Matching-adjusted indirect comparison of talquetamab vs selinexor-dexamethasone and vs belantamab mafodotin in patients with relapsed/refractory multiple myeloma.

OBJECTIVE: Talquetamab is the first GPRC5D-targeting bispecific antibody approved for the treatment of triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM). This matching-adjusted indirect comparison (MAIC) study was conducted to compare the effectiveness of talquetamab vs selinexor-dexamethasone (sel-dex) and vs belantamab mafodotin (belamaf) in patients with TCE RRMM. METHODS: An unanchored MAIC was performed using individual patient-level data from patients treated with subcutaneous talquetamab 0.4 mg/kg weekly (QW) and 0.8 mg/kg every other week (Q2W) from MonumenTAL-1 (NCT03399799/NCT04636552) and published summary data for sel-dex from STORM (NCT02336815) and belamaf from DREAMM-2 (NCT0325678). Patients from MonumenTAL-1 who met key eligibility criteria for STORM and DREAMM-2 were included. Outcomes of interest were overall response rate (ORR), complete response or better (≥CR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). RESULTS: After adjustment for cross-trial differences, patients treated with both dosing schedules of talquetamab showed significantly better ORR, ≥CR, and DOR vs sel-dex and significantly higher ORR and ≥ CR vs belamaf; DOR was relatively similar to belamaf. PFS was significantly improved with talquetamab Q2W and numerically in favor of talquetamab QW vs sel-dex and significantly improved with both dosing schedules of talquetamab vs belamaf. OS was significantly improved with both dosing schedules of talquetamab vs sel-dex and was numerically in favor of both dosing schedules of talquetamab vs belamaf. CONCLUSION: These analyses show superior effectiveness of both talquetamab dosing schedules vs sel-dex and vs belamaf for most outcomes and highlight talquetamab as an effective treatment option for patients with TCE RRMM.

Matching-Adjusted Indirect Comparison of the Efficacy and Safety of Erdafitinib vs Enfortumab Vedotin in Patients with Locally Advanced Metastatic Urothelial Carcinoma.

Background: For patients with locally advanced or metastatic urothelial carcinoma (la/mUC), prognosis is poor and effective treatment options are limited. Erdafitinib is an oral fibroblast growth factor receptor (FGFR) kinase inhibitor approved by the FDA for the treatment of adults with la/mUC harboring FGFR alterations whose disease progressed following at least 1 prior line of therapy, including a PD-1 or PD-L(1) inhibitor, based on the phase 3, randomized THOR trial (NCT03390504, Cohort 1). Objective: To compare the efficacy and safety of erdafitinib vs enfortumab vedotin-ejfv (EV) in the absence of head-to-head comparison via an anchored matching-adjusted indirect comparison (MAIC). Methods: An anchored MAIC was conducted according to the National Institute for Health and Care Excellence Decision Support Unit guidance, with physician's choice of chemotherapy (docetaxel/paclitaxel and vinflunine) as the common comparator. Individual patient data from THOR were adjusted to match published key eligibility criteria and average baseline characteristics of EV-301, such as Bellmunt risk score, liver or visceral metastases, primary site, among others. Erdafitinib was then indirectly compared with EV using the relative treatment effects for the reweighted THOR population and those published for EV-301. Results: After matching, the effective sample size for THOR was 126 patients. The MAIC-recalculated hazard ratio (95% credible interval) for erdafitinib vs EV was 0.92 (0.54, 1.57) for overall survival and 0.93 (0.55, 1.56) for progression-free survival, yielding Bayesian probabilities of erdafitinib being better than EV of 62.1% and 60.5%, respectively. For response outcomes, the MAIC-recalculated risk ratio was 1.49 (0.56, 3.90) for confirmed objective response rate and 2.89 (0.27, 30.33) for confirmed complete response with probabilities of 72.6% and 81.3% for erdafitinib being better than EV, respectively. For safety, MAIC-yielded risk ratios of 1.09 (0.99, 1.21) for any treatment-related adverse events, 0.86 (0.57, 1.28) for grade 3+ TRAEs, and 1.02 (0.98, 1.06) for any treatment-emergent adverse events. Conclusion: The MAIC indicates comparable efficacy of erdafitinib vs EV for overall survival and progression-free survival, with erdafitinib showing a higher probability of achieving deep responses. While erdafitinib is associated with slightly more adverse events compared with EV, these events seem to be less severe.

Comparative efficacy of ciltacabtagene autoleucel versus idecabtagene vicleucel in the treatment of patients with relapsed or refractory multiple myeloma previously treated with 2-4 prior lines of therapy: a matching-adjusted indirect comparison.

