Matching-adjusted Indirect Treatment Comparison Research Articles

Cost-effectiveness of axicabtagene ciloleucel versus tisagenlecleucel for the treatment of 3L + relapsed/refractory large B-cell lymphoma in the United States: incorporating longer survival results

Aims To provide an update on the cost-effectiveness of the chimeric antigen receptor (CAR) T-cell therapies axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) for the treatment of relapsed/refractory (r/r) large B-cell lymphoma (LBCL) among patients who have previously received ≥2 lines of systemic therapy using more mature clinical trial data cuts (60 months for axi-cel overall survival [OS] and 45 months for tisa-cel OS and progression-free survival [PFS]). Methods A partitioned survival model consisting of three health states (pre-progression, post-progression and death) was used to estimate quality-adjusted life years (QALYs) and costs associated with axi-cel and tisa-cel over a lifetime horizon. PFS and OS inputs for axi-cel and tisa-cel were based on a previously published matching-adjusted indirect treatment comparison (MAIC). Long-term OS and PFS were extrapolated using parametric survival mixture cure models (PS-MCMs). Costs of CAR-T cell therapy drug acquisition and administration, conditioning chemotherapy, apheresis, CAR T-specific monitoring, stem cell transplant, hospitalization, adverse events, routine care, and terminal care were sourced from US cost databases. Health state utilities were derived from previous publications. Model inputs were varied using a range of sensitivity and scenario analyses. Results Compared with tisa-cel, axi-cel resulted in 2.51 additional QALYs and $50,185 additional costs (an incremental cost-effectiveness ratio [ICER] of $19,994 per QALY gained). In probabilistic sensitivity analysis (PSA), the ICER for axi-cel versus tisa-cel was ≤$50,000/QALY in 99.4% of simulations and ≤$33,500 in 99% of simulations. Axi-cel remained cost-effective versus tisa-cel (assuming a willingness-to-pay threshold of $150,000 per QALY) across a range of scenarios. Conclusions With longer-term survival data, axi-cel continues to represent a cost-effective option versus tisa-cel for treatment of r/r LBCL among patients who have previously received ≥2 lines of systemic therapy, from a US payer perspective.

CO93 Matching-Adjusted Indirect Treatment Comparison (MAIC) of Teclistamab Versus Selinexor-Dexamethasone for the Treatment of Patients with Triple-Class Exposed (TCE) Relapsed/Refractory Multiple Myeloma (RRMM)

CO93 Matching-Adjusted Indirect Treatment Comparison (MAIC) of Teclistamab Versus Selinexor-Dexamethasone for the Treatment of Patients with Triple-Class Exposed (TCE) Relapsed/Refractory Multiple Myeloma (RRMM)

MSR42 A Parametric Method for Unanchored Matching-Adjusted Indirect Treatment Comparison (MAIC) Based on Survival Outcomes for Health Economic (HE) Models in Absence of Proportional Hazards (PH)

MSR42 A Parametric Method for Unanchored Matching-Adjusted Indirect Treatment Comparison (MAIC) Based on Survival Outcomes for Health Economic (HE) Models in Absence of Proportional Hazards (PH)

The Comparative Effectiveness of A+AVD vs PET-guided ABVD for the Management of Patients with Advanced Hodgkin Lymphoma: A Systematic Review and Matching-Adjusted Indirect Treatment Comparison

Introduction: In advanced Hodgkin lymphoma (aHL), adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine (ABVD) is a recommended chemotherapy regimen despite a substantial proportion of patients experiencing relapse or incomplete disease control. Per the National Comprehensive Care Network (NCCN) guidelines, positron-emission tomography (PET)-guided ABVD and brentuximab vedotin + adriamycin (doxorubicin), vinblastine and dacarbazine (A+AVD) are preferred options for the front-line treatment of aHL (NCCN Guidelines. Hodgkin lymphoma. Version 2. 2023). In the ECHELON-1 (E1) trial, superiority of A+AVD vs ABVD x6 cycles (without PET adaptation at cycle 2) was demonstrated statistically in terms of overall survival (OS) and progression-free survival (PFS). Six-year follow-up of E1 patients showed improved OS with A+AVD vs ABVD. The aim of this study was to indirectly compare the effectiveness (OS and PFS) of A+AVD vs PET-guided ABVD as front-line treatments in the management of patients aged ≤60 years with aHL (Stage III or IV). Methods: A systematic literature review was conducted using electronic databases such as MEDLINE, Embase, and the Cochrane Library (database inception to July 2022), supplementary sources and data on file for relevant materials reporting on the clinical efficacy of front-line treatments for aHL. Following the identification of relevant randomized controlled trials (RCTs), unanchored matching-adjusted indirect comparison was performed to compare the efficacy of A+AVD (the E1 trial) with PET-guided ABVD (the Risk-Adapted Therapy for aHL [RATHL] trial). As the outcomes used in the analyses were reported among the overall population in RATHL, rather than stratified by specific treatment, there was no potential anchor for the analysis. PFS and OS data from RATHL were only available for adult patients ≤60 years old with stage III/IV aHL, therefore the treatment comparison was limited to patients within this age group. Matching variables were selected based on literature review and the results of Cox regression analyses of the E1 trial data. The International Prognostic Score and Eastern Cooperative Oncology Group scores were used as matching factors as available. The weights generated from the matching procedure were incorporated in weighted Cox regression models to generate hazard ratios (HR) and corresponding 95% confidence intervals (CI). To account for the potential of violating the proportional hazards assumption, additional metrics were calculated including piecewise HRs (95% CI) using Cox regression models for specific time intervals (i.e., 0 to 24, 24 months +) and restricted mean survival times (RMST). Results : In adult patients aged ≤60 years with Stage III/IV aHL, treatment with A+AVD generally led to increased PFS and OS vs PET-guided ABVD (Table1). As the proportional hazard assumption was violated, additional metrics were calculated (RMST and piecewise HRs). HRs and RMST for survival outcomes are reported in Table1. Conclusions: The findings of this indirect treatment comparison support the improved efficacy of A+AVD relative to PET-guided ABVD with respect to OS and PFS in patients with stage III and IV aHL consistent with the results of E1 study.

