Assessment of Alectinib vs Ceritinib in ALK-Positive Non–Small Cell Lung Cancer in Phase 2 Trials and in Real-world Data

Abstract

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 PARTICIPANTSThis 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 MEASURESThe main outcome was OS. RESULTSIn 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 RELEVANCEAlectinib exposure was associated with longer OS compared with ceritinib in patients with ALK-positive NSCLC, and only substantial levels of bias examined reversed (continued)

Beyond Crizotinib: A Systematic Review and Meta-Analysis of the Next-Generation ALK Inhibitors as First-Line Treatment for ALK-Translocated Lung Cancer

“…The recent approval of second and third-generation ALKIs has dramatically changed the treatment algorithm of ALK-translocated lung cancer. In the absence of head-to-head comparisons between next-generation ALKIs, any next-generation ALKI may be considered a valid option as first-line therapy ( 33 , 34 ). Our meta-analysis showed consistency among efficacy and safety outcomes, highlighting a class-effect improvement over control therapies.…”

Addressing challenges with real-world synthetic control arms to demonstrate the comparative effectiveness of Pralsetinib in non-small cell lung cancer

“…Multiple imputation by chained equations of ECOG PS scores was performed under MAR and MNAR, then where consistent with eligibility criteria for this study, patients with imputed ECOG PS > 1 were excluded, and the comparisons of interest executed 8 .…”

“…This analysis was used to assess the robustness of the study by estimating the E-value 8 , 9 , 32 . The E-value represents the minimum association of a hypothetical unmeasured confounder with treatment assignment and outcome of interest (OS) on the risk ratio (RR) scale to nullify our estimated HRs.…”

“…These issues have all caused concern for decision-makers evaluating SCA comparisons 4 and suggestions have been made by both regulators and health technology assessment (HTA) agencies that the validity of any conclusions should be supported by analyses that quantify the impact of potential sources of bias 5 – 7 . Thus, the second of the two goals of this study was to demonstrate how we quantitatively assessed the robustness of our findings to potential sources of bias in a comprehensive and systematic fashion to act as a guide for future SCA studies using RWD 8 , 9 .…”

Targeting ALK Rearrangements in NSCLC: Current State of the Art

“…However, the toxicity profile of ceritinib from ASCEND-4 and ASCEND-5 indicated a higher frequency of dose interruptions and modifications due to adverse events (AEs) compared to chemotherapy. Real-world data comparing ceritinib versus alectinib in ALK+NSCLC found that alectinib exposure was associated with longer OS compared with ceritinib in ALK+ NSCLC ( 72 ). The pharmacokinetic (PK) data from the ASCEND-8 study ( 71 ) led to the FDA approval of ceritinib 450 mg QD, administered with food.…”