Comparative effectiveness of ZUMA-5 (axi-cel) vs SCHOLAR-5 external control in relapsed/refractory follicular lymphoma.

In the pivotal ZUMA-5 trial, axicabtagene ciloleucel (axi-cel; an autologous anti-CD19 chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in relapsed/refractory (r/r) follicular lymphoma (FL) patients. Here, outcomes from ZUMA-5 are compared with the international SCHOLAR-5 cohort, which applied key ZUMA-5 trial eligibility criteria simulating randomized controlled trial conditions. SCHOLAR-5 data were extracted from institutions in 5 countries, and from 1 historical clinical trial, for r/r FL patients who initiated a third or higher line of therapy after July 2014. Patient characteristics were balanced through propensity scoring on prespecified prognostic factors using standardized mortality ratio (SMR) weighting. Time-to-event outcomes were evaluated using weighted Kaplan-Meier analysis. Overall response rate (ORR) and complete response (CR) rate were compared using weighted odds ratios. The 143 ScHOLAR-5 patients reduced to an effective sample of 85 patients after SMR weighting vs 86 patients in ZUMA-5. Median follow-up time was 25.4 and 23.3 months for SCHOLAR-5 and ZUMA-5. Median overall survival (OS) and progression-free survival (PFS) in SCHOLAR-5 were 59.8 months and 12.7 months and not reached in ZUMA-5. Hazard ratios for OS and PFS were 0.42 (95% confidence interval [CI], 0.21-0.83) and 0.30 (95% CI, 0.18-0.49). The ORR and CR rate were 49.9% and 29.9% in SCHOLAR-5 and 94.2% and 79.1% in ZUMA-5, for odds ratios of 16.2 (95% CI, 5.6-46.9) and 8.9 (95% CI, 4.3-18.3). Compared with available therapies, axi-cel demonstrated an improvement in meaningful clinical endpoints, suggesting axi-cel addresses an important unmet need for r/r FL patients. This trial was registered at www.clinicaltrials.gov as #NCT03105336.

Benefit of axicabtagene ciloleucel versus chemoimmunotherapy in older patients and/or patients with poor ECOG performance status with relapsed or refractory large B-cell lymphoma after 2 or more lines of prior therapy.

Axicabtagene ciloleucel (axi-cel) in trials has demonstrated favorable efficacy compared with historical controls after ≥2 lines of therapy for the treatment of relapsed or refractory (R/R) large B cell lymphoma (LBCL). Herein, we compared the real-world effectiveness of axi-cel with efficacy and effectiveness of chemoimmunotherapy (CIT) in patients aged ≥65 years and patients with Eastern Cooperative Oncology Group performance status (ECOG PS) of 2. A total of 1146 patients treated with commercial axi-cel for R/R LBCL with ≥2 lines of prior therapy were included from the Center for International Blood and Marrow Transplantation Research prospective observational study, and 469 patients treated with CIT for R/R LBCL after ≥2 lines of prior therapy were included from SCHOLAR-1 (an international, multicohort, retrospective study). After propensity score matching, at a median follow-up of 24 months for patients receiving axi-cel and 60 months for patients receiving CIT, 12-month overall survival rates were 62% and 28%, respectively (hazard ratio, 0.30 [95% CI, 0.24-0.37]). Objective response rate (ORR) was 76% (complete response [CR] rate 58%) in patients receiving axi-cel versus 28% (CR rate 16%) for those receiving CIT. A 57% difference in ORR (55% difference in CR rate) favoring axi-cel over CIT was observed among patients aged ≥65 years. Increased magnitude of benefit in response rates for axi-cel versus CIT was also observed among patients with ECOG PS = 2. These findings further support the broader use of axi-cel in older patients and patients with ECOG PS = 2 with R/R LBCL.

Cost-Effectiveness of Axicabtagene Ciloleucel for Adult Patients With Relapsed or Refractory Follicular Lymphoma in the United States.