OBJECTIVE: To estimate the comparative efficacy of ciltacabtagene autoleucel (cilta-cel) versus idecabtagene vicleucel (ide-cel) in patients with relapsed/refractory multiple myeloma (RRMM) treated with 2-4 prior lines of therapy. METHODS: Matching adjusted indirect comparison (MAICs) were performed using individual patient-level data (IPD) for cilta-cel from CARTITUDE-1 and CARTITUDE-4 and published aggregated data for ide-cel from KarMMa-3. Cilta-cel patients who met inclusion criteria from KarMMa-3 were selected, and outcomes were compared against data for ide-cel using simulated IPD derived from aggregate-level data from KarMMa-3. Patient characteristics were adjusted by reweighting cilta-cel IPD to match the distribution of prognostic factors in KarMMa-3. Comparative efficacy was estimated for response outcomes using a weighted logistic regression analysis and for progression-free survival using a weighted Cox proportional hazards model. RESULTS: Patients treated with cilta-cel were 1.2 times more likely to achieve overall response (relative response ratio [RR]: 1.18 [95% confidence interval: 1.03-1.34]; p = 0.04), 1.3 times more likely to achieve very good partial response or better (RR: 1.34 [1.15-1.57]; p = 0.003), and 1.9 times more likely to achieve complete response or better (RR: 1.91 [1.54-2.37]; p < 0.0001) versus ide-cel patients from KarMMa-3. Cilta-cel was associated with a significant 49% reduction in risk of disease progression or death versus ide-cel (hazard ratio: 0.51 [95% confidence interval: 0.31, 0.84]; p = 0.0078). CONCLUSION: For patients with triple-class exposed RRMM treated with 2-4 prior lines of treatment, cilta-cel was found to provide superior clinical benefit over ide-cel in terms of response and progression-free survival.

Adjustment for imbalances in baseline characteristics in the MAGNITUDE phase 3 study confirms the clinical benefit of niraparib in combination with abiraterone acetate plus prednisone in patients with metastatic prostate cancer.

BACKGROUND: MAGNITUDE (NCT03748641) demonstrated favourable outcomes with niraparib plus abiraterone acetate plus prednisone (+AAP) versus placebo+AAP in patients with BRCA1/2-altered metastatic castration-resistant prostate cancer (mCRPC). Imbalances in prognostic variables were reported between arms, which impacts estimation of both the clinical benefit and cost­effectiveness of niraparib+AAP for healthcare systems. A pre-specified multivariable analysis (MVA) demonstrated improved overall survival (OS) with niraparib+AAP. Here, we used an inverse probability of treatment weighting (IPTW) model to adjust for covariate imbalances and assess time-to-event outcomes. METHODS: IPTW analysis of time-to-event outcomes was conducted using data from patients with BRCA1/2-altered mCRPC (N = 225) in MAGNITUDE. Patients received niraparib+AAP or placebo+AAP. OS, radiographic progression-free survival, time to symptomatic progression, time to initiation of cytotoxic chemotherapy and time to prostate-specific antigen progression were assessed. Weighted Kaplan-Meier curves were generated for each endpoint, and adjusted hazard ratios (HR) were obtained from a weighted Cox model. RESULTS: Improvements in survival outcomes were estimated for niraparib+AAP versus placebo+AAP: unadjusted median OS was 30.4 months versus 28.6 months, respectively (HR: 0.79; 95 % confidence interval [CI]: 0.55, 1.12; p = 0.183). Following IPTW, median OS increased to 34.1 months with niraparib+AAP versus a decrease to 27.4 with placebo (HR: 0.65; 95 % CI: 0.46, 0.93; p = 0.017). Similar improvements were observed for other time-to-event endpoints. CONCLUSIONS: IPTW adjustment provided a more precise estimate of the clinical benefit of niraparib+AAP versus placebo+AAP in patients with BRCA1/2-altered mCRPC. Results were consistent with the pre-specified MVA, and further demonstrated the value of adjusting for baseline imbalances, particularly in smaller studies. TRIAL REGISTRATION: NCT03748641 (MAGNITUDE).

Feasibility of Indirect Treatment Comparisons Between Niraparib Plus Abiraterone Acetate and Other First-Line Poly ADP-Ribose Polymerase Inhibitor Treatment Regimens for Patients with BRCA1/2 Mutation-Positive Metastatic Castration-Resistant Prostate Cancer.

