Comparative Efficacy of Daratumumab Monotherapy and Pomalidomide Plus Low-Dose Dexamethasone in the Treatment of Multiple Myeloma: A Matching Adjusted Indirect Comparison.

BACKGROUND: Daratumumab (a human CD38-directed monoclonal antibody) and pomalidomide (an immunomodulatory drug) plus dexamethasone are both relatively new treatment options for patients with heavily pretreated multiple myeloma. A matching adjusted indirect comparison (MAIC) was used to compare absolute treatment effects of daratumumab versus pomalidomide + low-dose dexamethasone (LoDex; 40 mg) on overall survival (OS), while adjusting for differences between the trial populations. MATERIALS AND METHODS: The MAIC method reduces the risk of bias associated with naïve indirect comparisons. Data from 148 patients receiving daratumumab (16 mg/kg), pooled from the GEN501 and SIRIUS studies, were compared separately with data from patients receiving pomalidomide + LoDex in the MM-003 and STRATUS studies. RESULTS: The MAIC-adjusted hazard ratio (HR) for OS of daratumumab versus pomalidomide + LoDex was 0.56 (95% confidence interval [CI], 0.38-0.83; p = .0041) for MM-003 and 0.51 (95% CI, 0.37-0.69; p < .0001) for STRATUS. The treatment benefit was even more pronounced when the daratumumab population was restricted to pomalidomide-naïve patients (MM-003: HR, 0.33; 95% CI, 0.17-0.66; p = .0017; STRATUS: HR, 0.41; 95% CI, 0.21-0.79; p = .0082). An additional analysis indicated a consistent trend of the OS benefit across subgroups based on M-protein level reduction (≥50%, ≥25%, and <25%). CONCLUSION: The MAIC results suggest that daratumumab improves OS compared with pomalidomide + LoDex in patients with heavily pretreated multiple myeloma. IMPLICATIONS FOR PRACTICE: This matching adjusted indirect comparison of clinical trial data from four studies analyzes the survival outcomes of patients with heavily pretreated, relapsed/refractory multiple myeloma who received either daratumumab monotherapy or pomalidomide plus low-dose dexamethasone. Using this method, daratumumab conferred a significant overall survival benefit compared with pomalidomide plus low-dose dexamethasone. In the absence of head-to-head trials, these indirect comparisons provide useful insights to clinicians and reimbursement authorities around the relative efficacy of treatments.

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.

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.

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.

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).

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.

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.

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.

Genomic biomarkers for a binary clinical outcome in early drug development microarray experiments.

In this article, we discuss methods to select three different types of genes (treatment related, response related, or both) and investigate whether they can serve as biomarkers for a binary outcome variable. We consider an extension of the joint model introduced by Lin et al. (2010) and Tilahun et al. (2010) for a continuous response. As the model has certain drawbacks in a binary setting, we also present a way to use classical selection methods to identify subgroups of genes, which are treatment and/or response related. We evaluate their potential to serve as biomarkers by applying DLDA to predict the response level.