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Jean-Pierre Pignon



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    MA07 - Clinical Questions and Potential Blood Markers for Immunotherapy (ID 125)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MA07.02 - Early Change of dNLR Is Correlated with Outcomes in Advanced NSCLC Patients Treated with Immunotherapy (Now Available) (ID 2676)

      13:30 - 15:00  |  Author(s): Jean-Pierre Pignon

      • Abstract
      • Presentation
      • Slides

      Background

      The [neutrophils/[leucocytes-neutrophils] ratio (dNLR) correlates with immune checkpoint inhibitors (ICI) outcomes in advanced non-small cell lung cancer (aNSCLC) patients. Significance of early dNLR change after the first course of ICI is unknown.

      Method

      Patients with NSCLC treated with ICI (PD(L)1+/-CTLA4) between Nov. 2012 and Jun. 2018 at 16 EU/US centers were included. A control group treated with chemotherapy (CT) only was also evaluated (NCT02105168). dNLR was collected at baseline (B) and at cycle 2 (C2). Patients were categorized as low vs high dNLR at each timepoint (defined as < vs > 3, as previously done), and the change between B and C2 (good = low at both timepoints, poor = high at both timepoints, mixed = different at each timepoint).

      Result

      1485 patients treated with ICI were analyzed. PDL1 was negative in 162 (11%), 1-49% in 178 (12%), ≥50% in 201 (14%), and missing in 944 (64%). dNLR at B and C2 did not associate with PD-L1 status.

      At baseline, dNLR was high in 509 (34%) patients and associated with worse PFS compared to those patients with low dNLR at baseline (HR 1.56, P<0.0001) and OS (HR 2.02, P<0.0001). At C2, dNLR was high in 484 (34%) and similarly associated with worse outcomes compared to patients with low dNLR at C2 (PFS HR 1.64, P<0.0001; OS HR 2.13, P<0.0001).

      Between B and C2, dNLR remained low in 804 (56%, « good ») or high in 327 (23%, « poor ») or changed in 310 pts (22%, « intermediate »). Those with a good dNLR demonstrated mPFS 5.3, mOS 18.6 mo), followed by those intermediate with mixed dNLR (mPFS 3, mOS 9.2 mo), and finally poor dNLR (mPFS 2, mOS 5mo). Outcomes were independant of PD-L1 expression (adjusted HR for PFS 1.94 for intermediate and 3.16 for poor groups, compared to good dNLR group, P<.001; adjusted HR for OS was 2.08 for intermediate and 3.67 for poor groups, P<0.001).A bootstrap tested the stability of OS/PFS prediction (P<0.001).

      In the chemo-cohort (n=173), high C1-dNLR (n=81, 47%) was not associated with OS (P=0.84).

      Conclusion

      dNLR at baseline, at cycle 2, and the change between these two timepoints associated with outcomes in patients treated with immunotherapy independent of PD-L1, but not in patients treated with chemotherapy alone. dNLR is specifically prognostic in the context of immunotherapy.

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    MA25 - Precision Medicine in Advanced NSCLC (ID 352)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA25.03 - Tumor-Infiltrating Lymphocytes (TIL) and Outcomes with Immunotherapy (ICI) or Chemotherapy in Advanced NSCLC (aNSCLC) Patients (Now Available) (ID 1374)

      14:30 - 16:00  |  Author(s): Jean-Pierre Pignon

      • Abstract
      • Presentation
      • Slides

      Background

      Tumor infiltrating lymphocytes (TIL) morphologically assessed is prognostic in early stages in several tumors. We previously reported the correlation of TIL with immune checkpoint inhibitors (ICI) outcomes in 98 advanced (a) NSCLC patients treated with ICI. We aimed to assess the role of TIL in a larger cohort treated with ICI, and in patients exclusively treated with chemotherapy (CT).

      Method

      aNSCLC patients with treated with single-agent ICI, with H&E stained sample available, were included between 11/2012 and 02/2017 in 3 cancer centers (immuno-cohort). Patient’s characteristics, biological data were retrospectively collected. The CT-cohort was extracted from the prospective MSN study (NCT02105168), between 06/2009 and 10/2016, enrolling aNSCLC patients treated with platinum-based CT, and tissue available. TIL in the stroma was evaluated in archival samples. High-TIL was defined as ≥10% density. Multivariate Cox model was used to study its prognostic values on overall and progression-free survival (OS, PFS).

      Result

      A total of 221 patients were included in the immuno-cohort: 142 (64%) male, with median (m) age of 63, 182 (84%) smokers, 161 (77%) PS≤1, 162 (63%) adenocarcinoma; 125 (57%) received ICI as second-line. High-TIL was observed in 49/221 (28%), non-assessable in 46. High-TIL had independent impact on OS and PFS (HR 0.40; 95% CI 0.25-0.63, P<0.0001). The mPFS and OS were 3.1months (mo.) (2.5-4.9) and 11mo. (7.0-13.2) respectively. The high-TIL group had mPFS of 13mo. (5.0-NR) vs. 2.2mo. (1.7-3.0) in low-TIL group (P<0.0001). High-TIL group had mOS not reached (NR) (12.2-NR) vs. 8.4 mo. (5.0-11.6) in low-TIL (P=0.007). The CT-cohort (N=189) had high-TIL in 103/189 (54%). The mPFS and mOS were 5.7mo. (4.9-6.7) and 11.7mo. (9.3-13.0) respectively, with no association with TIL.