Lisocabtagene Maraleucel Versus Axicabtagene Ciloleucel: Efficacy and Toxicity in a Real-World Setting

CD19 CAR-T therapy has revolutionized the management of high-risk and relapsed/refractory (R/R) large B-cell lymphoma (LBCL) but remains limited by significant toxicities leading to morbidity/mortality and high resource utilization. Single-arm studies have suggested differences in efficacy and toxicity across FDA-approved CD19 CAR-T products. A matching-adjusted indirect treatment comparison showed comparable efficacy and more favorable safety with lisocabtagene maraleucel (liso-cel) compared to axicabtagene ciloleucel (axi-cel), but was limited to clinical trial patients (pts) and suffered from an absence of patient-level data (Maloney, J Hematol Oncol, 2021). In the absence of randomized clinical trial data, adjusted comparative analyses using pt-level data are critically needed to guide product choice. Therefore, we retrospectively evaluated the impact of CAR-T product type on the outcomes of 129 LBCL pts receiving liso-cel or axi-cel per standard of care. All LBCL pts treated at our center with liso-cel or axi-cel outside of a clinical trial between 1/2018 and 5/2023 were included. Best response was determined within 3 months of CAR-T infusion by PET-CT imaging per Lugano 2014 criteria. Cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS) were graded using ASTCT criteria. Of 129 total pts, 37% (n=48) and 63% (n=81) received liso-cel and axi-cel, respectively. Seven pts received out-of-specification liso-cel on an expanded access protocol. Pts who received liso-cel were older (median 67 vs 62 years, p=.003). Other baseline characteristics, including male sex (liso-cel vs axi-cel: 63% vs 69%, p=.4), HCT-CI score (1.0 vs 1.0, p=.6), pre-lymphodepletion (LD) LDH (178 vs 214 U/L, p=.14) and ALC (0.65 vs 0.60 x 10³/µL, p=.3), largest lesion diameter (3.1 vs 3.0 cm, p=.4), and extranodal disease (56% vs 56%, p>.9) were similar. The vein-to-vein time (time from leukapheresis to CAR-T infusion) was longer for liso-cel: median, 35 vs 27 days (p<.001). After liso-cel, the total inpt duration was shorter (median, 5 vs 14 days, p<.001) and fewer pts had ≥2 admissions (8.3% vs 22%, p=0.043). In pts with measurable disease prior to LD (n=113), we observed comparable efficacy with liso-cel vs axi-cel: ORR, 82% vs 77% (p=.5); CR, 56% vs 51% (p=.8). After a median follow-up of 17.7 months, we observed comparable 1-year outcomes with liso-cel vs axi-cel: duration of response (DOR), 56% vs 61% (p=.7); progression-free survival (PFS), 47% vs 47% (p=.99; Figure); and overall survival (OS), 69% vs 60% (p=.39). In pts evaluable for toxicity assessment (n=129), liso-cel was associated with lower rates of CRS and ICANS compared to axi-cel: any grade CRS, 62% vs 88% (p=.001); ICANS any grade, 32% vs 56% (p=.010); days with fever, median 2 vs 5 days (p<.001). Grade 3-4 CRS, 2.1% vs 9.9% (p=.2) or grade 3-4 ICANS, 23% vs 19% (p=0.5) were similar. We measured lower peak serum inflammatory markers after liso-cel: CRP, 58 vs 114 mg/L (p<.001); ferritin, 622 vs 1,315 ng/mL (p=0.007); IL-6, 55 vs 204 pg/mL (p=.010); and D-dimer, 1.4 vs 2.4 mg/L (p=.017). The incidence of infectious complications after liso-cel vs axi-cel was as follows: bacteremia: 6% vs 9% (p=.7); CMV viremia: 13% vs 6.2% (p=.3). Post-infusion median nadir cytopenias were less severe after liso-cel: ANC, 0.32 vs 0.04 x 10³/µL (p<.001); Plt, 69 vs 35 x 10³/µL (p=.003); and Hgb, 8.9 vs 8.2 g/dL (p<.001). Fewer pts developed severe neutropenia after liso-cel: 72% vs 93% (p=0.002). In multivariable analysis including pre-LD LDH and ALC, largest lesion diameter, age and HCT-CI score, we could not confirm an independent impact of the product type on CR, PFS, or OS ( Table). However, axi-cel remained independently associated with a higher odds of any grade CRS (adjusted OR [aOR] 4.56, 95% CI 1.65-13.5, p=.004) and any grade ICANS (aOR 3.44, 95% CI 1.42-8.85, p=.008). Our analysis of CD19 CAR-T therapy for R/R LBCL in the non-trial setting showed similar rates of durable responses following liso-cel and axi-cel. Pts who received liso-cel were older, with otherwise comparable baseline characteristics. Although liso-cel was associated with less toxicity, its vein-to-vein time was longer. In multivariable analyses, pre-LD LDH and largest lesion diameter were the only factors independently associated with response outcomes. We conclude that liso-cel is a robust alternative to other CD19 CAR-T products in older and frailer LBCL pts.

