Clinical outcomes of chemotherapy-based therapies for previously treated advanced colorectal cancer: a systematic literature review and meta-analysis.

PURPOSE: The purpose of this study was to evaluate clinical outcomes of standard therapies in previously treated, advanced colorectal cancer (CRC) patients. METHODS: A systematic literature review was conducted in Embase, MEDLINE, and CENTRAL databases (January 2000-July 2021), annual oncology conferences (2019-2021), and clinicaltrials.gov to identify studies evaluating the use of licensed interventions in second-line or later settings. The primary outcome of interest was objective response rate (ORR) and secondary outcomes included progression-free survival (PFS) and overall survival (OS). ORR was pooled using the Freeman-Tukey double arcsine transformation. For survival outcomes, published Kaplan-Meier curves for OS and PFS were digitized to re-construct individual patient-level data and pooled following the methodology described by Combescure et al. (2014). RESULTS: Twenty-three trials evaluating standard chemotherapies with or without targeted therapies across 4,791 advanced CRC patients contributed to our meta-analysis. In the second-line setting, the random effects pooled estimate of ORR was 22.4% (95% confidence interval (CI): 18.0, 27.1), median PFS was 7.0 months (95% CI: 6.4, 7.4), and median OS was 14.9 months (95% CI: 13.6, 16.1). In the third-line or later setting, the random effects pooled estimate of ORR was 1.7% (95% CI: 0.8, 2.7), median PFS was 2.3 months (95% CI: 2.0, 2.8), and median OS was 8.2 months (95% CI: 7.1, 9.1). CONCLUSION: Standard treatments have limited efficacy in the second-line or later setting with worsening outcomes in later lines. Given the global burden of CRC, further research into novel and emerging therapeutic options following treatment failure is needed.

Network Meta-analysis of Ravulizumab and Alternative Interventions for the Treatment of Neuromyelitis Optica Spectrum Disorder.

INTRODUCTION: Anti-aquaporin-4 antibody-positive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD) is a complement-mediated autoimmune disease in which unpredictable and relapsing attacks on the central nervous system cause irreversible and accumulating damage. Comparative efficacy of new NMOSD therapies, such as ravulizumab, with established therapies is critical in making informed treatment decisions. METHODS: Efficacy of ravulizumab relative to established AQP4-Ab+ NMOSD treatments, such as eculizumab, inebilizumab, and satralizumab, was evaluated in a Bayesian network meta-analysis (NMA). Data were extracted from trials identified by a systematic literature review. The final evidence base consisted of 17 publications representing five unique and global studies (PREVENT, N-MOmentum, SAkuraSky, SAkuraStar, and CHAMPION-NMOSD). The primary endpoint was time-to-first relapse; other outcomes included annualized relapse rates (ARRs). RESULTS: For patients receiving monotherapy (monoclonal antibody only), ravulizumab was associated with a lower risk of relapse than inebilizumab (hazard ratio [HR] 0.09, 95% credible interval [CrI] 0.02, 0.57) or satralizumab (HR 0.08, 95% CrI 0.01, 0.55) and was comparable to eculizumab (HR 0.86, 95% Crl 0.16, 4.52). Ravulizumab + immunosuppressive therapy (IST) was associated with a lower risk of relapse than satralizumab + IST (HR 0.15, 95% CrI 0.03, 0.78); the comparison with eculizumab + IST suggested no difference. No patients treated with inebilizumab received background IST and were thus excluded from analysis. The ARR with ravulizumab monotherapy was 98% lower compared with inebilizumab (rate ratio [RR] 0.02, 95% Crl 0.00, 0.38) and satralizumab (RR 0.02, 95% Crl 0.00, 0.42) monotherapies. The ARR with ravulizumab ± IST showed the strongest treatment-effect estimates compared with other interventions. CONCLUSION: In the absence of head-to-head randomized controlled trials, NMA results suggest ravulizumab, a C5 inhibitor, is likely to be more effective in preventing NMOSD relapse in patients with AQP4-Ab+ NMOSD when compared with other treatments having different methods of action.

Anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder, also called AQP4-Ab+ NMOSD, is a rare autoimmune disease that causes repeated episodes of symptoms such as blindness, arm/leg weakness, painful spasms, vomiting, and hiccups, among other symptoms. Each episode can cause nervous system damage to worsen, making it more difficult to recover back to regular abilities. Repeated episodes are likely to cause permanent damage, such as blindness and paralysis. Medical treatments that reduce episodes also reduce the damage and the chances symptoms will become permanent. One treatment, ravulizumab, is being studied to treat adults with AQP4-Ab+ NMOSD. This analysis looked at information from published clinical studies to compare ravulizumab with three other treatments (eculizumab, inebilizumab, and satralizumab) to determine how well each treatment reduced NMOSD episodes. There are no studies that have tested all four treatments in one study. Here, the treatments were compared by a method used to estimate the likelihood of a treatment being better than the others. While all four treatments successfully reduced episodes in their own studies, this analysis predicts that ravulizumab would likely be best in preventing episodes compared with inebilizumab or satralizumab when used alone or in combination with other immunosuppressive treatments. These findings, in consideration along with other relevant factors such as cost, safety, dosing delivery method, and frequency of treatment, may help doctors and patients decide what is the best treatment option for each individual patient to prevent attacks in adults with AQP4-Ab+ NMOSD.

Matching-Adjusted Indirect Comparison of Brexucabtagene Autoleucel (ZUMA-2) and Pirtobrutinib (BRUIN) in Patients with Relapsed/Refractory Mantle Cell Lymphoma Previously Treated with a Covalent Bruton Tyrosine Kinase Inhibitor.

INTRODUCTION: Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) often require multiple lines of treatment and have a poor prognosis, particularly after failing covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy. Newer treatments such as brexucabtagene autoleucel (brexu-cel, chimeric antigen receptor T cell therapy) and pirtobrutinib (non-covalent BTKi) show promise in improving outcomes. METHODS: Without direct comparative evidence, an unanchored matching-adjusted indirect comparison was conducted to estimate the relative treatment effects of brexu-cel and pirtobrutinib for post-cBTKi R/R MCL. Using logistic propensity score models, individual patient-level data from ZUMA-2 brexu-cel-infused population (N = 68) were weighted to match pre-specified clinically relevant prognostic factors based on study-level data from the BRUIN cBTKi pre-treated cohort (N = 90). The base-case model incorporated the five most pertinent factors reported in ≥ 50% of both trial populations: morphology, MCL International Prognostic Index, number of prior lines of therapy, disease stage, and prior autologous stem cell transplant. A sensitivity analysis additionally incorporated TP53 mutation and Ki-67 proliferation. Relative treatment effects were expressed as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: In the base-case model, brexu-cel was associated with higher rates of objective response (OR 10.39 [95% CI 2.81-38.46]) and complete response (OR 10.11 [95% CI 4.26-24.00]), and improved progression-free survival (HR 0.44 [95% CI 0.25-0.75]), compared to pirtobrutinib. Overall survival and duration of response favored brexu-cel over pirtobrutinib but the differences crossed the bounds for statistical significance. Findings were consistent across the adjusted and unadjusted analyses. CONCLUSIONS: Findings suggest that brexu-cel may offer clinically and statistically significant benefits regarding objective response, complete response, and progression-free survival compared to pirtobrutinib among patients with R/R MCL after prior cBTKi therapy. Given the short follow-up and high degree of censoring in BRUIN, an analysis incorporating updated BRUIN data may provide more definitive overall survival results.

Efficacy and safety of treatments for advanced thymic carcinoma after failure of first-line platinum-based chemotherapy: A systematic literature review and meta-analysis.

Thymic carcinoma (TC) is a rare cancer and patients failing initial chemotherapy (relapse/refractory) face limited therapeutic options given no approved options or consensus standard of care. This study aimed to identify and summarize clinical outcomes of all regimens evaluated in clinical trials of relapsed or refractory patients. Interventional trials enrolling advanced TC patients who failed first-line chemotherapy and reported outcomes in this group were eligible for inclusion in our systemic literature review (SLR). Between-study heterogeneity was assessed to determine the feasibility of pooling specific studies and treatments. Objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and duration of response (DOR) endpoints were of interest for meta-analysis. Nineteen trials were identified in the SLR. Three trials with one or two TC patients were removed from our assessment to reduce publication bias. Response rates among studies with at least ten TC patients varied from 9 % to 38 %. Pooled ORRs in patients receiving S-1 (46 patients), sunitinib (46 patients), or pembrolizumab (66 patients) were 28 %, 24 %, and 21 %, respectively. Prolonged duration of response with pembrolizumab was observed with a pooled median of 23.8 months (95 % confidence interval [CI]: 12, not reached). Median PFS of five months or greater was reported in patients treated with sunitinib, lenvatinib, pembrolizumab, capecitabine + gemcitabine, everolimus, or S-1. Median OS of 20 months or greater was reported in trials evaluating S-1 or pembrolizumab; this endpoint was not reached in trials evaluating lenvatinib, regorafenib, or sunitinib. Generalizability of treatment effects is challenging in the research of rare diseases and meta-analysis of clinical outcomes may help to increase precision and relevance of results to the larger TC population. Our study found limited treatment options upon relapse, demonstrating a need for further investigations into novel therapeutics and well-powered clinical trials to better inform on optimal treatments.

