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R. Hui



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    ESMO-IASLC Best Abstracts (ID 61)

    • Event: ELCC 2018
    • Type: Best Abstract session
    • Track:
    • Presentations: 1
    • Now Available
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      233O - Time to deterioration of symptoms with durvalumab in stage III, locally advanced, unresectable NSCLC: Post-hoc analysis of PACIFIC patient-reported outcomes (Now Available) (ID 703)

      17:15 - 17:30  |  Author(s): R. Hui

      • Abstract
      • Presentation
      • Slides

      Background:
      Along with improving efficacy outcomes such as progression-free survival (PFS) after concurrent chemoradiotherapy (cCRT) in locally advanced, unresectable NSCLC, it is critical that new therapies are well tolerated in the curative intent setting. We studied the impact of 12 mo of durvalumab on disease symptoms in this setting using patient-reported outcomes (PROs). In a post-hoc analysis of time to deterioration, we adjusted for transient symptom changes by requiring two consecutive deterioration recordings.

      Methods:
      Patients whose disease did not progress after ≥2 cycles of platinum-based cCRT were randomised 2:1 1–42 days post-cCRT to durvalumab 10 mg/kg i.v. or placebo every 2 weeks for up to 12 mo/progression. Co-primary endpoints were PFS and overall survival. PROs were assessed using EORTC QLQ-C30 v3 and QLQ-LC13. Time to deterioration was defined as time from randomisation until the first clinically relevant deterioration (≥10 point change); in the post-hoc analysis, deterioration confirmation was required at the next time point. Hazard ratios (HR) and 95% confidence intervals (CIs) were estimated using a stratified Cox proportional-hazards model.

      Results:
      In the pre-specified analysis, there was no difference between treatment arms in time to deterioration besides other pain, which favoured durvalumab vs placebo (HR 0.72; 95% CI 0.58–0.89). Our post-hoc analysis indicated notable delays in deterioration of overall pain (HR 0.75; 95% CI 0.60–0.93), chest pain (HR 0.74; 95% CI 0.57–0.97), arm/shoulder pain (HR 0.74; 95% CI 0.58–0.95), nausea/vomiting (HR 0.72; 95% CI 0.54–0.97), insomnia (HR 0.75; 95% CI 0.58–0.97) and haemoptysis (HR 0.70; 95% CI 0.50–0.99) in favour of durvalumab, with no between-group differences for other items.

      Conclusions:
      PACIFIC primary analysis showed that durvalumab significantly improved PFS vs placebo (16.8 mo vs 5.6 mo, respectively) in the post-cCRT setting, and was well tolerated, largely without PRO deterioration. Our post-hoc analysis indicates a delay in several PROs with durvalumab not observed in the pre-specified analysis. Confirmation of worsening may provide a more precise picture of deterioration than one time point alone.

      Clinical trial identification:
      NCT02125461 (April 25, 2014)

      Legal entity responsible for the study:
      AstraZeneca PLC

      Funding:
      AstraZeneca

      Disclosure:
      R. Hui: Personal fees from the following: AstraZeneca, Merck Sharp and Dohme: Advisory Board Member and Speaker Honorarium; Novartis, Pfizer: Advisory Board Member; BMS, Boehringer Ingelheim: Speaker Honorarium. A. Villegas: Celgene, Alexion, BMS: Speaker's Bureau. A. Ryden, Y. Zhang, P. Dennis: AstraZeneca: full-time employment and stock ownership. S. Antonia: Moffitt Cancer Center: Full-time employment, Grants/research support; Novartis: Grants/research support, Advisory board, Honorarium recipient; BMS, Merck, Boehringer Ingelheim, AstraZeneca, Memgen: Advisory board, Honorarium recipient; CBMG: Advisory board, Stock/shareholder, Honorarium recipient. All other authors have declared no conflicts of interest.

