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Backgound Lenalidomide‐based regimens are commonly used for early relapse in patients with relapsed and/or refractory multiple myeloma (RRMM) receiving at least one prior line of therapy. In the absence of head‐to‐head comparison, matching‐adjusted indirect comparison (MAIC) was conducted to demonstrate efficacy and safety of isatuximab+carfilzomib+dexamethasone (Isa‐Kd) versus daratumumab + lenalidomide + dexamethasone (Dara‐Rd) in RRMM. Methods Patient‐level data from IKEMA trial (Isa‐Kd, n = 179) were matched to aggregate data from POLLUX (Dara‐Rd, n = 286). Hazard ratios (HR) and 95% confidence intervals (CI) for progression‐free survival (PFS) and overall survival (OS) were generated by weighted Cox proportional hazard models. Odds ratios (OR), 95% CI, and p‐value were calculated for ≥very good partial response (≥VGPR) and treatment‐emergent adverse events (TEAEs). Results After matching, no significant differences were observed between Isa‐Kd and Dara‐Rd in baseline characteristics except for patients with >3 prior lines (0.0% vs. 4.9%). Isa‐Kd showed significantly better PFS (HR [95% CI]: 0.46 [0.24–0.86]; p = 0.0155), statistically non‐significant improvement favoring Isa‐Kd in OS (0.47 [0.20–1.09]; 0.0798), and ≥VGPR (OR [95% CI]: 1.53 [0.89–2.64]; p = 0.1252) than Dara‐Rd. Odds of occurrence were significantly lower for some all‐grade and grade 3/4 TEAEs with Isa‐Kd than Dara‐Rd. Conclusion These results support Isa‐Kd as an efficacious treatment for early relapse in non‐lenalidomide refractory patients. Matching‐adjusted indirect comparison results for Isa‐Kd vs. Dara‐Rd: Kaplan‐Meier curves of progression‐free survival before matching and after inclusion criteria selection (A) and after matching (B); Kaplan‐Meier curves of overall survival before matching and after inclusion criteria selection (C) and after matching (D). CI, confidence interval; Dara‐Rd, daratumumab + lenalidomide + dexamethasone; HR, hazard ratio; Isa‐Kd, isatuximab + carfilzomib + dexamethasone. *Statistically significant at 0.05 level.

Population-adjusted indirect comparisons (PAICs) were developed in the 2010s to allow for comparisons between two treatments evaluated in different trials while accounting for differences in patient characteristics if individual patient data (IPD) are available for only one trial. Such comparisons are increasingly used in market access applications when a pharmaceutical company compares its new treatment (with IPD available) to another treatment developed by a competitor (with only aggregated data available). This study aimed to describe the characteristics of these PAICs, assess their methodology, and describe the reported results. Original articles reporting the use of at least one PAIC were searched on PubMed between January 1, 2010 and April 2, 2022. Two reviewers independently selected articles and extracted data. We included 133 publications reporting the results of 288 PAICs. Half of the articles were published on or after May 7, 2020, and 71 (53%) pertained to onco-hematology. The pharmaceutical industry was involved in 130 (98%) articles. Key methodological aspects were reported inconsistently, with only three articles adequately reporting all aspects. A total of 161 (56%) articles reported a statistically significant benefit for the treatment evaluated on IPD. Conversely, only one PAIC significantly favored the treatment evaluated on aggregated data. Although the number of published PAICs is increasing, the methodology and transparency need to be improved. Moreover, our study strongly suggests a reporting bias. This situation calls for strengthening guidelines to improve trust in PAIC results and thus their reliability in market access applications. [Display omitted] •Population-adjusted indirect comparisons have increased in popularity recently.•Most publications focused on oncologic and hematologic pathologies.•Methodology and reporting standards were insufficient.•Collected results suggest a major reporting and publication bias.•We propose some reporting guidelines to strengthen confidence in these methods.

