Pembrolizumab monotherapy or in combination with chemotherapy is approved as first-line treatment in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) based on improved overall survival (OS) versus EXTREME regimen in the KEYNOTE-048 trial. The clinical outcomes of pembrolizumab were compared with other recommended first-line treatments in R/M HNSCC in this study through a Bayesian network meta-analysis. A systematic literature review was conducted in July 2022, from which six trials that matched the KEYNOTE-048 patient eligibility criteria were included in the network. The OS and progression-free survival (PFS) outcomes were compared in the approved pembrolizumab indication (i.e., total population for pembrolizumab in combination with chemotherapy and combined positive score [CPS] ≥ 1 population for pembrolizumab monotherapy). A significant OS improvement was observed for pembrolizumab in combination with chemotherapy and pembrolizumab monotherapy versus EXTREME regimen (hazard ratio, 95% credible interval: 0.72, 0.60-0.86; 0.73, 0.60-0.88), platinum+5- FU (0.58, 0.43-0.76; 0.58, 0.44-0.78), and platinum+paclitaxel (0.53, 0.35-0.79; 0.53, 0.35-0.81), respectively. A non-significant numeric trend in OS improvement was observed versus the TPEx regimen. PFS was comparable with most first-line treatments and was improved versus platinum+5-FU (0.48, 0.36-0.64; 0.59, 0.45-0.79). Additional analyses in higher CPS subgroups also showed consistent results. Overall, our study results showed an improvement in OS outcomes versus alternative first-line treatments, consistent with the findings of the KEYNOTE-048 trial. These data support using pembrolizumab as a suitable firstline treatment option in R/M HNSCC.

Abstract Approximately 20% of people infected with COVID-19 develop at least one persistent condition potentially attributable to their SARS-CoV-2 infection. We sought to determine the effectiveness of early COVID-19 treatment interventions on long COVID symptoms. We conducted a multi-arm multi-stage adaptive platform trial at 12 public health clinics in Brazil between June 2020 and July 2022. Participants were followed for 60. Patients received one of six interventions (doxazosin, fluvoxamine, fluvoxamine in combination with inhaled budesonide, interferon-lambda, ivermectin, or metformin) or matching placebo. The primary outcome was persistence of COVID-19 symptoms at 60 days after randomization. We analyzed data from 5,700 participants across study cohorts. Overall, approximately 22% of patients reported at least one ongoing symptom 60 days after randomization, regardless of the early treatment they received. At day 60, we did not find any statistical benefit of any intervention on recovery, cure fractions, or PROMIS scores (mental and physical).

BackgroundOverall survival (OS) is the most patient-relevant outcome in oncology; however, in early cancers, large sample sizes and extended follow-up durations are needed to detect statistically significant differences in OS between interventions. Use of early time-to-event outcomes as surrogates for OS can help facilitate faster approval of cancer therapies. In locally advanced head and neck squamous cell carcinoma (LA-HNSCC), event-free survival (EFS) was previously evaluated as a surrogate outcome (Michiels 2009) and demonstrated a strong correlation with OS. The current study aimed to further assess the correlation between EFS and OS in LA-HNSCC using an updated systematic literature review (SLR) focusing on patients receiving definitive chemoradiation therapy (CRT).MethodsAn SLR was conducted on May 27, 2021 to identify randomized controlled trials assessing radiotherapy alone or CRT in the target population. Studies assessing CRT and reporting hazard ratios (HRs) or Kaplan-Meier data for OS and EFS were eligible for the analysis. CRT included any systemic treatments administered concurrently or sequentially with radiation therapy. Trial-level EFS/OS correlations were assessed using regression models, and the relationship strength was measured with Pearson correlation coefficient (R). Correlations were assessed across all CRT trials and in trial subsets assessing concurrent CRT, sequential CRT, RT+cisplatin, targeted therapies and intensity-modulated RT. Subgroup analysis was conducted among trials with similar EFS definitions (i.e. EFS including disease progression and/or death as events) and longer length of follow-up (i.e.≥ 5 years).ResultsThe SLR identified 149 trials of which 31 were included in the analysis. A strong correlation between EFS and OS was observed in the overall analysis of all CRT trials (R=0.85, 95% confidence interval: 0.72-0.93). Similar results were obtained in the sensitivity analyses of trials assessing concurrent CRT (R=0.88), sequential CRT (R=0.83), RT+cisplatin (R=0.82), targeted therapies (R=0.83) and intensity-modulated RT (R=0.86), as well as in trials with similar EFS definitions (R=0.87), with longer follow-up (R=0.81).ConclusionEFS was strongly correlated with OS in this trial-level analysis. Future research using individual patient-level data can further investigate if EFS could be considered a suitable early clinical endpoint for evaluation of CRT regimens in LA-HNSCC patients receiving definitive CRT.

