Replication of Overall Survival, Progression-Free Survival, and Overall Response in Chemotherapy Arms of Non-Small Cell Lung Cancer Trials Using Real-World Data

Thanh G N Ton, Navdeep Pal, Huong Trinh, Sami Mahrus, Michael T Bretscher, Robson J M Machado, Natalia Sadetsky, Nayan Chaudhary, Michael W Lu, Gregory J Riely, Thanh G N Ton, Navdeep Pal, Huong Trinh, Sami Mahrus, Michael T Bretscher, Robson J M Machado, Natalia Sadetsky, Nayan Chaudhary, Michael W Lu, Gregory J Riely

Abstract

Purpose: The utility of real-world data (RWD) for use as external controls in drug development is informed by studies that replicate trial control arms for different endpoints. The purpose of this study was to replicate control arms from four non-small cell lung cancer (NSCLC) randomized controlled trials (RCT) to analyze overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) using RWD.

Patients and methods: This study used RWD from a nationwide de-identified database and a clinico-genomic database to replicate OS, PFS, and ORR endpoints in the chemotherapy control arms of four first-line NSCLC RCTs evaluating atezolizumab [IMpower150-wild-type (WT), IMpower130-WT, IMpower131, and IMpower132]. Additional objectives were to develop a definition of real-world PFS (rwPFS) and to evaluate the real-world response rate (rwRR) endpoint.

Results: Baseline demographic and clinical characteristics were balanced after application of propensity score weighting methods. For rwPFS and OS, RWD external controls were generally similar to their RCT control counterparts. Across all four trials, the hazard ratio (HR) point estimates comparing trial controls with external controls were closer to 1.0 for the PFS endpoint than for the OS endpoint. An exploratory assessment of rwRR in RWD revealed a slight but nonsignificant overestimation of RCT ORR, which was unconfounded by baseline characteristics.

Conclusions: RWD can be used to reasonably replicate the OS and PFS of chemotherapy control arms of first-line NSCLC RCTs. Additional studies can provide greater insight into the utility of RWD in drug development.

Trial registration: ClinicalTrials.gov NCT02366143 NCT02367781 NCT02367794 NCT02657434.

©2022 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.
Figure 1.
Adjustment of baseline characteristics between the RCT and RWD arms for OS and rwPFS assessments. Adjustments of characteristics for IMpower150-WT (A), IMpower130-WT (B), IMpower131 (C), and IMpower132 (D) where red indicates raw data, green indicates data with trimming, and blue indicates data after weighting and trimming. Standardized mortality ratio with no trimming was applied to patients in the RCT. For final analysis, inverse probability weighting with average treatment effect for the treated population estimates with no trimming were applied to the RCT cohort to achieve cohort balancing. Ideal balance occurs when the data have SMD < 0.1 (bold line) for all baseline characteristics. BEV, bevacizumab; C, carboplatin; EC, external control; nabP; nab-paclitaxel; P, paclitaxel; PEM, pemetrexed; Plat, carboplatin/cisplatin. *, Duration was defined as the time from initial diagnosis to index date.
Figure 2.
Figure 2.
Primary results to replicate PFS of RCT control arms using RWD. Kaplan–Meier curves comparing PFS for the RCT control arms versus the RWD EC arms in the IMpower150-WT (A), IMpower130-WT (B), IMpower131 (C), and IMpower132 RCTs (D). Standard mortality ratio weighting without trimming was performed. Sample sizes may differ from OS, as some patients lacked follow-up data extending beyond baseline. EC, external control. *, WT intent-to-treat population without epidermal growth factor/anaplastic lymphoma kinase alterations.
Figure 3.
Figure 3.
Primary results to replicate OS of RCT control arms using RWD. Kaplan–Meier curves comparing OS for the RCT control arms versus the RWD EC arms in the IMpower150-WT (A), IMpower130-WT (B), IMpower131 (C), and IMpower132 RCTs (D). Standard mortality ratio weighting without trimming was performed. Sample sizes may differ from PFS, as some patients lacked follow-up data extending beyond baseline. EC, external control. *, WT intent-to-treat population without epidermal growth factor/anaplastic lymphoma kinase alterations.
Figure 4.
Figure 4.
Replication of PFS and OS of control arms of IMpower RCTs using RWD. HRs of PFS (A) and OS (B) of RCT control versus RWD EC arms in the IMpower150-WT, IMpower130-WT, IMpower131, and IMpower132 RCTs. EC, external control. *, Reference group is the RCT control arm.
Figure 5.
Figure 5.
RCT ORR and unadjusted rwRR according to restrictive criteria group. rwRR of RCT control versus RWD EC arms in the IMpower150-WT (A), IMpower130-WT (B), IMpower131 (C), and IMpower132 RCTs (D). EC, external control; ITT, intent to treat.

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