Aim: In the single-arm MOUNTAINEER trial (NCT03043313) tucatinib in combination with trastuzumab showed an objective response rate (ORR) of 39.3% in patients with previously treated, HER2+ unresectable or metastatic colorectal cancer (mCRC). This study compared the efficacy of tucatinib in combination with trastuzumab with other treatment options in this population. Materials & methods: An unanchored, matching-adjusted indirect comparison was conducted following a systematic literature review that identified the CORRECT trial (NCT01103323), which investigated regorafenib, and the RECOURSE trial (NCT01607957), which investigated trifluridine-tipiracil, as comparators for tucatinib in combination with trastuzumab. Patient and study characteristics, overall survival (OS), progression-free survival (PFS) and ORR data were extracted and compared assuming HER2 status was not prognostic. Differences in adjusted covariates across analyses included patient age, performance status, time since metastatic diagnosis and prior lines of therapy. OS and PFS were compared using Cox proportional hazard models to generate match-adjusted hazard ratios (HRs) and 95% CI. ORR was compared via match-adjusted odds ratios and 95% CIs. As MOUNTAINEER only included patients from Europe and North America, sensitivity analyses used non-Japanese patients from CORRECT and European and US patients from RECOURSE. Results: In the main analysis, the estimated adjusted HR (95% CI) for tucatinib in combination with trastuzumab versus regorafenib was 0.26 (0.14-0.46) for OS and 0.32 (0.23-0.46) for PFS; versus trifluridine-tipiracil, this was 0.34 (0.22-0.51) for OS and 0.38 (0.20-0.58) for PFS. Similar results were seen for OS and PFS in sensitivity analyses. ORR also favored tucatinib in combination with trastuzumab across analyses. Conclusion: These data support that tucatinib in combination with trastuzumab is an effective therapy option in patients with previously treated mCRC.

Identification of reliable biomarkers in Hepato-pancreatico-biliary (HPBC) and gastric cancers (GC) has been extremely challenging, and no effective screening modality is currently available. There is an increasing appreciation that the gut microbiome may be altered in these diseases and act as a predictor of disease or disease outcome. To examine the gut microbiota in a cohort of treatment naïve, newly diagnosed pancreatic, biliary and gastric cancer patients and age matched controls. Stool samples from 37 treatment naïve, newly diagnosed HPBC and GC patients and 47 age-matched non-cancer controls were prospectively collected. Microbiota composition was determined by 16 S rRNA amplicon sequencing. Differences in the microbial composition of HC and HPBC patients were assessed using linear discriminant analysis effect size. Predictive functional profiling of microbial communities was obtained with PICRUSt. The gut microbiota of HPBC patients was significantly different compared to the non-cancer controls. Enterococcus, Enterobacter, Streptococcus and Lactobacillus, were significantly increased in HPBC, while numerous Lachnospiraceae, Ruminococcaceae_UCG014, Bacteroides and Faecalibacterium were significantly reduced in HPBC. Enterobacter and Enterococcus best discriminated the HPBC samples, while Butyrivibrio and Lachnospira best discriminated the non-cancer controls. There was a trend towards decreased diversity and richness in cancer patients with increasing severity of cancer stage. We report a significant difference in microbial composition in patients with pancreatic and biliary cancer compared to non-cancer controls, which is associated with an increase in pathogens and a decrease in potential beneficial bacteria. Our results support the potential for the gut microbiota to act as an early biomarker for these highly fatal and poorly diagnosed gastrointestinal cancers.

The objective of this article is to bring together the key current information on practical considerations when conducting statistical analyses adjusting long-term outcomes for treatment switching, combining it with learnings from our own experience, thus providing a useful reference tool for analysts. When patients switch from their randomised treatment to another therapy that affects a subsequently observed outcome such as overall survival, there may be interest in estimating the treatment effect under a hypothetical scenario without the intercurrent event of switching. We describe the theory and provide guidance on how and when to conduct analyses using three commonly used complex approaches: rank preserving structural failure time models (RPSFTM), two-stage estimation (TSE), and inverse probability of censoring weighting (IPCW). Extensions and alternatives to the standard approaches are summarised. Important and sometimes misunderstood concepts such as recensoring and sources of variability are explained. An overview of available software and programming guidance is provided, along with an R code repository for a worked example, reporting recommendations, and a review of the current acceptability of these methods to regulatory and health technology assessment agencies. Since the current guidance on this topic is scattered across multiple sources, it is difficult for an analyst to obtain a good overview of all options and potential pitfalls. This paper is intended to save statisticians time and effort by summarizing important information in a single source. By also including recommendations for best practice, it aims to improve the quality of the analyses and reporting when adjusting time-to-event outcomes for treatment switching.