Background: Patients (pts) with RRMM who are triple-class exposed (TCE; to an immunomodulatory imide drug [IMiD® agent], proteasome inhibitor [PI], and anti-CD38 monoclonal antibody [mAb]) have poor clinical outcomes and poor health-related quality of life (HRQoL). The B-cell maturation antigen (BCMA)-directed CAR T cell therapy idecabtagene vicleucel (ide-cel, bb2121) received regulatory approval in the US for pts with RRMM with ≥4 prior lines of therapy (LOT), including an IMiD agent, PI, and anti-CD38 mAb, and in Europe and Japan for pts with RRMM with ≥3 prior LOTs including an IMiD agent, PI, and anti-CD38 mAb. Ide-cel showed frequent, deep, and durable responses in TCE pts with RRMM in KarMMa, a phase 2, single-arm trial (NCT03361748). Clinically meaningful improvements in HRQoL outcomes vs baseline were observed. The BCMA-targeted antibody-drug conjugate belantamab mafodotin (BM) was approved in the US and Europe for pts with RRMM with ≥4 prior LOTs including an IMiD agent, PI and anti-CD38 mAb, based on data from the phase 2, single-arm DREAMM-2 trial (NCT03525678). There is a paucity of evidence comparing HRQoL for different treatment options approved in RRMM. Aims: To compare HRQoL outcomes for TCE pts with RRMM treated with ide-cel vs BM. Methods: Data were analyzed using unanchored matching-adjusted indirect comparisons. Between-study differences in pt characteristics were adjusted using individual-level pt data from KarMMa to align with summary-level pt characteristics from DREAMM-2. The ide-cel-treated population (N=128; median follow-up 15.4 months) from KarMMa (of whom, 54 pts received the target dose of 450×106 CAR+ T cells) and the intention-to-treat population (N=97; median follow-up 13.0 months) from DREAMM-2 who received the 2.5 mg/kg dose of BM (Popat et al. HemaSphere 2020;4:S1. EP1746) were analyzed. Predefined outcomes of interest were differences in mean change from baseline scores for the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) pain, fatigue, and global health/QoL domains, and the QLQ-Multiple Myeloma (MY20) pain domain. Analyses were performed at 2, 3, 4, 6, 9, and 12 months of follow-up. Given differences in time points of evaluation between KarMMa and DREAMM-2, the nearest neighbor approach was used. Pt characteristics included as covariates in the propensity model included: age, sex, race, years from initial diagnosis, disease stage, and number of prior treatments. Sensitivity analyses included additional covariates: high-risk cytogenetics and extramedullary disease. Results: Ide-cel was associated with improved HRQoL vs BM at all evaluated time points for the QLQ-C30 global health status/QoL domain (Table). Improved HRQoL scores were statistically significant for ide-cel vs BM at 6 and 9 months for the QLQ-C30 fatigue domain (HRQoL scores were numerically better for ide-cel vs BM at all other time points). Similarly, HRQoL scores favored ide-cel vs BM at all evaluated time points for the QLQ-C30 pain and QLQ-MY20 pain domains, with statistically significant findings at 4, 6, and 9 months for QLQ-C30 and 3, 4, and 6 months for QLQ-MY20. Sensitivity analyses were consistent with the base case analyses. Image:Summary/Conclusion: While this analysis was limited by the availability of aggregate data from DREAMM-2, which may influence the outcomes of interest, results suggest that one-time treatment with ide-cel offers improved HRQoL vs BM across the QLQ-C30 pain, fatigue, and global health status/QoL domains, as well as the QLQ-MY20 pain domain.

