Network meta-analysis (NMA) methods for time-to-event (TTE) outcomes that allow for time-varying treatment effects are important for extrapolations when the proportional hazard (PH) assumption is uncertain. We propose a one-step fully Bayesian parametric NMA model that fits TTE outcome data based on (reconstructed) individual patient data (IPD) with the exact likelihood and allows for time-varying treatment effects.

Mixture cure models (MCMs) explore survival heterogeneity when there is potential for cure by estimating cure rates and the survival function of the uncured. We propose a novel unified network meta-analysis (NMA) framework to simultaneously estimate relative treatment effects on both outcomes of MCMs.

Most MCL patients relapse after first-line therapy, and disease progression after subsequent BTKi therapy (post-BTKi) often leads to poor outcomes. A systematic literature review and meta-analysis were conducted to estimate objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) post-BTKi in patients with R/R MCL.

Background: Approved first-line treatments for patients with BRAF V60-emutant advanced melanoma include nivolumab (a programmed cell death protein 1 inhibitor) plus ipilimumab (a cytotoxic T lymphocyte antigen-4 inhibitor; NIVO+IPI) and the BRAF/MEK inhibitors dabrafenib plus trametinib (DAB+TRAM), encorafenib plus binimetinib (ENCO+BINI), and vemurafenib plus cobimetinib (VEM+COBI). Results from prospective randomized clinical trials (RCTs) comparing these treatments have not yet been reported. This analysis evaluated the relative efficacy and safety of NIVO+IPI versus DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma using a matching-adjusted indirect comparison (MAIC). Patients and methods: A systematic literature review identified RCTs for DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma. Individual patient-level data for NIVO+IPI were derived from the phase III CheckMate 067 trial (BRAF-mutant cohort) and restricted to match the inclusion/exclusion criteria of the comparator trials. Treatment effects for overall survival (OS) and progression-free survival (PFS) were estimated using Cox proportional hazards and time-varying hazard ratio (HR) models. Safety outcomes (grade 3 or 4 treatment-related adverse events) with NIVO+IPI and the comparators were compared. Results: In the Cox proportional hazards analysis, NIVO+IPI showed improved OS compared with DAB+TRAM (HR = 0.53; 95% confidence interval [CI], 0.39-0.73), ENCO+BINI (HR = 0.60; CI, 0.42-0.85), and VEM+COBI (HR = 0.50; CI, 0.36-0.70) for the overall study period. In the time-varying analysis, NIVO+IPI was associated with significant improvements in OS and PFS compared with the BRAF/MEK inhibitors 12 months after treatment initiation. There were no significant differences between NIVO+IPI and BRAF/MEK inhibitor treatment from 0 to 12 months. Safety outcomes favored DAB+TRAM over NIVO+IPI, whereas NIVO+IPI was comparable to VEM+COBI. Conclusion: Results of this MAIC demonstrated durable OS and PFS benefits for patients with BRAF-mutant advanced melanoma treated with NIVO+IPI compared with BRAF/MEK inhibitors, with the greatest benefits noted after 12 months.

Recently, we developed a two-step network meta-analysis (NMA) for time-to-event data using alternative parametric distributions often used in health technology assessments (HTAs), including exponential, Weibull, Gompertz, log-normal, and log logistic. With these models the hazard ratio does not have to be assumed to be constant over time, thereby reducing the possibility of violating consistency in indirect comparisons. However, it is also possible to extend this approach to evaluate fractional polynomial distributions, which are increasingly being used in an HTA setting. First, for each arm of every randomized controlled trial (RCT) connected in the network of evidence simulated patient data were fit to alternative parametric distributions, including fixed and random effects first and second order fractional polynomials. Additionally, we compared these results to Weibull, Gompertz, exponential, log-normal, and log logistic. For each distribution, the resulting scale and shape parameters per arm were then included in a multivariate NMA, which preserved randomization and accounted for the correlation between the parameters. An illustrative analysis is presented for a network of RCTs evaluating interventions for advanced melanoma. The NMA was assessed for overall survival using alternative distributions, which were compared using Akaike information criterion (AIC), which can facilitate model averaging to propagate structural uncertainty in a cost-effectiveness analysis. Based on the AIC, fractional polynomial provides a good fitting alternative to the more traditional parametric distributions that can all be compared in a straightforward manner based on goodness of fit as well as clinical plausibility for each trial. A two-step NMA of survival data for fractional polynomials allows for a straightforward and efficient comparison of alternative models using the individual event times in the frequentist framework in the first step rather than an approximation based on discrete hazards in Bayesian framework. This approach provides a more generalizable evidence synthesis framework for HTA.