Network Meta-analysis of Food and Drug Administration-approved Treatment Options for Adults with Aquaporin-4 Immunoglobulin G-positive Neuromyelitis Optica Spectrum Disorder.

INTRODUCTION: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease defined by attacks on the central nervous system that cause irreversible damage. Recent approval of NMOSD therapies warrants investigations of comparative efficacy to inform treatment decisions. METHODS: A network meta-analysis (NMA) of all U.S. Food and Drug Administration-approved therapies (eculizumab, inebilizumab, and satralizumab) for adults with aquaporin-4 immunoglobulin G-positive (AQP4+) NMOSD was conducted via a systematic literature review (SLR) using data from randomized controlled trials (RCTs). Database searches of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were executed for the SLR. A fixed-effects proportional hazards Bayesian NMA was used to estimate relative treatment effects based on data extracted from RCTs identified during the SLR (search end date: 11 September 2020). Four unique RCTs (N-MOmentum, PREVENT, SAkuraSky, and SAkuraStar) were identified, and data from 29 publications were extracted for analysis. Network scenarios describing the most comparable patient population groups (such as by treatment settings) were evaluated in our analyses. Relative treatment effects were evaluated based on time-to-first relapse and were expressed as hazard ratios (HRs) with 95% credible intervals (CrIs). RESULTS: In patients treated with a monoclonal antibody only, eculizumab was associated with a lower risk of relapse compared with satralizumab (HR 0.10, 95% CrI 0.01, 0.65) and inebilizumab (HR 0.11, 95% CrI 0.02, 0.68). In patients treated with monoclonal antibody with or without background immunosuppressive therapy (IST), patients treated with eculizumab ± IST were also less likely to relapse than patients treated with satralizumab ± IST (HR 0.24, 95% CrI 0.06, 0.98). CONCLUSION: The NMA results suggest that complement component 5 (C5) inhibition prevents NMOSD relapses more effectively than broader mechanisms of action.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease characterized by inflammation that damages the brain and spinal cord. Many patients with NMOSD produce antibodies against a protein called aquaporin-4 (AQP4+). In the past two years, three drugs (eculizumab, inebilizumab, and satralizumab) have been approved by the U.S. Food and Drug Administration for the treatment of adults with AQP4+ NMOSD. Comparing the efficacy of these three drugs would help physicians make treatment decisions for their patients. In the absence of clinical trials directly comparing these three drugs, we conducted a Bayesian network meta-analysis in order to allow for simultaneous comparisons of these three drugs and estimate relative treatment effects between any pair of interventions in a connected network. With a Bayesian methodology, it is also possible to estimate the probability of being the best treatment out of all other interventions in a connected network. While all three drugs are safe and shown to prevent relapses in placebo-controlled trials, the results of our analysis suggests that eculizumab was the most efficacious in preventing relapses when compared with inebilizumab or satralizumab. These findings may help to inform physicians and their patients when determining the best treatment option for preventing the occurrence of relapses in adults with AQP4+ NMOSD.

Pembrolizumab plus chemotherapy for first-line treatment of metastatic nonsquamous non-small-cell lung cancer: a network meta-analysis.

AIM: A systematic review and network meta-analysis were conducted to evaluate the efficacy of pembrolizumab + pemetrexed + platinum relative to other regimens in metastatic nonsquamous non-small-cell lung cancer (NSq-NSCLC). PATIENTS & METHODS: Eligible studies evaluated first-line regimens in NSq-NSCLC patients without known targetable mutations. Relative treatment effects were synthesized with random effects proportional hazards Bayesian network meta-analyses. RESULTS: The hazard ratio (HR) for overall survival (OS) for pembrolizumab + pemetrexed + platinum was statistically significant over all platinum-doublet (HR range: 0.42-0.61), platinum-doublet + bevacizumab (HR range: 0.44-0.53) and platinum-doublet + atezolizumab regimens (HR range: 0.56-0.62). Additionally, pembrolizumab + pemetrexed + platinum numerically improved OS over atezolizumab + paclitaxel + carboplatin + bevacizumab (HR: 0.65; 95% credible interval: 0.43, 1.01). Pembrolizumab + pemetrexed + platinum had 95.6% probability of being the best treatment regimen for OS. CONCLUSION: Pembrolizumab + pemetrexed + platinum is likely the most efficacious first-line regimen for metastatic NSq-NSCLC.