Background Anchored covariate-adjusted indirect comparisons inform reimbursement decisions where there are no head-to-head trials between the treatments of interest, there is a common comparator arm shared by the studies, and there are patient-level data limitations. Matching-adjusted indirect comparison (MAIC), based on propensity score weighting, is the most widely used covariate-adjusted indirect comparison method in health technology assessment. MAIC has poor precision and is inefficient when the effective sample size after weighting is small. Methods A modular extension to MAIC, termed two-stage matching-adjusted indirect comparison (2SMAIC), is proposed. This uses two parametric models. One estimates the treatment assignment mechanism in the study with individual patient data (IPD), the other estimates the trial assignment mechanism. The first model produces inverse probability weights that are combined with the odds weights produced by the second model. The resulting weights seek to balance covariates between treatment arms and across studies. A simulation study provides proof-of-principle in an indirect comparison performed across two randomized trials. Nevertheless, 2SMAIC can be applied in situations where the IPD trial is observational, by including potential confounders in the treatment assignment model. The simulation study also explores the use of weight truncation in combination with MAIC for the first time. Results Despite enforcing randomization and knowing the true treatment assignment mechanism in the IPD trial, 2SMAIC yields improved precision and efficiency with respect to MAIC in all scenarios, while maintaining similarly low levels of bias. The two-stage approach is effective when sample sizes in the IPD trial are low, as it controls for chance imbalances in prognostic baseline covariates between study arms. It is not as effective when overlap between the trials’ target populations is poor and the extremity of the weights is high. In these scenarios, truncation leads to substantial precision and efficiency gains but induces considerable bias. The combination of a two-stage approach with truncation produces the highest precision and efficiency improvements. Conclusions Two-stage approaches to MAIC can increase precision and efficiency with respect to the standard approach by adjusting for empirical imbalances in prognostic covariates in the IPD trial. Further modules could be incorporated for additional variance reduction or to account for missingness and non-compliance in the IPD trial.

Background The goal of on-demand treatment for hereditary angioedema attacks is to halt attack progression to minimize morbidity and mortality. Four on-demand treatments have been approved thus far (ecallantide, icatibant, recombinant human C1 esterase inhibitor [rhC1INH], and plasma-derived C1INH). Results from the sebetralstat phase 3 KONFIDENT trial (NCT05259917) have been reported. To put these results into context without head-to-head trials, an indirect treatment comparison (ITC) was conducted to facilitate comparisons of efficacy and safety across treatment options. Methods Based on a systematic literature review and feasibility assessment, only the pivotal trial for intravenous rhC1INH (NCT01188564) reported necessary data for a comparable primary efficacy endpoint (time to beginning of symptom relief) to enable an ITC with oral sebetralstat. Bayesian fixed-effects network meta-analyses models were conducted to indirectly compare the efficacy and safety outcomes of sebetralstat and rhC1INH (NCT01188564, NCT00225147, NCT00262301). A matching-adjusted indirect comparison (MAIC) of efficacy was performed, adjusting for baseline attack severity and demographic characteristics. Results The fixed-effects model found no significant differences in time to beginning of symptom relief between sebetralstat 300 mg and rhC1INH 50 IU/kg (hazard ratio [95% credible interval], 0.96 [0.42–2.15] to 1.19 [0.58–2.45]). After adjusting for baseline attack severity, the MAIC showed numerically favorable results with sebetralstat compared with rhC1INH, regardless of whether baseline demographics were matched. The fixed-effects model found no significant differences in treatment-related treatment-emergent adverse events. All sensitivity analyses returned consistent results. Conclusions This ITC found no significant differences in time to beginning of symptom relief and overall treatment-related treatment-emergent adverse events between sebetralstat and rhC1INH.