Introduction: A systematic literature review (SLR) and network meta-analysis (NMA) were conducted to evaluate the comparative efficacy, durability and safety of faricimab, used in a Treat & Extend (T&E) regime with intervals up to every 16 weeks (Q16W), relative to other therapies currently in use for treatment of diabetic macular oedema (DME). Of particular interest were anti-vascular endothelial growth factor (VEGF) therapies applied in flexible dosing regimens such as Pro re nata (PRN) and T&E, which are the mainstay in clinical practice. Methods: An SLR identifying randomised controlled trials (RCTs) published before August 2021 was conducted, followed by a Bayesian NMA comparing faricimab T&E treatment to aflibercept, ranibizumab, bevacizumab, dexamethasone and laser therapy. Outcomes included in the analysis were change in best-corrected visual acuity (BCVA), change in central subfield thickness (CST), injection frequency, ocular adverse events (AE) and all-cause discontinuation, all of which were evaluated at 12 months. Subgroup analyses including patients' naive to anti-VEGF were conducted where feasible. Results: Twenty-six studies identified in the SLR were included in the NMA. Most importantly for decision making in clinical practise, faricimab T&E was associated with a statistically greater (95% credible intervals exclude zero) and clinically meaningful decrease in retinal thickness compared to all other flexible dosing regimens (greater retinal drying by 55-125 microns). Anatomical outcomes determine treatment efficacy and retreatment of patients. The NMA also showed a statistically greater increase in mean change in BCVA for faricimab T&E vs. flexible regimens using ranibizumab and bevacizumab (increase of 4.4-4.8 letters) as well as a numerical improvement vs. aflibercept PRN (two letters, 95% credible intervals including zero). Accordingly, the injection frequency was numerically lower versus other treatments using flexible dosing regimens (decrease by 0.92-1.43 injections). The analyses also indicated that the safety profile of faricimab T&E was comparable to those of ranibizumab and aflibercept, which have well-established safety profiles, with similar results for the number of all-cause discontinuations. Conclusion: Faricimab provides a new treatment option in DME with dual-pathway inhibition of VEGF and angiopoeitin-2 (Ang-2). To the authors' knowledge, this is the first indirect comparison of faricimab T&E in DME. The analyses indicate that faricimab T&E is associated with superior retinal drying along with numerically fewer injections compared to all other treatments given in flexible dosing regimens. It also showed superior visual acuity outcomes compared to ranibizumab and bevacizumab.

Tebentafusp (tebe) is a bispecific consisting of an affinity-enhanced T cell receptor fused to an anti-CD3 effector that can redirect T cells to target gp100+ cells. Tebe significantly improved overall survival (OS) compared to investigator’s choice of pembrolizumab, ipilimumab or dacarbazine (HR 0.51) in first line (1L) mUM [NCT03070392]. Here we evaluated the impact of subsequent therapy on long-term survival. Analyses were conducted on HLA-A*02:01+ patients with first line mUM recruited to the randomized phase III study (Study 202, N=378). Crossover to tebe was not permitted until the planned interim analysis demonstrated significant OS benefit. Inverse probability of censoring weighting (IPCW) was used to compare the tebentafusp and investigator’s choice (IC) arms by removing the effects of subsequent therapies (any versus CPI only). OS from the start of subsequent therapy was compared between arms using Cox regression models adjusted for prognostic baseline covariates. After a median follow-up of 37.8 months, a similar percentage of patients, ∼ 62%, received subsequent therapy in each arm. Median time to first subsequent therapy was longer for tebe pts (6.4 mo) vs. IC pts (4.5 mo). The most frequent subsequent therapy was CPI in both arms (received by 49% of tebe pts and 34% of IC pts); 17% of IC pts received subsequent tebe. When adjusting for the effect of subsequent therapy (any or CPI), the OS benefit from the ITT analysis was maintained. In an analysis of survival from the start of any first subsequent therapy, prior tebe patients tended to have longer OS compared to prior IC patients, HR (95% CI) 0.75 (0.55, 1.04). This difference was also seen when restricting to patients who received subsequent CPI therapy, HR (95% CI) 0.72 (0.48, 1.09). Based on IPCW analysis, the OS benefit in first line HLA-A*02:01+ mUM patients is predominantly due to tebentafusp and not due to subsequent therapy. This reinforces the use of tebentafusp in the first line setting. Updated data with a minimum 3 years of follow-up will be presented. 1. Yang J. et al. ASCO 2019 , J. Clin Oncol 37:15_suppl, 9592.

