Comparative Safety of Pulsed Field Ablation and Cryoballoon Ablation Technologies for Pulmonary Vein Isolation in Patients with Paroxysmal Atrial Fibrillation: A Critical Literature Review and Indirect Treatment Comparison.

INTRODUCTION: Cryoballoon ablation (CBA) is a standard catheter ablation technology with demonstrated clinical effectiveness for the treatment of paroxysmal atrial fibrillation (PAF); however, it can be associated with major adverse events, including phrenic nerve paralysis. Pulsed field ablation (PFA) is a novel, minimally thermal technology with comparable effectiveness and low safety risk. This study aimed to compare the safety profiles of PFA and CBA through critical analyses of the literature and indirect treatment comparisons. METHODS: Studies were identified by searching the MEDLINE database and the Clinicaltrials.gov registry. Registered clinical trials and/or Food and Drug Administration Investigation Device Exemption (FDA IDE) studies evaluating PFA or CBA in adult patients with drug-refractory PAF between January 2008 and March 2023 were selected. Comparative safety between PFA and CBA was assessed for major and prespecified adverse events. Indirect comparisons were conducted using the proportion of patients experiencing adverse events and confirmed with single-arm meta-analyses and sensitivity analyses. RESULTS: Data were extracted from three PFA publications including a total of 497 patients and six CBA studies including a total of 1113 patients. The analysis revealed that PFA was associated with significantly lower risk of major adverse events {risk difference - 4.3% [95% confidence interval (CI) - 5.8, - 2.8]; risk ratio 0.16 [95% CI 0.07, 0.45]} and prespecified adverse events [risk difference - 2.5% (95% CI - 4.4, - 0.5); risk ratio 0.53 (95% CI 0.31, 0.96)]. Meta-analyses confirmed the lower rate of major adverse events for PFA [0.4% (95% CI 0.0, 1.3)] vs. CBA [5.6% (95% CI 2.6, 8.6)] and prespecified adverse events for PFA [2.7% (95% CI 1.2, 4.1)] vs. CBA [5.8% (95% CI 2.7, 9.0)]. Sensitivity analyses exploring heterogeneity across studies confirmed robustness of the main analyses. CONCLUSION: The findings of this study show that PFA has a more favorable safety profile than CBA, with significantly lower risks of major and prespecified adverse events. These indirect comparisons help contextualize the safety of PFA compared to CBA for the treatment of drug-refractory PAF in the absence of head-to-head studies.

Updated results from a matching-adjusted indirect comparison of efficacy outcomes for ciltacabtagene autoleucel in CARTITUDE-1 versus idecabtagene vicleucel in KarMMa for the treatment of patients with relapsed or refractory multiple myeloma.

OBJECTIVE: This study used the latest available data cuts from the CARTITUDE-1 and KarMMa clinical trials to update previously published matching-adjusted indirect treatment comparisons (MAICs) assessing the comparative efficacy of ciltacabtagene autoleucel (cilta-cel) versus the FDA-approved idecabtagene vicleucel (ide-cel) dose range of 300 to 450 × 106 CAR-positive T-cells in the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were previously treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody (i.e. triple-class exposed). METHODS: MAICs were performed with the latest available individual patient data for cilta-cel (CARTITUDE-1) and published summary-level data for ide-cel (KarMMa). The analyses included treated patients from CARTITUDE-1 who satisfied the eligibility criteria for KarMMa. The MAIC adjusted for unbalanced baseline covariates of prognostic significance identified in the literature and by clinical expertise. Comparative efficacy was assessed for overall response rate (ORR), complete response or better (≥CR) rate, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). RESULTS: Cilta-cel was associated with statistically significantly improved ORR (odds ratio [OR]: 94.93 [95% confidence interval [CI]: 21.86, 412.25; p < .0001]; relative risk [RR]: 1.34), ≥CR rate (OR: 5.65 [95% CI: 2.51, 12.69; p < .0001]; RR: 2.23), DoR (hazard ratio [HR]: 0.52 [95% CI: 0.30, 0.88; p = .0152]), PFS, (HR: 0.38 [95% CI: 0.24, 0.62; p < .0001]), and OS (HR: 0.43 [95% CI: 0.22, 0.88; p = .0200]) compared with ide-cel. CONCLUSIONS: These analyses demonstrate improved efficacy with cilta-cel versus ide-cel for all outcomes over longer follow-up and highlight its therapeutic potential in triple-class exposed RRMM patients.

Meta-analysis of ciltacabtagene autoleucel versus physician's choice therapy for the treatment of patients with relapsed or refractory multiple myeloma.

Objective: In the absence of head-to-head trials, indirect treatment comparisons (ITCs) between ciltacabtagene autoleucel (cilta-cel; in CARTITUDE-1) and treatments used in real-world clinical practice (physician's choice of treatment [PCT]), were previously conducted. We conducted multiple meta-analyses using available ITC data to consolidate the effectiveness of cilta-cel versus PCT for patients with triple-class exposed relapsed or refractory multiple myeloma (RRMM).Methods: Five ITCs were assessed for similarity to ensure robust comparisons using meta-analysis. Effectiveness outcomes were overall survival (OS), progression-free survival (PFS), time to next treatment (TTNT), and overall response rate (ORR). A robust variance estimator was used to account for the use of CARTITUDE-1 in each pairwise ITC. Analyses were conducted in both treated and enrolled populations of CARTITUDE-1.Results: Four ITCs were combined for evaluation of OS. Results were statistically significantly in favor of cilta-cel versus PCT in treated patients (hazard ratio [HR]: 0.24, 95% confidence interval [CI]: 0.22-0.26). Three ITCs were combined for evaluation of PFS and TTNT. Cilta-cel reduced the risk of progression and receiving a subsequent treatment by 80% (HR: 0.20 [95% CI: 0.06, 0.70]) and 83% (HR: 0.17 [95% CI: 0.12, 0.26]), respectively. Three ITCs were combined for evaluation of ORR. Cilta-cel increased the odds of achieving an overall response by 86-times versus PCT in treated patients. Findings were consistent in the enrolled populations and across sensitivity analyses.Conclusions: Evaluating multiple indirect comparisons, cilta-cel demonstrated a significantly superior advantage over PCT, highlighting its effectiveness as a therapy in patients with triple-class exposed RRMM.

