Comparative effectiveness from a single-arm trial and real-world data: alectinib versus ceritinib

Davies, Jessica; Martinec, Michael; Delmar, Paul; Coudert, Mathieu; Bordogna, Walter; Golding, Sophie; Martina, Reynaldo; Crane, Gracy

doi:10.2217/cer-2018-0032

Cited by 50 publications

(53 citation statements)

References 29 publications

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“…In recent years, real-world (RW) analyses have increasingly been used to generate external comparator arms for clinical trials [13,14]. Regulatory bodies have recognized the need for a broader, more flexible framework incorporating RW data for decision-making, as outlined in the 21st Century Cures Act [15,16].…”

Section: Introductionmentioning

confidence: 99%

Developing real-world comparators for clinical trials in chemotherapy-refractory patients with gastric cancer or gastroesophageal junction cancer

Chau

Ott

et al. 2019

Gastric Cancer

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Background There are few third-line or later (3L+) treatment options for advanced/metastatic (adv/met) gastric cancer/gastroesophageal junction cancers (GC/GEJC). 3L+ Nivolumab demonstrated encouraging results in Asian patients in the ATTRACTION-2 study compared with placebo (12-month survival, 26% vs 11%), and in Western patients in the single-arm CheckMate 032 study (12-month survival, 44%). This analysis aimed to establish comparator cohorts of US patients receiving routine care in real-world (RW) clinical practice. Methods A 2-step matching process generated RW cohorts from Flatiron Health’s oncology database (January 1, 2011–April 30, 2017), for comparison with each trial: (1) clinical trial eligibility criteria were applied; (2) patients were frequency-matched with trial arms for baseline variables significantly associated with survival. Median overall survival (OS) was calculated by Kaplan–Meier analysis from last treatment until death. Results Of 742 adv/met GC/GEJC patients with at least 2 prior lines of therapy, matching generated 90 US RW ATTRACTION-2-matched patients (median OS: 3.5 months) versus 163 ATTRACTION-2 placebo patients (median OS: 4.1 months), and 100 US RW CheckMate 032-matched patients (median OS: 2.9 months) versus 42 CheckMate 032 nivolumab-treated patients (median OS: 8.5 months). Baseline characteristics were generally similar between clinical trial arms and RW-matched cohorts. Conclusions We successfully developed RW cohorts for comparison with data from clinical trials, with comparable baseline characteristics. Survival in US patients receiving RW care was similar to that seen in Asian patients receiving placebo in ATTRACTION-2; survival with nivolumab in CheckMate 032 appeared favorable compared with US RW clinical practice.

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Section: Introductionmentioning

confidence: 99%

Developing real-world comparators for clinical trials in chemotherapy-refractory patients with gastric cancer or gastroesophageal junction cancer

Chau

Ott

et al. 2019

Gastric Cancer

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“…(ii) Studies using Historical Control Arms compare retrospective RWD‐derived controls against an uncontrolled treatment arm . (iii) Studies using Synthetic (Real‐World) Control Arms pair an uncontrolled treatment arm with concurrent RWD controls …”

Section: Limitations For Rwe For Regulatory Decision Makingmentioning

confidence: 99%

“…50 (iii) Studies using Synthetic (Real-World) Control Arms pair an uncontrolled treatment arm with concurrent RWD controls. 22 Each of the three study designs of RWE has significant issues that prevent the ability to achieve a level of evidence on par with RCTs. Because of challenges in drawing causal conclusions of treatment efficacy from RWE they are not suited to replace RCTs.…”

Section: Limitations For Rwe For Regulatory Decision Makingmentioning

confidence: 99%

“…In particular, Congress has mandated that the FDA increase focus on RWE for regulatory decision making both for new approvals and evaluating additional indications for approved therapies and the FDA has testified on progress toward implementing this focus . The EMA recently accepted an RWE‐based control arm during their analysis of Alecensa effectiveness compared with the standard of care . In addition, the FDA has established partnerships with private companies whose goal is to use RWD in regulatory decision making, including using synthetic control arms…”

mentioning

confidence: 99%

“…19 The EMA recently accepted an RWE-based control arm during their analysis of Alecensa effectiveness compared with the standard of care. [20][21][22] In addition, the FDA has established partnerships with private companies whose goal is to use RWD in regulatory decision making, including using synthetic control arms. 20 Although some have been enthusiastic about the ability for observational RWD to substitute for RCTs, others have expressed caution.…”

mentioning

confidence: 99%

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Examining the Use of Real‐World Evidence in the Regulatory Process

Beaulieu‐Jones

Finlayson

Yuan

et al. 2019

Clin Pharma and Therapeutics

110

138

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The 21st Century Cures Act passed by the United States Congress mandates the US Food and Drug Administration to develop guidance to evaluate the use of real‐world evidence (RWE) to support the regulatory process. RWE has generated important medical discoveries, especially in areas where traditional clinical trials would be unethical or infeasible. However, RWE suffers from several issues that hinder its ability to provide proof of treatment efficacy at a level comparable to randomized controlled trials. In this review article, we summarized the advantages and limitations of RWE, identified the key opportunities for RWE, and pointed the way forward to maximize the potential of RWE for regulatory purposes.

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

et al. 2021

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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)

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Comparative effectiveness from a single-arm trial and real-world data: alectinib versus ceritinib

Abstract: Alectinib was associated with prolonged overall survival versus ceritinib, which is consistent with efficacy evidence from clinical trials.

Cited by 50 publications

References 29 publications

Developing real-world comparators for clinical trials in chemotherapy-refractory patients with gastric cancer or gastroesophageal junction cancer

Developing real-world comparators for clinical trials in chemotherapy-refractory patients with gastric cancer or gastroesophageal junction cancer

Examining the Use of Real‐World Evidence in the Regulatory Process

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

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