Májer, István

Introduction: Lenalidomide is increasingly used for the treatment of newly diagnosed multiple myeloma. However, most patients experience relapse during treatment or after prolonged exposure to lenalidomide, therefore, there is an emerging unmet need for new, highly efficacious lenalidomide-sparing regimens at relapse. CANDOR is an ongoing phase 3 randomized clinical trial (RCT) that compares the lenalidomide-free KdD regimen with carfilzomib 56mg/m2 twice-weekly with dexamethasone (Kd) in patients with relapsed and/or refractory multiple myeloma (RRMM). Based on the primary analysis, KdD was associated with a 37% reduction in the risk of progression or death compared to Kd (HR: 0.63, p=0.001).(Dimopoulos et al. 2020 Lancet) Besides the trial-based comparator Kd, DVd is considered as an additional relevant comparator. DVd is the most similar lenalidomide-free triplet regimen comprising a proteasome inhibitor, daratumumab, and dexamethasone. DVd was assessed in the phase 3 CASTOR RCT and demonstrated superior PFS versus 8 cycles (24 weeks) of bortezomib in combination with dexamethasone (Vd) (HR: 0.31, p<0.001).(Weisel et al. 2019 ASH) In the absence of a direct head-to-head trial comparing these treatments and an assessment suggesting that network meta-analysis is not feasible, matching-adjusted indirect comparisons (MAIC) were used (Signorovitch et al. 2010) to assess the efficacy of KdD relative to DVd. MAIC leverages all available data and compares outcomes across balanced populations. Method: Baseline characteristics and PFS data from the CANDOR and CASTOR trials were used in the analyses. Outcomes were compared in three steps. First, after aligning patient selection criteria of both trials, KdD patients in CANDOR were matched to the average characteristics of DVd patients in CASTOR using matching-adjusted indirect treatment comparisons methodology. The matching variables reflected tumor stage, disease burden, and treatment history, and were generally consistent with validated prognostic markers used in stratifying patients into different risk groups. Second, the published Kaplan-Meier PFS curves for DVd were digitized to generate virtual patient-level data that reconstructed the curves. Third, Cox regression models were fitted to the matched CANDOR data and the reconstructed virtual patient-level CASTOR data to estimate the efficacy of KdD versus DVd. The outcome measure was the hazard ratio (HR) for PFS. Outcomes were also compared for the first 24 weeks and for the period beyond 24 weeks to assess the impact of stopping Vd in DVd after 24 weeks on the HRs. Scenario and subgroup analyses were conducted to assess the robustness of results. Results: KdD patients in the CANDOR trial who were proteasome inhibitor-refractory (n=102) were removed from the data so that the KdD population was aligned with that of DVd in the CASTOR trial. Following the matching procedure, the effective sample size for KdD reduced to 82. In matched populations, PFS at 12 months was 73.1% for KdD and 59.9% for DVd. The MAIC results showed that treatment with KdD decreases the risk of progression or death versus DVd, with an overall HR of 0.61 (95% CI: 0.45-0.82). The time-dependent analysis demonstrated similar PFS for the two treatments for the first 24 weeks and a larger benefit for KdD over DVd after 24 weeks. Similar results were obtained in scenario analyses; in bortezomib-exposed patients the overall HR was 0.46 (95% CI: 0.33-0.64). Conclusions: After adjusting for cross-trial differences, KdD was associated with a significant reduction in the risk of progression or death compared with DVd. Although based on an approach in agreement with methods guide, the results are associated with inherent limitations due to the decreased sample size for KdD, and due to known (longer follow-up for DVd, different duration of proteasome inhibition) or unobserved differences in the trials (potential unobserved heterogeneity in patient characteristics). A comparison of overall survival was not considered due to immature data in CANDOR. The results are in line with those of the head-to-head ENDEAVOR trial that directly compared carfilzomib with bortezomib (HR for PFS for Kd vs Vd 0.53; 95% CI: 0.44-0.65) supporting the clinical validity of this study. The present analysis suggests that KdD improves outcomes compared with DVd in patients with RRMM and may provide a rationale for a preferential treatment. Disclosures Weisel: Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Adaptive: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Nooka:Sanofi: Consultancy, Honoraria; Spectrum Pharmaceuticals: Consultancy; Oncopeptides: Consultancy, Honoraria; Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Adaptive Technologies: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Terpos:Janssen: Honoraria, Research Funding; Genesis pharma SA: Honoraria, Other: travel expenses , Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Celgene: Honoraria; Sanofi: Honoraria; BMS: Honoraria. Spencer:AbbVie, Amgen, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Honoraria; AbbVie, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Consultancy; Amgen, Celgene, Haemalogix, Janssen, Servier and Takeda: Research Funding; Celgene, Janssen and Takeda: Speakers Bureau. Goldschmidt:Merck Sharp and Dohme (MSD): Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; Molecular Partners: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; GlaxoSmithKline (GSK): Honoraria; Incyte: Research Funding; Mundipharma GmbH: Research Funding. Majer:Amgen (Europe) GmbH: Current Employment, Current equity holder in publicly-traded company. DeCosta:Amgen Ltd: Current Employment, Current equity holder in publicly-traded company. Medhekar:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Yusuf:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Kumar:Karyopharm: Consultancy; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Sanofi: Research Funding; Carsgen: Other, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Cellectar: Other; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genecentrix: Consultancy; MedImmune: Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Tenebio: Other, Research Funding.