Tirzepatide 10 and 15 mg compared with semaglutide 2.4 mg for the treatment of obesity: An indirect treatment comparison.

To compare the efficacy of tirzepatide 10 and 15 mg with semaglutide 2.4 mg using an indirect treatment comparison. Using SURMOUNT-1 and STEP 1 trial data, mean percentage change in body weight from baseline and odds ratio (OR) of achieving 5% or greater weight loss were compared between tirzepatide 10 and 15 mg at week 72 and semaglutide 2.4 mg at week 68 using matching-adjusted indirect comparison of the efficacy estimand. Sensitivity analyses were completed using different methods, including the Bucher method, also using different estimands and/or time points. Greater reductions in percentage change in body weight were observed with tirzepatide 10 and 15 mg versus semaglutide 2.4 mg (tirzepatide 10 mg mean difference: -4.67% [95% CI -5.91%, -3.43%]; tirzepatide 15 mg mean difference: -5.92% [95% CI -7.16%, -4.68%]; both P < .001). Similarly, more participants achieved 5% or greater weight loss with tirzepatide 10 mg (OR 2.61 [95% CI 1.48, 4.57]; P < .001) and 15 mg (OR 2.75 [95% CI 1.57, 4.81]; P < .001) compared with semaglutide 2.4 mg. All sensitivity analyses were consistent, except for an OR of achieving 5% or greater weight loss with tirzepatide 10 mg using the Bucher method to analyse the treatment regimen estimand (P = .074). Currently there are no direct comparisons of tirzepatide and semaglutide for weight management. Using the matching-adjusted indirect treatment comparison method to compare the efficacy of tirzepatide and semaglutide for chronic weight management, this analysis showed greater weight loss with tirzepatide 10 and 15 mg versus semaglutide 2.4 mg.

A matching-adjusted indirect treatment comparison of elranatamab in patients with triple-class exposed relapsed/refractory multiple myeloma: Comparisons with belantamab mafodotin, selinexor plus dexamethasone, and real-world physician’s choice of treatment.

e20038 Background: Elranatamab, a bispecific antibody targeting B-cell maturation antigen on multiple myeloma (MM) cells and CD3 on T cells, is being evaluated as a monotherapy in the MagnetisMM-3 trial (MM3; NCT04649359) in patients with triple-class exposed (TCE) relapsed/refractory MM. While there is no standard of care for TCE MM, belantamab mafodotin (belamaf) and selinexor plus dexamethasone (sel-dex) are treatment options. LocoMMotion is a prospective, non-interventional study investigating real-world physician’s choice of treatment (PCT) in patients with TCE MM. In the absence of head-to-head trials, unanchored matching-adjusted indirect comparisons (MAIC) were conducted to compare the relative efficacy across comparators. Methods: Individual patient-level data were obtained for elranatamab from MM-3 (data cut Oct 2022). Aggregated data for belamaf, sel-dex, and PCT were obtained from DREAMM-2 (NCT03525678), STORM (NCT02336815), and LocoMMotion (NCT04035226). Unanchored MAICs were conducted to compare the relative treatment effect on objective response rate (ORR) accounting for potential different distributions of prognostic variables (PVs) and effect modifiers (EMs). In the base case, PVs identified via logistic regressions based on MM-3 data were adjusted. In sensitivity analyses, PVs/EMs identified from the literature were added. Relative treatment effects were measured by rate differences and odds ratios. Results: After MAIC adjustments, the selected PVs/EMs were balanced in each comparison. The table presents the results from the naïve comparison with no MAIC adjustment plus the MAIC base case. The ORR of elranatamab was statistically higher than belamaf, sel-dex, and PCT in LocoMMotion. Results were consistent across all sensitivity analyses. Conclusions: Elranatamab had a significantly higher ORR than belamaf, sel-dex, and real-world PCT in LocoMMotion for patients with TCE MM, demonstrating its clear clinical benefit for this population. [Table: see text]

Comparative Efficacy and Safety of Osilodrostat Vs Metyrapone for the Treatment of Cushing's Syndrome - a Matching-Adjusted Indirect Treatment Comparison

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

P-263: Matching-adjusted indirect treatment comparison (MAIC) of teclistamab vs approved therapies for the treatment of patients with triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM)

P-263: Matching-adjusted indirect treatment comparison (MAIC) of teclistamab vs approved therapies for the treatment of patients with triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM)

Matching-adjusted indirect treatment comparison (MAIC) of teclistamab (tec) versus belantamab mafodotin (belamaf) for the treatment of patients (pts) with triple-class exposed (TCE), relapsed/refractory multiple myeloma (RRMM).