Aim: To compare the efficacy of idecabtagene vicleucel (ide-cel, bb2121) versus conventional care (CC) in triple-class exposed relapsed and refractory multiple myeloma (RRMM) patients. Patients & methods: A matching-adjusted indirect comparison was conducted using individual patient-level data from the pivotal, phase II, single-arm KarMMa trial (NCT03361748) and aggregate-level data from MAMMOTH, the largest independent observational study of CC in heavily pretreated RRMM patients. Results: Ide-cel improved overall response rate (odds ratio: 5.30; 95% CI: 2.96-9.51), progression-free survival (hazard ratio: 0.50; 95% CI: 0.36-0.70) and overall survival (hazard ratio: 0.37; 95% CI: 0.25-0.56) versus CC. Conclusion: These results suggest ide-cel offers improvements in clinical outcomes relative to CC in this heavily pretreated RRMM population.

Background Our aim was to extend traditional parametric models used to extrapolate survival in cost-effectiveness analyses (CEAs) by integrating individual-level patient data (IPD) from a clinical trial with estimates from experts regarding long-term survival. This was illustrated using a case study evaluating survival of patients with triple-class exposed relapsed/refractory multiple myeloma treated with the chimeric antigen receptor (CAR) T cell therapy idecabtagene vicleucel (ide-cel, bb2121) in KarMMa (a phase 2, single-arm trial). Methods The distribution of patients expected to be alive at 3, 5, and 10 years given the observed survival from KarMMa (13.3 months of follow-up) was elicited from 6 experts using the SHeffield ELicitation Framework. Quantities of interest were elicited from each expert individually, which informed the consensus elicitation including all experts. Estimates for each time point were assumed to follow a truncated normal distribution. These distributions were incorporated into survival models, which constrained the expected survival based on standard survival distributions informed by IPD from KarMMa. Results Models for ide-cel that combined KarMMa data with expert opinion were more consistent in terms of survival as well as mean survival at 10 years (survival point estimates under different parametric models were 29–33% at 3 years, 5–17% at 5 years, and 0–6% at 10 years) versus models with KarMMa data alone (11–39% at 3 years, 0–25% at 5 years, and 0–11% at 10 years). Conclusion This case study demonstrates a transparent approach to integrate IPD from trials with expert opinion using traditional parametric distributions to ensure long-term survival extrapolations are clinically plausible.

To compare alternative methods for unanchored indirect comparisons of two interventions for overall survival when individual patient data (IPD) is available for both studies (IPD-IPD analyses), and when IPD is only available for one study and aggregate data (AD) for the other study (IPD-AD analyses). A case study comparing nivolumab with standard of care (SoC) in 3L small cell lung cancer was performed using the CheckMate032 trial and the Flatiron Health database to compare unanchored comparisons without population adjustment, IPD-IPD adjustment analyses using inverse probability treatment weighting (IPTW), regression adjustment (RA), and doubly robust methods (DRMIPD-IPD), and IPD-AD analyses using matching-adjusted indirect comparison (MAIC), simulated treatment comparison (STC), and a novel DRMIPD-AD. Relative treatment effects were expressed with Cox hazard ratios (HRs) and differences in restricted mean survival time (DRMST). A simulation study was performed evaluating the performance of the alternative methods in different scenarios. Conditional HRs from RA differed from the marginal HRs from IPTW due to non-collapsibility. Therefore, estimates of DRMST in months were used as the relative treatment effect measure for the case study, which provides a collapsible estimand for DR estimates and comparison between methods DRMST with nivolumab versus SoC was higher for RA (3.22) than IPTW (2.72) and DRMIPD-IPD (2.71). MAIC, STC, and DRMIPD-AD estimates were similar (2.88; 2.92; 2.88) but with more uncertainty. The simulations found that when covariates differed substantially between studies, IPTW performed poorly in comparison to RA and DRM. Analysts should be aware of differences between marginal and conditional treatment effects when performing indirect comparisons of time-to-event outcomes; DRMST may be considered. Regression-based or DRM models may be preferable over other adjustment methods in cases with limited overlap in covariates between studies indirectly compared. Having IPD for both studies is preferable over having IPD for only one.