Axi-cel and tisa-cel are approved, autologous anti-CD19 CAR T cell therapies for the treatment of patients (pts) with RR-LBCL. Both can induce durable responses; however, cross-trial comparisons are difficult due to differences in study design, patient population, bridging chemotherapy allowance, and time from leukapheresis to treatment. In this study, the registration trials of axi-cel and tisa-cel were compared using a matching adjusted indirect comparison (MAIC). A MAIC was performed to adjust for differences in pt characteristics between trials. The estimates for the ZUMA-1 (axi-cel) trial were adjusted using pt-level data to match the study population in JULIET (tisa-cel) for key variables: IPI, ECOG, stage, refractoriness or relapsed disease, double/triple hit status, cell-of-origin, and number of prior lines of therapy. The impact of leukapheresis to infusion time was modeled using published data (Crump, 2017). The endpoints analyzed were response, overall survival (OS), and adverse events. After adjusting for differences in pt characteristics between trials, axi-cel was associated with a greater objective response rate (relative risk [RR] =1.62 [95% CI 1.28-2.06]) and complete response (RR = 1.56 [1.10-2.20]) than tisa-cel among pts who underwent infusion. The OS from leukapheresis onward comparing axi-cel to tisa-cel had a hazard ratio of 0.43 (0.28 – 0.63). The mean survival for the 24-mo follow-up period from leukapheresis showed a difference of 6.3 mo (4.2 – 8.5) favoring axi-cel. The indirect comparison showed a higher rate of Grade 1-2 cytokine release syndrome (CRS) in ZUMA-1 compared with JULIET; (RR = 2.02 [1.55-2.65]), and similar rates of Grade ≥3 CRS, Grade 1-2 neurologic events (NE), and Grade ≥3 NE. Given available evidence limitation, this indirect comparison suggests axi-cel may have superior efficacy but a greater risk of Grade 1-2 CRS. Future studies are needed to confirm the relative efficacy and safety of CAR T therapies in RR-LBCL.

Background Targeted and checkpoint inhibitor therapies for advanced melanoma have led to major improvements in overall survival (OS). Using long-term evidence, the objective was to estimate the relative efficacy of nivolumab plus ipilimumab (NIVO+IPI) vs. relevant comparators among treatment-naive patients with advanced, unresectable stage III/IV melanoma. Methods A systematic literature review of randomized controlled trials (RCTs) of first-line advanced melanoma therapies was conducted in November 2018. Key comparators were immunotherapies (NIVO+IPI; NIVO; pembrolizumab [PEM]), and BRAF+MEK inhibitors (dabrafenib + trametinib [DAB+TRAM]; encorafenib + binimetinib [ENC+BIN]; vemurafenib + cobimetinib [VEM+COB]). Bayesian network meta-analysis (NMA) models were used to estimate comparative OS. The NMAs used models of constant (overall) hazard ratio (HR) over time, and fractional polynomials to estimate time-varying HR, along with 95% credible intervals (CrI). Subgroup analyses and alternate models were explored to evaluate effect modification of immunotherapies by BRAF-mutation status. Results In total, 12 RCTs formed the network of evidence for OS (maximum follow-up: 30 to 60 months). For NIVO+IPI vs. each BRAF+MEK inhibitor, the HR decreased steadily over time. The hazard of death was similar by 6 months and lower at 12 months; thereafter, NIVO+IPI was associated with a significantly reduced hazard of death. At 18 months, HRs for NIVO+IPI vs. each BRAF+MEK inhibitor ranged from 0.45 to 0.52; by 42 months (longest duration of observed data for BRAF+MEK inhibitors), HRs were 0.24 to 0.29 (all CrIs Conclusions NIVO+IPI confers similar or sustained improvements in long-term OS compared with immunotherapies and BRAF+MEK inhibitors. Legal entity responsible for the study The authors. Funding Bristol-Myers Squibb. Disclosure P. Mohr: Honoraria (self), To manually add email to ESMO: To manually add email to ESMO. K. Toor: Full / Part-time employment, KT is an employee of Precision Xtract. Precision Xtract received funding for this project from Bristol-Myers Squibb: Precision Xtract. S. Goring: Advisory / Consultancy, SG acted as a consultant to Precision Xtract. Precision Xtract received funding for this project from Bristol-Myers Squibb: Precision Xtract. K. Chan: Full / Part-time employment, KC is an employee of Precision Xtract. Precision Xtract received funding for this project from Bristol-Myers Squibb: Precision Xtract. M. Besada: Full / Part-time employment, MB is an employee of Precision Xtract. Precision Xtract received funding for this project from Bristol-Myers Squibb: Precision Xtract. H.M. Johnson: Advisory / Consultancy: Bristol-Myers Squibb. A. Moshyk: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. S. Kotapati: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb.