OBJECTIVES: The results of a recent single-arm trial (ZUMA-5) of axicabtagene ciloleucel (axi-cel) for relapsed/refractory (r/r) follicular lymphoma (FL) demonstrated high rates of durable response and tolerable toxicity among treated patients. To quantify the value of axi-cel compared with standard of care (SOC) to manage r/r FL patients who have had at least 2 prior lines of systemic therapy (3L+), a cost-effectiveness model was developed from a US third-party payer perspective. METHODS: A 3-state partitioned-survival cost-effectiveness model was developed with a lifetime horizon. Patient-level analyses of the 36-month ZUMA-5 (axi-cel) and SCHOLAR-5 (SOC) studies were used to extrapolate progression-free and overall survivals. After 5 years of survival, an estimated 40% of the modeled population was assumed to experience long-term remission based on literature. Results include the incremental cost-effectiveness ratio (ICER) measured as incremental cost per quality-adjusted life year (QALY) gained. One-way sensitivity analysis, probabilistic sensitivity analysis, and scenario analyses were performed. All outcomes were discounted 3% per year. RESULTS: Axi-cel led to an increase of 4.28 life-years, 3.64 QALYs, and a total cost increase of $321 192 relative to SOC, resulting in an ICER of $88 300 per QALY. Across all parameters varied in the one-way sensitivity analysis, the ICER varied between $133 030 and $67 277. In the probabilistic sensitivity analysis, axi-cel had a 99% probability of being cost-effective across 5000 iterations using a $150 000 willingness-to-pay threshold. CONCLUSIONS: Given the robustness of the model results and sensitivity analyses, axi-cel is expected to be a cost-effective treatment in 3L+ r/r FL.

Treatment patterns and outcomes in relapsed/refractory follicular lymphoma: results from the international SCHOLAR-5 study.

The SCHOLAR-5 study examines treatment patterns and outcomes of real-world follicular lymphoma (FL) patients on 3rd line of treatment (LoT) or higher, for whom existing data are limited. SCHOLAR-5 is a retrospective cohort study using data from adults (≥ 18 years) with grade 1-3a FL, initiating ≥3rd LoT after June 2014 at major lymphoma centers in the US and Europe. Objective response rate (ORR), complete response (CR), progression-free survival (PFS) and overall survival (OS) were analyzed by LoT. Time-to-event outcomes were assessed using Kaplan-Meier methods. Of 128 patients, 87 initiated 3rd LoT, 63 initiated 4th LoT, and 47 initiated 5th LoT. At 1st eligible LoT, 31% progressed within 24-months of 1st LoT anti-CD20 combination therapy, 28% had prior autologous stem cell transplantation, and 31% were refractory to the previous LoT. The most common regimen in each LoT was chemoimmunotherapy; however, experimental drugs were increasingly used at later LoT. In the US, anti-CD20 monotherapy was more common at ≥3rd LoT compared to Europe, where stem cell transplants were more common. ORR at 3rd LoT was 68% (CR 44%), but decreased after each LoT to 37% (CR 22%) in ≥5 LoT. Median OS and PFS at 3rd LoT were 68 and 11 months, respectively, and reduced to 43 and 4 months at ≥5 LoT. Treatments were heterogenous at each LoT in both the US and Europe. Few FL patients achieved CR in later LoT, and duration of response and survival diminished with each subsequent line.

Clinical outcomes in patients relapsed/refractory after ≥2 prior lines of therapy for follicular lymphoma: a systematic literature review and meta-analysis.

BACKGROUND: Patients with follicular lymphoma (FL) can have high response rates to early lines of treatment. However, among FL patients relapsed/refractory (r/r) after ≥2 prior lines of therapy (LOT), remission tends to be shorter and there is limited treatment guidance. This study sought to evaluate the clinical outcomes for r/r FL after ≥2 prior LOT identified through systematic literature review. METHODS: Eligible studies included comparative or non-comparative interventional or observational studies of systemic therapies among adults with FL r/r after ≥2 prior LOT published prior to 31st May 2021. Prior LOT must have included an anti-CD20 monoclonal antibody and an alkylating agent, in combination or separately. Overall response rate (ORR) and complete response (CR) were estimated using inverse-variance weighting with Freeman-Tukey double-arcsine transformations. Kaplan-Meier (KM) curves for progression-free survival (PFS) and overall survival (OS) estimated by reconstructing digitized curves using the Guyot algorithm, and survival analyses were conducted, stratified by ≥2 prior LOT and ≥ 3 prior LOT groups (as defined in the source material). Restricting the analyses to the observational cohorts was investigated as a sensitivity analysis. RESULTS: The analysis-set included 20 studies published between 2014 and 2021. Studies were primarily US and/or European based, with the few exceptions using treatments approved in US/Europe. The estimated ORR was 58.47% (95% confidence interval [CI]: 51.13-65.62) and proportion of patients with CR was 19.63% (95% CI: 15.02-24.68). The median OS among those ≥2 prior LOT was 56.57 months (95% CI: 47.8-68.78) and median PFS was 9.78 months (95% CI: 9.01-10.63). The 24-month OS decreased from 66.50% in the ≥2 prior LOT group to 59.51% in the ≥3 prior LOT group, with a similar trend in PFS at 24-month (28.42% vs 24.13%). CONCLUSIONS: This study found that few r/r FL patients with ≥2 prior LOT achieve CR, and despite some benefit, approximately 1/3 of treated patients die within 24 months. The shorter median PFS with increasing prior LOT suggest treatment durability is suboptimal in later LOT. These findings indicate that patients are underserved by treatments currently available in the US and Europe.