INTRODUCTION: Poly(ADP-ribose) polymerase inhibitors (PARPi) are a novel option to treat patients with metastatic castration-resistant prostate cancer (mCRPC). Niraparib plus abiraterone acetate and prednisone (AAP) is indicated for BRCA1/2 mutation-positive mCRPC. Niraparib plus AAP demonstrated safety and efficacy in the phase 3 MAGNITUDE trial (NCT03748641). In the absence of head-to-head studies comparing PARPi regimens, the feasibility of conducting indirect treatment comparisons (ITC) to inform decisions for patients with first-line BRCA1/2 mutation-positive mCRPC has been explored. METHODS: A systematic literature review was conducted to identify evidence from randomized controlled trials on relevant comparators to inform the feasibility of conducting ITCs via network meta-analysis (NMA) or population-adjusted indirect comparisons (PAIC). Feasibility was assessed based on network connectivity, data availability in the BRCA1/2 mutation-positive population, and degree of within- and between-study heterogeneity or bias. RESULTS: NMAs between niraparib plus AAP and other PARPi regimens (olaparib monotherapy, olaparib plus AAP, and talazoparib plus enzalutamide) were inappropriate due to the disconnected network, differences in trial populations related to effect modifiers, or imbalances within BRCA1/2 mutation-positive subgroups. The latter issue, coupled with the lack of a common comparator (except for olaparib plus AAP), also rendered anchored PAICs infeasible. Unanchored PAICs were either inappropriate due to lack of population overlap (vs. olaparib monotherapy) or were restricted by unmeasured confounders and small sample size (vs. olaparib plus AAP). PAIC versus talazoparib plus enzalutamide was not possible due to lack of published arm-level baseline characteristics and sufficient efficacy outcome data in the relevant population. CONCLUSION: The current randomized controlled trial evidence network does not permit robust comparisons between niraparib plus AAP and other PARPi regimens for patients with 1L BRCA-positive mCRPC. Decision-makers should scrutinize any ITC results in light of their limitations. Real-world evidence combined with clinical experience should inform treatment recommendations in this indication.

Overall survival of patients with CLL treated with ibrutinib in the first line compared to second-line ibrutinib after chemotherapy/chemoimmunotherapy.

OBJECTIVE: To evaluate the overall survival (OS) of patients with chronic lymphocytic leukemia (CLL) receiving either ibrutinib monotherapy as a first-line (1L) treatment or chemotherapy/chemoimmunotherapy-based (CT/CIT) regimens in 1L followed by ibrutinib in the second line (1L CT/CIT-2L ibrutinib) after disease progression by emulating a randomized trial comparing both treatment sequences. METHODS: Patient-level data from the RESONATE-2 trial (NCT01722487) and real-world PHEDRA databases were analyzed. Three scenarios were considered using the following data sources: (1) RESONATE-2, (2) combined RESONATE-2/PHEDRA, (3) combined RESONATE-2/PHEDRA for 1L ibrutinib and PHEDRA for 1L CT/CIT-2L ibrutinib. Propensity score-based weights and inverse probability of censoring weighting were used to adjust for baseline (Scenarios 2 and 3) and time-dependent confounding (all scenarios), and to address potential biases. A weighted Cox proportional hazards model was used to estimate the OS hazard ratio (HR) and 95% confidence interval (CI) for 1L ibrutinib versus 1L CT/CIT-2L ibrutinib. RESULTS: Results from Scenario 1 showed a significantly lower risk of death with 1L ibrutinib compared with 1L chlorambucil followed by 2L ibrutinib (HR 0.35 [95% CI 0.20-0.62]). Results from Scenarios 2 and 3 demonstrated a reduced risk of death with 1L ibrutinib compared with 1L CT/CIT-2L ibrutinib (HR 0.35 [0.21-0.61] and 0.64 [0.39-1.04], respectively). CONCLUSION: The analyses consistently showed a reduced risk of death when ibrutinib was used as a 1L treatment in CLL compared with delaying its use until 2L after CT/CIT regimens, which suggests that initiating ibrutinib in 1L is advantageous for improving survival outcomes.

Matching-adjusted indirect comparison (MAIC) results confirmed by head-to-head trials: a case study in psoriasis.

BACKGROUND: Head-to-head comparisons through randomized controlled trials (RCTs) provide high-quality evidence to inform healthcare decisions. In their absence, indirect comparisons are often performed; however, evidence is limited on how valid matching-adjusted indirect comparison (MAIC)-based comparative efficacy estimates are vs. RCT-based estimates. OBJECTIVES: Compare MAIC and RCT results of guselkumab vs. secukinumab and ixekizumab to provide insight into the validity of results generated using MAIC methods. METHODS: Previously reported results from MAICs of guselkumab vs. secukinumab and ixekizumab were compared with results from ECLIPSE and IXORA-R RCTs based on risk differences between Psoriasis Area and Severity Index (PASI) 90 response rates. RESULTS: Risk difference (95% confidence interval) in PASI 90 response rates at week 48 for guselkumab vs. secukinumab was 14.4% (9.4%; 19.4%) in ECLIPSE and 9.4% (4.7%; 14.0%) in the MAIC. The risk difference at week 24 for guselkumab vs. ixekizumab was 0.0% (-5.4%; 5.4%) in IXORA-R and 0.7% (-5.1%; 6.4%) in the MAIC. CONCLUSIONS: Comparative efficacy results were consistent between MAICs and RCTs of guselkumab vs. secukinumab and ixekizumab. This analysis demonstrates that MAIC methods can provide valid relative treatment effect estimates when direct comparisons are lacking, particularly when trials with similar designs and patient populations inform the analysis.