Aim: To estimate the comparative efficacy of cemiplimab, a programmed cell death protein 1 inhibitor, versus EGFR inhibitors, pembrolizumab and platinum-based chemotherapy in terms of overall survival (OS) and progression-free survival. Patients & methods: We performed an indirect treatment comparison of cemiplimab and other available systemic therapies for patients with advanced cutaneous squamous cell carcinoma. Results: Cemiplimab was associated with benefits in OS (hazard ratios range: 0.07-0.52) and progression-free survival (hazard ratios range: 0.30-0.67) versus EGFR inhibitors and pembrolizumab (data from KEYNOTE-629). Cemiplimab was more efficacious versus platinum-based chemotherapy in terms of OS. Conclusion: Cemiplimab may offer improvements in survival for advanced cutaneous squamous cell carcinoma patients compared with existing systemic therapies.

Improvement in OS is the gold standard for assessing treatment efficacy. To avoid delays in novel treatment approval, early treatment decisions may be based on validated surrogate endpoints which predict OS. A prior meta-analysis of clinical trials in LA HNSCC pts by Michiels 2009 showed a strong correlation of EFS with OS, supporting EFS as a surrogate endpoint in LA HNSCC. This study aimed to assess whether the correlation between EFS and OS is maintained with updated literature in pts with LA HNSCC ineligible for surgery and receiving chemoradiation therapy (CRT). A systematic literature review (SLR) conducted on May 20, 2020 identified randomized controlled trials assessing CRT regimens in the surgery ineligible LA HNSCC population. The primary endpoints of interest were OS and EFS, defined as time from randomization to progression, surgery, or death. Trials with progression-free survival, disease- and failure-free survival endpoints were included if definitions were sufficiently similar to EFS. Trials reporting hazard ratios (HRs) or Kaplan-Meier curves for OS and EFS were included in the analysis. Correlation was assessed with regression models across all CRT trials, as well as in subgroups defined by type of CRT (concurrent CRT, sequential CRT and cisplatin + RT). The strength of the relationship between EFS log HR and OS log HR was measured with Pearson’s correlation coefficient (R). The SLR identified 27 trials with OS and EFS results. A strong correlation between EFS and OS was observed in the overall CRT analysis (R=0.85, 95% confidence interval [CI]: 0.70-0.93). Similar results were found by type of CRT, and in studies with alternative EFS definitions (see table).Table: 872PAnalyses aR (95% CI)SlopeInterceptAll CRT trials (n=27)0.85 (0.70, 0.93)0.8250.033Concurrent CRT vs concurrent CRT trials (n=12)0.88 (0.62, 0.97)0.7070.12Sequential CRT vs any CRTb trials (n=15)0.83 (0.37, 0.96)1.1550.107Cisplatin + RT vs any CRTb trials (n=15)0.79 (0.47, 0.93)0.6940.031Cisplatin + RT vs concurrent CRT trials (n=9)0.82 (0.33, 0.96)0.6530.028All trials where EFS was defined as time from randomization to disease progression or death (n=19)0.87 (0.69, 0.95)0.7370.006a Conducted for all trials and subgroups of trials based on the use of any concurrent CRT, adjuvant/neoadjuvant (‘sequential’) CRT, or concurrent cisplatin + RT in their armsb Concurrent or sequential CRT Open table in a new tab a Conducted for all trials and subgroups of trials based on the use of any concurrent CRT, adjuvant/neoadjuvant (‘sequential’) CRT, or concurrent cisplatin + RT in their arms b Concurrent or sequential CRT Associations between OS and EFS were strong (R=0.79-0.88), suggesting EFS is a valid surrogate for OS in surgery ineligible LA HNSCC pts receiving CRT.