Background In 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). Methods Primary 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. Results The 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. Conclusions After 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

Abstract Background Without head-to-head trials comparing talazoparib plus enzalutamide (TALA+ENZA), olaparib plus abiraterone acetate and prednisone (OLAP+AAP), and niraparib plus abiraterone acetate and prednisone (NIRA+AAP) as first-line treatments for metastatic castration-resistant prostate cancer (mCRPC), treatment selection remains challenging. This study estimated the relative efficacy of TALA+ENZA vs OLAP+AAP and NIRA+AAP in unselected, homologous recombination repair (HRR)-deficient, and BRCA-mutated (BRCAm) populations. Methods Unanchored matching-adjusted indirect comparisons (MAICs) were conducted using individual patient data from TALAPRO-2 (TALA+ENZA) and published summary-level data from PROpel (OLAP+AAP) and MAGNITUDE (NIRA+AAP). TALAPRO-2 patients meeting PROpel/MAGNITUDE eligibility criteria were included; remaining patients were reweighted to align on key baseline characteristics. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for radiographic progression-free survival (rPFS) and overall survival (OS). Results In unselected patients, TALA+ENZA significantly prolonged rPFS vs OLAP+AAP (HR: 0.747; 95% CI, 0.583, 0.957), with no OS difference (HR: 0.821; 95% CI, 0.649, 1.039). In HRR-deficient patients, TALA+ENZA significantly prolonged rPFS vs OLAP+AAP (HR: 0.648; 95% CI, 0.423, 0.992), with no OS difference (HR: 0.834; 95% CI, 0.569, 1.223). Comparisons with OLAP+AAP in BRCAm were infeasible. Compared with NIRA+AAP, TALA+ENZA significantly prolonged rPFS and OS in HRR-deficient (HR: 0.406; 95% CI, 0.251, 0.655; HR: 0.554; 95% CI, 0.340, 0.902) and BRCAm patients (HR: 0.394; 95% CI, 0.222, 0.698; HR: 0.472; 95% CI, 0.247, 0.902). Conclusions MAICs showed improved clinical benefit with TALA+ENZA vs OLAP+AAP and NIRA+AAP across multiple mCRPC populations and endpoints. Despite limitations of indirect comparisons, findings support TALA+ENZA as a first-line treatment option for mCRPC.

Blockade of the PD-L1/PD-1 pathway combined with chemotherapy has demonstrated significant survival benefits as first‑line therapy for esophageal squamous cell carcinoma (ESCC). However, comprehensive benefit-risk comparisons among approved agents remain limited. This study conducted an indirect comparison of serplulimab versus other anti-PD-1/PD-L1 antibodies plus chemotherapy in treatment-naïve ESCC patients. A systematic review with matching-adjusted indirect comparisons (MAICs) was conducted using individual patient data (IPD) from ASTRUM-007 and aggregate data (AgD) from seven comparator trials, including CheckMate 648, ESCORT-1st, GEMSTONE-304, JUPITER-06, KEYNOTE-590, ORIENT-15, and RATIONALE-306. IPD were reweighted to match key baseline characteristics. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were estimated using the Bucher method. Subgroup analyses were further explored using Bayesian network meta-analysis. Eight Phase 3 randomized controlled trials comprising 4,702 patients were included. After adjusting for baseline imbalances, serplulimab demonstrated comparable efficacy to other PD-1/PD-L1 inhibitors. The pooled adjusted OS HR was 0.98 (95% CI, 0.87-1.11), with numerically favorable OS versus nivolumab (HR, 0.76; 95% CI 0.47-1.24) and comparable OS versus pembrolizumab (HR, 0.93; 95% CI, 0.71-1.22) and camrelizumab (HR, 0.93; 95% CI, 0.70-1.24). The pooled adjusted PFS HR was 0.91 (95% CI, 0.81-1.02), significantly favoring serplulimab over nivolumab (HR, 0.56; 95% CI, 0.33-0.96), with favorable trends versus pembrolizumab (HR, 0.83; 95% CI, 0.63-1.10) and sugemalimab (HR, 0.86; 95% CI, 0.63-1.16). Subgroup analyses suggested greater relative benefit in women and patients with locally advanced disease. Grade 3-5 treatment-related adverse events occurred in 52.9% of serplulimab-treated patients, comparable to other PD-1/PD-L1 inhibitors (range, 47.4%-71.9%). This indirect comparison provides comparative benefit-risk evidence to inform first‑line treatment selection for locally advanced or metastatic ESCC. Serplulimab plus chemotherapy demonstrated a clinically meaningful PFS benefit, comparable OS after matching, and a manageable safety profile consistent with the PD-1/PD-L1 inhibitor class.