Fractional polynomials (FP) provide flexible parametric modeling approaches for meta-analyzing time-to-event data. Our objective was to present a model selection heuristic that improves transparency of model selection and incorporates clinical plausibility of model extrapolations. An FP-based network meta-analysis (NMA) in first-line advanced melanoma served as an example.

Objective. The aim of this study was to explore factors that modify treatment effects of non-conventional biologics versus placebo in patients with psoriatic arthritis.Methods. A systematic literature review and meta-regression was conducted. The biologics included etanercept, infliximab, adalimumab, golimumab, certolizumab, ustekinumab, tocilizumab, anakinra, abatacept, rituximab, and secukinumab. Outcomes included American College of Rheumatology (ACR) 20 and 50, Psoriasis Area Severity Index (PASI) 75, and 36-Item Short Form Health Survey (SF-36) Physical and Mental Component Summaries (PCS and MCS).Results. Twelve RCTs were eligible for meta-regression. Treatment effects for ACR-20 at 12 weeks were higher in trials with longer disease durations (OR=2.94), and lower in trials enrolling older patients (OR=0.48), and those recently published (OR=0.49). Treatment effects for ACR-50 at 12 weeks were higher in trials with more males (OR=2.27), but lower in trials with high prior anti-TNF use (OR=0.28) and recently published trials (OR=0.37). For PASI-75, trials with more male patients (24 weeks: OR=2.56), and with higher swollen and tender joint counts (12 weeks: OR=8.33; 24 weeks: OR=14.44) showed higher treatment effects, and trials with high prior antiTNF use had lower effects (OR=0.41). Treatment effects for SF-36 PCS at 24 weeks were higher in trials with longer psoriasis disease durations (OR=2.95) and PsA disease durations (OR=4.76), and those published earlier (OR=4.19).Conclusion. Our analyses show that differences in baseline characteristics may explain some of the differences in response to biologics versus placebo across different trials. Accounting for these factors in future studies will likely be important.

Objective:Antiretrovirals do not prevent anal intraepithelial neoplasia. However, the influence of antiretrovirals in the natural history of invasive anal cancer is less clear. The objective is to investigate the impact of antiretrovirals in the time to the development of anal cancer in HIV-positive MSM. Design:A retrospective analysis of cases of anal cancer in a cohort of HIV-positive MSM receiving antiretrovirals between 1988 and 2008. Methods:Time from first CD4+ cell count or HIV RNA viral load test to anal cancer diagnosis was analysed using Cox regression and Kaplan–Meier curves. Anal cancer cases treated in the era prior to HAART (<1996) were compared with those treated later (1996–2008). Results:Anal cancer cases (n = 37) were compared with a cohort of 1654 HIV-positive MSM on antiretrovirals. Antiretrovirals were started in the pre-HAART era by 70% of cancer cases, and median CD4+ cell count nadir was 70 cells/&mgr;l (10–130). Time to development of anal cancer was shorter for cases treated during the pre-HAART era [adjusted hazard ratio (AHR) 3.04, 95% confidence interval (95% CI) 1.48–6.24, P = 0.002], with a CD4+ cell count nadir less than 100 cells/&mgr;l (AHR 2.21, 95% CI 1.06–4.62, P = 0.035) and longer duration of CD4+ cell count less than 100 cells/&mgr;l (AHR 1.33, 95% CI 1.11–1.58, P = 0.002). Conclusion:Results show that severe immunosuppression and starting therapy pre-HAART are associated with an increased risk of anal cancer. HIV-positive MSM initiating antiretrovirals during the HAART era (1996–2008) had a longer time to the development of anal cancer than those treated pre-HAART. Our results suggest that early use of HAART may delay progression to anal cancer.

