Evaluating the Role and Policy Implications of Using External Evidence in Survival Extrapolations: A Case Study of Axicabtagene Ciloleucel Therapy for Second-Line DLBCL

Abstract

Background and objective: Health technology assessment (HTA) of haemato-oncology therapies typically requires extrapolation of long-term survival beyond a trial's follow-up. Health technology assessment agencies must balance caution around uncertainty in early follow-up trial data whilst aiming to provide timely access. This study qualitatively and quantitatively assessed how eight HTA agencies considered maturing data and external evidence.

Methods: The eight HTA appraisals were based on ZUMA-7, a phase III trial for axicabtagene ciloleucel (axi-cel) for second-line diffuse large B-cell lymphoma. ZUMA-7 survival data were submitted with either a 25-month ('Interim') or 47-month ('Primary') follow-up. To inform axi-cel Interim survival extrapolations, external evidence was available from a prior mature single-arm trial for third-line or later diffuse large B-cell lymphoma (ZUMA-1). A qualitative assessment of eight different submissions to HTA agencies was undertaken to determine key discussion points. The value and cost of waiting for evidence to mature between Interim and Primary analyses were quantified using value of information methods to evaluate the impact of waiting for further evidence collection on population health.

Results: Agencies used varied approaches to account for uncertainty in survival extrapolations in both Interim and Primary analyses. No agency considered external evidence fully during Interim submissions; one used it partially to inform clinical plausibility; four did not consider it. Health technology assessment agencies that did not consider the relevance of ZUMA-1 were more inclined to wait for more mature evidence to mitigate uncertainty. When ZUMA-1 aided in determining a plausible range for Interim extrapolations, the less valuable more mature evidence became, with the cost of waiting for Primary analysis results exceeding the value conferred.

Conclusions: There was limited consideration of external evidence during the included HTA submissions. In the future, it is recommended that external evidence should be considered to a greater degree by both manufacturers and HTA agencies when extrapolating survival to ensure appropriate and timely HTA decisions that minimise the undue burden on healthcare systems.

Fig. 1

Structure of the analysis. 2L second-line, DLBCL diffuse-large B-cell lymphoma, EVPI expected value of perfect information, HTA health technology assessment, OS overall survival

Fig. 2

Axi-cel overall survival: Interim ZUMA-7 (left) and Primary ZUMA-7 (right). MCM mixture-cure modelling

Fig. 3

Axi-cel OS: Interim ZUMA-7 extrapolations based on parametric distributions and ZUMA-1 Kaplan–Meier (KM) and the extrapolation based on the log-logistic distribution. MCM mixture-cure modelling

Fig. 4

Axi-cel overall survival: Primary ZUMA-7 distributions, with the ZUMA-7 Interim company and agency preferred curves. CDA-AMC Canada’s Drug Agency-L’Agence des Médicaments du Canada, KM Kaplan–Meier, MCM mixture-cure modelling, NICE National Institute for Health and Care Excellence

Fig. 5

Uncertainty reduction between the Interim and Primary analyses. EVPI expected value of perfect information