BACKGROUND:Tebentafusp demonstrated a superior overall survival (OS) benefit [hazard ratio (HR) 0.51] compared to investigator's choice (82% pembrolizumab) in a randomized, phase III trial (IMCgp100-202; N = 378) in untreated metastatic uveal melanoma (mUM). The 1-year OS rates for tebentafusp and pembrolizumab were 73% and 59%, respectively. In the single-arm GEM1402 (N = 52), the 1-year OS rate for nivolumab plus ipilimumab (N+I) in mUM was 52%. Due to limitations in conducting randomized trials in mUM, we compared OS on tebentafusp or pembrolizumab (IMCgp100-202) to N+I (GEM1402) in untreated mUM using propensity scoring methods. PATIENTS AND METHODS:Analyses were adjusted using propensity score-based inverse probability of treatment weighting (IPTW), balancing age, sex, baseline lactate dehydrogenase (LDH), baseline alkaline phosphatase, disease location, Eastern Cooperative Oncology Group status, and time from primary diagnosis to metastasis. OS was assessed using IPT-weighted Kaplan-Meier and Cox proportional hazard models. Sensitivity analyses using alternative missing data and weights methods were conducted. RESULTS:The primary IPTW analysis included 240 of 252 patients randomized to tebentafusp from IMCgp100-202 and 45 of 52 N+I-treated patients from GEM-1402. Key baseline covariates, including LDH, were generally well balanced before weighting. The IPTW-adjusted OS favored tebentafusp, HR 0.52 [95% confidence interval (CI) 0.35-0.78]; 1-year OS was 73% for tebentafusp versus 50% for N+I. Sensitivity analyses showed consistent superior OS for tebentafusp with all IPTW HRs ≤0.61. IPTW analysis of pembrolizumab versus N+I showed no significant difference in OS (HR 0.72; 95% CI 0.50-1.06). CONCLUSIONS:Tebentafusp was previously shown to provide an OS benefit compared to checkpoint inhibitors or chemotherapy in untreated mUM. Propensity score analysis demonstrated a similar OS benefit for tebentafusp compared with N+I. These data further support tebentafusp as the standard of care in previously untreated human leukocyte antigen (HLA)-A∗02:01+ adult patients with mUM.

9585 Background: Tebentafusp (tebe) is the first T cell receptor therapeutic to demonstrate overall survival (OS) benefit in a randomized Phase 3 study vs investigator’s choice (IC) [ NCT03070392 ]. OS benefit was also observed in patients (pts) with best objective response (BOR) PD (HR 0.43), and in pts who had tumor growth ≥20% as best change in tumor size (HR 0.41), suggesting tebe-treated pts may exhibit atypical radiological responses and could benefit from treatment beyond radiographic progression (TBP), a well-established concept in immuno-oncology. Here we analyzed tumor kinetics and clinical benefit in pts treated with tebe beyond initial radiographic progression (TBP). Methods: 378 mUM pts were randomized 2:1 to tebe vs. IC. BOR was assessed by investigators using RECIST v1.1. TBP was permitted until: 1) additional ≥20% increase in tumor burden with absolute increase of ≥5 mm, or 2) unequivocal PD of non-target lesions; or 3) new non-measurable lesions. A Cox model adjusted for baseline covariates and for covariates at time of progression for TBP-eligible pts was used to compare survival post progression between those who did (TBP) and did not receive TBP (non-TBP). Stepwise selection of covariates (using p < 0.1 as the entry and staying criterion) was applied. Analysis performed on data cut-off 13Oct2020. Results: 183 tebe pts were eligible for TBP per protocol; 60% (109/183) received TBP with median duration of 8 wks. 21% of all tebe doses were administered as TBP. The proportion of pts with new lesions at initial progression (44% vs 57%) and median time to initial progression (2.9 mo vs 2.9 mo) were similar between TBP and non-TBP pts. Pts receiving TBP were more likely to have favorable key prognostic factors at baseline or at time of progression. After adjusting for these differences, a numerical benefit in post-progression OS favoring TBP was observed (HR 0.67, 95% CI [0.38,1.19]). Serial review of radiographic time points identified initial progression of sum of target lesions followed by stabilization for > 3 months after initial progression in some TBP pts. Safety profile during TBP was consistent with that expected for pts established on tebe and no pts experienced an AE leading to treatment discontinuation. Conclusions: An OS benefit observed for tebentafusp among mUM patients who have initial radiographic progression demonstrates that RECIST assessment underestimates benefit. In a post-hoc analysis of OS following initial radiographic progression, continued treatment with tebentafusp was associated with numerically longer OS after adjusting for key prognostic variables. Tebentafusp treatment beyond progression was tolerated without new safety signals and, in some patients, was associated with radiological stabilization of sum of target lesions for > 3 months following the initial progression. Clinical trial information: NCT03070392.

Tebentafusp (tebe) demonstrated an overall survival (OS) benefit, HR 0.51, compared to investigator choice (IC) in a Ph3 trial in untreated metastatic uveal melanoma (mUM). 82% of the IC arm was pembrolizumab (pembro); ipilimumab + nivolumab (ipi + nivo) was not studied. The 1-yr OS rate for tebe and pembro were 73% and 59%, respectively, while the 1-yr OS rate for ipi + nivo in GEM-1402 was 52%. Using individual patient data (IPD), we conducted a propensity score (PS) weighted analysis to compare OS on tebe or pembro (IMCgp100-202) to ipi+nivo (GEM-1402) in untreated mUM. Two analyses were conducted: 1) an initial match-adjusted indirect comparison (MAIC) of tebe or pembro with ipi+nivo and 2) a PS analysis of tebe with ipi+nivo. To adjust for differences in patient characteristics, PS from a logistic regression model were used to generate inverse probability of treatment weights (IPTW). OS was compared using weighted Cox models and Kaplan-Meier curves. The primary analysis was complete case with ATT (average treatment effect of the treated) weights. Sensitivity analyses used alternative missing data methods and weights. MAICs favored tebe vs ipi+nivo (HR 0.51, 95% CI 0.32-0.79) with no significant difference for pembro vs ipi+nivo (HR 0.74, 95% CI 0.45-1.21). 237 tebe and 45 ipi + nivo patients were included in the primary IPTW analysis. Key baseline covariates including LDH, ALP and ECOG were generally well balanced across treatments, with some differences in disease location. After IPT weighting, all key baseline characteristics were balanced. The IPTW adjusted OS favored tebe, HR 0.43 (95% CI 0.29-0.64); 1-yr OS 74% vs 50%, respectively. Sensitivity analyses showed consistent superior OS for tebe with all IPTW HRs <0.48. An IPTW analysis of pembro vs ipi + nivo based on full IPD will be presented. Tebentafusp is the only therapy to demonstrate an OS benefit in previously untreated mUM against an IC arm that was mostly pembro. A patient-level propensity analysis comparison to ipi + nivo demonstrates a similarly strong OS benefit for tebentafusp. These data support initial use of tebentafusp in previously untreated HLA-A*0201+ mUM patients as the standard of care.