8035 Background: Pts with RRMM who are TCE to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies have limited treatment options. While there is no standard of care for treatment of pts with TCE RRMM, belamaf is a recently approved, novel therapeutic option. MajesTEC-1 (NCT04557098) is a single-arm phase 1/2 study evaluating tec, a B-cell maturation antigen × CD3 bispecific antibody in pts with TCE RRMM who received ≥3 prior lines of therapy (LOT). Given the absence of a control arm in MajesTEC-1, we compared efficacy outcomes of pts who received tec at the recommended phase 2 dose in MajesTEC-1 with those of pts treated with belamaf in the phase 2 DREAMM-2 trial (NCT03525678). Methods: An unanchored MAIC was performed using individual pt-level data (IPD) from MajesTEC-1 (tec 1.5 mg/kg weekly; N = 150) at a clinical cutoff of Sep 7, 2021, and published summary-level data from pts who received the approved dose of belamaf in DREAMM-2 (2.5 mg/kg every 3 weeks; N = 97). The DREAMM-2 eligibility criteria were applied to pts from the intent-to-treat population of MajesTEC-1. IPD from MajesTEC-1 were weighted to match the aggregated DREAMM-2 baseline pt characteristics. Baseline characteristics of prognostic significance (refractory status, cytogenetic profile, International Staging System stage, presence of extramedullary disease, and number of prior LOT) were adjusted for in the analysis. Comparative efficacy of tec vs belamaf was estimated for overall response rate (ORR), complete response or better (≥CR) rate, progression-free survival (PFS), overall survival (OS), and duration of response (DOR). For binary endpoints (ORR and ≥CR rate), the relative effects of tec vs belamaf were quantified using an odds ratio (OR) and 95% CI derived from a weighted logistic regression analysis, while time-to-event endpoints (DOR, PFS, OS) were estimated using a weighted Cox proportional hazards model. Results: After adjustment, the effective sample size (ESS) of the MajesTEC-1 cohort was 33 and baseline characteristics for the reweighted MajesTEC-1 population were balanced with the DREAMM-2 population. Pts treated with tec had an improved ORR (OR 2.05; 95% CI 0.92–4.57; P= 0.0786), ≥CR rate (OR 2.13; 95% CI 0.80–5.65; P= 0.1283), PFS (HR 0.63; 95% CI 0.34–1.15; P= 0.1338), OS (HR 0.95; 95% CI 0.47–1.92; P= 0.8897), and DOR (hazard ratio [HR] 0.19; 95% CI 0.05–0.73; P= 0.0149) compared with belamaf. The reduced ESS following adjustment may account for the lack of statistical significance for most outcomes. Conclusions: These analyses demonstrated statistically improved DOR for tec vs belamaf and numerically favorable results for other outcomes, highlighting its potential as a treatment for pts with TCE RRMM who received ≥3 prior LOT.

Matching-adjusted indirect treatment comparison of the efficacy of enzalutamide versus apalutamide for the treatment of nonmetastatic castration-resistant prostate cancer

BackgroundTo date, the efficacy of the androgen receptor inhibitors enzalutamide and apalutamide for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC) has not been compared directly in a clinical trial setting. Indirect comparisons can be used to assess relative efficacy and provide important information to guide treatment decisions. PROSPER and SPARTAN were double-blind, randomized, placebo-controlled, phase III trials in patients with nmCRPC with overall similar study designs and inclusion and exclusion criteria. Using an anchored matching-adjusted indirect comparison, based on the final data from the PROSPER and SPARTAN studies, we assessed the comparative efficacy of enzalutamide and apalutamide, both plus androgen deprivation therapy.MethodsUsing placebo as the common comparator, individual patient data from PROSPER were matched to the aggregate patient data from SPARTAN and efficacy endpoints from PROSPER were re-weighted accordingly. Patient baseline characteristics and endpoints were clinically and statistically tested to identify potential effect modifiers, according to National Institute for Health and Care Excellence guidelines. Hazard ratios for overall survival (OS), metastasis-free survival (MFS), and time to chemotherapy (TTCx) were re-estimated for PROSPER using weighted Cox proportional hazards models and indirectly compared with those of SPARTAN using a Bayesian network meta-analysis.ResultsEstimated hazard ratios [95% credible interval (CrI)] for enzalutamide versus apalutamide were 0.80 (95% CrI 0.58-1.10) for OS, 0.94 (95% CrI 0.69-1.29) for MFS2, and 0.90 (95% CrI 0.63-1.29) for TTCx. Similar results were seen for sensitivity analyses conducted for OS and MFS. Bayesian probability analyses showed a 91.7% favoring enzalutamide for OS, 65.1% for MFS, and 71.4% for TTCx.ConclusionsThe results of this matching-adjusted indirect comparison of final data from PROSPER and SPARTAN indicate comparable efficacy of enzalutamide and apalutamide with potentially a greater probability of longer MFS, OS, and TTCx in patients with nmCRPC treated with enzalutamide versus apalutamide.

FC083: Finerenone and Canagliflozin in the Treatment of Chronic Kidney Disease and Type 2 Diabetes: Matching-Adjusted Indirect Treatment Comparison of Fidelio-DKD and Credence

