Short-, Mid-, and Long-Term Efficacy of Deucravacitinib Versus Biologics and Nonbiologics for Plaque Psoriasis: A Network Meta-Analysis.

INTRODUCTION: Deucravacitinib, a newly approved oral medication for the treatment of patients with moderate to severe plaque psoriasis, demonstrated efficacy versus apremilast and placebo in two phase 3 randomized controlled trials (RCTs). A systematic review and network meta-analysis (NMA) indirectly compared deucravacitinib with other relevant systemic biologic/nonbiologic treatments. METHODS: Online databases were searched for RCTs published through October 2021. Eligible studies were head-to-head comparisons between systemic therapies and/or placebo reporting 50%, 75%, 90%, or 100% improvement in Psoriasis Area and Severity Index (PASI) from baseline in adults with moderate to severe plaque psoriasis. Comparisons included tumor necrosis factor inhibitors, interleukin (IL)-17, IL-23, and IL 12/23 inhibitors, and systemic nonbiologics. A multinomial Bayesian NMA was used to derive estimates of the relative efficacy of deucravacitinib and other systemic therapies. Response probabilities for each treatment and corresponding 95% credible intervals (CrIs) for achieving a PASI response were calculated over short-, mid-, and long-term follow-up (weeks 10-16, 24-28, and 44-60). RESULTS: The NMA included 47 RCTs. Deucravacitinib showed the highest PASI 75 response rates among nonbiologic systemic therapies across time points. Deucravacitinib PASI 75 response rate (95% CrI) over short-term follow-up was 54.1% (46.5-61.6), within the range of first-generation biologics (etanercept, 39.7% [31.6-48.3]; infliximab, 79.0% [74.0-83.5]). At mid-term follow-up, deucravacitinib PASI 75 increased to 63.3% (58.0-68.4). At long-term follow-up, deucravacitinib PASI 75 was 65.9% (58.0-73.4), comparable to first-generation biologics adalimumab (62.8%; 55.3-69.6) and ustekinumab (68.0%; 64.6-71.5). CONCLUSIONS: Patients receiving deucravacitinib were more likely to achieve PASI 75 response versus apremilast and methotrexate across all time points. The long-term PASI 75 response rate for deucravacitinib was similar to those of adalimumab and ustekinumab. The approval of deucravacitinib offers patients the choice of an oral therapy with long-term efficacy similar to that of some biologics.

Tafasitamab Plus Lenalidomide Versus 3 Rituximab-Based Treatments for Non-Transplant Eligible Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Matching-Adjusted Indirect Comparison.

INTRODUCTION: Tafasitamab plus lenalidomide (TAFA + LEN) received accelerated US Food and Drug Administration approval and conditional European Medicines Agency approval for treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) not eligible for autologous stem cell transplant. This study investigates the relative efficacy of TAFA + LEN versus comparator treatments. METHODS: Matching-adjusted indirect comparisons (MAICs) of TAFA + LEN were performed using data from L-MIND, and comparator studies assessing rituximab-based combination therapies, including polatuzumab vedotin + bendamustine + rituximab (POLA + BR) bendamustine + rituximab (BR), and gemcitabine + oxaliplatin + rituximab (R-GEMOX) to provide relative efficacy estimates for overall survival (OS), progression-free survival (PFS), duration of response (DOR), objective response rate (ORR), and complete response rate (CRR). Patient-level data from L-MIND were weighted to match reported distributions of clinically validated prognostic factors and effect modifiers in comparator trials. MAIC results versus multiple BR studies were pooled using meta-analysis. RESULTS: MAICs were feasible versus POLA + BR and BR. Compared to POLA + BR, TAFA + LEN was associated with significantly longer DOR [hazard ratio (HR) 0.34 (95% CI 0.12, 0.98); p = 0.045]. Due to concerns about the proportional hazard assumption for OS and PFS, separate HRs were estimated before and after 4 months of follow-up. OS after 4 months, was significantly greater for TAFA + LEN versus POLA + BR [HR 0.41 (95% CI 0.19, 0.90); p = 0.026]. Compared with BR, TAFA + LEN was associated with significantly improved OS [GO29365 comparator trial: HR 0.39 (95% CI 0.18, 0.82); p = 0.014], PFS (pooled data: HR 0.39 (95% CI 0.29, 0.53); p < 0.001], DOR [pooled data: HR 0.35 (95% CI 0.25, 0.50); p < 0.001], and CRR [pooled data: odds ratio 2.43 (95% CI 1.33, 4.41); p = 0.004]. CONCLUSION: In MAIC analyses, treatment with TAFA + LEN for R/R DLBCL provided better OS and PFS outcomes than standard treatment regimens. Validation from large, randomized, phase 3 clinical trials is required to confirm these results.