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    Poster Display session (Friday) (ID 65)

    • Event: ELCC 2018
    • Type: Poster Display session
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 4/13/2018, 12:30 - 13:00, Hall 1
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      188P - Treatment switching–adjusted overall survival (OS) in KEYNOTE-024: First-line pembrolizumab versus chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) (ID 622)

      12:50 - 12:50  |  Author(s): R. Hui

      • Abstract

      Background:
      In KEYNOTE-024, pembrolizumab was superior to chemotherapy for advanced untreated NSCLC with PD-L1 tumor proportion score (TPS) ≥50% and no sensitizing EGFR mutations/ALK translocations. We present OS adjusted for the potential bias introduced by switching treatment from chemotherapy to pembrolizumab after a median of 25.2 months of follow-up.

      Methods:
      Patients were randomized to pembrolizumab 200 mg every 3 weeks or investigator-choice platinum-doublet chemotherapy with optional pemetrexed maintenance for patients with nonsquamous histology. Patients in the chemotherapy arm could switch to pembrolizumab (prior to the second interim analysis that revealed superiority, only patients with progressive disease confirmed by blinded, independent central radiology review were eligible). Three statistical methods were applied to adjust for treatment switching: the simplified 2-stage method, the rank preserving structural failure time (RPSFT) method, and the inverse probability of censoring weighting (IPCW) method.

      Results:
      305 patients were randomized; all but 1 patient in the chemotherapy arm received protocol-specified treatment. 82 (54%) patients had switched from chemotherapy to pembrolizumab per protocol. OS results per the intent-to-treat (ITT) analysis and the 3 adjustment methods are listed in the Table. The 3 methods adjusting for treatment switching in the chemotherapy arm provided larger treatment estimates (lower HRs) than the ITT estimate. As there was some evidence towards a deviation from the common treatment effect assumed in the RPSFT method, and the IPCW method is more prone to bias in the presence of relatively small sample sizes, the simplified 2-stage method was the favored method in this study. Results obtained with the RPSFT and IPCW methods were consistent with those from the 2-stage analyses.Table: (Abstract: 188P)Treatment switching–adjusted OS in KEYNOTE-024 after median follow-up of 25.2 months

      Median OS, months (95% CI)Pembrolizumab(n = 154)Chemotherapy(n = 151)HR (95% CI)
      ITT analysis30.0 (18.3–not reached)14.2 (9.8–19.0)0.63 (0.47–0.86) 2-sided log-rank P = 0.003
      2-stage methodN/A8.7 (7.3–11.5)0.49 (0.34–0.69)
      RPSFT methodN/A11.8 (8.7–not reached)0.52 (0.33–0.75)
      IPCW methodN/A11.8 (8.7–21.3)0.52 (0.33–0.80)


      Conclusions:
      In this study, pembrolizumab demonstrated an OS advantage compared to chemotherapy as first-line therapy, which becomes more pronounced when utilizing treatment switching analyses that adjust for bias introduced when switching from chemotherapy to pembrolizumab. Pembrolizumab remains a standard-of-care first-line therapy for patients with advanced NSCLC expressing PD-L1 TPS ≥50%.

      Clinical trial identification:
      NCT02142738

      Legal entity responsible for the study:
      Merck & Co., Inc., Kenilworth, NJ, USA

      Funding:
      This study and medical writing assistance were funded by Merck & Co., Inc., Kenilworth, NJ, USA.

      Disclosure:
      M. Reck: Advisory board member for Roche, Lilly, AstraZeneca, BMS, MSD, Merck, Boehringer-Ingelheim, Celgene, Pfizer, and Novartis; Speakers’ bureaus for Roche, Lilly, AstraZeneca, BMS, MSD, Merck, Boehringer-Ingelheim, Celgene, Pfizer, and Novartis; Research funding from Boehringer-Ingelheim. A.G. Robinson: Honoraria from Merck & Co., Inc., Kenilworth, NJ; his institution has received research funding from AstraZeneca, Merck & Co., Inc. (Kenilworth, NJ USA), Bristol-Myers Squibb, and Roche Canada. R. Hui: Honoraria from MSD, BMS, AstraZeneca, Boehringer-Ingelheim, and Pfizer; Consulting or Advisory role for MSD, AstraZeneca, Pfizer, and Novartis. K. Vandormael: Employee of MSD Europe. W. Malbecq: Employee of and owns stock in MSD Europe. M.C. Pietanza: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA. J. Brahmer: Advisory board member for BMS (uncompensated), Celgene, Eli Lilly, Merck; Research funding from BMS, MedImmune/AstraZeneca, Merck. All other authors have declared no conflicts of interest.