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.

Matching-Adjusted Indirect Treatment Comparison to Assess the Comparative Efficacy of Ciltacabtagene Autoleucel in CARTITUDE-1 Versus Belantamab Mafodotin in DREAMM-2, Selinexor-Dexamethasone in STORM Part 2, and Melphalan Flufenamide-Dexamethasone in HORIZON for the Treatment of Patients With Triple-Class Exposed Relapsed or Refractory Multiple Myeloma.

INTRODUCTION: This study estimated the comparative efficacy of ciltacabtagene autoleucel (cilta-cel; CARTITUDE-1), a chimeric antigen receptor (CAR)-T-cell therapy, versus 3 non-CAR-T therapies (belantamab mafodotin [DREAMM-2], selinexor plus dexamethasone [STORM Part 2], and melphalan flufenamide plus dexamethasone [HORIZON]), each with distinct mechanisms of action, for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were triple-class exposed to an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody. PATIENTS AND METHODS: Pairwise matching-adjusted indirect treatment comparisons (MAICs) were conducted using patient-level data for cilta-cel from CARTITUDE-1 and summary level data for each comparator (2.5 mg/kg cohort in DREAMM-2, modified intention-to-treat population in STORM Part 2, and triple-class refractory patients in HORIZON). Treated patients from CARTITUDE-1 who satisfied the eligibility of the comparator trial were included. MAICs adjusted for imbalances in important prognostic factors between CARTITUDE-1 and the comparator populations. Comparative efficacy of cilta-cel versus each therapy was estimated for overall response rate, complete response or better rate, progression-free survival, and overall survival. RESULTS: After adjustment, patients treated with cilta-cel demonstrated at least a 3.1-fold and at least a 10.3-fold increase in the likelihood of achieving an overall response or complete response or better, respectively, at least a 74% reduction in the risk of disease progression or death, and at least a 47% reduction in the risk of death. These results were statistically significant. CONCLUSION: Cilta-cel showed improved efficacy over each comparator for all outcomes, demonstrating its potential as an efficacious treatment for patients with triple-class exposed RRMM.

Prevalence of Epidermal Growth Factor Receptor Exon 20 Insertion Mutations in Non-small-Cell Lung Cancer in Europe: A Pragmatic Literature Review and Meta-analysis.

BACKGROUND: Information on the epidemiology of uncommon EGFR mutations including exon 20 insertions amongst non-small-cell lung cancer (NSCLC) is lacking. OBJECTIVE: The objective of this pragmatic literature review (PLR) and meta-analysis was to generate robust prevalence and incidence estimates based on ranges of exon 20 insertion mutations reported in the literature. MATERIALS AND METHODS: Searches of MEDLINE, Embase, congresses and reference lists for articles published from 2013 in key European countries of interest (Belgium, France, Germany, Italy, The Netherlands, Spain, Sweden, Switzerland, United Kingdom) were performed. Articles were reviewed against pre-specified criteria and their quality was appraised using a published checklist. Prevalence estimates were synthesised by random-effects meta-analyses. RESULTS: Eighty unique studies of moderate-to-high quality were included in the PLR. The meta-analysed prevalence for EGFR mutations was 12.5% (95% confidence interval [CI]: 11.0, 14.1) in any stage NSCLC and 14.8% (12.8, 17.1) in advanced/metastatic NSCLC. The prevalence of exon 20 insertions was 0.7% (0.4, 1.1) in any stage NSCLC and 6.1% (4.0, 9.4) in any stage EGFR-positive NSCLC. Mutation status was primarily measured using direct sequencing or a combination of methods. One study reporting exon 20 insertions in advanced/metastatic disease was identified, which reported a prevalence of 0.5% in overall NSCLC and 4.0% in EGFR-positive NSCLC. CONCLUSIONS: EGFR exon 20 insertion mutations are rare in NSCLC. There is a high unmet need in patients with exon 20 insertions, including effective therapies. Prospective cohort studies are needed to better clinically characterise these patients.

Apalutamide Compared with Darolutamide for the Treatment of Non-metastatic Castration-Resistant Prostate Cancer: Efficacy and Tolerability in a Matching-Adjusted Indirect Comparison.