Tafasitamab in combination with lenalidomide has been recently approved for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma. There are no clinical trials to directly compare the outcomes of tafasitamab + lenalidomide against other treatments for diffuse large B-cell lymphoma. Matching-adjusted indirect comparisons allow an estimate of the relative efficacy of treatments to be derived in the absence of head-to-head comparisons from clinical trials. Matching-adjusted indirect comparisons analyses utilizing data from previously published clinical trials were conducted to compare the combination of tafasitamab + lenalidomide against 3 standard treatments for relapsed or refractory diffuse large B-cell lymphoma: polatuzumab vedotin + bendamustine + rituximab, bendamustine + rituximab, and rituximab + gemcitabine + oxaliplatin. Compared to those treated with polatuzumab vedotin + bendamustine + rituximab, patients treated with TAFA + LEN maintained their response to treatment for longer and are more likely to experience long-term survival. When compared to those treated with bendamustine + rituximab, patients treated with TAFA + LEN had increased survival, a higher level of response, and maintained their response to treatment for longer. Overall, the findings suggest that treatment with TAFA + LEN for R/R DLBCL is likely to result in significantly better outcomes compared with standard rituximab-based treatments.

A criterion-based approach to systematic and transparent comparative effectiveness: a case study in psoriatic arthritis.

Aim: Indirect treatment comparisons are used when no direct comparison is available. Comparison networks should satisfy the transitivity assumption, that is, equal likelihood of treatment assignment for a given patient based on comparability of studies. Materials & methods: Seven criteria were evaluated across 18 randomized controlled trials in psoriatic arthritis: inclusion/exclusion criteria, clinical trial design and follow-up, patient-level baseline characteristics, disease severity, prior therapies, concomitant and extended-trial treatment and placebo response differences. Results: Across studies, placebo was a common comparator, and key efficacy end points were reported. Collectively, several potential sources of insufficient transitivity were identified, most often related to trial design and population differences. Conclusion: Potential challenges in satisfying transitivity occur frequently and should be evaluated thoroughly.

Overall survival of glasdegib in combination with low-dose cytarabine, azacitidine, and decitabine among adult patients with previously untreated AML: comparative effectiveness using simulated treatment comparisons.