Burden of illness and outcomes in second-line large B-cell lymphoma treatment: real-world analysis of Medicare beneficiaries.

Aims: To characterize elderly large B-cell lymphoma patients who progress to second-line treatment to identify potential unmet treatment needs. Patients & methods: Retrospective USA cohort study, patients receiving second-line autologous stem cell transplant (SCT) preparative regimen ('ASCT-intended') versus those who did not; stratified further into those who received a stem cell transplant and those who did not. Primary outcomes were: healthcare resource utilization, costs and adverse events. Results: 1045 patients (22.0%) were included in the ASCT-intended group, 23.3% of whom received SCT (5.1% of entire second-line population). Non-SCT patients were older and had more comorbidities and generally higher rates of healthcare resource utilization and costs. Conclusion: Elderly second-line large B-cell lymphoma patients incurred substantial costs and a minority received potentially curative SCT, suggesting significant unmet need.

Lay abstract Large B-cell lymphoma (LBCL) is an aggressive form of cancer. Although chemotherapy is often initially successful, LBCL recurs in about 50% of patients. For many years, the standard of care for recurrent LBCL has been a course of strong chemotherapy followed by stem cell transplant (SCT). However, many older patients cannot tolerate or do not respond well to chemotherapy and therefore cannot proceed to SCT. In this real-world study of Medicare patients, we found that only 5.1% of patients with recurrent LBCL ever received potentially curative SCT. They also had higher healthcare costs than similar patients who did receive SCT. This shows a significant unmet need in elderly LBCL patients that may potentially be addressed with recent treatment innovations.

Gender differences in health-related quality of life at the time of a positive HIV test - a cross-sectional study in a resource-poor, high prevalence setting in Nairobi, Kenya.

Few studies have examined gender differences in sub-Saharan Africa, where HIV disproportionately affects women. Objectives of this cross-sectional study were to determine gender differences in HRQoL at the time of a positive HIV test, and whether factors associated with HRQoL differed between men and women. Adults testing HIV-positive were recruited from two clinics located in informal settlements. HRQoL was measured with the SF-12. Multiple linear regression was used to test whether there were gender differences in physical (PCS) and mental composite summary (MCS) scores. Separate models were built for men and women to examine factors associated with HRQoL. Between April 2013 and June 2015, 775 individuals from were recruited. The mean PCS score was higher in women (adjusted mean difference 2.49, 95% CI 0.54 to 4.44, p = 0.012). There was no significant gender difference in MCS scores. Similar factors were associated with better physical HRQoL in men and women: secondary education, younger age, higher CD4, and employment. Employment was the only factor associated with MCS in men, while less social support and low CD4 were associated with poorer MCS scores in women. Gender differences in factors related to HRQoL should be considered in broader policy and interventions to improve the HRQoL in those diagnosed with HIV.

The impact of pharmacy-based immunization services on the likelihood of immunization in the United States.

OBJECTIVES: A major policy to increase immunization rates against infectious diseases in the United States has included pharmacy-based immunization services. We aimed to determine the impact of pharmacy-based immunization services on the likelihood of adult influenza and pneumococcal immunization. DESIGN: National individual-level immunization data were merged with pharmacy-level data on the availability of immunization services for 8466 pharmacies from a national pharmacy chain. County-level variation in availability of vaccines from 2006 to 2010 was used to characterize exposure to immunization services. We used a longitudinal logistic regression model to estimate the impact of pharmacy-based immunization services on the outcomes of interest. SETTING AND PARTICIPANTS: We conducted the main analysis in the U.S. adult population. We conducted subgroup analyses of high-risk populations, including people 65 years of age or older. OUTCOME MEASURES: Odds of being immunized for influenza or pneumococcal disease after exposure to the service compared with before the service while controlling for existing trends in immunization rate growth and other confounders. RESULTS: Each additional year of exposure to pharmacy-based immunization services was associated with a 1.023 (CI 1.012-1.034) greater odds of reporting an influenza immunization and a 1.016 (CI 1.006-1.027) greater odds of reporting a pneumococcal immunization. Five years after national implementation, we estimate that 6.2 million additional influenza immunizations and 3.5 million additional pneumococcal immunizations are attributable to pharmacy-delivered immunization services each year. Subgroup analyses further indicate that the policy increased the odds of immunization for both diseases over time among adults 65 years of age or older (influenza odds ratio [OR] 1.025, CI 1.013-1.038; and pneumococcal OR 1.026, CI 1.010-1.042). CONCLUSION: Pharmacy-based immunization services increased the likelihood of immunization for influenza and pneumococcal diseases, resulting in millions of additional immunizations in the United States.

