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Miriam Alonso Garcia



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    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
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      OA14.04 - Five-Year Outcomes From the Randomized, Phase 3 Trials CheckMate 017/057: Nivolumab vs Docetaxel in Previously Treated NSCLC (ID 894)

      11:30 - 13:00  |  Author(s): Miriam Alonso Garcia

      • Abstract
      • Slides

      Background

      Historically, outcomes for advanced non-small cell lung cancer (NSCLC) have been poor, with 5-year survival rates < 5% with conventional chemotherapy. Nivolumab, a programmed death-1 (PD-1) inhibitor, was approved in 2015 for patients with previously treated advanced NSCLC based on two randomized phase 3 trials, CheckMate 017 (NCT01642004; squamous) and CheckMate 057 (NCT01673867; non-squamous), which demonstrated improved overall survival (OS) vs docetaxel. We report 5-year pooled efficacy and safety from these trials, representing the longest survival follow-up for randomized phase 3 trials of an immune checkpoint inhibitor in advanced NSCLC.

      Method

      Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG performance status (PS) ≤ 1, and progression during or after first-line platinum-based chemotherapy, were randomized 1:1 to nivolumab 3 mg/kg Q2W or docetaxel 75 mg/m2 Q3W until progression or unacceptable toxicity. After completion of the primary analyses, patients in the docetaxel arm no longer receiving benefit could cross over to receive nivolumab. OS was the primary endpoint for both studies.

      Result

      At 5-year follow-up, 50 nivolumab patients and 9 docetaxel patients were alive. Baseline characteristics of 5-year survivors in both arms were similar to the overall population and patients who survived < 1 year, except for a higher percentage of patients with ECOG PS 0 or tumor programmed death ligand-1 (PD-L1) expression ≥ 1% on nivolumab and ECOG PS 0 and Stage IIIB NSCLC on docetaxel. Nivolumab continued to show long-term OS and progression-free survival (PFS) benefit vs docetaxel with 5-year OS rates 13% vs 3% (HR, 0.68 [95% CI, 0.59–0.78]) and PFS rates 8% vs 0% (0.79 [0.68–0.92]). OS benefit with nivolumab vs docetaxel was observed across subgroups including patients with tumor PD-L1 expression < 1%, baseline liver and adrenal metastases, neutrophil-to-lymphocyte ratio < median, lactate dehydrogenase ≥ upper limit of normal or no baseline proton-pump inhibitor use. Among patients with an objective response to nivolumab (20%) or docetaxel (11%), 32% remained in response at 5 years vs none on docetaxel, with a median duration of response of 19.9 vs 5.6 months, respectively. Of the 5-year nivolumab vs docetaxel survivors, 36% vs 0% were on study drug, 20% vs 67% received subsequent immunotherapy (on or off study), and 10% vs 0% were off study drug, progression free, with no subsequent therapy. No new safety signals were observed with longer follow-up. Between 3 and 5 years’ follow-up, 8 of the 31 (26%) nivolumab-treated patients reported a treatment-related adverse event, 1 (3%) grade 3–4. The most common select adverse events (events with a potential immunological cause) were related to skin, in 4 (13%) patients, none of which were grade 3–4.

      Conclusion

      CheckMate 017 and 057 are the first phase 3 trials to report 5-year outcomes for a PD-1 inhibitor in previously treated advanced NSCLC, demonstrating a greater than 4-fold increase in 5-year OS rates with nivolumab (13%) over docetaxel (3%). Nivolumab remained well tolerated with no new safety signals.

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    P1.18 - Treatment of Locoregional Disease - NSCLC (ID 190)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.18-01 - RELAY EU/US Subset: Ramucirumab Plus Erlotinib Improves Progression-Free Survival in First-Line EGFR Mutation-Positive NSCLC (Now Available) (ID 356)

      09:45 - 18:00  |  Author(s): Miriam Alonso Garcia

      • Abstract
      • Slides

      Background

      Dual blockade of EGFR and VEGFR pathways in EGFR mutation-positive NSCLC augments anti-tumor efficacy versus EGFR inhibition alone. The RELAY (NCT02411448) phase 3 study demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for erlotinib plus ramucirumab versus erlotinib plus placebo in patients with previously untreated EGFR mutation-positive metastatic NSCLC (median PFS 19.4 vs 12.4mo, HR 0.591 (95% CI 0.461–0.760), p<0.0001). Here we report efficacy and safety data of the EU/US subset.

      Method

      Eligible patients (untreated, metastatic NSCLC with an EGFR exon 19 deletion or exon 21 (L858R) substitution mutation and no CNS metastasis) were randomized (1:1) to receive 150 mg daily oral erlotinib plus 10 mg/kg intravenous ramucirumab (RAM+ERL) or placebo (PL+ERL) Q2W until progressive disease or unacceptable toxicity. Patients were stratified by geographic region (East Asia vs ‘other’, i.e. EU/US). Primary endpoint was investigator-assessed PFS. Other key objectives included safety, ORR, DoR, PFS2, and OS.

      Result

      In the EU/US, 113 (25.2%) of 449 total patients (58 RAM+ERL, 55 PL+ERL) were randomized between Feb 2016-Feb 2018. Baseline characteristics were balanced between treatment arms: ~60% female, ~52% never-smokers and ~66% Ex19del. RAM+ERL improved PFS and had a longer DoR (Table). PFS2 and OS data were immature. Grade≥3 TEAEs occurring in >5% of patients included (RAM+ERL vs PL+ERL): hypertension (29.8% vs 7.3%), diarrhea (12.3% vs 1.8%), AST increased (7.0% vs 3.6%), ALT increased (7.0% vs 1.8%), dermatitis acneiform (5.3% vs 9.1%), fatigue (5.3% vs 0%), and rash (0% vs 5.5%).

      Abbreviations: CI=confidence interval; DoR=duration of response; ERL=erlotinib; HR=hazard ratio; N=total population; n=total responders; NR=no response; ORR=overall response rate; OS=overall survival; PFS=progression-free survival; PL=placebo; RAM=ramucirumab
      RAM + ERL (N=58) PL + ERL (N=55) Unstratified HR (95% CI) p-value
      PFS
      Median, months (95% CI) 20.6 (14.7-26.0)
      10.9 (8.3-19.4)
      0.605 (0.362-1.010) 0.0523

      Censoring rate

      52% 38%

      ORR, % (95% CI)

      74.1 (62.9-85.4) 76.4 (65.1-87.6) NA 0.8319
      DoR, for responders only n=43 n=42
      Median, months (95% CI) 18.0 (12.7-22.0) 10.0 (7.1-17.7) 0.527 (0.296-0.939) 0.0274

      Censoring rate

      54% 33%
      PFS2
      Median, months (95% CI) NR NR 0.632 (0.304-1.313) 0.2143
      Censoring rate 79% 67%
      OS
      Median, months (95% CI) NR NR 1.096 (0.465-2.582) 0.8344
      Censoring rate 81% 82%

      Conclusion

      The EU/US subset analysis was consistent with the full ITT population where RAM+ERL demonstrated a statistically significant improvement in PFS over PL+ERL. Efficacy and tolerability were similar to that of the overall RELAY study population. Ramucirumab is an effective and safe addition to standard-of-care EGFR-TKI for treating EGFR mutation-positive metastatic NSCLC.

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