Original Title: The CAR T cell therapies tisagenlecleucel (Kymriah®) and axicabtagene ciloleucel (Yescarta®) for the treatment of B cell acute lymphoblastic leukaemia, diffuse large B cell lymphoma and primary mediastinal B cell lymphoma

Authors' objectives: The chimeric antigen receptor (CAR) T-cell therapies tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel) are provisionally listed in Appendix 1 of the Health Insurance Benefits Ordinance in Switzerland until 31 December 2024 for the third-line treatment of B-cell acute lymphoblastic leukaemia (B-ALL), diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL). This health technology assessment (HTA) evaluates the available evidence regarding the efficacy, effectiveness, safety, costs, cost-effectiveness and budget impact of tisa-cel and axi-cel compared to standard care in these populations. Ethical, legal, social and organisational issues associated with these therapies are also explored.

Authors' results and conclusions: Clinical evaluation It was not feasible to evaluate DLBCL and PMBCL populations separately, therefore studies that included either population were aggregated into a broader ‘LBCL’ population. For all outcomes reported in single-arm studies, the certainty of evidence was very low, meaning that the true effects are probably different from the estimated effects. The certainty of evidence for NRSIs is noted below. Relative effects were calculated as comparator/CAR T (except where noted). Tisa-cel for B-ALL: One NRSI and 7 single-arm studies investigated tisa-cel in the B-ALL population. The reported hazard ratio (HR) for OS comparing conventional chemotherapy to tisa-cel at 150 days in patients admitted to intensive care (n=205) reported no evidence of a significant difference (HR 0.89, 95% CI: 0.38 to 2.11; very low certainty evidence). Results from single-arm studies are summarised in a table (see report). Axi-cel for LBCL: Two NRSIs and 14 single-arm studies investigated axi-cel in the LBCL population. At 16 months axi-cel reported favourable OS (HR 0.14; 95% CI: 0.05 to 0.38), PFS (HR 0.04; 95% CI: 0.01 to 0.17) and ORR (RR 0.05; 95% CI: 0.00 to 0.77), and no evidence of a statistically significant difference in CRR (RR 0.09; 95% CI: 0.01 to 1.37) compared to no axi-cel (very low certainty evidence). At 24 months, axi-cel reported favourable OS (HR 0.27; 95% CI: 0.0 to 0.38), CRR (RR 0.22; 95% CI: 0.16 to 0.32) and ORR (RR 0.42; 95% CI: 0.35 to 0.50) compared to salvage chemotherapy (moderate certainty evidence). The NRSIs did not report other relevant outcomes. Results from single-arm studies are summarised in a table (see report). Tisa-cel for LBCL: One NRSI and 9 single-arm studies investigated tisa-cel in the LBCL population. At 50-90 months, the NRSI reported OS favouring tisa-cel (HR 0.60, 95% CI: 0.44 to 0.77), and no evidence of a statistically significant difference in ORR (RR 1.31, 95% CI: 0.97 to 1.77), compared to standard care (very low certainty evidence). The NRSI did not report other relevant outcomes. Results from single-arm studies are summarised in a table (see report). Economic evaluation Incremental cost-effectiveness ratios (ICERs) are presented; however, the calculations underpinning these ICERs were based on very low-quality evidence and naÔve treatment comparisons. Concerns raised by other HTA bodies in their reviews of company-submitted economic evidence (e.g. lack of comparative safety and efficacy; uncertainty in the extrapolation of OS; majority of quality-adjusted life years [QALYs] gained over the period of extrapolation; applicability of the historical control comparator evidence) are also key concerns with the ICERs presented here (both the existing Swiss values from the literature and the newly generated ICERs). In summary, there is significant uncertainty in the results presented. Tisa-cel for B-ALL The existing Swiss evaluation reported a base case ICER of CHF36,419 (Swiss francs) per QALY gained for tisa-cel relative to blinatumomab.1 In this HTA, an ICER for tisa-cel relative to blinatumomab was generated using updated outcome data for the ELIANA cohort.2 An ICER of CHF70,634 per QALY gained was estimated. While this comparator aligned with existing evaluations and HTAs, it failed to capture complexities in the treatment of r/r B-ALL—for example, blinatumomab may be used as a bridge to CAR T-cell therapy. The time horizon and discount rate were shown to be important drivers of the ICER in scenario analysis, highlighting the relative benefit of tisa-cel on long term outcomes as a critical component. Axi-cel for LBCL No existing economic evidence on axi-cel for the treatment of r/r LBCL in the Swiss healthcare context was identified. In this HTA, an ICER for axi-cel relative to historical salvage chemotherapy control of CHF88,346 per QALY gained was generated. Concern around the applicability of the historical control to contemporary Swiss practice—due to rituximab-naÔve cohorts of the CORAL extension studies (source of OS estimates for the control arm) and given temporary listings of several alternative comparators for r/r DLBCL or PMBCL—is noted. The time horizon and discount rate were again shown to be important drivers of the ICER. The ICER was higher when compared to polatuzumab (in combination with rituximab and bendamustine; POLA-BR) (CHF102,220 per QALY gained). Tisa-cel for LBCL The existing Swiss evaluation reported a base case ICER of CHF113,179 per QALY gained for tisacel relative to salvage chemotherapy for the management of r/r DLBCL.1 In this HTA, an ICER for tisa-cel relative to historical salvage chemotherapy control was generated using long-term follow-up data from the JULIET cohort3 and a similar control group to the existing evaluation (i.e. CORAL extension cohorts). An ICER of CHF129,840 per QALY gained was estimated. Concerns around the applicability of the historical control to contemporary Swiss practice noted above also apply to this comparison. The time horizon and discount rate were again shown to be important drivers of the ICER. The ICER was higher when compared to POLA-BR (CHF157,437 per QALY gained). Budget Impact Base case estimates of financial impact for tisa-cel in the management of r/r B-ALL suggest treatment costs of CHF3.4 million and CHF3.8 million in 2023 and 2027, respectively (assuming 6 successfully infused patients in 2023 and 7 in 2027). Accounting for cost offsets for potential comparators, net cost of CHF2.5 million in 2023 was estimated, increasing to CHF2.7 million by 2027. Base case estimates of financial impact for CAR T-cell therapy in patients with r/r DLBCL or PMBCL are presented at the population level. These estimates suggest treatment costs of CHF37.3 million and CHF60.9 million in 2023 and 2027, respectively (assuming 77 successfully infused patients in 2023 [49 axi-cel; 28 tisa-cel] and 125 in 2027 [80 axi-cel; 45 tisa-cel]). Accounting for cost offsets for potential comparators, net cost of CHF30.0 million isn 2023 was estimated, increasing to CHF49.0 million by 2027. Ethical, legal, social and organisational issues Overall, 5 publications addressed organisational issues and 2 addressed ethical issues. Key ethical issues include wait times, issues with patient referrals, and acquiring confirmation of cost coverage prior to treatment. Four key organisational considerations were identified: managing patients’ health status between leukapheresis and CAR T-cell therapy infusion; identification, management and treatment of toxicities; ensuring comprehensive education of medical practitioners around CAR T products and processes; the relatively lesser hospital resource use of CAR T (excluding manufacturing) compared to adult stem cell transplant in some settings. Conclusions Limited, very low certainty comparative evidence was available to evaluate the relative effectiveness and safety of tisa-cel compared to standard care for the treatment of B-ALL and LBCL. Limited, moderate to very low certainty evidence reported favourable outcomes for axi-cel compared to salvage chemotherapy or no axi-cel, respectively, for effectiveness outcomes; safety data was not reported. Overall, the majority of evidence was single-arm in nature, which is unable to inform research questions regarding relative safety and effectiveness. Given the lack of ongoing comparative studies, the prospect of better evidence in the future is unlikely. Due to limited comparative evidence comparing CAR T-cell therapies to alternative therapy options, naive comparisons were relied upon to estimate the incremental benefit of axi-cel and tisa-cel in the economic evaluation, introducing high levels of uncertainty into the results. These comparisons suggest ICERs of approximately CHF70,000 for tisa-cel for r/r B-ALL relative to blinatumomab, and of CHF88,000 for axi-cel in r/r LBCL and CHF130,000 for tisa-cel in r/r DLBCL relative to historical salvage chemotherapy control. It is possible that base case ICERs (LBCL populations) are biased in favour of CAR T-cell therapy due to the reliance on historical control. In summary, there are important limitations underpinning the ICERs, including limited comparative safety and efficacy evidence, applicability of the comparator evidence to contemporary practice, and uncertainty in the extrapolation of survival outcomes.