9584 Background: All immune therapies that rapidly activate T cells, including T cell engagers, can induce cytokine release syndrome (CRS). Tebentafusp (tebe), a T cell receptor bispecific (gp100 x CD3) can also induce skin adverse events (AEs), due to gp100+ cutaneous melanocytes. CRS and skin AEs may require management with short term corticosteroids, which may also be used as premedication for subsequent tebe doses. Here we report the first analysis of systemic corticosteroid use and correlation with efficacy from a Phase (Ph) 3 trial for any T cell engager. Methods: Post hoc analyses were performed on the tebe arm of the Ph3 [NCT03070392] study in previously untreated HLA-A*02:01+ metastatic uveal melanoma (mUM) (N = 245). Due to the low rate of severe AEs in Ph1 trials, prophylactic corticosteroids were not mandated. The association between overall survival (OS) and corticosteroid use (new start within 30 days of first tebe dose) was investigated using landmark analyses in the safety population. Multivariate analyses were adjusted for key patient characteristics and AEs of special interest: CRS, rash, and liver function test (LFT) elevation. Steroid type (hydrocortisone vs. others) and treatment duration (1 vs. > 1 day) were also investigated. Results: In the Ph3 trial, 64/245 (26%) patients received new systemic corticosteroid within 30 days after the first dose of tebe, mostly for treatment of AEs (56/64, 88%) or pre-medication due to previous AE (14/64, 22%). 25 of the 64 patients received corticosteroids only for a single day. The most frequent AEs (≥15%) were rash (18/64, 28%), CRS (15/64, 23%), and hypotension (12/64, 19%). In a logistic regression model, elevated baseline LDH, the dominant prognostic marker, was most strongly associated with use of corticosteroids (p = 0.01). In the multivariate analysis, corticosteroids were not associated with any significant OS difference (HR 1.41, 95% CI 0.83-2.4, p = 0.2) and this effect did not differ in patients with or without CRS, rash or LFT elevation (all interaction tests p > 0.2). There was no difference in OS according to corticosteroid type or whether administered for 1 vs > 1 day. Conclusions: This is the first analysis from a phase 3 trial of the impact of systemic corticosteroids on survival for a T cell engaging cancer therapy. The vast majority of tebe-treated patients (84%) either did not require corticosteroids (74%) or only received them on a single day (10%). The most frequent reason for corticosteroid use was an emergent AE, including CRS and rash. Corticosteroid use following the pre-specified AE guidelines was not associated with any significant impact on OS. Clinical trial information: NCT03070392.

Introduction/Aims Trials incorporating placebo-to-active treatment crossover are encouraged in fatal conditions like amyotrophic lateral sclerosis (ALS) but may underestimate active treatment survival benefit. Here, we apply methods for modeling survival without crossover, including the rank-preserving structural failure time model (RPSFTM), to data from the CENTAUR trial of sodium phenylbutyrate and taurursodiol (PB and TURSO) in ALS incorporating both randomized placebo-controlled and open-label extension (OLE) phases. Methods Intent-to-treat (ITT) and RPSFTM survival analyses were performed with final data at a July 2020 cutoff date. Analyses of subgroups based on randomized treatment and OLE phase participation were also performed. Results Hazard ratios (95% confidence intervals) of death for PB and TURSO versus participants initially on placebo were 0.57 (0.35-0.92) on ITT analysis and 0.39 (0.17-0.88) in the primary on-treatment RPSFTM analysis (p = .023). Median ITT survival duration for PB and TURSO (25.8 mo) was 6.9 mo longer than placebo (18.9 mo) on ITT analysis and 10.6 mo longer than the median RPSFTM-adjusted survival duration for placebo (15.2 mo). Median survival duration was 18.8 mo longer in the PB and TURSO-randomized subgroup who continued into the OLE phase versus the placebo-randomized subgroup who did not continue into the OLE phase (p < .0001), although OLE phase selection bias may have potentially confounded these results. Discussion Similar to the prespecified ITT analysis, post hoc analyses adjusting for treatment crossover in CENTAUR showed a significant survival benefit for PB and TURSO. Such methods may provide clinical context for observed survival outcomes in future ALS crossover trials.