BACKGROUND: Until recently, treatments for older patients with AML ineligible to receive intensive chemotherapies were limited to hypomethylating agents, low-dose cytarabine (LDAC), or clinical trials. In 2018, the FDA approved combination glasdegib (GLAS) plus LDAC based on Phase II results demonstrating improved overall survival (OS) versus LDAC alone in previously untreated AML. However, no randomized clinical trials have directly compared GLAS + LDAC with other AML treatments. OBJECTIVE: Using both indirect treatment comparison (ITC) and simulated treatment comparison (STC), which adjusts for baseline differences between trials, the comparative effectiveness of GLAS + LDAC was compared with hypomethylating agent azacitidine (AZA) or decitabine (DEC). METHODS: A systematic literature review identified published trials of AZA or DEC versus LDAC among older AML patients ineligible for high-intensity chemotherapy. In addition to standard and covariate-adjusted ITC, STC was performed following guidance from the NICE Decision Support Unit (DSU). Using individual patient data from the Phase II GLAS + LDAC study, population-specific OS hazard ratios (HR) for GLAS + LDAC versus AZA or DEC were compared. Furthermore, covariate-adjusted ITC (Cox multivariate models) and STC were repeated using GLAS + LDAC versus LDAC data propensity-weighted for within-trial mean cytogenetic risk. As this initial step was not specified in the DSU, results from this second method were compared to the first STC following DSU guidance only. RESULTS: Standard ITC and STC both demonstrated significantly improved OS for GLAS + LDAC versus either AZA or DEC. Adjusting for key covariates, STC stepwise exponential models demonstrated GLAS + LDAC superiority to both AZA (HR=0.424; 95% CI: 0.228, 0.789) and DEC (HR=0.505; 95% CI: 0.269, 0.949). These significant results held using full or step-wise approaches, following DSU guidance only or the weighted STC approach. CONCLUSION: Using ITC and STC, GLAS + LDAC demonstrated superior OS to AZA or DEC in an adult population with previously untreated AML for whom intensive chemotherapy is not an option.

Indirect treatment comparisons including network meta-analysis: Lenvatinib plus everolimus for the second-line treatment of advanced/metastatic renal cell carcinoma.

BACKGROUND: In the absence of clinical trials providing direct efficacy results, this study compares different methods of indirect treatment comparison (ITC), and their respective impacts on efficacy estimates for lenvatinib (LEN) plus everolimus (EVE) combination therapy compared to other second-line treatments for advanced/metastatic renal cell carcinoma (a/mRCC). METHODS: Using EVE alone as the common comparator, the Bucher method for ITC compared LEN + EVE with cabozantinib (CAB), nivolumab (NIV), placebo (PBO) and axitinib (AXI). Hazard ratios (HR) for overall survival (OS) and progression-free survival (PFS) estimated the impact of applying three versions of the LEN+EVE trial data in separate ITCs. Last, to overcome exchangeability bias and potential violations to the proportional hazards assumption, a network meta-analysis using fractional polynomials was performed. RESULTS: Bucher ITCs demonstrated LEN + EVE superiority over EVE for PFS, indirect superiority to NIV, AXI, and PBO, and no difference to CAB. For OS, LEN + EVE was superior to EVE and indirectly superior to PBO, applying original HOPE 205 data. Using European Medicines Agency data, LEN + EVE was directly superior to EVE for OS. Fractional polynomial HRs for PFS and OS substantially overlapped with Bucher estimates, demonstrating LEN+EVE superiority over EVE, alone, NIV, and CAB. However, there were no statistically significant results as the credible intervals for HR crossed 1.0. CONCLUSIONS: Comparing three Bucher ITCs, LEN + EVE demonstrated superior PFS when indirectly compared to NIV, AXI, and PBO, and mixed results for OS. While fractional polynomial modelling for PFS and OS failed to find statistically significant differences in LEN + EVE efficacy, the overall HR trends were comparable.

Divergence from osteoporosis screening guidelines in older breast cancer patients treated with anti-estrogen therapy: A population-based cohort study.

PURPOSE: Older Breast Cancer (BC) survivors are an increased risk of osteoporosis due to natural aging and long-term cancer treatment-related toxicity. It is well known that anti-estrogen therapy (AET), especially aromatase inhibitors (AI), is associated with rapid bone loss and thus increases the risk of osteoporosis. This study characterizes patterns and predictors of receiving guideline-recommended bone densitometry (BD) screening at AET initiation. METHODS: A retrospective cohort study (1998-2012) of all women ≥65 years of age initiating AET was designed using claims data from Quebec's universal health care. Associations with BD screening were estimated using a generalized estimating equations regression model, adjusting for clustering of patients within physicians. RESULTS: Among 16,480 women initiating AET, 36.1% received a baseline BD. Among AI users, the rate was 58.4%. In the multivariate analysis, age, lower socioeconomic status, tamoxifen use, lack of periodic health exam and having a general practitioner as the AET prescriber were associated with lower odds of BD screening. In terms of quality of care-related variables, lack of guideline-appropriate radiotherapy (OR: 0.69 (95% CI, 0.57-0.83), or chemotherapy consideration (0.82 (95% CI, 0.71-0.94)) and non-adherence to AET (0.76 (95% CI, 0.68-0.84)) were associated with lower odds of receiving BD screening. Women diagnosed with BC after 2003 had significantly better odds of being screened. CONCLUSION: Despite an increase in rates since 2003, BD screening remains suboptimal, especially for women at higher risk of osteoporosis. Coordination of health care and service-delivery monitoring can potentially optimize long-term management of treatment-related toxicity in older BC survivors.

