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O. Arén Frontera



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    ORAL 02 - PD1 Axis Immunotherapy 2 (ID 87)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL02.01 - Phase 3, Randomized Trial (CheckMate 017) of Nivolumab (NIVO) vs Docetaxel in Advanced Squamous (SQ) Cell Non-Small Cell Lung Cancer (NSCLC) (ID 736)

      10:45 - 12:15  |  Author(s): O. Arén Frontera

      • Abstract
      • Presentation
      • Slides

      Background:
      Treatment options for patients with advanced SQ NSCLC who fail platinum-based doublet chemotherapy (PT-DC) are limited. NIVO, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor, demonstrates activity across NSCLC histologies and is approved in the US for treatment of metastatic SQ NSCLC with progression on or after platinum-based chemotherapy. We report results from a randomized, open-label, global phase 3 study (CheckMate 017; NCT01642004) comparing NIVO vs docetaxel in patients with previously treated SQ NSCLC and disease progression during/after one prior PT-DC regimen.

      Methods:
      Patients (N=272) were randomized 1:1 to receive either NIVO 3 mg/kg every 2 weeks (Q2W; n=135) or docetaxel 75 mg/m[2] Q3W (n=137) until disease progression or discontinuation due to toxicity or other reasons. For NIVO patients, treatment after initial progression was permitted at the investigator’s discretion, per protocol criteria. The primary objective was overall survival (OS). Secondary objectives included investigator-assessed objective response rate (ORR; per RECIST v1.1), progression-free survival (PFS), efficacy by PD-L1 expression (PD-L1 testing not required for enrollment), patient-reported outcomes (PRO), and safety. PRO analyses are presented in a separate abstract.

      Results:
      Treatment with NIVO led to 41% reduction in risk of death (hazard ratio [HR]=0.59; 95% CI: 0.44, 0.79; P=0.00025) and improved ORR (20% vs 9%; P=0.0083) and PFS (HR=0.62; 95% CI: 0.47, 0.81; P=0.0004) vs docetaxel (Table). Twenty-eight patients were treated with NIVO beyond initial progression, nine of whom demonstrated a non-conventional pattern of benefit (ie, reduction in target lesions with simultaneous appearance of new lesions, initial progression followed by tumor reduction, or no further progression for ≥2 tumor assessments). Across pre-specified cut-points (1%, 5%, and 10%), PD-L1 expression was neither prognostic nor predictive of benefit. OS HRs favored NIVO across most predefined patient subgroups. Grade 3–4 drug-related adverse events (AEs) were reported in 7% (9/131) of NIVO and 55% (71/129) of docetaxel patients. Grade 3–4 drug-related select AEs are shown below (Table). No deaths were related to NIVO vs 3 docetaxel-related deaths. Figure 1



      Conclusion:
      CheckMate 017 achieved its primary objective, demonstrating clinically superior and statistically significant OS with NIVO vs docetaxel in patients with advanced, previously treated SQ NSCLC. Benefit was seen regardless of PD-L1 status. The safety profile of NIVO 3 mg/kg Q2W is favorable vs docetaxel and consistent with prior studies. AEs were manageable with established guidelines. NIVO represents a new standard of care in this patient population. Updated OS and safety data will be presented.

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    P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P3.01-057 - Randomized Phase 2 Study of Plinabulin and Docetaxel in Patients with Advanced Non-Small Cell Lung Cancer - Mechanism-Based Efficacy Analyses (ID 1505)

      09:30 - 17:00  |  Author(s): O. Arén Frontera

      • Abstract
      • Slides

      Background:
      Plinabulin (N), a tubulin binding agent, which depolarizes microtubules, resulting in tumor vasculature obliteration, apoptosis via JNK pathway and maturation of dendritic cells. A multicenter randomized phase 2 study was performed to compare overall survival (OS) between plinabulin/docetaxel (DN) and docetaxel (D). Results of Intent-to-treat (ITT) analyses have been presented at ASCO 2014. The primary objective of OS prolongation was not met, however, exploratory mechanism based analysis revealed improvement in outcomes in patients with large tumors.

      Methods:
      From November 2008 to July 2011 172 patients with advanced NSCLC who progressed after at least one chemotherapy were enrolled. Patients were treated with D 75mg/m[2] on day 1 and N 30 mg/[2] on days 1 and 8. A second cohort of N 20 mg/m[2] was also enrolled. This exploratory analysis is based on 105 patients (50 DN arm and 55 D arm) receiving 30 mg/m[2] dose, which was selected for an ongoing Phase 3 study and explains the population chosen for future investigation.

      Results:
      Median OS was 8.7 months (m) (CI 6.6-12.6) in DN arm and 7.5 m (6.3-10.5) in D arm (p=0.899, HR=0.97). PFS was 2.8 m and 3.5 m and ORR was 14.0% vs 14.5% respectively. Among clinical parameters, lesion size (Table 1) and presence of pulmonary disease were identified to impact OS. The OS in patients with pulmonary disease was 11.3 m (6.7-15.1) in DN and 6.7 m (6-9.8) in D, respectively (p=0.29, HR=0.76) regardless of lesion size. Table 1: Exploratory Analysis of Overall Survival by Tumor Size

      Patients Tumor size Median OS Months (95% CI) Hazard Ratio P-value
      DN (30mg/m[2]) D
      ITT 1 and 2 prior chemo-therapy All 8.68 (6.33, 12.63) N=50 7.47 (6.17, 10.60) N=55 0.972 0.8993
      ≤ 3 cm 6.45 (3.73, NA) N=16 6.47 (5.6, 22.43) N=19 0.934 0.8687
      > 3 cm 8.98 (6.60, 12.63) N=34 7.47 (4.77, 11.60) N=36 0.967 0.8990
      > 5 cm 8.98 (4.57, 19.23) N= 20 6.70 (4.07, 12.93) N=21 0.750 0.4176
      > 7 cm 7.32 (4.57, 19.23) N= 8 5.03 (2.93, 6.70) N= 10 0.507 0.1936
      CI = confidence interval; D = docetaxel; DN, docetaxel + plinabulin; ITT = intent-to-treat; OS = overall survival (Months).

      Conclusion:
      Mechanism-based exploratory analyses of Phase 2 results have identified advanced NSCLC patients with lung lesion size >3 cm to have benefited from plinabulin. A Phase 3 to confirm this observation is on-going.

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