Abstract BACKGROUND AND AIMS Finerenone (FIN: an oral, nonsteroidal mineralocorticoid receptor antagonist) and canagliflozin (CAN: a sodium-glucose cotransporter 2 inhibitor) demonstrated cardiorenal efficacy in patients with chronic kidney disease and type 2 diabetes on top of renin–angiotensin system blockade in phase III placebo-controlled studies (FIDELIO-DKD [NCT02540993] for FIN; CREDENCE [NCT02065791] for CAN) [3,2]. In the absence of head-to-head studies, we assessed FIN and CAN in this patient population while appropriately accounting for meaningful differences between the trials. METHOD We performed an anchored matching-adjusted indirect comparison (MAIC), with placebo (PBO) as a common comparator, to generate measures of efficacy and safety while accounting for differences between the two study populations [3]. Individual patient-level data from FIDELIO-DKD and published data from CREDENCE were used [1,[2]. Weights were calculated and assigned to each patient in FIDELIO-DKD so the weighted population of FIDELIO-DKD matched that of CREDENCE for selected baseline characteristics, e.g. mean estimated glomerular filtration rate (eGFR; 44.3 and 56.2 mL/min/1.73 m2 in FIDELIO-DKD and CREDENCE, respectively). Weights were obtained from a logistic regression model of the odds of enrolment in CREDENCE and FIDELIO-DKD for baseline characteristics believed to be effect modifiers. Hazard ratios (HRs) with 95% confidence intervals (CIs) comparing FIN and PBO for time-to-event endpoints were estimated based on the weighted population of FIDELIO-DKD. HRs with 95% CIs comparing FIN and CAN were then calculated from results of the previous step and published data from CREDENCE [2]. This analysis evaluated the cardiorenal composite endpoint from CREDENCE (kidney failure [dialysis, transplantation or sustained eGFR &amp;lt; 15 mL/min/1.73 m2), a doubling of serum creatinine level or death from kidney or cardiovascular disease) [2] and hyperkalaemia. A sensitivity analysis that matched patients based on their history of heart failure was performed. RESULTS Calculation of the weights for the FIDELIO-DKD population (N = 5674) resulted in an effective sample size of 1288 for the pseudo-population formed by the weighting to compare with the CREDENCE population (N = 4401). For the cardiorenal composite endpoint, the HR (95% CI) for FIN and PBO based on reweighted FIDELIO-DKD data was 0.72 (0.59–0.90) and the MAIC-based HR (95% CI) for FIN and CAN was 1.03 (0.79–1.35) (P = 0.802). For hyperkalaemia, the MAIC-based HR (95% CI) for FIN and CAN was 2.25 (1.67–3.03) (P &amp;lt; 0.001). Similar efficacy and safety results were demonstrated in the sensitivity analysis. CONCLUSION The MAIC for FIDELIO-DKD and CREDENCE enabled more robust assessment of FIN and CAN when a similar patient population was considered. There was no evidence of a significant difference between FIN and CAN in the cardiorenal composite endpoint as assessed in CREDENCE. These results are consistent with a recent analysis using a different payer-accepted method that also accounted for differences between the FIDELIO-DKD and CREDENCE inclusion criteria and endpoints [3,4].

Matching-adjusted indirect treatment comparison of chimeric antigen receptor T-cell therapies for third-line or later treatment of relapsed or refractory large B-cell lymphoma: lisocabtagene maraleucel versus tisagenlecleucel

BackgroundThere are no head-to-head clinical studies comparing chimeric antigen receptor (CAR) T-cell therapies for the treatment of relapsed or refractory aggressive large B-cell lymphomas. Naive, indirect comparisons may be inappropriate, as the study designs and patient populations could differ substantially. Matching-adjusted indirect comparisons (MAIC) can reduce many biases associated with indirect comparisons between studies. To determine the comparative efficacy and safety of lisocabtagene maraleucel (liso-cel) to tisagenlecleucel, we describe an unanchored MAIC of the pivotal studies TRANSCEND NHL 001 (TRANSCEND; NCT02631044; liso-cel) and JULIET (NCT02445248; tisagenlecleucel).MethodsIndividual patient data (IPD) from TRANSCEND were available to the authors; for the JULIET pivotal study, summary-level data from the published study were used. To balance the populations between two studies, IPD from TRANSCEND were adjusted to match the marginal distribution (e.g., mean, variance) of clinical factors among patients from JULIET.ResultsResults from the primary MAIC showed liso-cel had statistically significant greater efficacy than tisagenlecleucel (objective response rate: odds ratio [OR] = 2.78, 95% confidence interval [CI]: 1.63‒4.74; complete response rate: OR = 2.01, 95% CI: 1.22‒3.30; progression-free survival: hazard ratio [HR] = 0.65, 95% CI: 0.47‒0.91; overall survival: HR = 0.67, 95% CI: 0.47‒0.95). MAIC of safety outcomes showed lower ORs for all-grade and grade ≥ 3 cytokine release syndrome, and grade ≥ 3 prolonged cytopenia for liso-cel when compared with tisagenlecleucel; there were no statistically significant differences detected for other safety outcomes.ConclusionsOverall, this MAIC of two CAR T-cell therapies indicates liso-cel had favorable efficacy and a comparable or better safety profile relative to tisagenlecleucel.Clinical trial registration: ClinicalTrials.gov identifiers: NCT02631044 and NCT02445248.

Carfilzomib 56 mg/m2 twice-weekly in combination with dexamethasone and daratumumab (KdD) versus daratumumab in combination with bortezomib and dexamethasone (DVd): a matching-adjusted indirect treatment comparison

Given the increasing use of frontline lenalidomide-based therapies in multiple myeloma (MM), there is an emerging need for lenalidomide-sparing regimens at relapse. Carfilzomib plus dexamethasone and daratumumab (KdD) and daratumumab plus bortezomib and dexamethasone (DVd) are lenalidomide-sparing triplet regimens that are approved for relapsed and/or refractory MM (R/RMM). In the absence of a head-to-head trial comparing these treatments, a matching-adjusted indirect treatment comparison (MAIC) was conducted to assess the efficacy and safety of KdD versus DVd. Results showed that treatment with KdD decreases the risk of progression or death versus DVd (HR 0.64; 95% confidence interval (CI): 0.46–0.90). Time-dependent analysis demonstrated a larger benefit for KdD after the first eight cycles. Unmatched subgroup analysis indicated that KdD may be particularly effective in lenalidomide-exposed and -refractory patients. The present analysis suggests that KdD improves outcomes compared with DVd in patients with R/RMM and may provide a rationale for a preferential treatment.