Faricimab is a bispecific antibody targeting ANG-2 and VEGF for the treatment of neovascular age-related macular degeneration (nAMD). In the TENAYA and LUCERNE trials, patients treated with individualized dosing of faricimab followed by a Treat & Extend (T&E) regime required less frequent treatments compared to aflibercept given every eight weeks (Q8W) without compromising efficacy. About 80% of patients treated with faricimab could extend their intervals beyond Q8W. However, clinical practice in nAMD is typically characterized by T&E as well as pro re nata (PRN) regimens. This research aims to assess the durability profile of faricimab vs. anti-VEGF treatments applied in such regimens. A systematic literature review was conducted to identify randomized clinical trials of anti-VEGF treatments in nAMD. The main outcome was the mean number of injections after two years. 14 studies with relevant data were eligible informing a Bayesian Network Meta-Analysis to estimate the durability of faricimab vs. other anti-VEGF treatments. Differences and the probability of faricimab being better were calculated using random-effects (RE) and fixed-effect (FE) models. At the two year time point, the mean differences in number of injections favored faricimab vs. T&E and PRN regimens using a RE model. The point estimate vs. bevacizumab, ranibizumab, aflibercept and brolucizumab applied in a T&E regimen was -6.71, -4.43, -1.76 and -1.89 respectively. The associated probability of faricimab requiring less frequent dosing than comparators was 96%, 95%, 80% and 84%. For PRN regimens, a comparison was possible vs. ranibizumab with a mean difference of -3.72 and an associated probability of faricimab requiring less frequent dosing of 90%. FE results were consistent. The results indicate that there is a high probability that faricimab is associated with a better durability profile than current treatment options administered in flexible regimes that are typically used in clinical practice.

9526 Background: Tebentafusp (tebe) is a bispecific consisting of an affinity-enhanced T cell receptor fused to an anti-CD3 effector that can redirect T cells to target gp100+ cells. Tebe significantly improved OS compared to investigator’s choice (IC) in first line (1L) mUM [NCT03070392]. In a phase (ph) 2 study of tebe in 2L+ mUM (NCT02570308), several checkpoint inhibitor (CPI) refractory pts who were retreated with CPI after tebe achieved durable clinical benefit [1]. We therefore evaluated clinical outcomes of post-tebe CPI in patients treated on the ph3 trial of tebe versus investigator’s choice (IC) [NCT03070392]. Methods: In the ph3 trial, 378 HLA-A*02:01+ 1L mUM pts were randomized 2:1 to tebe (n=252) or IC (n=126) [pembrolizumab (82%), ipilimumab (12%) or dacarbazine (6%)]. No crossover to tebe was permitted, investigators were free to choose subsequent therapy, and there was no re-randomization at time of subsequent therapy. This analysis was conducted on the first interim analysis (data extracted Nov-2020). When pts received more than one subsequent therapy, the first was used in these analyses. Medians and 1-yr OS from the start of post-study therapy are obtained from standard Kaplan-Meier analyses; hazard ratios (HR) are from Cox regression models adjusted for age and gender. Results: 106/252 (42%) tebe pts received ≥ 1 subsequent therapy: 35% CPI, 9% chemo, 6% liver directed therapy (LDT), 6% other. 55/126 (44%) of IC pts received ≥ 1 subsequent therapy: 21% CPI, 10% chemo, 12% LDT, 10% other. Median time to first subsequent therapy was longer for tebe pts at 5.2 mo vs. IC pts at 3.8 mo. The median duration from start of first subsequent CPI to end date was longer in the prior tebe pts at 4 mo vs prior IC pts at 2.8 mo. From the start of any first subsequent therapy, prior tebe pts had longer OS compared to prior IC pts, HR 0.67 (95% CI 0.42, 1.07). Most of the subsequent therapy was CPI, and the OS benefit was also seen in this subset, HR 0.62 (95% CI 0.34, 1.14). For prior tebe pts, the median and 1-yr OS rates from start of any first subsequent therapy were 13 mo and 53% and from start of first subsequent CPI were 16 mo and 63%. Both were higher than the sequence of IC followed by any therapy (11 mo and 44%), IC followed by CPI (9 mo and 47%) and a recent meta-analysis of 2L+ mUM (7 mo and ̃35% 1-yr OS rate). Conclusions: Pts who progressed on tebe and then received CPI had better OS compared to pts who progressed on IC and then received CPI. Further analysis will explore whether confounding factors are influencing this effect. These exploratory data suggest that tebe, relative to IC, may improve outcomes to subsequent CPI. (1)Yang J. et al. ASCO 2019, J . Cli n Oncol 37:15_suppl, 9592. Clinical trial information: NCT03070392.

