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Edouard Auclin



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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: 2
    • Now Available
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      MA07.01 - Circulating Immature Neutrophils, Tumor-Associated Neutrophils and dNLR for Identification of Fast Progressors to Immunotherapy in NSCLC (Now Available) (ID 1618)

      13:30 - 15:00  |  Author(s): Edouard Auclin

      • Abstract
      • Presentation
      • Slides

      Background

      Neutrophils are active regulators of the antitumor immune response, with pro- and antitumor- properties, but generally are associated with progression (PD) and poor outcomes. We reported that pretreatment dNLR ((neutrophils/[leucocytes-neutrophils]; high>3) correlated with immune checkpoint inhibitor (ICI) outcomes in advanced (a) NSCLC pts. Although neutrophil population is heterogeneous, the immature neutrophils (i.e. CD15+CD244-CD16low, among others) seem to be a key subpopulation linked to PD. Tumor-associated neutrophils (TAN) can be also modulator on the microenvironment. We aimed to assess the role of pretreatment circulating immature-neutrophils and tissue-TAN, combined with dNLR, on ICI outcomes in aNSCLC pts.

      Method

      aNSCLC pts treated with ICI at our institution between 11/2012 and 08/2018 were eligible. Pretreatment immunophenotyping of monocytes, monocytic MDSC (mMDSC) and granulocytes (CD15, CD11b, CD33, CD244, CD16, CD14, CD32, CD64, HLA-DR) was prospectively performed by flow cytometry in fresh whole blood in 58 pts; we defined immature-neutrophils as CD15+CD244-CD16low. TAN in the stroma were assessed using H&E staining from archival specimen, available from 80 pts. dNLR was retrospectively collected; available from 343 pts. Correlation between baseline circulating neutrophils phenotype, TAN and dNLR was evaluated as well as their impact on outcomes: progression-free survival (PFS), overall (OS), including death before 12 weeks (12wk-death) (fast-PD)

      Result

      366 pts included; 320 (90%) smokers, median age 63; 280 (77%) nonsquamous, 117 (64%) ≥1%PDL1 and 183 missing. Median PFS (mPFS) was 1.93 months (m) [95%CI, 1.8-2.3] and mOS 8.8m [6.5-11.6]. Overall, 12wk-death rate was 31% [25.9-35.6].

      Pretreatment high-dNLR (143/343; 42%) was correlated with poor PFS (P=0.002), OS P=0.0003) and a 12wk-death rate of 43% [34.5-50.9]. Pretreatment high immature-neutrophils (30/58; 53%), defined by logrank maximization method (>0.22%), were also associated with poor PFS (P=0.04), OS (P=0.0007) and a 12wk-death rate of 48.7% [26.7-64.1]. TAN (9/80; 11%) were not correlated with outcomes. There was not a correlation between immature-neutrophils, tissue-TAN and dNLR.

      When evaluating pretreatment immature-neutrophils and dNLR together, we identified a fast-PD phenotype (high immature-neutrophils/high-dNLR, 10/58; 17%), with a mOS of 1.3m [0.73- not reached (NR)] and 12wk-death rate of 60% [14.5-81.3] compared to a responder-phenotype (low immature-neutrophils/low-dNLR, 12/58; 21%), associated with good outcomes: mOS NR [18.23-NR] (P=0.002).

      Conclusion

      Pretreatment high circulating immature-neutrophils (CD15+CD244-CD16low) correlate with early failure to ICI and fast-PD phenotype. The combination of circulating immature-neutrophils and dNLR could improve the identification of this population. The impact of immature-neutrophils on ICI should be more deeply explored.

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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): Edouard Auclin

      • 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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    MA21 - Non EGFR/MET Targeted Therapies (ID 153)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA21.09 - Tyrosine Kinase Inhibitors' Plasma Concentration and Oncogene-Addicted Advanced Non-Small Lung Cancer (aNSCLC) Resistance (Now Available) (ID 830)

      14:30 - 16:00  |  Author(s): Edouard Auclin

      • Abstract
      • Presentation
      • Slides

      Background

      The development of TKIs against driver molecular alteration has changed treatment paradigm in aNSCLC patients (pts). All tumors eventually progress and a resistance mechanism is identified in only a fraction of pts. Plasma concentration of TKI can decrease after chronic exposition but limited data are available. Our hypothesis is that an insufficient plasma exposure could contribute to tumor progression (PD).