Matching-Adjusted Indirect Treatment Comparison (MAIC) of Acalabrutinib Alone or in Combination with Obinutuzumab Versus Ibrutinib or Venetoclax Plus Obinutuzumab in Patients with Treatment-Naïve Chronic Lymphocytic Leukemia

Introduction: Acalabrutinib (A) and ibrutinib (I) are both highly effective Bruton tyrosine kinase inhibitors (BTKi) approved for the treatment of chronic lymphocytic leukemia (CLL) and given as continuous treatments until disease progression or unacceptable toxicity. Venetoclax is a BH3 mimetic compound and B-cell lymphoma-2 inhibitor prescribed in combination with obinutuzumab (V+O) for a fixed (12-cycle) duration in treatment-naïve CLL patients. Although the ELEVATE-RR study demonstrated an improved safety profile of A compared with I in a head-to-head clinical trial, this study did not include treatment-naïve CLL patients (Byrd et al. J Clin Oncol. 2021). This MAIC builds upon the published analysis by Davids et al (Leuk Lymphoma. 2021) in treatment-naïve patients with CLL (which demonstrated a favorable safety profile for A-based therapy compared with other targeted therapies without compromising efficacy) by including longer follow-up data for A and the comparators.Methods: Individual patient data for A ± obinutuzumab (A+O) from ELEVATE-TN (47 months median follow-up) (Sharman et al. ASCO 2021) were weighted to match the aggregate baseline characteristics of the I monotherapy arm from the ALLIANCE trial (Woyach et al. NEJM. 2018) (I + rituximab was not included as this treatment is not approved for CLL) and the V+O arm from the CLL-14 trial (Al-Sawaf et al. Lancet Oncol 2020). These baseline characteristics, TP53 mutation, serum β 2 microglobulin, ECOG, IGHV status, del(11q), CrCl, Rai stage or CLL-IPI, are potential prognostic variables (PV). Pseudo-individual patient data were generated from the digitized Kaplan-Meier curves published in the aforementioned comparator trials. An unanchored MAIC was conducted to adjust for these PVs between trials. The PVs selected were based on literature, clinical judgement, and demonstrated statistically significant association with progression-free survival (PFS) in univariate and multivariate regression analysis (Ahn et al. J Clin Oncol. 2020; Eichorst and Hallek. Hematol Am Soc Hematol Educ Prog. 2016). After matching, a weighted Cox proportional hazard model was used to analyze PFS and overall survival (OS) while a weighted logistic regression model was used for comparative safety analysis (grade ≥3 adverse events [AEs]). Two-sided p<0.05 was considered statistically significant.Results: This MAIC included 47-month data from ELEVATE-TN, 38-month data from ALLIANCE, and 40-month data from CLL-14 as opposed to 28-month data from ELEVATE-TN, 29-month data from RESONATE-2, and 29-month data from CLL-14 included in the previously published analysis. In the A vs I comparison, the PFS (hazard ratio [HR] 0.83 [95% CI 0.50, 1.37]) and OS (HR 0.69 [95% CI 0.37, 1.29]) numerically favored A but the difference was not significant. The A vs V+O comparison did not show significant differences in PFS (HR 0.96 [95% CI 0.56, 1.65] and OS (HR 0.99 [95% CI 0.51, 1.91]). For A+O vs I, significant differences in PFS (HR 0.48 [95% CI 0.27, 0.88]) and OS (HR 0.41 [95% CI 0.18, 0.91]) were observed. Similarly, for A+O vs V+O, significant differences were observed for PFS (HR 0.38 [95% CI 0.20, 0.73]) and OS (HR 0.43 [95% CI 0.19, 0.99]). Significant differences in rate of grade ≥3 AEs in favor of A and A+O were observed vs I for atrial fibrillation, hypertension, decreased neutrophil count, and decreased platelet count. Compared with V+O, patients treated with A had significantly lower rates of febrile neutropenia, leukopenia, neutropenia, thrombocytopenia, non-melanoma skin cancer, and secondary primary malignancies, excluding non-melanoma skin cancer. For A+O vs V+O, significantly lower rates of infusion-related reaction, neutropenia, and non-melanoma skin cancer were observed among patients treated with A+O.Conclusions: Based on these MAIC results, A and A+O are associated with a favorable safety profile vs both I and V+O while, with longer follow-up, these MAIC results demonstrate that A+O is associated with a significant efficacy benefit vs both I and V+O. A limitation of this MAIC is not including all potential PVs as a trade-off to conserve the effective sample size. Our findings are consistent with the results of ELEVATE-RR comparing A with I in the relapsed population and also provide insight into comparisons of A-based therapy with V+O as we await more definitive prospective data on this question from a phase 3 trial. [Display omitted] DisclosuresDavids: Genentech: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly and Company: Consultancy; BMS: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Janssen: Consultancy; Novartis: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy. Emeribe: AstraZeneca: Current Employment, Current holder of stock options in a privately-held company. Gaitonde: AstraZeneca: Current Employment, Current holder of stock options in a privately-held company, Research Funding. Cai: AstraZeneca: Current Employment, Current equity holder in publicly-traded company; Google: Current equity holder in publicly-traded company; Celgene Corporation: Ended employment in the past 24 months.

