (systemic therapy [chemotherapy, anti-programmed death 1 antibodies, or BRAF ± MEK inhibitors], radiotherapy, and radiosurgery). In the overall population, median age was 64 years, 60% were male, 78% were from Europe, and 78% had received previous treatment for advanced melanoma. In the ipilimumab-treated cohort, 780 (71%) patients did not receive subsequent therapy (IPI-noOther) and 314 (29%) received subsequent non-ipilimumab therapy (IPI-Other) on study. In the non-ipilimumab-treated cohort, 205 (78%) patients remained on or received other subsequent non-ipilimumab therapy (Other-Other) and 57 (22%) received subsequent ipilimumab therapy (Other-IPI) on study. Among 1151 patients who received ipilimumab at any time during the study (IPI-noOther, IPI-Other, and Other-IPI), 296 (26%) reported CTCAE grade ≥ 3 treatment-related adverse events, most occurring in year 1. Ipilimumab-treated and non-ipilimumab-treated patients who switched therapy (IPI-Other and Other-IPI) had longer OS than those who did not switch (IPI-noOther and Other-Other). Patients with prior therapy who did not switch therapy (IPI-noOther and Other-Other) showed similar OS. In treatment-naive patients, those in the IPI-noOther group tended to have longer OS than those in the Other-Other group. Patient-reported outcomes were similar between treatment cohorts. CONCLUSIONS: With long-term follow-up (≥ 3 years), safety and OS in this real-world population of patients treated with ipilimumab 3 mg/kg were consistent with those reported in clinical trials. Patient-reported quality of life was maintained over the study period. OS analysis across both pretreated and treatment-naive patients suggested a beneficial role of ipilimumab early in treatment. TRIAL REGISTRATION: ClinicalTrials.gov , NCT01511913. Registered January 19, 2012 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT01511913

Health-related quality of life results from the phase III CheckMate 067 study

Background Nivolumab, a monoclonal antibody of immune checkpoint programmed death 1 on T cells (PD-1), combined with ipilimumab, an immune checkpoint cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, as combination therapy on the one hand and nivolumab as monotherapy on the other, have both demonstrated improved efficacy compared with ipilimumab alone in the CheckMate 067 study. However, the combination resulted in a higher frequency of grade 3/4 adverse events (AEs), which could result in diminished health-related quality of life (HRQoL). Here we report analyses of HRQoL for patients with advanced melanoma in clinical trial CheckMate 067.Patients and methods HRQoL was assessed at weeks 1 and 5 per 6-week cycle for the first 6 months, once every 6 weeks thereafter, and at two follow-up visits using the European Organization for Research and Treatment of Care Core Quality of Life Questionnaire and the EuroQoL Five Dimensions Questionnaire. In addition to the randomised population, patient subgroups, including BRAF mutation status, partial or complete response, treatment-related AEs of grade 3/4, and those who discontinued due to any reason and due to an AE, were investigated.Results Nivolumab and ipilimumab combination and nivolumab alone both maintained HRQoL, and no clinically meaningful deterioration was observed over time compared with ipilimumab. In addition, similar results were observed across patient subgroups, and no clinically meaningful changes in HRQoL were observed during follow-up visits for patients who discontinued due to any cause.Conclusion These results further support the clinical benefit of nivolumab monotherapy and nivolumab and ipilimumab combination therapy in patients with advanced melanoma. The finding that the difference in grade 3/4 AEs between the arms did not translate into clinically meaningful differences in the reported HRQoL may be relevant in the clinical setting.Study number NCT01844505

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

Background:Background: While 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. Abstract: Objective:Objective: To 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. Abstract: Methods:Methods: Data 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 &dollar;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. Abstract: Results:Results: 6470 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 &dollar;US5565 per patient per month versus &dollar;US1031, &dollar;US1440 and &dollar;US2275 for stage IIB/C, IIIA/B and IIIC patients, respectively (p < 0.0001). Adjusted total costs were &dollar;US11 471 per month for stage IV subjects, compared with &dollar;US2338, &dollar;US3395 and &dollar;US6885 for stages IIB/C, IIIA/B and IIIC, respectively (p < 0.0001). Abstract: Conclusion:Conclusion: The per-patient cost of advanced melanoma is high. Hospital services are the largest component of these costs. Monthly costs for subjects with stage IV melanoma were 67% higher than costs for subjects with stage IIIC disease and >3-fold higher than costs for patients with stages IIIA/B and IIB/C. However, when combining estimated monthly costs with median follow-up duration (a proxy for survival time), total costs incurred by Medicare appear to be highest for patients diagnosed at stage IIIA/B.