      Method

      We assessed the plasma concentration of TKI in pts with aNSCLC harboring ALK rearrangement, EGFR or BRAF V600E mutation. We defined chronic exposure as a treatment administered > 3 months. Patients’ characteristics and co-medications were collected. Residual plasma concentrations were measured using Ultra Performance Liquid Chromatography coupled with tandem mass spectrometry validated methods. We compared results to currently recommended therapeutic targets and correlated exposure levels to treatment benefit.

      Result

      Between Apr. 2014 and Feb. 2019, 51 samples were prospectively collected (gefitinib n=11, osimertinib n=10, erlotinib n=13, crizotinib n=7, dabrafenib + trametinib n=5) in 41 pts. Median time of exposure was 20.3 months (range 2.18 - 67.813). Low plasma concentration was observed in 31 (61%) samples. Out of 14 samples collected in pts with ongoing benefit, 10 (71%) had low plasma exposure. Smoking status was associated with low plasma TKI concentration (P=0.01) whatever the TKI used. A total of 37 samples were collected at PD, 21 (57%) had low plasma exposure. The median time to treatment failure (TTF) in the ‘low exposure group' (n=31) was 14.9 months (95% CI 12.48 – 33.2) vs. 24.6 months (95% CI 8.65 -not reached (NR) in the ‘normal exposure group’ (P=0.55). No significant impact of protons pump inhibitors on TTF was found (p=0.12), including with gefitinib and erlotinib (p=0.76; n=24). In case of isolated brain PD (n=4), 3 pts (75%) had low plasma exposure. TKI dose was reduced in 14 pts because of toxicity, median TTF was 17.0 months (95% CI 10.4-NR) vs. 20.1 months (95% CI 10.4-59.8, P=0.45 in pts treated with standard dose. In the EGFR mutated aNSCLC population at PD (n=19), T790M resistance mutation was more frequent in the ‘normal exposure group’ (37.5%, n= 3/8,) than in the ‘low exposure group’ (9.1%, n=1/11), OR=0.13 95%CI (0.01-1.29), p=0.08.

      Conclusion

      TKI is underdose in the majority of aNSCLC patients at PD. Low TKI concentration were more frequent in pts without tumor resitance mechanism. Altogether, it suggests that low TKI exposure might contribute to PD.

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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): Edouard Auclin

      • 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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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-31 - Immunosenescence Correlates with Poor Outcome from PD-(L)1 Blockade but Not Chemotherapy in Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 2268)

      09:45 - 18:00  |  Author(s): Edouard Auclin

      • Abstract
      • Slides

      Background

      CD28, CD57 and KLRG1 on circulating T-lymphocytes have been identified as markers of immunosenescence. The characterization of a senescent immune phenotype (SIP) in advanced NSCLC (aNSCLC) and its impact on anti-PD(L)-1 (IO) or platinum-based chemotherapy (PCT) treatments are unknown.

      Method

      The percentage of circulating CD8+CD28-CD57+KLRG1+ T-lymphocytes (SIP) was assessed by flow cytometry on fresh blood from aNSCLC patients treated with IO or PCT. A SIP cut-off was identified by log-rank maximation method. Correlations with categorical or continuous variables were performed by logistic regression or t-test. Survival curves were estimated with Kaplan Meier and compared with log-rank.

      Result

      In the IO cohort, 43 patients were evaluated for SIP: 32% ≥ 65 years, 92% non-squamous, 51% with tumoral PD-L1 expression ≥1%, 93% chemotherapy pretreated. Disease control rate (DCR), median PFS and OS and FU were 57%, 4.6 (95% CI 0.5; 8.8) months, 13 (95% CI 2.8-23.2) months, and 14 (95% CI 8.8-19.8) months, respectively.