Belantamab mafodotin for the treatment of relapsed/refractory multiple myeloma in heavily pretreated patients: a US cost-effectiveness analysis

ABSTRACT Background Patients with relapsed/refractory multiple myeloma (RRMM) require several lines of therapy, with typically shorter remission duration with each additional line. Research design and methods The cost-effectiveness of belantamab mafodotin (belamaf; DREAMM-2; NCT03525678) was compared with selinexor plus dexamethasone (SEL+DEX; STORM Part 2; NCT02336815) among patients with RRMM who have received at least four prior therapies. The base case used a US commercial payer’s perspective over a 10-year time horizon. Efficacy data were based on parametric survival analysis of DREAMM-2 and matching-adjusted indirect treatment comparison between DREAMM-2 and STORM Part 2, which assessed relative treatment effects between belamaf and SEL+DEX. Cost inputs included drug treatment, concomitant medications, adverse event management, subsequent treatments, and disease management. Results Belamaf decreased total treatment costs per patient by $14,267 and increased patient life years by 0.74 and quality-adjusted life years (QALYs) by 0.49 versus SEL+DEX. Patients receiving belamaf accrued 0.12 fewer progression-free life years versus patients on SEL+DEX. Conclusions From a US commercial payer’s perspective, belamaf had lower costs, and increased QALYs and life-year gain, compared with SEL+DEX. Belamaf is therefore likely to be a cost-effective treatment option for patients with RRMM who have received four or more prior lines of therapy.

Matching-adjusted indirect treatment comparison of liso-cel versus axi-cel in relapsed or refractory large B cell lymphoma

BackgroundIn the absence of randomized studies directly comparing chimeric antigen receptor T cell therapies, this study used matching-adjusted indirect comparisons (MAIC) to evaluate the comparative efficacy and safety of lisocabtagene maraleucel (liso-cel) versus axicabtagene ciloleucel (axi-cel) in patients with relapsed or refractory large B cell lymphoma (LBCL).MethodsPrimary data sources included individual patient data from the TRANSCEND NHL 001 study (TRANSCEND [NCT02631044]; N = 256 for efficacy set, N = 269 for safety set) for liso-cel and summary-level data from the ZUMA-1 study (NCT02348216; N = 101 for efficacy set, N = 108 for safety set) for axi-cel. Inter-study differences in design, eligibility criteria, baseline characteristics, and outcomes were assessed and aligned to the extent feasible. Clinically relevant prognostic factors were adjusted in a stepwise fashion by ranked order. Since bridging therapy was allowed in TRANSCEND but not ZUMA-1, the initial efficacy and safety analyses included bridging therapy use as a matching factor (TRANSCEND patients who received bridging therapy were removed). Subsequent sensitivity analyses excluded this matching factor.ResultsThe initial analysis showed similar MAIC-weighted efficacy outcomes between TRANSCEND and ZUMA-1 for overall and complete response rates (odds ratio [95% confidence interval (CI)], 1.40 [0.56–3.49] and 1.21 [0.56–2.64], respectively) and for overall survival and progression-free survival (hazard ratio [95% CI], 0.81 [0.44–1.49] and 0.95 [0.58–1.57], respectively). MAIC-weighted safety outcomes favored liso-cel, with significantly lower odds of all-grade and grade ≥ 3 cytokine release syndrome (odds ratio [95% CI], 0.03 [0.01–0.07] and 0.08 [0.01–0.67], respectively) and study-specific neurological events (0.16 [0.08–0.33] and 0.05 [0.02–0.15], respectively). Efficacy and safety outcomes remained similar in sensitivity analyses, which did not include use of bridging therapy as a matching factor.ConclusionsAfter matching and adjusting for clinically relevant prognostic factors, liso-cel demonstrated comparable efficacy and a more favorable safety profile compared with axi-cel in patients with third- or later-line relapsed or refractory LBCL.Trial registration: NCT02631044 and NCT02348216

Matching-adjusted indirect treatment comparison of onasemnogene abeparvovec and nusinersen for the treatment of symptomatic patients with spinal muscular atrophy type 1

Objective Onasemnogene abeparvovec, a one-time intravenous gene replacement therapy, and nusinersen, an antisense oligonucleotide that requires ongoing intrathecal administration, have been evaluated as treatments for spinal muscular atrophy (SMA) type 1 in separate Phase III trials, but no head-to-head comparison studies have been conducted. Onasemnogene abeparvovec was compared with nusinersen using a matching-adjusted indirect comparison (MAIC) to estimate the treatment effect of onasemnogene abeparvovec relative to nusinersen for the treatment of symptomatic patients with SMA type 1 for up to 24 months of follow-up. Methods In the absence of studies for both onasemnogene abeparvovec and nusinersen with a common comparator, a Bayesian naïve indirect treatment comparison (ITC) and MAIC between onasemnogene abeparvovec and nusinersen were conducted to compare efficacy and safety of onasemnogene abeparvovec with nusinersen. Outcomes of interest were event-free survival (EFS), overall survival (OS), and motor milestone achievements (independent sitting and independent walking). Relative treatment effects were expressed as relative risk (RR) and risk difference. Results Pooled and weighted patient-level data illustrated a favorable effect toward onasemnogene abeparvovec, suggesting longer EFS for patients compared with nusinersen (HR of onasemnogene abeparvovec vs. nusinersen: 0.19 [95% CI: 0.07–0.54; 99% CI: 0.05–0.74]). At 24 months of follow-up, patients receiving onasemnogene abeparvovec were statistically significantly more likely to achieve the motor milestone of sitting independently compared with patients treated with nusinersen. Although statistically significant differences were not observed at 6 to 18 months between treatment options, the likelihood of sitting independently at 12 and 18 months numerically favored onasemnogene abeparvovec. A numerically greater likelihood of walking by 18 and 24 months was also observed for patients treated with onasemnogene abeparvovec compared with nusinersen. Onasemnogene abeparvovec therapy was also associated with a favorable (but statistically nonsignificant) outcome for OS and may be associated with prolonged survival compared with nusinersen (HR of onasemnogene abeparvovec vs. nusinersen: 0.35 [95% CI: 0.09–1.32; 99% CI: 0.06–2.01]). Bayesian naïve ITC results were similar to the MAIC analysis for EFS, OS, and motor milestone achievements. Small sample size limited covariate matching to baseline CHOP INTEND and nutritional support requirement, leading to wider CIs and statistically inconclusive outcomes for some of the results. Conclusions Despite limitations of the current MAIC analysis (mainly a small sample size for statistical testing, even for the pooled onasemnogene abeparvovec trials, and potential differences in prognostic and predictive factors between studies), the relative treatment effects in EFS, OS, and motor milestone achievement indicate that onasemnogene abeparvovec may offer continued benefit compared with nusinersen through 24 months of follow-up.

