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Matilde Saggese



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    MA15 - Colliding Approaches - EGFR and Immunotherapy (ID 916)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 107
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      MA15.03 - PD-L1 Expression in Untreated EGFRm Advanced NSCLC and Response to Osimertinib and SoC EGFR-TKIs in the FLAURA Trial (ID 12989)

      13:40 - 13:45  |  Author(s): Matilde Saggese

      • Abstract
      • Presentation
      • Slides

      Background

      In the Phase III FLAURA trial (NCT02296125), osimertinib significantly improved PFS relative to SoC EGFR-TKIs (gefitinib/erlotinib) in patients with untreated Ex19del/L858R positive (EGFRm) NSCLC. EGFRm NSCLC tumors can exhibit high PD-L1 expression, an important biomarker for immunotherapy treatment decisions. The frequency and clinical relevance of exhibiting both biomarkers prior to treatment are unclear. We report PD-L1 expression in patients with EGFRm advanced NSCLC and association with clinical outcomes following EGFR-TKI treatment.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Tissue samples from 994 patients with advanced NSCLC were screened for EGFR Ex19del/L858R mutations for enrolment in FLAURA; 556 were randomized to treatment. 197 tissue-blocks from the screened population (including EGFR mutation-positive and -negative samples) were tested for PD-L1 using the SP263 (Ventana) immunohistochemical assay; positive tumour cell (TC) staining PD-L1 TC≥25% and TC≥1% thresholds were applied. PFS was investigator-assessed, per RECIST 1.1, according to PD-L1-expressers (TC≥1%) or -negatives (TC<1%) in randomized patients.

      4c3880bb027f159e801041b1021e88e8 Result

      193/197 blocks had sufficient tumor tissue for staining. 65/193 patients were EGFR mutation-negative. 128/193 patients were EGFR mutation-positive: 106/128 were randomized to treatment (osimertinib: 54; SoC: 52). The table presents PD-L1 expression according to EGFR mutation status. For PD-L1-expressers (TC≥1%), median PFS was 18.4 months for osimertinib and 6.9 months for SoC (HR 0.30 [95% CI 0.15, 0.60]). For PD-L1-negative patients (TC<1%), median PFS was 18.9 months for osimertinib and 10.9 months for SoC (HR 0.37 [95% CI 0.17, 0.74]).

      PD-L1 TC≥1%, n (%)

      PD-L1 TC≥25%, n (%)

      EGFR mutation-negative (n=65)

      Screened population (n=65)

      44 (68)

      23 (35)

      EGFR mutation-positive (n=128)

      Screened population (n=128)

      65 (51)

      10 (8)

      Randomized to treatment (n=106)

      52 (49)

      8 (8)

      Randomized to osimertinib (n=54)

      28 (52)

      3 (6)

      Randomized to SoC EGFR-TKI (n=52)

      24 (46)

      5 (10)

      8eea62084ca7e541d918e823422bd82e Conclusion

      There was PFS benefit with osimertinib versus SoC regardless of whether tumors were PD-L1-expressers (TC≥1%) or -negatives (TC<1%). Using the TC≥25% threshold, PD-L1 prevalence was lower in EGFR mutation-positive than mutation-negative samples; there were insufficient patients with TC≥25% tumors for PFS assessment.

      These results support the efficacy of EGFR-TKIs, including osimertinib, as first-line treatment of EGFRm advanced NSCLC, irrespective of PD-L1 expression.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-112 - Osimertinib vs Standard of Care (SoC) EGFR-TKI as First-Line Treatment in Chinese Patients With EGFRm Advanced NSCLC (ID 12211)

      16:45 - 18:00  |  Author(s): Matilde Saggese

      • Abstract
      • Slides

      Background

      Osimertinib is an irreversible, central nervous system (CNS) active EGFR-TKI, selective for both EGFRm and T790M resistance mutations. FLAURA (NCT02296125) is a PhIII, double-blind, randomized study assessing efficacy and safety of osimertinib vs SoC EGFR-TKI (erlotinib/gefitinib) in first-line patients with EGFRm advanced NSCLC. FLAURA results (556 patients, globally) are published. We present the China cohort results.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The cohort included self-identified Chinese patients, enrolled in China. Eligible patients: ≥18 years, Ex19del/L858R EGFRm advanced NSCLC, no prior EGFR-TKI/systemic anti-cancer therapy for advanced disease. Neurologically stable patients with CNS metastases were allowed, if definitive treatment/corticosteroids were completed ≥2 weeks before enrolment. Patients were randomized 1:1 to osimertinib 80 mg once daily (qd) orally or SoC EGFR-TKI (gefitinib 250 mg qd orally selected by all Chinese sites), stratified by mutation status (Ex19del/L858R). Primary endpoint: progression-free survival (PFS) by RECIST v1.1, per investigator. Data cutoff: 10/01/2018.