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      193TiP - Phase 3 study of epacadostat plus pembrolizumab with or without platinum-based chemotherapy vs pembrolizumab plus chemotherapy for first-line metastatic non-small cell lung cancer (mNSCLC): ECHO-306/KEYNOTE-715 (ID 415)

      12:50 - 12:50  |  Author(s): R. Hui

      • Abstract

      Background:
      Combination therapies targeting broad immunosuppression in the tumor microenvironment (TME) may prolong survival. Upregulation of the indoleamine 2,3 dioxygenase-1 (IDO1) enzyme within TME contributes to an immunosuppressive state responsible for tumor escape from immune surveillance. Epacadostat (E), a potent and selective inhibitor of IDO1, is under investigation in several tumor types. Pembrolizumab (P) is FDA-approved for NSCLC. In a phase 1/2 study, E + P showed minimal additive toxicity vs monotherapy and encouraging efficacy in NSCLC. The ECHO-306/KEYNOTE-715 global study compares the efficacy and safety of first-line E + P±chemotherapy vs P + chemotherapy in patients with mNSCLC.

      Trial design:
      Eligible patients: age ≥18, stage IV NSCLC (no EGFR-sensitizing mutation and ROS1/ALK translocations), ECOG PS ≤1, no prior systemic therapy for mNSCLC, and no prior IDO1 inhibitors or immune checkpoint therapies. Patients (∼1062) will be randomized 1:1:1 (E 100 mg oral BID + P 200 mg IV Q3W±platinum-based chemotherapy [nonsquamous: pemetrexed 500 mg/m[2] + cisplatin 75 mg/m[2] or carboplatin AUC 5 Q3W for 4 cycles followed by pemetrexed 500 mg/m[2] Q3W; squamous: paclitaxel 175–200 mg/m[2] + carboplatin AUC 5–6 Q3W for 4 cycles]; or E-matched placebo + P + chemotherapy) and stratified by tumor histology (squamous vs nonsquamous), PD-L1 status (tumor proportion score <50% vs ≥50%), ECOG PS (0 vs 1), and region (East Asia vs non-East Asia). Patients will receive treatment for ≤35 cycles of P or until disease progression (PD), intolerable toxicity, or investigator/patient decision to withdraw. Treatment may continue after initial radiographic PD in eligible patients. Patients may discontinue treatment after confirmed complete response. Primary endpoints: OS and PFS. Secondary endpoints: ORR per RECIST v1.1 (blinded central review; weeks 6, 12, 18, Q9W up to week 54 and Q12W thereafter), safety and tolerability, and E pharmacokinetics. Adverse events (AEs) will be monitored throughout the study and for 30 days (90 days for serious AEs) after end of treatment and graded per CTCAE v4.0.

      Clinical trial identification:
      NCT03322566

      Legal entity responsible for the study:
      Incyte Corporation, Wilmington, DE, USA and Merck & Co., Inc., Kenilworth, NJ, USA

      Funding:
      Incyte Corporation, Wilmington, DE, USA and Merck & Co., Inc., Kenilworth, NJ, USA

      Disclosure:
      M. Garassino: Received research funding from AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Lilly (Inst), Merck Sharp & Dohme (Inst), and Roche (Inst), and received travel/accommodations/expenses from AstraZeneca, Bristol-Myers Squibb, and Roche. S. Rubin, Y. Zhao: Employee and stockholder of Incyte. Y. Luo, A. Samkari: Employee and stockholder of Merck. R. Hui: Advisory board member for Merck Sharp and Dohme, AstraZeneca, Novartis, Roche, and Bristol-Myers Squibb. Received speaker honorarium from Merck Sharp and Dohme.