Impact of pharmacist administration of influenza vaccines on uptake in Canada.

BACKGROUND: Uptake of influenza vaccination in Canada remains suboptimal despite widespread public funding. To increase access, several provinces have implemented policies permitting pharmacists to administer influenza vaccines in community pharmacies. We examined the impact of such policies on the uptake of seasonal influenza vaccination in Canada. METHODS: We pooled data from the 2007-2014 cycles of the Canadian Community Health Survey (n = 481 526). To determine the impact of influenza vaccine administration by pharmacists, we estimated the prevalence ratio for the association between the presence of a pharmacist policy and individual-level vaccine uptake using a modified Poisson regression model (dependent variable: vaccine uptake) with normalized weights while controlling for numerous health and sociodemographic factors. RESULTS: Across all survey cycles combined, 28.8% of respondents reported receiving a seasonal influenza vaccine during the 12 months before survey participation. Introduction of a policy for pharmacist administration of influenza vaccine was associated with a modest increase in coverage (2.2%) and an individual's likelihood of uptake (adjusted prevalence ratio 1.05, 95% confidence interval 1.02-1.08). INTERPRETATION: Uptake of influenza immunization was modestly increased in Canadian jurisdictions that allowed pharmacists to administer influenza vaccines.

The validity of the SF-12 and SF-6D instruments in people living with HIV/AIDS in Kenya.

BACKGROUND: Health-related quality of life (HRQoL) and health state utility value (HSUV) measurements are vital components of healthcare clinical and economic evaluations. Accurate measurement of HSUV and HRQoL require validated instruments. The 12-item Short-Form Health Survey (SF-12) is one of few instruments that can evaluate both HRQoL and HSUV, but its validity has not been assessed in people living with HIV/AIDS (PLWHA) in east Africa, where the burden of HIV is high. METHODS: This cross-sectional study used baseline data from a randomized trial involving PLWHA in Kenya. Data included responses from a translated and adapted SF-12 survey as well as key demographic and clinical data. Construct validity of the survey was examined by testing the SF-12's ability to distinguish between groups known in advance to have differences in their health based on their disease severity. We classified disease severity based on established definitions from the US Center for Disease Control (CDC) and WHO, as well as a previously studied viral load threshold. T-tests and ANOVA were used to test for differences in HRQoL and HSUV scores. Area under the receive operator curve (AUC) was used to test the discriminative ability of the HRQoL and HSUV instruments. RESULTS: Differences in physical component scores met the minimum clinically important difference among participants with more advanced HIV when defined by CD4 count (4.3 units) and WHO criteria (compared to stage 1, stages 2, 3 and 4 were 2.0, 7.2 and 9.8 units lower respectively). Mental score differences met the minimum clinically important difference between WHO stage 1 and stage 4 patients (4.4). Differences in the HSUV were statistically lower in more advanced HIV by all three definitions of severity. The AUC showed poor to weak discriminatory ability in most analyses, but had fair discriminatory ability between WHO clinical stage 1 and clinical stage 4 individuals (AUC = 0.71). CONCLUSION: Our findings suggest that the Kiswahili translated and adapted version of the SF-12 could be used as an assessment tool for physical health, mental health and HSUV for Kiswahili-speaking PLHWA. TRIAL REGISTRATION: Clinical trials.gov identifier: NCT00830622 . Registered 26 January 2009.

Targeting an alcohol intervention cost-effectively to persons living with HIV/AIDS in East Africa.