Authors' methods: A systematic review of clinical studies was conducted in Medline, Embase, the Cochrane Library and the INAHTA HTA database up to 13 April 2023. Systematic reviews, randomised controlled trials (RCTs), non-randomised studies of interventions (NRSI) and single-arm studies were eligible for inclusion. Indirect comparisons between single-arm studies of CAR T-cell therapies and standard care were deemed inappropriate for the clinical evaluation due to the significant risk of confounding. Relevant outcomes were overall survival (OS), progression-free survival (PFS), complete response rate (CRR), overall response rate (ORR), treatment-free interval (TFI), health-related quality of life (HRQoL), treatment discontinuation, and adverse events including B-cell aplasia, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The overall certainty of evidence for critical outcomes was assessed using the Grading of Recommendation, Assessment, Development and Evaluations (GRADE) approach. Random-effects meta-analyses were conducted using R. A systematic review of economic studies was undertaken in the same databases as the clinical evaluation, plus Econlit and the websites of HTA institutes. Data were extracted from retrieved cost and cost-effectiveness studies, and the results described narratively. One study was directly applicable to the HTA context, having been conducted from the perspective of the Swiss healthcare payer. This study was funded by the company (Novartis) who developed KymriahÆ (tisa-cel proprietary drug). Additional evaluations were made to assess the cost-effectiveness of axi-cel for patients with relapsed or refractory (r/r) large B-cell lymphoma (LBCL) in the Swiss setting, and to provide comparable evaluations for tisa-cel for patients with r/r B-ALL or DLBCL. The methodology adopted was guided by the existing literature.

Project Status: Completed

URL for project: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-projekte/carttherapien.html

URL for protocol: https://www.bag.admin.ch/dam/bag/en/dokumente/kuv-leistungen/leistungen-und-tarife/hta/berichte/h0075cart-hta-protocol.pdf.download.pdf/h0075cart-hta-protocol.pdf

Year Published: 2024

URL for published report: https://www.bag.admin.ch/dam/bag/en/dokumente/kuv-leistungen/leistungen-und-tarife/hta/berichte/h0075cart-hta-report.pdf.download.pdf/h0075cart-hta-report.pdf

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: Switzerland

Organisation Name: Swiss Federal Office of Public Health (FOPH)

Contact Address: Federal Office of Public Health, Schwarzenburgstrasse 157, CH-3003 Berne, Switzerland

Contact Name: Stephanie Vollenweider

Contact Email: hta@bag.admin.ch

Copyright: Swiss Federal Office of Public Health