Journal of Comparative Effectiveness ResearchVol. 10, No. 17 Letter to the EditorFree AccessLetter to the Editor: comparison of ofatumumab and other disease-modifying therapies for relapsing multiple sclerosis: a network meta-analysisKrupa Parekh & Claire WatkinsKrupa Parekh*Author for correspondence: Tel.: +41 798 014 522; E-mail Address: krupa.parekh@roche.comF Hoffmann-La Roche Ltd, Basel, SwitzerlandSearch for more papers by this author & Claire WatkinsClarostat Consulting Ltd, Bollington, Macclesfield, UKSearch for more papers by this authorPublished Online:5 Oct 2021https://doi.org/10.2217/cer-2021-0123AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: disease-modifying therapiesmultiple sclerosisnetwork meta-analysisrelapsing multiple sclerosisWe read with interest the original article entitled ‘Comparison of ofatumumab and other disease-modifying therapies for relapsing multiple sclerosis: a network meta-analysis’ by Samjoo et al. [1]. Based on this network meta-analysis (NMA), the authors claim that for this population, for all outcomes (annualized relapse rate and confirmed disability progression [CDP] at 3 and 6 months [CDP-3 and CDP-6]), ofatumumab was as effective as other highly efficacious monoclonal antibody disease-modifying therapies (DMTs), i.e., alemtuzumab, natalizumab and ocrelizumab. NMA is a useful method for informing comparative effectiveness research; however, caution must be exercised when using certain methods and interpreting the results. To this end, we would like to highlight several limitations regarding this article, which we believe may lead to misinterpretation of the NMA methodology and final results, and hence, could be potentially misleading to the reader.The authors present base case evidence network diagrams of the possible comparisons for evaluated outcomes. A key assumption of the NMA is that there is no difference between the trials in the distribution of effect-modifying variables; however, greater distances in the network diagrams increases the chance of an imbalance in effect modifiers, or a within-trial bias in one of the links. In the network diagrams for time to CDP-3 and time to CDP-6 (Figures 3 & 5, respectively; Samjoo et al. [1]), the distance in the networks between ofatumumab and ocrelizumab/alemtuzumab is large; in Figure 5, the shortest path from ofatumumab to ocrelizumab/alemtuzumab is via a chain of at least five pairwise links. Unfortunately, these large distances pose several limitations, which are not highlighted by the authors; importantly, they increase the risk of violating the key assumptions of the NMA, which could introduce bias into the effect estimate of ofatumumab versus ocrelizumab/alemtuzumab, i.e., the greater the distance between two treatments in the network, the less reliable the estimate is. Furthermore, in networks consisting of only one or two trials per treatment comparison, as per the majority included in the networks in Samjoo et al. [1], indirect comparisons are highly vulnerable to systematic variation resulting from imbalances in effect-modifier distributions [2]. As acknowledged by the authors, population-adjusted indirect comparisons, such as Matching-Adjusted Indirect Comparison or Simulated Treatment Comparison [2], represent alternatives to an NMA, which may help to address these limitations. Population-adjusted indirect comparisons use individual patient data from one or more trials to adjust for between-trial differences in the distribution of variables that influence outcome. These can adjust for imbalances in measured-effect modifiers and do not use intermediate linking studies, hence, can provide a valid estimate of relative treatment effects when standard indirect comparisons are either inappropriate, unreliable or infeasible. It must be acknowledged, however, that such analyses rely on their own set of strong assumptions that should also be carefully evaluated.We would also like to highlight our concern regarding lack of details around the rederivation of the CDP outcomes. The NMA includes CDP data from ASCLEPIOS [3] that has been aligned with the CDP definition from the OPERA I and OPERA II trials [4] (‘OPERA-aligned CDP’); however, the authors failed to mention several limitations of these OPERA-aligned analyses. Notably, making outcome definitions more consistent across trials can reduce bias; however, the OPERA-aligned CDP definition could only be applied to the ASCLEPIOS trial, meaning that the several linking trials between ASCLEPIOS and OPERA did not have this consistent definition applied. Moreover, the NMA protocol containing a definition of the post-hoc OPERA-aligned CDP does not appear to have been prospectively registered, and the authors failed to mention the different variations of the definition that were evaluated; therefore, the variations in the OPERA-aligned CDP analyses cannot be reconciled, as it is not known how many variations of the aligned definitions were analyzed to model the change in hazard ratio prior to the final definition that was included in the NMA. The post-hoc OPERA-aligned CDP analyses for ASCLEPIOS have been previously presented only at investor relations calls [5–7], but these were not included in the article’s reference list or in the systematic literature review. As per NICE guidelines (Guide to the methods of technology appraisal 2013 [8]), attempts should be made to identify unpublished and part-published evidence that is not in the public domain, as well as evidence from sources other than randomized controlled trials. Such information must be critically appraised and, when appropriate, sensitivity analysis conducted to examine the effects of its incorporation or exclusion. Notably, the OPERA-aligned input data were not critically appraised; therefore, the quality of the data may be disputed. Furthermore, sensitivity analyses were not carried out to assess the effects of including the OPERA-aligned CDP data in the NMA; thus, the results cannot be interpreted reliably and may be misleading, particularly when presented in the main body of evidence. To avoid any potential misinterpretations, the effect of including the OPERA-aligned CDP data should ideally be assessed using sensitivity analyses, which included input data for all DMTs using the OPERA-aligned definition and for all DMTs using the ASCLEPIOS-aligned definition; however, we acknowledge that without access to individual patient data this is not possible. The authors should recognize this limitation in the discussion.Finally, we believe that in order to make a more balanced conclusion, the authors should have reported the safety end points in the main article alongside the efficacy outcomes, as this would have allowed the readers to assess and understand the benefit–risk profile of each DMT.We agree with the authors’ statement that effective treatment of patients with relapsing multiple sclerosis requires an understanding of the comparative efficacy and safety of different DMTs; payers and other decision makers highly rely on NMAs; therefore, we believe that these important transparency concerns should be addressed and key limitations highlighted, so that the results of the NMA can be correctly interpreted to help guide treatment decisions.Financial & competing interests disclosureK Parekh is an employee of F Hoffmann-La Roche Ltd. C Watkins provided consultancy services funded by F Hoffmann-La Roche Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Writing and editorial assistance was provided by Eleanor Foy PhD of Articulate Science, UK, and was funded by F Hoffmann-La Roche Ltd, Basel, Switzerland.References1. Samjoo IA, Worthington E, Drudge C et al. Comparison of ofatumumab and other disease-modifying therapies for relapsing multiple sclerosis: a network meta-analysis. J. Comp. Eff. Res. 9(18), 1255–1274 (2020).Link, Google Scholar2. Phillipo DM, Ades T, Dias S, Palmer S, Abrams KR, Welton N. NICE DSU technical support document 18: methods for population-adjusted indirect comparisons in submission to NICE (2016). www.nicedsu.org.uk/wp-content/uploads/2017/05/Population-adjustment-TSD-FINAL.pdfGoogle Scholar3. Hauser SL, Bar-Or A, Cohen JA et al. Ofatumumab versus teriflunomide in multiple sclerosis. N. Engl. J. Med. 383(6), 546–557 (2020).Crossref, Medline, CAS, Google Scholar4. Hauser SL, Bar-Or A, Comi G et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N. Engl. J. Med. 376(3), 221–234 (2017).Crossref, Medline, CAS, Google Scholar5. Novartis AG Investor Relations. Novartis R&D day (2019). www.novartis.com/sites/www.novartis.com/files/2019-12-05-novartis-r-d-day-investor-presentation.pdfGoogle Scholar6. Novartis AG Investor Relations. Kesimpta® US approval investor call (2020). www.novartis.com/sites/www.novartis.com/files/2020-08-kesimpta-us-approval-investor-call-presentation.pdfGoogle Scholar7. Novartis AG Investor Relations. Meet Novartis management (2020). www.novartis.com/sites/www.novartis.com/files/meet-novartis-management-2020-presentation.pdfGoogle Scholar8. NICE. Part 6: the appraisal of the evidence and structured decision-making. In: Guide to the Methods of Technology Appraisal (2013). www.nice.org.uk/process/pmg9/chapter/the-appraisal-of-the-evidence-and-structured-decision-makingGoogle ScholarFiguresReferencesRelatedDetailsCited ByLetter in replyImtiaz A Samjoo, Evelyn Worthington, Christopher Drudge, Melody Zhao, Chris Cameron, Dieter A Häring, Dee Stoneman, Luisa Klotz & Nicholas Adlard5 October 2021 | Journal of Comparative Effectiveness Research, Vol. 10, No. 17 Vol. 10, No. 17 Follow us on social media for the latest updates Metrics Downloaded 640 times History Received 27 May 2021 Accepted 24 August 2021 Published online 5 October 2021 Published in print December 2021 Information© 2021 Future Medicine LtdKeywordsdisease-modifying therapiesmultiple sclerosisnetwork meta-analysisrelapsing multiple sclerosisFinancial & competing interests disclosureK Parekh is an employee of F Hoffmann-La Roche Ltd. C Watkins provided consultancy services funded by F Hoffmann-La Roche Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Writing and editorial assistance was provided by Eleanor Foy PhD of Articulate Science, UK, and was funded by F Hoffmann-La Roche Ltd, Basel, Switzerland.PDF download