BACKGROUND: In the current report, we ask if targeting a cognitive behavioral therapy (CBT)-based intervention aimed at reducing hazardous alcohol consumption to HIV-infected persons in East Africa would have a favorable value at costs that are feasible for scale-up. METHODS: Using a computer simulation to inform HIV prevention decisions in East Africa, we compared 4 different strategies for targeting a CBT intervention-(i) all HIV-infected persons attending clinic; (ii) only those patients in the pre-antiretroviral therapy (ART) stages of care; (iii) only those patients receiving ART; and (iv) only those patients with detectable viral loads (VLs) regardless of disease stage. We define targeting as screening for hazardous alcohol consumption (e.g., using the Alcohol Use Disorders Identification Test and offering the CBT intervention to those who screen positive). We compared these targeting strategies to a null strategy (no intervention) or a hypothetical scenario where an alcohol intervention was delivered to all adults regardless of HIV status. RESULTS: An intervention targeted to HIV-infected patients could prevent 18,000 new infections, add 46,000 quality-adjusted life years (QALYs), and yield an incremental cost-effectiveness ratio of $600/QALY compared to the null scenario. Narrowing the prioritized population to only HIV-infected patients in pre-ART phases of care results in 15,000 infections averted, the addition of 21,000 QALYs and would be cost-saving, while prioritizing based on an unsuppressed HIV-1 VL test results in 8,300 new infections averted, adds 6,000 additional QALYs, and would be cost-saving as well. CONCLUSIONS: Our results suggest that targeting a cognitive-based treatment aimed at reducing hazardous alcohol consumption to subgroups of HIV-infected patients provides favorable value in comparison with other beneficial strategies for HIV prevention and control in this region. It may even be cost-saving under certain circumstances.

Mobile health for early retention in HIV care: a qualitative study in Kenya (WelTel Retain).

Many people newly diagnosed with HIV are lost to follow-up before timely initiation of antiretroviral therapy (ART). A randomised controlled trial (RCT), WelTel Kenya1, demonstrated the effectiveness of the WelTel text messaging intervention to improve clinical outcomes among patients initiating ART. In preparation for WelTel Retain, an RCT that will evaluate the effect of the intervention to retain patients in care immediately following HIV diagnosis, we conducted an informative qualitative study with people living with HIV (n = 15) and healthcare providers (HCP) (n = 5) in October 2012. Study objectives included exploring the experiences of people living with HIV who have attempted to engage in HIV care, the use of cell phones in everyday life, and perceptions of communicating via text message with HCP. Participants were recruited through convenience sampling. Semi-structured, qualitative interviews were conducted and recorded, transcribed verbatim and analysed using NVivo software. Analysis was guided by the Theory of Reasoned Action and the Technology Acceptance Model. Results indicate that while individuals have many motivators for engaging in care after diagnosis, structural and individual barriers including poverty, depression and fear of stigma prevent them from doing so. All participants had access to a mobile phone, and most were comfortable communicating through text messages, or were willing to learn. Both people living with HIV and HCP felt that increased communication via the text messaging intervention has the potential to enable early identification of problems, leading to timely problem solving that may improve retention and engagement in care during the first year after diagnosis.

An updated cost-effectiveness analysis of axicabtagene ciloleucel in second-line large B-cell lymphoma patients in the United States.

AIMS: This economic evaluation of axicabtagene ciloleucel (axi-cel) versus previous standard of care (SOC; salvage chemotherapy followed by high-dose therapy with autologous stem cell rescue) in the second line (2L) large B-cell lymphoma population is an update of previous economic models that contained immature survival data. METHODS: This analysis is based on primary overall survival (OS) ZUMA-7 clinical trial data (median follow-up of 47.2 months), from a United States (US) payer perspective, with a model time horizon of 50 years. Mixture cure models were used to extrapolate updated survival data; subsequent treatment data and costs were updated. Patients who remained in the event-free survival state by 5 years were assumed to have achieved long-term remission and not require subsequent treatment. RESULTS: Substantial survival and quality of life benefits were observed despite 57% of patients in the SOC arm receiving subsequent cellular therapy: median model-projected (ZUMA-7 trial Kaplan-Meier estimated) OS was 78 months (median not reached) for axi-cel versus 25 months (31 months) for SOC, resulting in incremental quality-adjusted life year (QALY) difference of 1.63 in favor of axi-cel. Incrementally higher subsequent treatment costs were observed in the SOC arm due to substantial crossover to cellular therapies, thus, when considering the generally accepted willingness to pay threshold of $150,000 per QALY in the US, axi-cel was cost-effective with an incremental cost-effectiveness ratio of $98,040 per QALY. CONCLUSIONS: Results remained consistent across a wide range of sensitivity and scenario analysis, including a crossover adjusted analysis, suggesting that the mature OS data has significantly reduced the uncertainty of axi-cel's cost-effectiveness in the 2L setting in the US. Deferring treatment with CAR T therapies after attempting a path to transplant may result in excess mortality, lower quality of life and would be an inefficient use of resources relative to 2L axi-cel.

