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Paul Howarth
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OA07 - Precision Medicine Involves Biology and Patients (ID 132)
- Event: WCLC 2019
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Silvia Novello, Fabrice Barlesi
- Coordinates: 9/09/2019, 11:00 - 12:30, Copenhagen (1980)
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OA07.01 - Osimertinib Plus Platinum/Pemetrexed in Newly-Diagnosed Advanced EGFRm-Positive NSCLC; The Phase 3 FLAURA2 Study (Now Available) (ID 2383)
11:00 - 12:30 | Author(s): Paul Howarth
- Abstract
- Presentation
Background
Osimertinib is a third-generation, CNS-active EGFR-TKI that potently and selectively inhibits both sensitizing EGFR and T790M mutations. Osimertinib is considered the standard of care for patients with newly-diagnosed advanced/metastatic NSCLC harbouring EGFR-activating mutations, based on results of the phase 3 FLAURA trial, which demonstrated a statistically and clinically significant progression-free survival (PFS) benefit for osimertinib over erlotinib or gefitinib. Evidence indicates that adding chemotherapy to gefitinib improves efficacy outcomes versus EGFR TKI monotherapy in newly-diagnosed patients with EGFRm NSCLC (Nakamura et al JCO 2018;36:9005). Adding platinum/pemetrexed to osimertinib could further improve outcomes for newly-diagnosed patients with EGFRm-positive NSCLC.
Method
The phase 3, open-label, FLAURA2 study aims to assess the efficacy and safety of osimertinib plus cisplatin/carboplatin plus pemetrexed in adults with locally-advanced/metastatic EGFRm-positive (Ex19del and/or L858R) NSCLC who have not received prior therapy for advanced disease. Patients are required to have a WHO performance status (PS) 0-1, life expectancy >12 weeks and not be amenable to curative surgery or radiotherapy. An initial non-randomised run-in phase (n=30) will assess the safety and tolerability of osimertinib 80 mg once daily (QD) with either cisplatin or carboplatin, and pemetrexed, both administered every 3 weeks (Q3W) for 4 cycles, followed by osimertinib 80 mg QD plus pemetrexed maintenance Q3W until progression or discontinuation. Based on evaluation of safety data from the run-in after ≥12 patients from each group have received ≥3 cycles of study treatment or discontinued therapy, the second phase will randomise approximately 556 patients 1:1 to receive osimertinib 80 mg QD with pemetrexed and cisplatin/carboplatin for 4 cycles followed by osimertinib plus pemetrexed maintenance Q3W or osimertinib alone (80 mg QD), to be continued until progression or discontinuation. Randomisation will be stratified by race (Chinese/Asian vs. non-Chinese/Asian vs. non-Asian), WHO PS (0 vs. 1), and tissue EGFR mutation test at enrolment (cobas® EGFR Mutation Test vs local assessment). A futility analysis of the randomized phase is planned for when approximately 83 PFS events have occurred. The primary endpoint is PFS based on investigator assessment of response using RECIST 1.1 criteria (blinded central assessment is included as a sensitivity analysis). Secondary endpoints include overall survival, objective response rate, duration of response, PFS2, health-related quality of life and safety. Effects on CNS metastases in patients with lesions at baseline will be included as an exploratory endpoint. Enrolment is planned for Q3 2019 for the safety run-in and Q1 2020 for the randomized phase.
Result
Section not applicable
Conclusion
Section not applicable
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-134 - SAVANNAH: Phase II Trial of Osimertinib + Savolitinib in EGFR-Mutant, MET-Driven Advanced NSCLC, Following Prior Osimertinib (ID 2209)
09:45 - 18:00 | Author(s): Paul Howarth
- Abstract
Background
The toxicity profile of the third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) osimertinib makes it an attractive backbone for combination with other targeted agents, possibly overcoming acquired resistance mechanisms. Combination with a MET-inhibitor is an intuitive approach as MET-amplification was identified as the most common mechanism of resistance to osimertinib in preliminary ctDNA data from the Phase III FLAURA (15% of patients) and AURA3 (19% of patients) studies. Savolitinib (AZD6094, HMPL-504, volitinib) is an oral, potent and highly selective MET-TKI that had an acceptable safety profile when combined with osimertinib in the Phase Ib TATTON study, providing the basis for this Phase II SAVANNAH study (NCT03778229). Other mechanisms of acquired resistance to osimertinib, including secondary EGFR mutations (e.g. C797S), RAS/RAF activation, and oncogenic gene fusions, provide additional opportunities for developing osimertinib-based combinations.
Method
Eligible patients will have histologically or cytologically confirmed EGFR-mutant, locally advanced or metastatic non-small cell lung cancer (NSCLC), and MET-driven (MET+) disease by central fluorescence in situ hybridization (FISH), central immunohistochemistry (IHC), or local next-generation sequencing (NGS; retrospectively confirmed by central FISH/IHC). Patients must have documented radiological progression following 1–3 lines of prior therapy (must include osimertinib). Patients will receive osimertinib plus savolitinib in 28-day cycles. The primary objective is efficacy (RECIST 1.1) by overall response rate (ORR) in patients who are MET+ by central FISH. Secondary endpoints include: ORR (MET+ by central IHC and all patients); progression-free survival, overall survival, duration of response, percent change in tumor size, HRQoL, and EGFR mutation ctDNA clearance (MET+ by central FISH, central IHC, and all patients); safety, and pharmacokinetics (all patients). Based on the TATTON study, we anticipate enrolling ~172 patients with MET+ disease, to include ≥117 patients with MET+ disease by central FISH. Enrolment began in Q1 2019. Ongoing development of complementary trials targeting other osimertinib resistance mechanisms will also be discussed.
Result
Section not applicable
Conclusion
Section not applicable