Toombak is a smokeless tobacco produced from the Nicotiana rustica tobacco plant from Sudan. Pre-prepared and ready to buy Toombak samples were analysed using mass spectrometry (heavy metals), gas and liquid chromatography (metabolomics), 16S rRNA metagenomic sequencing (microbiome) and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt), scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX) and pH analysis.Chromium, cobalt, and copper were high in the pre-prepared form of Toombak while iron, tobacco specific nitrosamines (TSNAs), formaldehyde and acetaldehyde were high in both types. Firmicutes and Actinobacteria dominated Toombak. Samples of ready to buy Toombak showed inter-variational differences depending on place of purchase. We found Virgibacillus were increased in the pre-prepared form while Corynebacterium casei, Atopococus tabaci, Atopostipes suicloacalis, Oceanobacillus chironomi and Staphylococcus gallinarum were the most abundant species in the ready to buy forms. PICRUSt analysis highlighted increased activity of metal transport systems in the ready to buy samples as well as an antibiotic transport system. SEM-EDX highlighted large non-homogenous, irregular particles with increased sodium, while pH of samples was in the alkaline range.The final composition of Toombak is affected by its method of preparation and the end product has the potential to impart many negative consequences on the health of its users. TSNA levels observed in Toombak were some of the highest in the world while the micro-environment of Toombak supports a distinct microbiota profile.