Cost-effectiveness of axicabtagene ciloleucel versus tisagenlecleucel for the treatment of 3L + relapsed/refractory large B-cell lymphoma in the United States: incorporating longer survival results.

AIMS: To provide an update on the cost-effectiveness of the chimeric antigen receptor (CAR) T-cell therapies axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) for the treatment of relapsed/refractory (r/r) large B-cell lymphoma (LBCL) among patients who have previously received ≥2 lines of systemic therapy using more mature clinical trial data cuts (60 months for axi-cel overall survival [OS] and 45 months for tisa-cel OS and progression-free survival [PFS]). METHODS: A partitioned survival model consisting of three health states (pre-progression, post-progression and death) was used to estimate quality-adjusted life years (QALYs) and costs associated with axi-cel and tisa-cel over a lifetime horizon. PFS and OS inputs for axi-cel and tisa-cel were based on a previously published matching-adjusted indirect treatment comparison (MAIC). Long-term OS and PFS were extrapolated using parametric survival mixture cure models (PS-MCMs). Costs of CAR-T cell therapy drug acquisition and administration, conditioning chemotherapy, apheresis, CAR T-specific monitoring, stem cell transplant, hospitalization, adverse events, routine care, and terminal care were sourced from US cost databases. Health state utilities were derived from previous publications. Model inputs were varied using a range of sensitivity and scenario analyses. RESULTS: Compared with tisa-cel, axi-cel resulted in 2.51 additional QALYs and $50,185 additional costs (an incremental cost-effectiveness ratio [ICER] of $19,994 per QALY gained). In probabilistic sensitivity analysis (PSA), the ICER for axi-cel versus tisa-cel was ≤$50,000/QALY in 99.4% of simulations and ≤$33,500 in 99% of simulations. Axi-cel remained cost-effective versus tisa-cel (assuming a willingness-to-pay threshold of $150,000 per QALY) across a range of scenarios. CONCLUSIONS: With longer-term survival data, axi-cel continues to represent a cost-effective option versus tisa-cel for treatment of r/r LBCL among patients who have previously received ≥2 lines of systemic therapy, from a US payer perspective.

Matching-adjusted indirect comparisons of axicabtagene ciloleucel to mosunetuzumab for the treatment of relapsed/refractory follicular lymphoma.

BACKGROUND: Axicabtagene ciloleucel (axi-cel) was the first chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL) patients, while mosunetuzumab was the first bispecific monoclonal antibody approved in this population. In the absence of head-to-head evidence, this study sought to conduct a matching-adjusted indirect comparison (MAIC) to estimate the comparative efficacy and safety of these treatments in 3rd line or higher (3L+) FL. METHODS: The evidence base consisted of individual patient data (IPD) of all enrolled patients, regardless of infusion status, from the single-arm axi-cel trial, ZUMA-5 (NCT03105336), and aggregate data from the mosunetuzumab FL trial (NCT02500407) from publications identified through a systematic review. Efficacy outcomes were progression-free survival (PFS), duration of response (DoR), objective response rate (ORR), complete response rate (CRR). Analyses used independent central review for both trials, where possible. Safety outcomes were cytokine release syndrome (CRS), neurological events (NE), and treatment-related adverse events (TRAEs). Unanchored MAICs were conducted to align ZUMA-5 to the patient characteristics of the mosunetuzumab trial. For each outcome, prognostic factors were identified a priori through quantitative analysis and clinical experts. For time-to-event outcomes, hazard ratios (HRs) were estimated using Cox regression using IPD from ZUMA-5 and pseudo-IPD extracted from Kaplan-Meier plots for mosunetuzumab. RESULTS: Patient characteristics were well-aligned between trials leading to large effective-sample sizes after matching, ranging from 93.4 to 115.5, for ZUMA-5 (n=127). In comparisons to mosunetuzumab (n=90), axi-cel was associated with improved PFS (HR: 0.39; 95% confidence interval [CI]: 0.24-0.62) and DoR (HR: 0.45; 95% CI: 0.27-0.76). Similarly, axi-cel led to higher ORR (OR: 3.87; 95% CI: 1.53-9.76) and CRR (OR: 2.80; 95% CI: 1.50-5.26). Although axi-cel was associated with a higher rate of all-grade CRS (OR: 5.54; 95% CI: 2.63-8.94) and NEs (OR: 3.54; 95% CI: 1.28-9.83), differences in grade ≥3 CRS and TRAEs were not statistically significant. CONCLUSIONS: Findings from this study show improved efficacy and more durable response for the treatment of 3L+ R/R FL with axi-cel relative to mosunetuzumab, with increased odds of all-grade CRS and NE, but not G3+ CRS and TRAEs.