e18012 Background: In the KEYNOTE-048 trial, pembrolizumab as monotherapy (P) and in combination with platinum+5FU chemotherapy (P+C) versus cetuximab+platinum+5FU (EXTREME regimen) significantly improved overall survival (OS) in the combined positive score (CPS) ≥1 (hazard ratio: 0.74; 95% confidence interval: 0.61-0.90) and total (0.72; 0.60-0.87) R/M HNSCC populations, respectively, and was approved by the FDA in these patient populations. While the EXTREME regimen is considered standard of care in 1L R/M HNSCC, other systemic treatment options including cetuximab+platinum+docetaxel (TPEx regimen), platinum+paclitaxel/taxane (Pt+T), and platinum+5FU (Pt+F) are also commonly used. Due to lack of head-to-head comparisons with pembrolizumab, an NMA was conducted to estimate the comparative efficacy of P and P+C versus these interventions in 1L R/M HNSCC. Methods: A systematic literature review (SLR) was conducted on November 13, 2019 to identify randomized controlled trials for the relavant interventions. Data were extracted for the OS and progression-free survival (PFS) outcomes. NMA analyses were conducted for the total population and for the CPS ≥1 and CPS ≥20 subgroups in a Bayesian framework using proportional hazards (base case) and time-varying (sensitivity analysis) treatment-effect models. The deviance information criterion was used to compare the goodness-of-fit of the alternative survival models. Results: The SLR identified 28 trials, of which six trials matched the trial eligibility criteria of KEYNOTE-048 and were included in the NMA. Results from the fixed-effects NMA for P and P+C are summarized in table below for the FDA indicated population. Improvement in OS was noted for P and P+C versus EXTREME, Pt+T, and Pt+F, and a trend in improved OS versus TPEx was observed. The sensitivity analysis showed improved OS over time across all comparisons. PFS was improved with P and P+C versus Pt+F and comparable versus other interventions. These results were generally consistent for P and P+C in the CPS (CPS ≥1 or CPS ≥20) patient subgroups. Additionally, NMA results versus EXTREME were consistent with the KEYNOTE-048 trial results. Conclusions: Pembrolizumab (P or P+C), showed improved OS and comparable PFS outcomes versus alternative 1L R/M HNSCC interventions, consistent with the efficacy results versus EXTREME observed in the KEYNOTE-048 trial. [Table: see text]

Introduction: Idecabtagene vicleucel (ide-cel, bb2121) is a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy approved in the US by the Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody, i.e. triple-class exposed (TCE).

BACKGROUND: Most cutaneous squamous cell carcinomas (CSCCs) can be treated with surgical excision or radiation; however, approximately 1% of patients develop advanced disease. In 2018, the FDA approved cemiplimab-rwlc as the first programmed cell death-1 (PD-1) monoclonal antibody for the treatment of patients with metastatic CSCC or locally advanced CSCC who are not candidates for curative surgery or curative radiation. In June 2020, pembrolizumab, another PD-1 monoclonal antibody, was approved for the treatment of patients with recurrent or metastatic CSCC who are not candidates for curative surgery or radiation. We previously reported on the cost-effectiveness of cemiplimab vs historical standard of care for the treatment of advanced CSCC from a US perspective. OBJECTIVE: To estimate the cost-effectiveness of cemiplimab vs pembrolizumab for patients with advanced CSCC in the United States. METHODS: A “partitioned survival” framework was used to assess the cost-effectiveness of cemiplimab vs pembrolizumab. Clinical inputs were based on the most recent data cut of the phase 2 trials for cemiplimab (EMPOWER-CSCC-1; NCT02760498) and pembrolizumab (KEYNOTE-629). Progression-free survival and overall survival were extrapolated using parametric models until all patients had progressed or died. Health state utilities were derived from data collected in the EMPOWER-CSCC-1 trial. Costs included drug acquisition, drug administration, disease management, terminal care, and adverse events and were based on published 2020 US list prices. To assess model uncertainty, 1-way sensitivity and probabilistic sensitivity analyses (PSA) were conducted, alongside scenario analyses evaluating key modeling assumptions. RESULTS: In the base case, cemiplimab resulted in an incremental gain of 3.44 life-years (discounted) and incremental cost-effectiveness ratio (ICER) of $130,329 per quality-adjusted life-year (QALY) vs pembrolizumab. At a willingness-to-pay threshold of $150,000/QALY, PSA indicated a 71% probability that cemiplimab is cost-effective when compared with pembrolizumab. Scenario analysis resulted in ICERs ranging from $115,909 to $187,374. CONCLUSIONS: Findings suggest that cemiplimab is a cost-effective treatment for patients with advanced CSCC, compared with pembrolizumab. These results should be interpreted cautiously in the absence of head-to-head trials; however, in the absence of such data, these results can be used to inform health care decisions over resource allocation.