BACKGROUND:Although dietary intakes and dietary intake patterns (DPs) have been associated with single metabolites, it is unclear whether DPs are also reflected in specific metabolite patterns (MPs). Moreover, the influence of groups of gut bacteria on the relationship between DPs and MPs is underexplored. OBJECTIVES:We aimed to investigate the association of DPs and serum MPs and also the modifying effect of the gut bacteria compositional patterns (BCPs). METHODS:This is a cross-sectional investigation among 225 individuals (median age: 63 y; 53% women) from the European Prospective Investigation into Cancer and Nutrition study. Dietary intakes were assessed by three 24-h dietary recalls, gut bacteria composition was quantified by 16S rRNA gene sequencing, and the serum metabolome was profiled by an untargeted approach. We identified DPs and BCPs by the treelet transform analysis. We modeled associations between DPs and 8 previously published MPs and the modifying effect of BCPs by fitting generalized linear models using DataSHIELD R. RESULTS:We identified 5 DPs and 7 BCPs. The "bread, margarine, and processed meat" and "fruiting vegetables and vegetable oils" DPs were positively associated with the "amino acids" (β = 0.35; 95% CI: 0.02, 0.69; P = 0.03) and "fatty acids" MPs (β = 0.45; 95% CI: 0.16, 0.74; P = 0.01), respectively. The "tea and miscellaneous" was inversely associated with the "amino acids" (β = -0.28; 95% CI: -0.52, -0.05; P = 0.02) and "amino acid derivatives" MPs (β = -0.21; 95% CI: -0.39, -0.02; P = 0.03). One BCP negatively modified the association between the "bread, margarine, and processed meat" DP and the "amino acids" MP (P-interaction = 0.01). CONCLUSIONS:In older German adults, DPs are reflected in MPs, and the gut bacteria attenuate 1 DP-MP association. These MPs should be explored as biomarkers of these jointly consumed foods while taking into account a potentially modifying role of the gut bacteria.

Perinatal factors impact gut microbiota development in early life, however, little is known on the effects of these factors on microbes in later life. Here we sequence DNA from faecal samples of children over the first four years and reveal a perpetual evolution of the gut microbiota during this period. The significant impact of gestational age at birth and delivery mode on gut microbiota progression is evident in the first four years of life, while no measurable effects of antibiotics are found in the first year. Microbiota profiles are also characteristic in children dependant on gestational age and maturity. Full term delivery is characterised by Bacteroides (year one), Parabacteroides (year two) and Christensenellaceae (year four). Preterm delivery is characterised by Lactobacillus (year one), Streptococcus (year two) and Carnobacterium (year four). This study reveals that the gut retains distinct microbial profiles of perinatal factors up to four years of age.

To compare the efficacy and safety of R2 with bendamustine and rituximab (BR) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment of R/R FL using an MAIC. A systematic literature review of clinical trials and observational studies reporting survival and adverse events (AEs) of systemic treatments for R/R FL up to September 1, 2017 was conducted using MEDLINE, EMBASE, CENTRAL, and ClinicalTrials.gov databases, and EU and US conference proceedings. Primary outcomes of interest were PFS and OS. AEs were analyzed including all-grade nausea/vomiting and grade ≥3 neutropenia. Pseudo-individual patient data (IPD) generated from digitized KM curves were compared with actual IPD from the AUGMENT and MAGNIFY R2 trials. An unanchored MAIC was conducted to adjust for potential effect modifiers and prognostic variables (EM/PV) between trials. Cox proportional hazards and parametric survival models were fitted to match-adjusted IPD and digitized KM data. Aggregate data from 1 R-CHOP and 3 BR studies were compared with AUGMENT and MAGNIFY data. PFS did not significantly differ between R2 and R-CHOP (HR 0.94, 95% CI 0.52–1.7; p=0.837) or R2 and BR (HR 1.26, 95% CI 0.7–2.27; p=0.441). OS did not significantly differ between R2 and R-CHOP (HR 0.77, 95% CI 0.25–2.43; p=0.660); OS data were unavailable for BR. No significant differences in AEs were observed between R2 and BR except lower rates of nausea/vomiting for R2 (17% vs 50%; OR 0.21, 95% CI 0.09–0.47; p=0.0001). Grade ≥3 neutropenia was 48% for R2 vs 55% for R-CHOP (OR 0.77, 95% CI 0.42–1.40; p=0.386). Consistent with the RELEVANCE trial, R2 efficacy seems comparable with that of R-chemo in R/R FL. Point estimates varied depending on the ability to match for variables including prior rituximab exposure. Limitations include the inability to simultaneously adjust for all potential EM/PV.