Pharmacoeconomic Analysis of Amphotericin B Lipid Complex versus Liposomal Amphotericin B in the Treatment of Fungal Infections

Background: Potential differences in toxicity, potency and acquisition price among the liposomal amphotericin B formulations makes it unclear which agent is less costly when total resource consumption and treatment-associated costs are considered. Design: A retrospective cost-minimisation analysis in 51 patients was performed to compare the cost of amphotericin B lipid complex (ABLC) and liposomal amphotericin B (L-AMB) from the hospital perspective. Costs ($US, 2001 values) were divided into level I (acquisition price only), level II (costs of all associated treatment, i.e. adverse events, failures, etc.) and level III (total fungal-related hospitalisation) costs. Results: No significant differences in patient demographics or length of therapy were apparent among those receiving ABLC or L-AMB. The clinical success rate in this population was similar between ABLC and L-AMB (53$US340 versus L-AMB $US435, p = 0.002; level II: ABLC$US361 versus L-AMB $US454, p = 0.027). The costs attributable to the prevention or treatment of adverse events were not different between the two treatments, and the economic outcome in this analysis was highly sensitive to the acquisition price and dosage of the lipid antifungal formulation. Two-way sensitivity analysis revealed that as long as the milligram price of L-AMB was greater than 135% of the milligram price of ABLC, ABLC remained the less costly formulation. Conclusion: In this patient population, total hospitalisation costs were not different between lipid antifungal formulations. However, after controlling for duration of therapy, ABLC was less costly than L-AMB, when considering acquisition costs of the lipid antifungal agent and costs associated with concomitant antifungal therapy and the treatment of adverse events or lipid failures, indicating that the acquisition price of these agents should be predictive of their cost differences.Amphotericin-B-liposomal, Cost-minimisation, Mycoses

Societal preferences for adjuvant melanoma health states: UK and Australia

Abstract Background No studies have measured preference-based utility weights for specific toxicities and outcomes associated with approved and investigational adjuvant treatments for patients with resected high-risk melanoma. Methods A cross-sectional study was conducted in the United Kingdom and Australia to obtain utilities for 14 adjuvant melanoma health states. One-on-one interviews were conducted using standard gamble; utility weights range from 0.0, dead, to 1.0, full health. Supplemental risk questions also were asked. Results Among 155 participants (52% male; mean age, 46 years) “adjuvant treatment no toxicities” (0.89) was most preferred, followed by “induction treatment” (0.88), and “no treatment” (0.86). Participants least preferred “cancer recurrence” (0.62); the utility for “cancer recurrence and 10-year survival with treatment” was 0.70. Disutilities for grade 2 toxicities ranged from −0.06 for fatigue to −0.13 for hypophysitis. The mean maximum acceptable risk of a life-threatening event ranged from 30% for a 6% increase in the chance of remaining cancer free over 3 years to 40% for an 18% increase; Australian respondents were willing to take higher risks. Conclusion Reproducible health utilities for adjuvant melanoma health states were obtained from the general population in two countries. These utilities can be incorporated into treatment-specific cost-effectiveness evaluations

Additional file 1: of Societal preferences for adjuvant melanoma health states: UK and Australia

Interview Script. (PDF 259 kb

Health related quality of life outcomes for unresectable stage III or IV melanoma patients receiving ipilimumab treatment

BACKGROUND: In an international, randomized Phase III trial ipilimumab demonstrated a significant overall survival benefit in previously treated advanced melanoma patients. This report summarizes health-related quality of life (HRQL) outcomes for ipilimumab with/without gp100 vaccine compared to gp100 alone during the clinical trial’s 12 week treatment induction period. METHODS: The Phase III clinical trial (MDX010-20) was a double-blind, fixed dose study in 676 previously treated advanced unresectable stage III or IV melanoma patients. Patients were randomized 3:1:1 to receive either ipilimumab (3 mg/kg q3w x 4 doses) + gp100 (peptide vaccine; 1 mg q3w x 4 doses; ipilimumab plus gp100, n = 403); gp100 vaccine + placebo (gp100 alone, n = 136); or ipilimumab + placebo (ipilimumab alone, n = 137). The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) assessed HRQL. Baseline to Week 12 changes in EORTC QLQ-C30 function, global health status, and symptom scores were analyzed for ipilimumab with/without gp100 vaccine compared to gp100 alone. Mean change in scores were categorized “no change” (0–5), “a little” (5–10 points), “moderate” (10–20 points), and “very much” (>20). RESULTS: In the ipilimumab plus gp100 and ipilimumab alone groups, mean changes from baseline to Week 12 generally indicated “no change” or “a little” impairment across EORTC QLQ-C30 global health status, function, and symptom subscales. Significant differences in constipation, favoring ipilimumab, were observed (p < 0.05). For ipilimumab alone arm, subscales with no or a little impairment were physical, emotional, cognitive, social function, global health, nausea, pain, dyspnea, constipation, and diarrhea subscales. For the gp100 alone group, the observed changes were moderate to large for global health, role function, fatigue, and for pain. CONCLUSIONS: Ipilimumab with/without gp100 vaccine does not have a significant negative HRQL impact during the treatment induction phase relative to gp100 alone in stage III or IV melanoma patients. TRIAL REGISTRATION: Clinicaltrials.gov identification number NCT0009465