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H. Mann
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MA 12 - Circumventing EGFR Resistance (ID 665)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Wan Ling Tan, Nobuyuki Yamamoto
- Coordinates: 10/17/2017, 11:00 - 12:30, F205 + F206 (Annex Hall)
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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)
11:40 - 11:45 | Author(s): H. Mann
- Abstract
- Presentation
Background:
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.
Method:
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.
Result:
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.
Conclusion:
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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P2.04 - Clinical Design, Statistics and Clinical Trials (ID 705)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.04-006 - ADAURA: PhIII, Double-Blind, Randomized Study of Osimertinib vs Placebo in EGFR Mutation-Positive NSCLC Post-Tumor Resection (ID 8989)
09:30 - 09:30 | Author(s): H. Mann
- Abstract
Background:
EGFR-TKIs are standard first-line therapy in patients with EGFR sensitizing mutation (EGFRm)-positive advanced NSCLC. EGFR T790M resistance mutation is observed in >50% of patients with acquired resistance to EGFR-TKIs. Osimertinib is a third-generation, irreversible, CNS-active EGFR-TKI selective for EGFRm and T790M, recommended in patients with T790M-positive advanced NSCLC who have progressed on first-line EGFR-TKIs. In a recent study (NCT01405079), gefitinib treatment in patients with resected EGFRm-positive NSCLC significantly increased disease-free survival (DFS) vs vinorelbine+cisplatin: median 28.7 vs 18.0 months (hazard ratio 0.60 (95% CI 0.42–0.87), p=0.005), warranting further investigation of EGFR-TKIs in this setting (Wu et al, J Clin Oncol 2017;35:suppl;abs8500). Osimertinib may prolong DFS in adjuvant EGFRm-positive NSCLC.
Method:
Trial Design ADAURA (NCT02511106) is a global, Phase III, double-blind, randomized study, assessing efficacy and safety of osimertinib vs placebo in patients with stage IB–IIIA non-squamous EGFRm-positive NSCLC with complete tumor resection. Approximately 700 patients from 210 sites will be randomized. A planned 60% of patients will be recruited from Asia, 40% from non-Asian countries; 70% stage II–IIIA, 30% stage IB. Patients must be adults ≥18 years (Japan/Taiwan: ≥20) with primary NSCLC staged post-operatively as IB/II/IIIA, and central confirmation of Ex19del or L858R (alone or combined with other EGFR mutations including T790M). Complete surgical resection of the primary NSCLC is mandatory; patients will have baseline CT scans within 28 days prior to treatment confirming radiographic absence of residual disease. Complete surgical recovery is required for randomization; treatment to start at least 4 weeks following surgery. Patients who have received radiation therapy, pre-operative chemotherapy, prior anticancer therapy or neoadjuvant/adjuvant EGFR-TKI treatment are exempt. Standard post-operative adjuvant chemotherapy, consisting of a platinum-based doublet for 4 cycles maximum, is allowed; no more than 10 and 26 weeks may have elapsed between surgery and randomization for patients who have not or have received adjuvant chemotherapy, respectively. Patients will be randomized 1:1 to once-daily osimertinib 80 mg or placebo and stratified by stage (IB/II/IIIA), mutation type (Ex19Del/L858R) and race (Asian/non-Asian). Treatment may continue for 3 years in absence of discontinuation criteria including disease recurrence. Primary objective is to assess the efficacy of osimertinib vs placebo, measured by investigator-assessed DFS. Secondary objectives include assessment of the safety profile of osimertinib vs placebo; DFS rate at 2, 3, 5 years; overall survival (OS); 5-year OS rate; health-related quality of life; pharmacokinetics. Estimated primary completion date (final DFS data collection date): July 2021.
Result:
Section not applicable.
Conclusion:
Section not applicable.