Palbociclib versus abemaciclib in HR+/HER2- advanced breast cancer: an indirect comparison of patient-reported end points.

Aim: To assess the relative impact of palbociclib plus fulvestrant (PAL + FUL) and abemaciclib plus fulvestrant (ABEM + FUL) on patient-reported outcomes in patients with hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer. Patients & methods: Anchored matching-adjusted indirect comparisons were conducted using individual patient data from PALOMA-3 (PAL + FUL) and summary-level data from MONARCH-2 (ABEM + FUL). Outcomes included the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items (EORTC QLQ-C30) and its breast cancer-specific module (QLQ-BR23). Results: Significantly different changes from baseline favoring PAL + FUL compared with ABEM + FUL were observed in global quality of life (6.95 [95% CI: 2.19-11.71]; p = 0.004) and several functional/symptom scales, including emotional functioning, nausea/vomiting, appetite loss, diarrhea and systemic therapy side effects. Conclusion: PAL + FUL was associated with more favorable patient-reported outcomes than ABEM + FUL in patients with HR+/HER2- advanced breast cancer.

Matching-adjusted indirect comparison of efficacy outcomes for ciltacabtagene autoleucel in CARTITUDE-1 versus idecabtagene vicleucel in KarMMa for the treatment of patients with relapsed or refractory multiple myeloma.

OBJECTIVE: This study estimated the comparative efficacy of ciltacabtagene autoleucel (cilta-cel) versus the approved idecabtagene vicleucel (ide-cel) dose range of 300-460 × 106 CAR-positive T-cells for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were previously treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody (i.e. triple-class exposed) using matching-adjusted indirect treatment comparisons (MAICs). METHODS: MAICs were performed with individual patient data for cilta-cel (CARTITUDE-1; NCT03548207) and published summary-level data for ide-cel (KarMMa; NCT03361748). Treated patients from CARTITUDE-1 who satisfied the eligibility criteria for KarMMa were included in the analyses. The MAIC adjusted for unbalanced baseline covariates of prognostic significance identified in the literature and by clinical expertise. Comparative efficacy was estimated for overall response rate (ORR), complete response or better (≥CR) rate, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). RESULTS: Cilta-cel was associated with statistically significantly improved ORR (odds ratio [OR]: 94.93 [95% confidence interval [CI]: 21.86, 412.25; p < .0001]; relative risk [RR]: 1.34), ≥CR rate (OR: 5.49 [95% CI: 2.47, 12.21; p < .0001]; RR: 2.21), DoR (hazard ratio [HR]: 0.50 [95% CI: 0.29, 0.87; p = .0137]), and PFS (HR: 0.37 [95% CI: 0.22, 0.62; p = .0002]) when compared with ide-cel. For OS, the results were in favor of cilta-cel and clinically meaningful but with a CI overlapping one (HR: 0.55 [95% CI: 0.29, 1.05; p = .0702]). CONCLUSIONS: These analyses demonstrate improved efficacy with cilta-cel versus ide-cel for all outcomes, highlighting its therapeutic potential in patients with triple-class exposed RRMM.

Matching-adjusted indirect comparison of palbociclib versus ribociclib and abemaciclib in hormone receptor-positive/HER2-negative advanced breast cancer.

Aim: Palbociclib (PAL), ribociclib (RIB) and abemaciclib (ABM), in combination with fulvestrant (FUL), are approved for the treatment of hormone receptor-positive, HER2-negative advanced breast cancer. This study aims to determine relative efficacy of PAL+FUL versus RIB+FUL and ABM+FUL using matching-adjusted indirect treatment comparisons. Patients & methods: Anchored matching-adjusted indirect treatment comparisons were conducted using individual patient data from PALOMA-3 and published summary-level data from MONARCH 2 and MONALEESA-3. The primary outcome was overall survival (OS). Results: OS was similar for PAL+FUL versus ABM+FUL (hazard ratio: 0.87; 95% CI: 0.54-1.40) and RIB+FUL (hazard ratio: 0.89; 95% CI: 0.48-1.63). Conclusion: Adjusting for cross-trial differences suggests similar OS between treatments, underscoring the importance of accounting for these differences when indirectly comparing treatments.

Lay abstract Palbociclib (PAL), ribociclib (RIB) and abemaciclib (ABM) are used with fulvestrant to treat hormone receptor-positive, HER2-negative advanced breast cancer. This study aims to use data from clinical trials to compare how long patients live after starting treatment with PAL versus RIB and ABM. Since patients who enroll in different trials may have different characteristics, it is important to adjust for these differences for a more accurate comparison. Adjusting for these differences showed that patients with hormone receptor-positive, HER2-negative advanced breast cancer treated with PAL lived for a similar length of time compared with those treated with RIB or ABM.