      OS, Immuno-cohort (n=221) OS, Chemo-cohort (n=188)

      Hazard ratio (HR)
      95% confidence interval (CI)

      P-value

      HR
      95% CI

      P-value

      TIL
      ≥10% (high)

      0.46 (0.28-0.81) 0.006 1.03 (0.76-1.41) 0.84
      Age
      ≥65 y
      0.86 (0.50-1.46) 0.57 0.99 (0.72-1.38) 0.99
      Line of treatment*
      second line
      0.69 (0.44-1.09) 0.11 0.84 (0.60-1.16) 0.29

      N# metastatic sites
      >2

      1.40 (0.88-2.20) 0.16 1.50 (1.07-2.12) 0.02
      Performance status
      ≥2
      2.75 (1.73-4.37) <0.0001 1.94 (1.23-3.04) 0.004
      Histology
      Squamous
      1.13 (0.70-1.81) 0.62 1.09 (0.65-1.83) 0.75
      *Line of treatment: lines of immunotherapy for the Immuno-cohort; lines of chemotherapy for the Chemo-cohort.

      Conclusion

      High-TIL (≥10%) is a simple and accessible marker associated with better ICI outcomes, but not with CT. This suggests a potential predictive value that must be validated in larger prospectively studies.

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    OA12 - Profiling the Multidisciplinary Management of Stage III NSCLC (ID 144)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
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      OA12.01 - PCI for Radically Treated Non-Small Cell Lung Cancer: A Meta-Analysis Using Updated Individual Patient Data of Randomized Trials (Now Available) (ID 2624)

      15:45 - 17:15  |  Author(s): Jean-Pierre Pignon

      • Abstract
      • Presentation
      • Slides

      Background

      In localized non-small cell lung cancer (NSCLC), prophylactic cranial irradiation (PCI) reduced the incidence of brain metastases (BM) (relative risk 0.35), but without a demonstrated effect on overall survival (OS). This may be due to the small sample size in these individual randomized clinical trials (RCTs).

      Therefore, we aimed to assess the impact of PCI on long term OS for radically treated stage III NSCLC patients compared to observation using updated individual patient data (IPD) from RCTs.

      Method

      The main endpoint was OS and secondary endpoints were progression-free survival (PFS), BM-free survival (BMFS) and toxicity. All analyses were performed based on the intention-to-treat principle. The median follow-up was estimated using the inverse Kaplan-Meier method. The log-rank observed minus expected number of events and its variance were used to calculate individual and overall pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) with a fixed effects model. Heterogeneity was studied using the Cochrane test and I2. Survival curves and 5-year difference between arms were estimated using the Peto method. Interaction between prognostic factors (age, performance status, and histology) and treatment allocation were assessed using Cox proportional hazards models. Toxicities grade ≥ 3 were reported descriptively.

      Result

      Data on four of the seven eligible trials (SWOG 8300, RTOG 0214, Guangzhou 2005 and NVALT-11) were available for this IPD meta-analysis. In total, 924 patients were analyzed of which 68% was male, median age was 61 years, 94% of the patients had a performance status ≤ 1 and 37% had squamous histology. The median follow-up was 8.1 years. All trials provided sufficient IPD for the three endpoints, except for the SWOG 8300 trial (OS only). This trial explained inter-trial heterogeneity. Because of the qualitative interaction with the other trials (p=0.0062) it was separately analyzed (N=254). Compared to observation, OS was significantly lower for PCI in the SWOG 8300 trial (HR 1.38, 95% CI [1.07 to 1.79] p=0.013, 5-year absolute difference -0.9%, 95% CI [-5.9 to 4.1]). However, for the other trials (N=670) no significant OS difference was observed (HR 0.90, 95% CI [0.76 to 1.07] p=0.228, 5-year absolute difference 1.8%, 95% CI [-5.2 to 8.8]). PFS (HR 0.78, 95% CI [0.65 to 0.92] p=0.004, 5-year absolute difference 4.8%, 95% CI [-1.2 to 10.8]) and BMFS (0.38, 95% CI [0.27 to 0.53] p<0.001, 5-year absolute difference 20.7%, 95% CI [12.2 to 29.2]) were significantly higher in the PCI arm. There was no interaction between prognostic factors and treatment allocation for OS. Toxicity data for the PCI arm was available in all trials except the SWOG 8300 trial. The total number of patients with at least one grade ≥3 toxicity (for the adverse events pre-specified in the protocol) in the PCI arm was 19/456, including 11/86 in the NVALT-11 trial. Toxicity for the observation arm was only available in the NVALT-11 trial, including 4/88 patients with at least one grade ≥3 toxicity.

      Conclusion

      Although PFS and BM-free survival were improved for patients who received PCI, no significant PCI benefit for OS was observed.

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