INTRODUCTION: Apalutamide and darolutamide are next-generation androgen receptor inhibitors that have demonstrated superior efficacy compared to placebo in men with non-metastatic castration-resistant prostate cancer (nmCRPC) receiving androgen deprivation therapy (ADT). In the absence of head-to-head studies, the present study sought to indirectly compare the efficacy and tolerability between these two treatments. METHODS: This anchored matching-adjusted indirect comparison (MAIC) used patient-level data from the phase 3, randomized, controlled SPARTAN study (apalutamide + ADT), weighted to match aggregate published data from the ARAMIS study (darolutamide + ADT) for clinically relevant baseline measures. Hazard ratios (HR) and 95% credible intervals (CrI) were estimated for efficacy endpoints: metastasis-free survival (MFS), prostate-specific antigen (PSA) progression, progression-free survival (PFS), and overall survival (OS). Odds ratios were estimated for tolerability outcomes: adverse events and serious adverse events. RESULTS: Before weighting, baseline characteristics from SPARTAN versus ARAMIS were different for median PSA (7.8 vs. 9.2 ng/mL), Eastern Cooperative Oncology Group performance status of 1 (23% vs. 31%), use of bone-targeted agents (10% vs. 4%), median time from initial diagnosis (94.9 vs. 85.4 months), and proportion of patients from North America (35% vs. 12%) and Europe (50% vs. 64%). After matching (n = 455), our analysis demonstrated that apalutamide + ADT had a Bayesian probability of being more effective than darolutamide + ADT for MFS [98.3%; HR 0.70 (95% CrI 0.51, 0.98)], PSA progression [~ 100%; HR 0.46 (95% CrI 0.33, 0.64)], and PFS [93.2%; HR 0.79 (95% CrI 0.59, 1.08)]. Results for OS and tolerability were similar between apalutamide + ADT and darolutamide + ADT. CONCLUSION: This anchored MAIC analysis of pivotal phase 3 studies in patients with nmCRPC suggests that apalutamide + ADT is more effective than darolutamide + ADT for MFS, progression-free survival (PFS), and prostate-specific antigen (PSA) progression, with a similar OS benefit and tolerability profile. TRIAL REGISTRATION: ARAMIS ClinicalTrials.gov number: NCT02200614; SPARTAN ClinicalTrials.gov number: NCT01946204.

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.

Efficacy of ustekinumab vs. advanced therapies for the treatment of moderately to severely active ulcerative colitis: a systematic review and network meta-analysis.

Objective: To compare the relative efficacy of ustekinumab (UST) vs. other therapies for 1-year response and remission rates in patients with moderate-severe UC.Methods: Randomized controlled trials reporting induction and maintenance efficacy of anti-TNFs (infliximab [IFX], adalimumab [ADA], golimumab [GOL]), vedolizumab (VDZ), tofacitinib (TOF) or UST were identified through a systematic literature review (SLR). Analyses were conducted for clinical response, clinical remission and endoscopic-mucosal healing for populations with and without failure of prior biologics (non-biologic failure [NBF]; biologic failure [BF]). Maintenance data from trials with re-randomized response designs were re-calculated to correspond to treat-through arms. Bayesian network meta-analyses (NMA) were conducted to obtain posterior distribution probabilities for UST to perform better than comparators.Results: Six trials included NBF patients and four included BF patients. In NBF patients, UST as a 1-year regimen showed higher probabilities of clinical response, remission and endoscopic-mucosal healing vs. all treatments: Bayesian probabilities of UST being better than active therapies ranged from 91% (VDZ) to 100% (ADA) for response; 82% (VDZ) to 99% (ADA) for remission and 82% (IFX) to 100% (ADA and GOL) for endoscopic-mucosal healing. In BF patients, UST was the most effective treatment (Q8W dose); however, effect sizes were smaller than in the NBF population.Conclusions: Results indicate a higher likelihood of response, remission and endoscopic-mucosal healing at 1 year with UST vs. comparators in the NBF population. In BF patients, a higher likelihood of response to UST vs. the most comparators was also observed, although results were more uncertain.

Matching-Adjusted Indirect Comparison of Health-Related Quality of Life and Adverse Events of Apalutamide Versus Enzalutamide in Non-Metastatic Castration-Resistant Prostate Cancer.

