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M. Green

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    MA 12 - Circumventing EGFR Resistance (ID 665)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA 12.07 - Adjusted Indirect Comparison of Osimertinib to Chemotherapy in NSCLC Patients with EGFRm T790M Who Progressed after EGFR-TKI (ID 8558)

      11:00 - 12:30  |  Author(s): M. Green

      • Abstract
      • Presentation
      • Slides

      Osimertinib was granted conditional marketing authorization from the EMA and accelerated approval by the FDA based on single-arm trial (SAT) data. Subsequent full FDA approval was supported by the RCT AURA3 (NCT02151981) and based on superior progression-free survival (PFS) of osimertinib versus platinum-based doublet chemotherapy (PDC) for patients with epidermal growth factor receptor (EGFRm) T790M-positive non-small-cell lung cancer (NSCLC). Accelerated and conditional approval coupled with a large treatment effect led to increased treatment switching post-progression from the control arm to the intervention arm in the RCT as clinicians and patients demanded the new treatment. This will confound analysis of overall survival (OS) benefit in the RCT. Adjusted indirect comparison from other sources can offer a robust analysis of OS without confounding owing to treatment switching and difference in subsequent therapies post-progression.

      Recent SAT data (data cut-off, 1 November 2016) for osimertinib were provided by the AURA (NCT01802632) and AURA2 (NCT02094261) studies (N=405). Data for PDC were provided for a subgroup of the control arm of an RCT, IMPRESS (NCT01544179), which comprised patients with centrally confirmed EGFRm T790M-positive NSCLC whose prior treatment with an EGFRm TKI had failed and were subsequently treated with PDC (N=61). A propensity score (PS) approach was used to adjust for differences in baseline demographics and disease characteristics. Baseline characteristics of both groups were compared using statistical tests.

      Following estimation of PS for each patient and adjustment for heterogeneity across the groups by matching, 288 patients from the osimertinib group and 53 patients from the PDC group were retained for analysis. Osimertinib demonstrated a statistically significant improvement in median PFS of 10.9 months versus 5.3 months for PDC (HR 0.28, 95% CI 0.19 to 0.41, P<0.0001), which was consistent with the gain in PFS from the RCT AURA3 (10.1 months versus 4.4 months; HR 0.30, 95% CI 0.23 to 0.41, P<0.001), and a statistically significant improvement in OS (HR 0.41, 95% CI 0.27 to 0.62, P<0.0001). Median OS for osimertinib was not reached and was 14.1 months for PDC.

      The indirect comparison estimated a statistically significant improvement in PFS and OS with osimertinib compared with PDC. The PFS benefit was consistent with that of the confirmatory RCT. The combined evidence from RCT data and indirect comparisons described may bridge the potential gap and confounding in evidence for OS produced by subsequent treatments after first progression in the RCT.

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