Cost-effectiveness of treating relapsed or refractory 3L+ follicular lymphoma with axicabtagene ciloleucel vs mosunetuzumab in the United States.

Introduction: Novel therapies for 3L+ relapsed/refractory (r/r) follicular lymphoma (FL) have been approved recently by the US Food and Drug Administration including anti-CD19 CAR-T therapies such as axicabtagene ciloleucel (axi-cel) and CD20 × CD3 T-cell-engaging bispecific monoclonal antibodies such as mosunetuzumab (mosun). The objective of this study was to assess the cost-effectiveness of axi-cel compared to mosun in 3L+ r/r FL patients from a US third-party payer perspective. Methods: A three-state (progression-free, progressed disease, and death) partitioned-survival model was used to compare two treatments over a lifetime horizon in a hypothetical cohort of US adults (age ≥18) receiving 3L+ treatment for r/r FL. ZUMA-5 and GO29781 trial data were used to inform progression-free survival (PFS) and overall survival (OS). Mosun survival was modeled via hazard ratios (HRs) applied to axi-cel survival curves. The PFS HR value was estimated via a matching-adjusted indirect comparison (MAIC) based on mosun pseudo-individual patient data and adjusted axi-cel data to account for trial populations differences. One-way sensitivity analysis (OWSA) and probabilistic sensitivity analyses (PSA) were conducted. Scenario analyses included: 1) the mosun HRs were applied to the weighted (adjusted) ZUMA-5 24-month data to most exactly reflect the MAIC, 2) mosun HR values were applied to axi-cel 48-month follow-up data, and 3) recent axi-cel health state utility values in diffuse large B-cell lymphoma patients. Results: The analysis estimated increases of 1.82 LY and 1.89 QALY for axi-cel compared to mosun. PFS for axi-cel patients was 6.42 LY vs. 1.60 LY for mosun. Increase of $257,113 in the progression-free state was driven by one-time axi-cel treatment costs. Total incremental costs for axi-cel were $204,377, resulting in an ICER of $108,307/QALY gained. The OWSA led to ICERs ranging from $240,255 to $75,624, with all but two parameters falling below $150,000/QALY. In the PSA, axi-cel had an 64% probability of being cost-effective across 5,000 iterations using a $150,000 willingness-to-pay threshold. Scenarios one and two resulted in ICERs of $105,353 and $102,695, respectively. Discussion: This study finds that axi-cel is cost-effective compared to mosun at the commonly cited $150,000/QALY US willingness-to-pay threshold, with robust results across a range of sensitivity analyses accounting for parameter uncertainty.

Network meta-analysis of CAR T-Cell therapy for the treatment of 3L+ R/R LBCL after using published comparative studies.

INTRODUCTION: Studies have compared chimeric antigen receptor (CAR) T-cell therapies and salvage chemotherapy in relapsed/refractory large B-cell lymphoma (LBCL) patients, but further evidence of their relative effectiveness is warranted. METHODS: Our systematic review identified studies comparing efficacy and safety outcomes of axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel) and tisagenlecleucel (tisa-cel) trials to salvage chemotherapy cohorts in LBCL patients with ≥2 prior lines of treatment; and an extended evidence network included indirect comparisons comparing CAR T-cell therapies. We conducted network meta-analyzes using Bayesian hierarchical modeling. RESULTS: Three studies comparing ZUMA-1 (axi-cel), TRANSCEND (liso-cel) and JULIET (tisa-cel) trials to salvage chemotherapy within the SCHOLAR-1 cohort were identified. Axi-cel (odds ratio [OR]:5.63; 95% credible interval [CrI]:2.66-12.42) and liso-cel (OR:4.26; 95%CrI:2.33-7.93) showed a significant increased overall response rate compared to tisa-cel, but not to one-another. Axi-cel demonstrated significant improvements in overall survival relative to liso-cel (hazard ratio [HR]:0.54; 95%CrI:0.37-0.79) and tisa-cel (HR:0.47; 95%CrI:0.26-0.88). Higher rates of grade ≥3 neurological events were observed with axi-cel than with tisa-cel and liso-cel. CONCLUSIONS: We highlight important differences in clinical outcomes between CAR T-cell therapies. Axi-cel demonstrated improved overall survival compared to tisa-cel and liso-cel, and both axi-cel and liso-cel showed higher response rates compared to tisa-cel.