INTRODUCTION: The present study aimed to indirectly compare apalutamide and enzalutamide with respect to tolerability and health-related quality of life (HRQoL) among men with non-metastatic castration-resistant prostate cancer (nmCRPC). METHODS: Patient-level data from the SPARTAN study [apalutamide + androgen deprivation therapy (ADT) versus placebo + ADT] and aggregate published data from the PROSPER study (enzalutamide + ADT versus placebo + ADT) were used. Anchored matching-adjusted indirect comparison (MAIC) was conducted by weighting patients' baseline characteristics from SPARTAN to match aggregated baseline characteristics in PROSPER. Odds ratios (ORs) of reported adverse events (AEs) and baseline-to-follow-up least squares mean differences in HRQoL [measured with Functional Assessment of Cancer Therapy-Prostate (FACT-P) score] with 95% credible intervals were re-estimated for SPARTAN arms using weighted population and indirectly compared with those in PROSPER through a Bayesian framework. Events of special interest included fatigue, hot flush, nausea, diarrhea, hypertension, falls, dizziness, decreased appetite, arthralgia, asthenia and headache. In addition, any AEs and serious AEs were explored. RESULTS: Of 1207 SPARTAN patients, 1171 were matched to 1401 PROSPER patients. Relative to enzalutamide, apalutamide demonstrated better tolerability as evidenced by the highest probability of reduced occurrence of fatigue [p(OR < 1) = 99.5%], hypertension [p(OR < 1) = 99.2%], decreased appetite [p(OR < 1) = 98.3%], fall [p(OR < 1) = 90.3%], headaches [p(OR < 1) = 86.7%], and nausea [p(OR < 1) = 80.0%]. The probabilities of reduced occurrence of any AEs and SAEs with apalutamide versus enzalutamide were 66.9% and 90.9%, respectively. Relative to enzalutamide, apalutamide treatment was associated with a higher probability of a better HRQoL based on the FACT-P total score [p(diff > 0) = 73.1%]. The probability of a better HRQoL with apalutamide versus enzalutamide was highest for the physical [p(diff > 0) = 97.3%] and functional [p(diff > 0) = 86.7%] wellbeing subscales, and the pain-related subscale [p(diff > 0) = 90.1%]. CONCLUSION: Anchored MAIC suggests that treatment of men with nmCRPC with apalutamide is associated with a higher probability of better tolerability due to fewer AEs and better HRQoL than enzalutamide.

Matching-Adjusted Indirect Comparison of the Efficacy of Apalutamide and Enzalutamide with ADT in the Treatment of Non-Metastatic Castration-Resistant Prostate Cancer.

INTRODUCTION: Apalutamide and enzalutamide are next-generation androgen receptor inhibitors that demonstrated efficacy in placebo-controlled studies (SPARTAN for apalutamide; PROSPER for enzalutamide) when used in combination with androgen deprivation therapy (ADT) for treatment of non-metastatic castration-resistant prostate cancer (nmCRPC). In the absence of comparative studies between these agents, the present study sought to indirectly compare metastasis-free survival (MFS) and overall survival (OS) in patients with nmCRPC who received these therapies. METHODS: Individual patient-level data from SPARTAN (apalutamide plus ADT) and published data from PROSPER (enzalutamide plus ADT) were utilized. An anchored matching-adjusted indirect comparison (MAIC) was conducted by weighting the patients from the SPARTAN study to match baseline characteristics reported for PROSPER. Hazard ratios (HRs) for MFS and OS were re-estimated for SPARTAN using weighted Cox proportional hazards models and indirectly compared with those of PROSPER using a Bayesian network meta-analysis. RESULTS: From the SPARTAN population (N = 1207), a total of 1171 patients were matched to the PROSPER population (N = 1401). The recalculated HRs (95% confidence interval) for apalutamide versus ADT based on the reweighted SPARTAN data to mimic the PROSPER patient population were 0.26 (0.21; 0.33) for MFS and 0.62 (0.41; 0.94) for OS. MAIC-based HRs (95% credible interval) for apalutamide versus enzalutamide were 0.91 (0.68; 1.22) for MFS and 0.77 (0.46; 1.30) for OS. The Bayesian probabilities of apalutamide being more effective than enzalutamide were 73.6% for MFS and 83.5% for OS. CONCLUSIONS: MAIC results suggest that nmCRPC patients treated with apalutamide have a higher probability of a more favorable MFS and OS compared with those treated with enzalutamide.

Impact of Abiraterone Acetate plus Prednisone or Enzalutamide on Patient-reported Outcomes in Patients with Metastatic Castration-resistant Prostate Cancer: Final 12-mo Analysis from the Observational AQUARiUS Study.