Idecabtagene vicleucel (ide-cel, bb2121), a chimeric antigen receptor (CAR) T cell therapy, has been investigated in patients with relapsed and refractory multiple myeloma (RRMM) who have received an immunomodulatory drug, proteasome inhibitor, and anti-CD38 antibody in the single-arm phase 2 KarMMa clinical trial. Two therapies with distinct mechanisms of action - selinexor plus dexamethasone (Sd) and belantamab mafodotin (BM) - are currently approved in the United States for heavily pretreated patients, including those who are triple-class refractory. To compare ide-cel versus Sd and ide-cel versus BM, matching-adjusted indirect comparisons were performed. Ide-cel extended progression-free survival (PFS) and overall survival (OS) versus both Sd and BM (hazard ratio (HR); 95% confidence interval (CI)). PFS: ide-cel versus Sd, 0.46; 0.28-0.75; ide-cel versus BM, 0.45; 0.27-0.77. OS: ide-cel versus Sd, 0.23; 0.13-0.42; ide-cel versus BM, 0.35; 0.14-0.87. These results suggest ide-cel offers clinically meaningful improvements over currently approved regimens for patients with heavily pretreated RRMM.

Background Cost-effectiveness analyses (CEA) of new treatments often need LTS extrapolations, but models can lack clinical expert evaluation. A systematic process can integrate expert opinion (EO) in an unbiased way. In the global multicenter, single-arm phase 2 KarMMa trial (NCT03361748), ide-cel, a B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cell therapy, showed deep, durable responses in triple-class exposed (TCE) pts with RRMM, with survival data reported up to 12 months (Munshi NC, et al. NEJM 2021;384:705-716). Without EO, predicted LTS varies with the extrapolation model. This study estimated expected survival rates at 3, 5, and 10 years for pts treated with ide-cel, based on integrating observed trial data with EO. Methods This prospective qualitative study incorporated semi-structured interviews, adapted from the Sheffield Elicitation Framework. Oncologists and hematologists with experience in treating pts with RRMM with BCMA-targeted therapies including CAR T cell therapies participated in the elicitation exercise (n=6). Evidence on pts in the KarMMa clinical trial from the Jan 2020 data cut (median follow-up 13.3 months) and conventional care (CC) for TCE pts with RRMM were summarized to give a common baseline data set for EO. In a facilitator-guided web-based application, experts gave upper and lower plausible limits and likely survival values at 3, 5, and 10 years. Experts were given the blinded, individual estimates and collectively gave consensus estimates from a ‘rationale impartial observer’ perspective. To assess the impact of incorporating EO, separate models were based on observed data with or without EO. Exponential, Weibull, Gompertz, generalized gamma (GG), lognormal, and log-logistic survival distributions were used to assess model fit. Analyses used a Frequentist framework and the Akaike information criterion compared the goodness-of-fit in survival models. This process estimated LTS for CC from the observational studies KarMMa-RW (Jagannath S, et al. JCO 2020;38;8525) and MAMMOTH (Gandhi UH, et al. Leukemia 2019;33:2266-2275). Results The best-fitting distributions for models using observed ide-cel (KarMMa) data only vs observed data and EO were Gompertz and GG, respectively. Survival estimates were 11% (without EO) to 35% (with EO) at 3 years; 0% (without) to 15% (with) at 5 years; and 0% (without) to 2% (with) at 10 years. In comparison, for the real-world CC cohort in KarMMa-RW survival estimates (with EO) were 16%, 6%, and 1% at 3, 5, and 10 years, respectively, for the best-fitting (GG) model. For the MAMMOTH CC cohort, survival estimates (with EO) were 5%, 0%, and 0% at 3, 5, and 10 years for the best-fitting (GG) model. Conclusion These findings suggest when observed data and EO are integrated, ide-cel treatment provides extended estimated survival rates vs CC. This study indicates that including EO is informative in assisting decision-making processes. Cost-effectiveness analyses (CEA) of new treatments often need LTS extrapolations, but models can lack clinical expert evaluation. A systematic process can integrate expert opinion (EO) in an unbiased way. In the global multicenter, single-arm phase 2 KarMMa trial (NCT03361748), ide-cel, a B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cell therapy, showed deep, durable responses in triple-class exposed (TCE) pts with RRMM, with survival data reported up to 12 months (Munshi NC, et al. NEJM 2021;384:705-716). Without EO, predicted LTS varies with the extrapolation model. This study estimated expected survival rates at 3, 5, and 10 years for pts treated with ide-cel, based on integrating observed trial data with EO. This prospective qualitative study incorporated semi-structured interviews, adapted from the Sheffield Elicitation Framework. Oncologists and hematologists with experience in treating pts with RRMM with BCMA-targeted therapies including CAR T cell therapies participated in the elicitation exercise (n=6). Evidence on pts in the KarMMa clinical trial from the Jan 2020 data cut (median follow-up 13.3 months) and conventional care (CC) for TCE pts with RRMM were summarized to give a common baseline data set for EO. In a facilitator-guided web-based application, experts gave upper and lower plausible limits and likely survival values at 3, 5, and 10 years. Experts were given the blinded, individual estimates and collectively gave consensus estimates from a ‘rationale impartial observer’ perspective. To assess the impact of incorporating EO, separate models were based on observed data with or without EO. Exponential, Weibull, Gompertz, generalized gamma (GG), lognormal, and log-logistic survival distributions were used to assess model fit. Analyses used a Frequentist framework and the Akaike information criterion compared the goodness-of-fit in survival models. This process estimated LTS for CC from the observational studies KarMMa-RW (Jagannath S, et al. JCO 2020;38;8525) and MAMMOTH (Gandhi UH, et al. Leukemia 2019;33:2266-2275). The best-fitting distributions for models using observed ide-cel (KarMMa) data only vs observed data and EO were Gompertz and GG, respectively. Survival estimates were 11% (without EO) to 35% (with EO) at 3 years; 0% (without) to 15% (with) at 5 years; and 0% (without) to 2% (with) at 10 years. In comparison, for the real-world CC cohort in KarMMa-RW survival estimates (with EO) were 16%, 6%, and 1% at 3, 5, and 10 years, respectively, for the best-fitting (GG) model. For the MAMMOTH CC cohort, survival estimates (with EO) were 5%, 0%, and 0% at 3, 5, and 10 years for the best-fitting (GG) model. These findings suggest when observed data and EO are integrated, ide-cel treatment provides extended estimated survival rates vs CC. This study indicates that including EO is informative in assisting decision-making processes.

