OBJECTIVES : German and Canadian HTAs rejected reimbursement of alectinib for second-line (2L) ALK+ NSCLC citing possible biases from (i) unmeasured confounding and (ii) missing ECOG performance status (PS) data in real-world evidence (RWE) for 2L ceritinib submitted as comparator to single-arm alectinib trials. We sought to evaluate this HTA decision using post-launch real-world data from the United States, where alectinib was approved.

METHODS : Quantitative bias analysis was used to compare the effectiveness of alectinib versus ceritinib in 2L post-crizotinib ALK+ NSCLC using treatment arms derived from pooled single-arm alectinib trials (n=183) and records from a US nationwide Flatiron Health electronic health record (EHR)-derived de-identified database (n=87 and 102 for alectinib and ceritinib). Propensity score weighting was used to balance baseline characteristics between treatment arms.

RESULTS : Large imbalances were observed in age, CNS metastases and prior chemotherapy. After adjustment for baseline covariates, alectinib-treated patients (n=55) had significantly longer median overall survival (OS) of 28 months (95% CI: 20-37) than ceritinib (11 months, 95% CI: 8-27; n=44) using complete case analysis (hazard ratio (HR): 0.64, 0.43-0.91). An unmeasured confounder associated with OS and alectinib exposure by a risk ratio >2.1-fold was needed to nullify the observed treatment effect. Under a missing-at-random assumption (MAR) for ECOG PS scores (49% missing for ceritinib arm) using multiple imputation, the pooled HR was 0.64 (0.5-0.8). The observed treatment effect was robust to all deviations from MAR where balance in baseline characteristics could be achieved. Alectinib maintained a significantly longer median OS (28 months versus 13 months, HR: 0.70, 0.54-0.85) after shifting an additional 10-40% patients to a poorer ECOG PS than expected under MAR.

CONCLUSIONS : Only implausible levels of bias reversed our conclusions. These methods could provide a framework to explore uncertainty in RWE and aid decision-making for HTAs to enable patient access to innovative therapies.