Assessment Of Alectinib Vs Ceritinib In Alk-Positive Non-Small Cell Lung Cancer In Phase 2 Trials And In Real-World Data

Question How robust are conclusions about the comparative effectiveness of the ALK inhibitor alectinib vs ceritinib in crizotinib-refractory, ALK-positive non-small cell lung cancer from indirect comparisons using real-world data (RWD)? Findings This comparative effectiveness study including 355 patients found that alectinib exposure was associated with improved survival compared with ceritinib in both single-group trials and multicenter US RWD. Results were robust to a range of plausible assumptions about unmeasured confounding and missing Eastern Cooperative Oncology Group Performance Status and underrecorded comorbidities in RWD. Meaning These findings suggest that alectinib is preferable to ceritinib for crizotinib-refractory, ALK-positive non-small cell lung cancer, providing validity to single-group trial data vs RWD comparisons.This comparative effectiveness research study examines the effectiveness of alectinib vs ceritinib in terms of overall survival in patients with ALK-positive, crizotinib-refractory, non-small cell lung cancer (NSCLC).Importance Quantitative assessment of bias from unmeasured confounding and missing data can help evaluate uncertainty in findings from indirect comparisons using real-world data (RWD). Objective To compare the effectiveness of alectinib vs ceritinib in terms of overall survival (OS) in patients with ALK-positive, crizotinib-refractory, non-small cell lung cancer (NSCLC) and to assess the sensitivity of these findings to unmeasured confounding and missing data assumptions. Design, Setting, and Participants This comparative effectiveness research study compared patients from 2 phase 2 alectinib trials and real-world patients. Patients were monitored from June 2013 to March 2020. Comparisons of interest were between alectinib trial data vs ceritinib RWD and alectinib RWD vs ceritinib RWD. RWD treatment groups were selected from nationally representative cancer data from US cancer clinics, the majority from community centers. Participants were ALK-positive patients aged 18 years or older with advanced NSCLC, prior exposure to crizotinib, and Eastern Cooperative Oncology Group Performance Status (PS) of 0 to 2. Data analysis was performed from October 2020 to March 2021. Exposures Initiation of alectinib or ceritinib therapy. Main Outcomes and Measures The main outcome was OS. Results In total, there were 355 patients: 183 (85 men [46.4%]) in the alectinib trial, 91 (43 men [47.3%]) in the ceritinib RWD group, and 81 (38 men [46.9%]) in the alectinib RWD group. Patients in the alectinib trial were younger (mean [SD] age, 52.53 [11.18] vs 57.97 [11.71] years), more heavily pretreated (mean [SD] number of prior therapy lines, 1.95 [0.72] vs 1.47 [0.81]), and had more favorable baseline ECOG PS (ECOG PS of 0 or 1, 165 patients [90.2%] vs 37 patients [77.1%]) than those in the ceritinib RWD group. The alectinib RWD group (mean [SD] age, 58.69 [11.26] years) had more patients with favorable ECOG PS (ECOG PS of 0 or 1, 49 patients [92.4%] vs 37 patients [77.1%]) and more White patients (56 patients [72.7%] vs 53 patients [62.4%]) compared with the ceritinib group. Compared with ceritinib RWD, alectinib-exposed patients had significantly longer OS in alectinib trials (adjusted hazard ratio [HR], 0.59; 95% CI, 0.44-0.75; P < .001) and alectinib RWD (HR, 0.46; 95% CI, 0.29-0.63; P < .001) after adjustment for baseline confounders. For the worst-case HR estimate of 0.59, residual confounding by a hypothetical confounder associated with mortality and treatment by a risk ratio greater than 2.24 was required to reverse the findings. Conclusions were robust to plausible deviations from random missingness for missing ECOG PS and underrecorded comorbidities and central nervous system metastases in RWD. Conclusions and Relevance Alectinib exposure was associated with longer OS compared with ceritinib in patients with ALK-positive NSCLC, and only substantial levels of bias examined reversed the findings. These findings suggest that quantitative bias analysis can be a useful tool to address uncertainty of findings for decision-makers considering RWD.