Patterns and predictors of emergency department visits among older patients after breast cancer surgery: A population-based cohort study.

OBJECTIVES: To characterize rates, reasons for, and associated predictors for emergency department (ED) visits after breast cancer (BC) surgery. METHODS: All women over 65 years undergoing curative surgery for non-metastatic incident BC (1998-2012) were identified using Quebec's universal healthcare administrative databases. Reasons for ED visits within 45days of operation were reported. Associated factors were estimated using Cox regression. RESULTS: Of 24,463 patients, 12.8% had postoperative ED visits. Most frequent reasons were: superficial infection, noninfectious gastrointestinal, trauma or wound (other than breast), noninfectious respiratory, and breast wound disruption. Significant predictors included localized (aHR, 1.24, CI 1.04-1.49) or regional disease (aHR 1.64, CI 1.41-1.92), mastectomy (aHR 1.22, CI 1.10-1.34), each operation before definitive oncologic control (aHR 1.12, CI 1.03-1.21), lower institutional volume (aHR 1.23, CI 1.09-1.38), having 6-10 prescriptions (aHR 1.23, CI 1.15-1.31) or >10 (aHR 1.53, CI 1.33-1.77), benzodiazepine use (aHR 1.09, CI 1.01-1.18), anticoagulant use (aHR 1.29, CI 1.13-1.46), cardiovascular disease (aHR 1.15, CI 1.05-1.26), diabetes (aHR 1.11, CI 1.00-1.24), past hospitalization (aHR 1.25, CI 1.17-1.34), and lower income (aHR 1.12, CI 1.04-1.20). CONCLUSION: Identification of risk factors in older patients before BC surgery could help prevent postoperative ED visits.

Neighborhood socioeconomic conditions and depression: a systematic review and meta-analysis.

PURPOSE: The evidence linking neighborhood socioeconomic conditions (NSEC) with depression is mixed. We performed a systematic review of this literature, including a rigorous quality assessment that was used to explore if methodological or contextual factors explained heterogeneity across studies. METHODS: A systematic literature search in three databases identified longitudinal studies among adolescents and adults living in high-income countries. Two independent reviewers screened studies for inclusion and performed data abstraction. We conducted a formal quality assessment and investigated sources of study heterogeneity. RESULTS: Our database search identified 3711 articles, 84 of which were determined to be potentially relevant, and 14 articles were included in this review. About half of the studies found a significant association between NSEC and depression, and pooled estimates suggest poorer socioeconomic conditions were associated with higher odds of depression (OR = 1.14, 95% CI 1.01, 1.28). Study results varied by follow-up time. Among studies with less than 5 years of follow-up, there was a significant association between NSEC and depression (OR = 1.28, 95% CI 1.13, 1.44), although pooling of study results may not be warranted due to heterogeneity across studies. Among studies with at least 5 years of follow-up, which were homogeneous, there was no association (OR = 1.00, 95% CI 0.95, 1.06) between NSEC and depression. CONCLUSIONS: We found inconsistent evidence in support of a longitudinal association between NSEC and depression, and heterogeneity according to the length of follow-up time might partly explain the mixed evidence observed in the literature on NSEC and depression.