Background Edaravone dexborneol and dl-3-n-butylphthalide are two innovative brain cytoprotective drugs from China that have been approved and widely prescribed for acute ischemic stroke, and the cost of the two drugs are partially paid by the Chinese medical insurance system. This study aimed to investigate and compare the cost-effectiveness of edaravone dexborneol versus dl-3-n-butylphthalide for acute ischemic stroke from the Chinese healthcare system’s perspective. Methods A model combining a short-term decision tree model with 90 days and a long-term Markov model with a life-time horizon (40 years) was developed to simulate the cost-effectiveness of edaravone dexborneol versus dl-3-n-butylphthalide for acute ischemic stroke over a lifetime horizon. Since the absence of a head-to-head clinical comparison of two therapies, an unanchored matching-adjusted indirect comparison (MAIC) was conducted by adjusting the patient characteristics using individual patient data from pivotal phase III trial of edaravone dexborneol and published aggregated data of dl-3-n-butylphthalide. Health outcomes were measured in quality-adjusted life years (QALYs). Utilities and costs (Chinese Yuan, CNY) were derived from publications and open-access database. One-way and probabilistic sensitivity analyses were performed to evaluate the robustness of results. Results Compared with patients in dl-3-n-butylphthalide arm, edaravone dexborneol arm was found to be cost-effective in 90 days and highly cost-effective as the study horizons extended. With a similar direct medical cost, patients in edaravone dexborneol arm slightly gained an additional 0.1615 QALYs in life-time. In the long term (40 years), patients in edaravone dexborneol arm and dl-3-n-butylphthalide arm yielded 8.0351 and 7.8736 QALYs with the overall direct medical cost of CNY 29,185.23 and CNY 29,940.28, respectively. The one-way sensitivity analysis suggested that the incremental cost-effectiveness ratio was most sensitive to the price of edaravone dexborneol and dl-3-n-butylphthalide. Conclusion Edaravone dexborneol is a cost-effective alternative compared with dl-3-n-butylphthalide for acute ischemic stroke patients in current medical setting of China.

Objective: Dinutuximab beta (DB) and naxitamab (NAXI) with GM-CSF are used for maintenance treatment of relapsed/refractory neuroblastoma. The objective of this study was to systematically assess comparative efficacy of the two therapies within their designated indications in accordance with established clinical guidelines. Methods: Relevant evidence was identified in systematic literature review. Individual patient data (IPD) from prospective clinical trials of DB were assessed and data on patients with disease in bone or bone marrow, as assessed in MRI, CT, mIBG or biopsy, with incomplete response to previous therapy were included. Patients with complete response, progressive disease and/or soft tissue disease were excluded. DB population was adjusted for sex, MYCN amplification, disease type (relapsed, refractory), and disease site (bone marrow and/or bone) to balance aggregated characteristics of NAXI population. More characteristics were included in sensitivity analyses, including DB treatment without interleukin-2, as currently recommended. Overall response rate (ORR) was assessed as best response. Results: Aggregated data for NAXI from Study 201 (n = 52) and Study 230 (n = 38) and IPD from DB studies (APN311-202, APN311-304, c = 77) met the inclusion criteria. Compared to NAXI, DB significantly extended progression-free survival (PFS): hazard ratio, DB vs. NAXI of 0.47 (95% CI: 0.26 to 0.87, p = 0.015). ORR was 60.1% (95% CI: 48.5% to 71.6%) for DB vs. 43.3% (33.1% to 53.6%) for NAXI (ORR odds ratio, DB vs. NAXI was 1.97, 95% CI: 1.02 to 3.80, p = 0.044). Sensitivity analyses and unadjusted comparisons supported the results. Conclusion: In the indirect comparison, dinutuximab beta significantly extended PFS and increased ORR compared to naxitamab.