Abstract Background : Carfilzomib is an innovative second generation proteasome inhibitor (PI) that binds irreversibly and selectively to the proteasome. Carfilzomib exhibits sustained inhibition of the proteasome with minimal off-target activity. Kd was approved in 2016 as a treatment (Tx) option for R/RMM patients who have received one to three prior lines of therapy.In the ENDEAVOR phase 3, open label, multicenter randomized controlled trial assessing Kd vs Vd, median progression-free survival (PFS) was 18.7 months (95% CI:15.6 - could not be estimated) in the Kd group vs 9.4 months (8.4 - 10.4) in the Vd group at an a priori, pre-specified interim analysis (hazard ratio [HR]: 0.53 [95% CI: 0.44 - 0.65]; p<0.0001). OS data at the 1st interim analysis were immature. In the current study, we assessed the cost-effectiveness (CE) of Kd vs Vd from a US payer perspective using data from ENDEAVOR and long-term overall survival (OS) data from the Surveillance, Epidemiology, and End Results Program (SEER). Methods: A partitioned-survival model with a progression-free (PF), a post-progression (PP) and a death state was built with a 30 year horizon. PFS was modelled using separately fitted log-logistic parametric curves. In order to estimate measures of efficacy for OS and to incorporate treatment effect into the model, time-dependent multiple semiparametric Cox regression analyses were implemented for OS outcomes, which controlled for baseline covariates. OS for Vd in the base case was modelled with a separately fitted Weibull parametric curve, which was fitted to the Vd data. The time-dependent multiple Cox model generated a HR for 0 to 12 months and a HR beyond 12 months for Kd vs Vd, which were applied to model the Kd OS curve. The OS curves beyond 36 months were extrapolated with SEER data. A Weibull distribution was used for the extrapolation by matching the SEER registry data to the ENDEAVOR population, which was assumed to represent the Vd survival rate. To this extrapolated survival curve beyond 36 months, the OS treatment effect was applied in order to model the Kd curve. Grade ≥ 3 adverse events (AEs) with ≥ 2% incidence in any ENDEAVOR arm were included. Utilities were derived from the literature and adjusted for the treatment specific improvement in QoL observed when patients were PF in ENDEAVOR. Costs related to drug (WAC prices), administration, monitoring, AE management, and subsequent Tx were considered. The base case utilized OS results from an updated OS dataset (March 2016) that resulted in an ad hoc OS analysis. A 3% discount rate was applied to costs and health outcomes. Results: In the base-case, results from the model showed thatKd was more effective compared to Vd, providing 1.874 PfLY, 1.854 LY, and 1.654 QALY gains over the modelled horizon. Kd incurred $227,703 in total additional costs and the ICER vs Vd was 137,660$/QALY. Conclusions: The model predicts that Kd delivers 1.85 additional life years over the the comparator Vd. Per the base case, Kd is cost-effective vs Vd at generally accepted willingness-to-pay thresholds of $150,000/QALY and $300,000/QALY in the US. Based on the ENDEAVOR data, Kd is a superior PI-based doublet compared to Vd, and should be preferred whenever doublets are appropriate for the patient, Furthermore, this CE analysis shows that Kd delivers considerable incremental value to patients with relapsed or refractory MM and to payers who must allocate budgets for the treatment of patients. Table Table. Disclosures Jakubowiak: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Majer:Amgen Inc: Employment, Equity Ownership. Houisse:Amgen Inc: Consultancy. Benedict:Amgen Inc: Consultancy. Campioni:Amgen: Employment, Other: Holds Amgen Stock. Panjabi:Amgen Inc: Employment, Equity Ownership. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy.

e18356 Background: Carfilzomib plus dexamethasone (Kd) dosed once weekly at 70 mg/m2 (QW Kd70) was recently approved in the US for treating patients with relapsed and refractory multiple myeloma (RRMM). To assess the cost-effectiveness (CE) of QW Kd70 vs twice weekly Kd dosed at 27 mg/m2 (BIW Kd27), data from the phase 3 ARROW trial, which directly compared these regimens in patients with 2-3 prior lines of therapy were used. Methods: A partitioned survival model was developed for the CE analysis. Time to treatment discontinuation, progression-free survival, and overall survival (OS) were estimated from the ARROW trial. Long-term OS was extrapolated using Surveillance Epidemiology and End Results registry data after matching characteristics of patients in the registry and ARROW trial. Direct costs were estimated from a US health care payer perspective. Utilities collected in the ARROW trial using the five-level version of the EuroQol questionnaire (EQ-5D-5L) were applied to estimate the quality-adjusted life years (QALYs). Uncertainty was explored using sensitivity analyses. Two subgroups of patients refractory to lenalidomide or bortezomib were assessed. Main outcomes were mean life-years (LYs), QALYs, lifetime costs, and incremental cost-effectiveness ratios (ICERs). Results: For QW Kd70 and BIW Kd27, the model predicted mean LYs of 4.17 and 3.07 years, QALYs of 2.98 and 2.03 years, and mean total lifetime costs of $444,563 and $373,364, respectively. The incremental LYs gain, QALY gain, and incremental costs of QW Kd70 vs BIW Kd27 were estimated to be 1.10 years, 0.95 year, and $71,199, respectively, resulting in an ICER of $64,595 per LY gained and $75,204 per QALY gained. For patients refractory to lenalidomide and bortezomib, similar results were found with ICERs of $79,988 and $76,793, respectively. Conclusions: In line with ARROW trial results, this CE analysis showed that QW Kd70 is expected to provide considerable additional benefit in terms of LYs and QALYs gained compared with BIW Kd27. In the RRMM setting, QW Kd70 is cost-effective with ICERs below accepted willingness to pay thresholds in US and represents an efficient utilization of the health care budget.