      SIP median value was 15.4% (min 1.6%, max 57.7%). 32% of patients had >21.72% CD28-CD57+KLRG1+CD8+ lymphocytes (SIP+). SIP was not significantly associated with clinical characteristics. SIP changed according to IO response by T-sne algorithm (Figure 1A). Compared to SIP-, SIP+ patients had significantly lower DCR (81% vs 28%, p=0.002), PFS [7.3 (95% CI 4.1; 10.4) vs 1.7 (95% CI 1.2; 2.3), p=0.02] and OS [NR (95% CI 6.04; NR) vs 2.4 (95% CI 1.7; 3.1), p=0.01].

      SIP was significantly associated with specific immune populations [higher peripheral activated (Ox40+ICOS+PD1+) T-regulatory (CD25highCD127low) cells, TEMRA (CCR7-CD45RA+) CD8+ and T-helper 1 (CXCR5-CXCR3+CCR4-CCR6-CCR10-) CD4+] (Figure 1B). The PCT cohort included 61 patients, 43% SIP+. No significant difference in DCR, PFS or OS were observed according to SIP.

      figure 1a-1b.jpg

      Conclusion

      Immunosenescence is observed in 32% of aNSCLC patients before IO and correlates with specific immune phenotypes. Immunosenescence predicts lower DCR, PFS and OS from IO but not from PCT.

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    P1.10 - Prevention and Tobacco Control (ID 175)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Prevention and Tobacco Control
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.10-06 - Pathological Characterization of Radon-Induced Lung Cancer in Rats  (ID 1616)

      09:45 - 18:00  |  Author(s): Edouard Auclin

      • Abstract

      Background

      Radon is a radioactive gas, considered the leading cause of lung cancer in non-smokers. Although the risk of lung cancer is linear, there is no safe level and even low dose can be associated with risk. In humans, no specific pathological subtypes of lung cancer have been clearly associated with radon. In animals, the French Atomic Energy Commission (CEA) exposed to low dose of radon (25 working level month, WLM) a large cohort of rats in a radon-exposure chamber, showing lung cancer induced by low exposure (Chameaud J, Radiation Prot Dosimetry 1984). We aimed to describe pathological features of radon-induced tumors in rats from the CEA’s cohort.

      Method

      Retrospective assessment of archival samples available of the rats exposed to low-dose radon in the Laboratoire de Pathologie Pulmonaire Experimentale, COGEMA (France), between 1989 and 1992. Autopsy reports were also reviewed. The pathological assessment was performed for a thoracic oncology pathologist (JA) in H&E staining slides according to the current WHO histological classification.

      Result

      Samples from 117 rats were collected. Among 104 tumors, to date the analysis has been performed in 94. Forty tumors (43%) were classified as malignant, 28 (30%) as uncertain malignant potential (UMP) and 26 (28%) benign. In 2 rats (2%) synchronous malignant and non-malignant tumors were observed.

      Among the malignant tumors, 23 (58%) were epithelial and 17 (42%) non-epithelial. Lung carcinoma was the most common primary epithelial tumor (n=10, 43%), followed by abdominal area tumors (n=5, 22%), and thyroid (n=3, 13%). In the UMP group, 7 (25%) were epithelial and 21 (75%) non-epithelial, with no lung tumors observed. In the benign group, most of them (n=24, 92%) were epithelial, with 4 cases with lung atypical adenomatous hyperplasia-like lesions; 2 synchronous with other malignant tumors (n=1 lymphoma, n=1 cutaneous squamous cell carcinoma).

      A total of 26 tumors (27%) had thoracic involvement: 4 (15%) primary lung non-malignant lesions, 11 primary lung malignancies (42%) and 11 with metastases from other tumors (42%). As primary malignant lung tumors, we observed: 7 (64%) adenocarcinoma in situ, one papillary adenocarcinoma, one undifferentiated large cell carcinoma with bilateral metastases, one metastatic squamous carcinoma and one metastatic undifferentiated tumor, compatible with sarcoma

      Conclusion

      In this cohort of radon-induced tumors in rats, we observed different tumor types, from non-malignant lesions to aggressive malignancies, with predominance of epithelial tumors. Lung carcinoma was the most common primary tumor and adenocarcinoma the histological subtype more observed, with histological similarities with humans.