In indirect treatment comparisons (ITC) involving cancer immunotherapies, the proportional hazard (PH) assumption often does not hold. Using synthesis methods that assume constant hazard ratios may lead to biased and inaccurate estimates of treatment effects, especially when extrapolated in cost-effectiveness analyses. Our aim was to identify ITC or network meta-analysis (NMA) synthesis methods (or comparisons of methods) for time-to-event outcomes that do not rely on the PH assumption. A pre-defined search of EMBASE and MEDLINE from 2010 onwards was performed using terms related to ITCs, time-to-event outcomes, and survival methods. A search of citations and co-citations based on known methods papers was also performed using ‘CoCites’. A search of recommendations regarding time-to-event analyses was also performed for ITC/NMA guidelines identified by Laws et al 2019. Relevant details were extracted from full-text publications, including the methodology to address non-PH and the mathematical notation of the model, the analyzed data source, the incorporation of between-study heterogeneity, and whether the analysis was implemented in a frequentist or Bayesian framework. A total of nine publications were identified which were categorized as: 1) one-step multidimensional NMAs (Ouwens et al. 2010; Jansen 2011; Vickers et al. 2019); 2) two-step multidimensional NMAs (Cope et al. 2020); 3) NMAs with cubic splines for baseline hazard (Freeman et al. 2017); and 4) restricted mean survival NMAs (Petit et al. 2019; Niglio et al. 2019; Connock et al. 2019). No guidance was identified regarding appropriate synthesis models to adopt when confronted with this issue. This study identified limited guidance on synthesis methods for NMA of survival data where the PH assumption is violated. Further evaluation of the methods that are available is warranted.