      4c3880bb027f159e801041b1021e88e8 Result

      Overall, 136 patients were randomized (osimertinib n=71; SoC n=65); 19 were also included in the global analysis. Baseline characteristics were balanced across arms (osimertinib/SoC): female 61/71%; smoking history 25/23%; WHO performance status 1 90/80%; Ex19del 51/51%, L858R 49/49%; CNS metastases 24/32%.

      Efficacy endpoint Osimertinib
      n=71
      SoC
      n=65

      PFS events, total patients
      (% maturity)

      40
      (56%)
      51
      (78%)
      PFS hazard ratio (HR)*
      (95% CI)
      0.56 (0.37, 0.85); p=0.007
      Median PFS, months
      (95% CI)
      17.8
      (13.6, 20.7)
      9.8
      (8.3, 13.8)
      Objective response rate (ORR),
      % (95% CI)
      83%
      (72, 91)
      75%
      (63, 85)

      Median duration of response (DoR), months
      (95% CI)

      16.4
      (12.3, NC)
      10.9
      (8.3, 13.8)
      *A hazard ratio <1 favours osimertinib.

      PFS benefit was observed across all subgroups, irrespective of EGFR mutation status and including patients with/without CNS metastases at study entry. Median total treatment duration: osimertinib, 18.9 months; SoC, 13.6 months. No new safety signals were reported. Numerical increase in grade ≥3 AEs was reported in the osimertinib arm (49%) versus SoC arm (23%). Most grade ≥3 AEs in the osimertinib arm were investigator-reported laboratory and disease-related AEs; incidence of non-laboratory-related events was low. AEs leading to discontinuation: osimertinib, 13%; SoC, 6%. In the osimertinib arm, most AEs leading to discontinuation were fatal disease-related events.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Osimertinib improved PFS vs SoC EGFR-TKI (HR: 0.56) as first-line treatment in Chinese patients with EGFRm advanced NSCLC, consistent with the global analysis.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-88 - Osimertinib Maintenance After Definitive Chemoradiation in Patients with Unresectable EGFRm-Positive Stage III NSCLC (LAURA) (ID 13684)

      16:45 - 18:00  |  Author(s): Matilde Saggese

      • Abstract
      • Slides

      Background

      The standard of care for patients with stage III unresectable NSCLC is definitive platinum-based chemoradiation, regardless of epidermal growth factor receptor mutation (EGFRm) status. There is evidence that following chemoradiation, patients with EGFRm-positive NSCLC have superior local control but inferior distant control, including an increased incidence of CNS metastases, compared with patients with EGFR wild type (EGFRwt)-NSCLC. This supports the rationale for evaluation of EGFR tyrosine kinase inhibitor (TKI) maintenance in EGFRm-positive patients without disease progression following chemoradiation. Osimertinib is a third-generation, CNS-active EGFR-TKI that potently and selectively inhibits both sensitizing EGFR and T790M mutations. It has shown superior progression-free survival (PFS) vs. standard EGFR-TKIs in first-line treatment of patients with EGFRm-positive advanced NSCLC, including patients with or without CNS metastases at trial entry.1 These data further support the rationale for evaluation of osimertinib in the even earlier disease setting of EGFR-TKI-naïve stage III NSCLC following definitive chemoradiation where it has the potential to prevent/delay progression, including in the CNS, and improve survival compared with chemoradiation alone.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      LAURA is a double-blind, randomized, placebo-controlled, multicenter, phase 3 study designed to assess efficacy and safety of osimertinib as maintenance therapy in patients with locally advanced, unresectable, EGFRm-positive, stage III NSCLC without disease progression following definitive platinum-based chemoradiation therapy. All patients will have tumors bearing exon 19 deletion or L858R mutation (centrally or locally confirmed by cobas®EGFR Mutation Test v2), age >18 years, and a WHO performance status of 0-1. Patients will have received prior concurrent (CCRT) or sequential (SCRT) chemoradiation treatment (including ≥2 cycles of platinum-based chemotherapy and radiation of 60 Gy ±10% [54-66 Gy]). Key exclusion criteria include a history of interstitial lung disease, symptomatic pneumonitis following chemoradiation, other unresolved toxicity >Grade 2, cardiac abnormalities, and inadequate organ function. Approximately 200 patients will be randomized 2:1 to osimertinib 80 mg oral once daily or placebo, within 6 weeks of completion of chemoradiation, until disease progression. Stratification factors are prior chemoradiation strategy (CCRT vs SCRT), tumor stage (IIIA vs IIIB/IIIC), and China vs non-China. The primary endpoint is RECIST 1.1 assessed PFS based on blinded independent central review (BICR). Key secondary endpoints include time to CNS PFS, overall survival, objective response rate, disease-related symptoms and health-related QoL, safety and tolerability, and pharmacokinetics. Study enrollment will commence from July 2018.

      1Soria et al N Engl J Med 2018; 378:113-125

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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