BACKGROUND: Few studies have examined patient-reported outcomes (PROs) with abiraterone acetate plus prednisone (abiraterone) versus enzalutamide in metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVE: To determine the impact of abiraterone and enzalutamide on PROs. DESIGN, SETTING, AND PARTICIPANTS: AQUARiUS (NCT02813408) was a prospective, 12-mo, observational study in patients with mCRPC from Denmark, France, and the UK. INTERVENTION: Abiraterone or enzalutamide treatment according to routine practise. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PROs were collected over 12 mo using Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog), Brief Fatigue Inventory-Short Form (BFI-SF), Brief Pain Inventory-Short Form, and European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire (QLQ-C30) at baseline and routine visits. Outcomes included mean change in PROs, patients with clinically meaningful worsening (CMW) in PROs, and safety. Data were analysed using repeated measures linear and logistic models adjusted for baseline characteristics. RESULTS AND LIMITATIONS: Abiraterone-treated (N = 105) and enzalutamide-treated (N = 106) patients were included. Key PRO items (cognitive impairments and fatigue) were significantly (p < 0.05) in favour of abiraterone versus enzalutamide during the study. "Perceived cognitive impairment" and "comments from others" (FACT-Cog); "fatigue right now", "usual level of fatigue", and "worst level of fatigue" (BFI-SF); and "cognitive functioning" and "fatigue" (QLQ-C30) were significantly in favour of abiraterone over enzalutamide for three or more consecutive periods up to month 12. From study initiation, significantly fewer patients receiving abiraterone experienced one or more CMW episode in cognition and fatigue. Fatigue and asthenia (adverse events) were lower with abiraterone than with enzalutamide (5% vs 15% and 10% vs 11%, respectively). There were no treatment-related deaths. Limitations included lack of randomisation. CONCLUSIONS: In a real-world setting, this 12-mo analysis suggests an advantage of abiraterone acetate plus prednisone over enzalutamide on fatigue and cognitive function; this finding occurred early after treatment initiation. This difference should be considered when choosing treatment. PATIENT SUMMARY: This study looked at the effect of two treatments (abiraterone acetate plus prednisone and enzalutamide) for metastatic castration-resistant prostate cancer on patient quality of life over 12 mo. Using established questionnaires, patients reported that they experienced less fatigue and cognitive impairments (including memory loss and reduced thinking abilities) with abiraterone acetate plus prednisone than with enzalutamide.

Adjusting Overall Survival Estimates for Treatment Switching in Metastatic, Castration-Sensitive Prostate Cancer: Results from the LATITUDE Study.

BACKGROUND: LATITUDE was the first phase 3 trial examining the survival benefit of adding abiraterone acetate (AA) + prednisone (P) to androgen-deprivation therapy (ADT) in newly diagnosed metastatic, castration-sensitive prostate cancer (mCSPC). Due to significant improvement in overall survival after the first interim analysis, patients in the placebos + ADT arm could switch to AA + P + ADT during an open-label extension. As in other studies where switching is allowed, statistical adjustments are needed to assess the real benefit of new drugs. PATIENTS AND METHODS: This was a post hoc analysis to estimate the true survival benefit of AA + P + ADT in patients with newly diagnosed mCSPC by applying statistical adjustments commonly used to adjust for treatment switching. RESULTS: Of 112 patients still receiving placebos + ADT at the first interim analysis, 72 switched to AA + P + ADT during the open-label extension. Final analysis was conducted after median follow-up of 51.8 months. Compared to the placebos + ADT arm, the risk of death in the AA + P + ADT arm was 34% lower [hazard ratio (HR) = 0.663 (95% confidence interval 0.566-0.778)] by unadjusted intent-to-treat analysis, 37% lower [HR = 0.629 (95% confidence interval 0.526-0.753)] by rank preserving structure failure time modeling, and 38% lower [HR = 0.616 (95% confidence interval 0.524-0.724)] by inverse probability of censoring weights. CONCLUSIONS: Analyses adjusting for treatment switching using two different statistical approaches confirm the improved survival benefit of adding AA + P to ADT in patients with newly diagnosed mCSPC. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01715285.

Survival benefit, disease progression and quality-of-life outcomes of abiraterone acetate plus prednisone versus docetaxel in metastatic hormone-sensitive prostate cancer: A network meta-analysis.

AIM: Androgen deprivation therapy (ADT) has long been the gold standard for patients with metastatic hormone-sensitive prostate cancer (mHSPC). Clinical trials have demonstrated significant survival benefits when docetaxel (DOC) or abiraterone acetate (AA) and prednisone (P) are added to ADT, necessitating comparison of these combination treatments. METHODS: A systematic review of randomised controlled trials (RCTs) of AA-/ADT-/DOC-containing treatment regimens in newly diagnosed patients with high-risk and/or high-volume mHSPC identified three RCTs (LATITUDE, CHAARTED and GETUG-AFU 15). Network meta-analyses (NMAs) using fixed effects Bayesian methods were performed to compare relative benefits of each treatment on overall survival (OS), radiographic progression-free survival (rPFS) and quality of life (QoL) measured by the Brief Pain Inventory, and the Functional Assessment of Cancer Therapy-Prostate questionnaire. One trial, STAMPEDE, was assessed in exploratory OS analyses. RESULTS: The hazard ratio (HR) for OS ranged from 0.85 to 0.92, with the Bayesian probability of AA + P + ADT being better than DOC + ADT ranging between 72% and 87%. For rPFS, the HR ranged between 0.71 and 0.76 (Bayesian probability range: 93%-97%). Exploratory analyses including STAMPEDE found similar trends. AA + P + ADT also showed improved QoL compared with DOC + ADT for at least 1 year of therapy, with results being more pronounced at 3 months. CONCLUSION: Our findings suggest that AA + P + ADT is at least as effective as DOC + ADT in reducing the risk of death in men with mHSPC and better at preventing disease progression and improving QoL. The NMA provides useful insights to clinicians and other decision-makers on the relative efficacy of treatment options for men with mHSPC.