Background Recent studies have suggested that failing nonnucleoside reverse transcriptase inhibitor (NNRTI)‐based regimens may have greater potential to induce the development of resistance mutations, which may limit options for second‐line therapy. Methods Antiretroviral therapy (ART)‐naïve individuals aged ≥18 years who initiated triple combination ART between January 2000 and June 2006 in British Columbia, Canada were enrolled in the study. We compared genotypic sensitivity scores (GSSs) derived from the development of resistance mutations between participants who initiated ART with ritonavir‐boosted protease inhibitors (PIs) with those who initiated ART with NNRTIs, and determined the effects of these mutations on remaining active drugs. Results A total of 1666 participants initiated ART, 818 (49.1%) with NNRTI‐based regimens and 848 (50.9%) with boosted PI‐based regimens. Among participants who developed resistance mutations, those who initiated NNRTI‐based regimens had a lower median GSS than those on boosted PI‐based regimens (9.8 vs . 11.0, respectively; P <0.001). Participants on boosted PI‐based regimens [adjusted odds ratio (AOR) 3.68; 95% confidence interval (CI) 2.25, 6.01], those with ≥95% adherence to highly active antiretroviral therapy (HAART) (AOR 1.84; 95% CI 1.16, 2.92) and those with baseline CD4 count >200 cells/μL (AOR 3.44; 95% CI 1.73, 6.84) were more likely to have the maximum number of drug options. Conclusion The use of NNRTI‐based first‐line ART regimens may limit the options for second‐line treatment when the number of available drugs is limited.

Background Housing is a known determinant of health behaviour, including adherence to antiretroviral therapy. Within the Longitudinal Investigations into Supportive and Ancillary Health Services (LISA) cohort, unstable housing is inversely associated with adherence. The Maximally Assisted Therapy (MAT) program uses a multidisciplinary approach to support people living with HIV/AIDS (PHA) who have a history of addictions, mental health disorders and homelessness. We investigated the efficacy of support services, including the MAT program, in improving adherence for unstably housed PHA. Methods The LISA cohort is a cross-sectional study of individuals on antiretroviral therapy in British Columbia. Interviewer-administered surveys collect information regarding housing, drug use, utilisation of health services and other clinically relevant socio-demographic factors. Clinical variables, such as CD4 count and viral load, were obtained through longitudinal linkages with the Drug Treatment Program (DTP) at the BC Centre for Excellence in HIV/AIDS. Logistic regression was used to determine factors associated with adherence (≥95% vs <95%) among unstably housed LISA participants (n=212). Results Between 2007 and 2010 approximately 1000 participants were interviewed. This analysis is based on 644 interviews, of which the DTP reports optimal adherence [≥95% 12 month refill] for 367 (57%) individuals. Median age was 46 and 475 (73.7%) were male. We found that unstably housed participants attending the MAT program were 4.76 times more likely to be ≥95% adherent [95% CI 1.72 to 13.13] than those who did not. Other factors associated with optimal adherence included recent incarceration (Adjusted OR [AOR]=0.20 [95% CI 0.05 to 0.80]) and not currently using illicit drugs (AOR=0.40 [95% CI 0.16 to 0.99]). Conclusion The MAT program provides a model for other urban centers dealing with concurrent and interrelated adherence barriers: high-risk drug use, mental health disorders and homelessness. In the absence of sustainable housing solutions, programs such as MAT are crucial to achieving optimal treatment adherence in this population.

HIV drug resistance testing is recommended as routine part of clinical practice in HIV/AIDS treatment and care. Our objective is to assess the determinants of accessing HIV drug resistance testing and examine the factors associated with resistance testing prior to or after starting highly active antiretroviral therapy (HAART) in a setting where access to HIV care is free and universal. The Longitudinal Investigation into Supportive and Ancillary health services (LISA) study is an open prospective cohort of HIV-positive persons on HAART in British Columbia (BC), Canada. Non-clinical data were collected through an interviewer-administered survey and clinical data were obtained through the BC Centre for Excellence in HIV/AIDS Drug Treatment Program. Independent associations between key explanatory variables and resistance testing were analyzed using logistic regression. We restricted our post-HAART analyses to those patients who met the criteria for resistance testing after HAART initiation. Of 359 LISA participants who started HAART after 2000 and at a time when resistance testing was available free of charge, almost half did not receive a baseline resistance test. Post-HAART initiation, 165 of 359 study subjects met the criteria for resistance testing based on current therapeutic guidelines due to virological failure. About 37.6% of them remain untested for resistance. Multivariable analyses show that baseline testing was less likely performed for persons of Aboriginal ethnicity and more likely performed for patients initiating HAART in 2004 or after. Additionally, persons initiating HAART in 2004 or after were less likely to have received a resistance test after virologic failure. Our results show that despite existing clinical guidelines, resistance testing is underused, even in an environment where the service is available free of charge. Further, resistance testing is particularly underutilized among vulnerable populations. Urgent efforts are needed to ensure the optimal use of resistance testing at baseline and at the time of virologic failure as recommended by current guidelines.