A Comparison of 3-Year Follow-up of ZUMA-5 (Axicabtagene Ciloleucel) With SCHOLAR-5 in Relapsed/Refractory Follicular Lymphoma.

In the pivotal ZUMA-5 trial, axicabtagene ciloleucel (axi-cel; an autologous anti-CD19 chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in relapsed/refractory follicular lymphoma patients. SCHOLAR-5 is an external control cohort designed to act as a comparator to ZUMA-5. Here, we present an updated comparative analysis of ZUMA-5 and SCHOLAR-5, using the 36-month follow-up data and the intent-to-treat population of ZUMA-5. Using propensity-score methods, 127 patients in ZUMA-5 were compared to 129 patients in SCHOLAR-5. At this extended follow-up, axi-cel continues to demonstrate clinically meaningful benefits in survival compared to historically available treatments in this population.

A 24-month updated analysis of the comparative effectiveness of ZUMA-5 (axi-cel) vs. SCHOLAR-5 external control in relapsed/refractory follicular lymphoma.

BACKGROUND: In the ZUMA-5 trial (Clinical trials identification: NCT03105336), axicabtagene ciloleucel (axi-cel; a chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in relapsed/refractory (r/r) follicular lymphoma (FL) patients and clear superiority relative to the SCHOLAR-5 external control cohort. We update this comparison using the ZUMA-5 24-month data. RESEARCH DESIGN AND METHODS: The SCHOLAR-5 cohort is comprised of r/r FL patients who initiated ≥3rd line of therapy after July 2014 and meeting ZUMA-5 eligibility criteria. Groups were balanced for patient characteristics through propensity scoring on prespecified prognostic factors using standardized mortality ratio (SMR) weighting. The overall response rate was compared using a weighted logistic regression. Time-to-event outcomes were evaluated using a Cox regression. RESULTS: For SCHOLAR-5, the sum of weights for the 143 patients was 85 after SMR weighting, versus 86 patients in ZUMA-5. The median follow-up was 29.4 months and 25.4 months for ZUMA-5 and SCHOLAR-5, respectively. The hazard ratios for overall survival and progression-free survival were 0.52 (95% confidence interval (CI): 0.28-0.95) and 0.28 (95% CI: 0.17-0.45), favoring axi-cel. CONCLUSION: This updated analysis, using a longer minimum follow-up than a previously published analysis, shows that the improved efficacy of axi-cel, relative to available therapies, in r/r FL is durable. .

Approaches to Selecting "Time Zero" in External Control Arms with Multiple Potential Entry Points: A Simulation Study of 8 Approaches.

BACKGROUND: When including data from an external control arm to estimate comparative effectiveness, there is a methodological choice of when to set "time zero," the point at which a patient would be eligible/enrolled in a contemporary study. Where patients receive multiple lines of eligible therapy and thus alternative points could be selected, this issue is complex. METHODS: A simulation study was conducted in which patients received multiple prior lines of therapy before entering either cohort. The results from the control and intervention data sets are compared using 8 methods for selecting time zero. The base-case comparison was set up to be biased against the intervention (which is generally received later), with methods compared in their ability to estimate the true intervention effectiveness. We further investigate the impact of key study attributes (such as sample size) and degree of overlap in time-varying covariates (such as prior lines of therapy) on study results. RESULTS: Of the 8 methods, 5 (all lines, random line, systematically selecting groups based on mean absolute error, root mean square error, or propensity scores) showed good performance in accounting for differences between the line at which patients were included. The first eligible line can be statistically inefficient in some situations. All lines (with censoring) cannot be used for survival outcomes. The last eligible line cannot be recommended. CONCLUSIONS: Multiple methods are available for selecting the most appropriate time zero from an external control arm. Based on the simulation, we demonstrate that some methods frequently perform poorly, with several viable methods remaining. In selecting between the viable methods, analysts should consider the context of their analysis and justify the approach selected. HIGHLIGHTS: There are multiple methods available from which an analyst may select "time zero" in an external control cohort.This simulation study demonstrates that some methods perform poorly but most are viable options, depending on context and the degree of overlap in time zero across cohorts.Careful thought and clear justification should be used when selecting the strategy for a study.