Objectives: To evaluate the cost-effectiveness of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC) from a payer perspective in the United States. Methods: A partitioned survival model was developed to assess the cost-effectiveness of cemiplimab versus historical standard of care (SOC). All inputs were identified based on a systematic literature review, supplemented by expert opinion where necessary. Clinical inputs for cemiplimab were based on individual patient data from a cemiplimab phase 2 single-arm trial (NCT27060498). For SOC, analysis was based on a pooled analysis of single-arm clinical trials and retrospective studies evaluating chemotherapy and epidermal growth factor receptor inhibitors (cetuximab, erlotinib, and gefitinib) identified via a systematic literature review (6 of the 27 included studies). Overall survival and progression-free survival were extrapolated over a lifetime horizon. Costs were included for drug acquisition, drug administration, management of adverse events, subsequent therapy, disease management, and terminal care. Unit costs were based on published 2019 US list prices. Results: In the base case, cemiplimab versus SOC resulted in an incremental cost-effectiveness ratio of $99 447 per quality adjusted-life year (QALY), where incremental costs and QALYs were $372108 and 3.74, respectively. At a willingness-to-pay threshold of $150 000/QALY, the probabilistic sensitivity analysis suggests a 90% probability that cemiplimab is cost-effective compared to SOC. Scenario analyses resulted in incremental cost-effectiveness ratios ranging from $90 590 to $148 738. Conclusions: Compared with historical SOC, cemiplimab is a cost-effective use of US payer resources for the treatment of advanced CSCC and is expected to provide value for money.

Background. Fabry disease is a rare, X-linked genetic disorder that, if untreated in patients with the Classic phenotype, often progresses to end-stage kidney disease. This meta-analysis determined the effect of agalsidase beta on loss of estimated glomerular filtration rate (eGFR) in the Classic phenotype using an expansive evidence base of individual patient-level data. Methods. The evidence base included four Sanofi-Genzyme studies and six studies from a systematic literature review. These were restricted to Classic Fabry patients meeting the eligibility criteria from Phases III and IV agalsidase beta trials, including 315 patients (161 treated). Linear regression was first used to model annual change in eGFR for each patient and the resulting annualized eGFR slopes were modelled with treatment and covariates using quantile regression. These results were then used to estimate median annualized eGFR change in agalsidase beta treated versus untreated groups. Results. Imbalances across treatment groups were found in baseline age, sex and proteinuria, but not in the use of renin- angiotensin system blockers. The adjusted model suggests that treated (agalsidase beta) patients experienced a slower median eGFR decrease [2.46 mL/min/1.73 m(2)/year slower; 95% confidence interval (CI) 0.63-4.29; P = 0.0087] than comparable untreated patients. The median eGFR decrease was 2.64 mL/min/1.73 m(2)/year slower (95% CI 0.53-4.78; P = 0.0141) in treated Classic males. Conclusions. Using an expansive evidence base and robust modelling approach, these data indicate that agalsidase betatreated patients with the Classic phenotype conserve their renal function better than untreated patients.

Placebo can affect subjective outcomes like pain. Cost-effectiveness analyses (CEAs) that compare interventions versus no intervention (rather than "sham intervention/placebo") should account for the placebo effect. We demonstrate a method to adjust network meta-analysis (NMA) for placebo effects (specifically, by route of treatment administration [ROA]). A Cochrane review of pain treatments estimated a standardized mean placebo effect, which was assumed to reflect the difference between no treatment and mean placebo effect. Bannuru 2015 estimated differences in placebo effect between three ROAs. It was assumed that three levels of placebo in Bannuru 2015 center around the mean placebo effect as estimated by Cochrane and that distribution of these ROAs correspond to the differences between subcutaneous (SC), intramuscular (IM), and intravenous (IV) ROAs. We applied these to an NMA of change in monthly migraine days (MMDs) informing a CEA of monoclonal antibody calcitonin gene-related peptide inhibitors (both IV and SC) or onabotulinumtoxinA (IM) over weeks 1-4 in patients with chronic migraine. We evaluated the impact of placebo adjustment on observed outcomes modeled as the additive effect of placebo and treatment. Compared to no adjustment, estimates for SC treatments with adjustment had decreased treatment effect (increase in MMDs) over weeks 1-4, ranging from 0.59 to 1.51 days depending on the specific treatment. Results over weeks 1-4 for IM treatment showed an improvement in treatment effect of -0.74 days, while IV treatment showed an improved treatment effect of -1.92 days. When added to the treatment effect, inclusion of the adjustment resulted in IV treatment having higher absolute improvements over all other treatments. Results were consistent with an analysis of weeks 9-12. This case study illustrates the importance of addressing varying placebo responses in indirect treatment comparisons informing CEAs.