Impact of abiraterone acetate plus prednisone or enzalutamide on fatigue and cognition in patients with metastatic castration-resistant prostate cancer: initial results from the observational AQUARiUS study.

Introduction: Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are commonly prescribed for metastatic castration-resistant prostate cancer (mCRPC). Data comparing their effects on patient-reported outcomes (PROs) from routine clinical practice are limited. Methods: AQUARiUS (NCT02813408) is an ongoing, two-cohort, prospective, observational, non-randomised, multicentre, phase IV European study assessing the effects of AAP and ENZ on PROs in 211 patients with mCRPC over 12 months. Patients receive AAP or ENZ per routine clinical practice. Data on cognition, fatigue, pain and health-related quality of life are measured using the Functional Assessment of Cancer Therapy-Cognitive Function, Brief Fatigue Inventory-Short Form, Brief Pain Inventory-Short Form and European Organization for Research and Treatment of Cancer Quality of Life-C30 questionnaires, respectively. Results: This 3-month analysis was conducted in 105 patients; 46 received AAP and 59 received ENZ. There were statistically significant differences in mean change from baseline favouring AAP over ENZ at months 1, 2 and 3 for perceived cognitive impairments and cognitive functioning. At each time-point, ENZ-treated patients had a significantly higher risk of experiencing clinically meaningful worsening in perceived cognitive impairments versus those receiving AAP.Statistically significant differences in mean change from baseline favouring AAP over ENZ were seen for usual level of fatigue and fatigue interference at months 2 and 3 and for current fatigue and worse level of fatigue at month 3. Differences favouring AAP versus ENZ were seen for the fatigue scale of the QLQ-C30 questionnaire (months 1 and 3). There was a significantly higher risk of clinically meaningful worsening in usual level of fatigue with ENZ versus AAP at month 3.No significant differences between cohorts were observed for pain (BPI-SF) at any time-point. Conclusion: This analysis suggests more favourable outcomes with AAP versus ENZ for cognition and fatigue in the first 3 months of treatment initiation for mCRPC. These findings require confirmation from future analyses of data from AQUARiUS from a larger number of patients with a longer follow-up period.

An Indirect Comparison of Changes in the Impact of Weight on Quality of Life Among Subjects with Type 2 Diabetes Treated with Antihyperglycemic Agents in Dual Therapy with Metformin.

INTRODUCTION: It is important to capture the patient experience with a diabetes treatment in clinical trials; however, use of instruments to assess patient-reported outcomes (PROs) in diabetes trials is inconsistent and results may not be reported alongside primary efficacy data. In lieu of head-to-head data, indirect comparisons can be used to compare competing interventions. In this study, we used indirect comparison methods to assess differences in PRO score changes between canagliflozin and other antihyperglycemic agents as add-on to metformin. METHODS: Literature searches were performed to identify studies that reported the same PRO instruments that were collected across four trials of canagliflozin in dual or triple therapy. Extensive searches identified only one study that was sufficiently similar in design and reported common PRO results using the Impact of Weight on Quality of Life-Lite (IWQoL-Lite): the DURATION-2 study of exenatide once-weekly (QW) versus sitagliptin and pioglitazone. This study was compared with the CANTATA-D study of canagliflozin versus sitagliptin. Bayesian indirect comparisons were performed to assess mean change in IWQoL-Lite total score. A fixed-effects model with noninformative priors was used to estimate between-treatment differences. Sensitivity analyses examined differences in trial populations. RESULTS: In the primary analysis, the probability that canagliflozin treatment results in greater improvement in IWQoL-Lite total score versus exenatide, sitagliptin, and pioglitazone was 60.0%, 89.9%, and 99.5%, respectively. When the CANTATA-D population was restricted using DURATION-2 inclusion/exclusion criteria, canagliflozin was also associated with a higher probability of having greater improvement in IWQoL-Lite than exenatide, sitagliptin, and pioglitazone. CONCLUSIONS: These findings suggest that improvements in the impact of weight on health-related quality of life may be greater with canagliflozin than exenatide, sitagliptin, and pioglitazone. This analysis also demonstrates the application of indirect comparison methodology to PRO data and provides examples of advantages and challenges associated with performing indirect comparisons of PRO data.