Effectiveness of Radiofrequency Catheter Ablation Using Ablation Index Versus Second Generation Cryoballoon in the Treatment of Persistent Atrial Fibrillation: A Matching-Adjusted Indirect Comparison.

IntroductionBoth radiofrequency (RF) and cryoballoon (CB) ablation are treatment options for persistent atrial fibrillation (PsAF). An important recent innovation in RF ablation is Ablation Index (AI), known also as the VISITAG SURPOINT™ Module, a composite lesion quality marker whose use has been shown to significantly reduce the incidence of acute and late pulmonary vein (PV) reconnection and the recurrence of atrial arrhythmias in PsAF. Due to a lack of direct comparative evidence between the latest generations of technologies, there is uncertainty regarding the best treatment option in PsAF. The objective of the present study was to conduct a matching-adjusted indirect treatment comparison (MAIC) using individual patient-level data (IPD) to assess the comparative effectiveness of the THERMOCOOL SMARTTOUCH™ Catheter or the THERMOCOOL SMARTTOUCH™ SF Catheter with AI/VISITAG SURPOINT™ Module (STAI) versus the second-generation CB catheter (Arctic Front Advance™; herein referred to as CB) with respect to 12-month atrial arrhythmia recurrence, fluoroscopy time, and procedural efficiency.MethodsIPD for STAI were obtained from four investigator-initiated studies and were pooled. Comparable CB studies identified from a systematic literature review were also pooled. In the absence of a common treatment arm between STAI and CB studies, an unanchored MAIC was conducted. The primary analysis compared the pooled STAI IPD to the pooled CB cohort, with corrections for differences across trials, including eligibility criteria and patient baseline characteristics. Scenario and sensitivity analyses were conducted to assess the robustness of the primary analysis.ResultsIn the primary analysis, which was adjusted for left atrial diameter (LAD), age, diabetes, and sex, STAI was associated with a statistically significant 65% relative reduction in the rate of arrhythmia recurrence compared to CB at 12-month follow-up (HR 0.35; 95% CI 0.23, 0.52). STAI was associated with shorter total fluoroscopy time than CB but longer procedure time. Results were consistent across scenario and sensitivity analyses.ConclusionRadiofrequency ablation with AI significantly reduced atrial arrhythmia recurrence at 12-month follow-up and fluoroscopy time compared to CB, with longer procedure times.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01846-z.

Matching-adjusted indirect treatment comparison of ozanimod versus teriflunomide for relapsing multiple sclerosis

BackgroundA growing number of immunomodulating disease-modifying therapies are available for treatment of relapsing multiple sclerosis (RMS). In the absence of randomized head-to-head trials, matching-adjusted indirect comparisons (MAICs) can be used to adjust for cross-trial differences and evaluate the comparative efficacy and safety of these agents. We used MAIC methodology to indirectly compare key outcomes with ozanimod (OZM) and teriflunomide (TERI) in the treatment of RMS. MethodsA systematic literature review was conducted to identify clinical trials evaluating the efficacy and safety of OZM vs TERI. Given the absence of head-to-head trials of OZM vs TERI, we used a matching-adjusted indirect comparison to adjust for potential treatment effect modifiers and prognostic factors while assessing confirmed disability progression (CDP), relapse, and safety outcomes. Individual patient data for OZM (SUNBEAM and RADIANCE Part B trials) and aggregate level data for TERI (ASCLEPIOS I/II, TOWER, OPTIMUM, and TEMSO trials) were used to evaluate the following outcomes: annualized relapse rate (ARR), proportion of patients relapsed, CDP at 3 and 6 months, overall adverse events (AEs), serious AEs (SAEs), and discontinuations due to AEs. ResultsAfter matching, baseline patient characteristics were balanced between OZM and TERI. Compared with TERI, OZM demonstrated significant improvements in ARR (rate ratio: 0.73; 95% CI: 0.62–0.84), proportion of patients relapsed (odds ratio [OR]: 0.56; 95% CI: 0.44–0.70), overall AEs (OR: 0.35; 95% CI: 0.29–0.43), SAEs (OR: 0.53; 95% CI: 0.37–0.77), and discontinuations due to AEs (OR: 0.14; 95% CI: 0.09–0.21). OZM demonstrated statistically significant improvements in CDP at 3 months (hazard ratio [HR]: 0.78; 95% CI: 0.66–0.92) but nonsignificant differences at 6 months (HR: 0.78; 95% CI: 0.60–1.01) compared with TERI. ConclusionIn this indirect treatment comparison of patients with RMS, OZM appeared to have an improved benefit–risk profile over TERI.