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Roberto Ferrara

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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: 12
    • 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  |  Presenting Author(s): Laura Mezquita  |  Author(s): Patricia Martin-Romano, Edouard Auclin, Boris Duchemann, Lydie Cassard, David Planchard, Marie Naigeon, Ithar Gataa, Melinda Charrier, Roberto Ferrara, Lisa Boselli, Jonathan Grivel, Maud Ngocamus, Julien Adam, Nathalie Chaput, Benjamin Besse

      • 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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      • 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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      MA07.03 - A Circulating MicroRNAs-Based Test as Biomarker of Primary and Secondary Resistance in PD-L1 ≥50% NSCLC Treated with Immunotherapy (Now Available) (ID 2495)

      13:30 - 15:00  |  Presenting Author(s): Claudia Proto  |  Author(s): Arsela Prelaj, Carla Verri, Diego Signorelli, Giuseppe Lo Russo, Roberto Ferrara, Giulia Galli, Benedetta Trevisan, Mavis Mensah, Filippo Guglielmo Maria De Braud, Marina Chiara Garassino, Gabriella Sozzi, Mattia Boeri

      • Abstract
      • Presentation
      • Slides

      Background

      PD-L1 represents the only clinically approved biomarker to select patients for immunotherapy. However, about 20-25% of PD-L1≥50% NSCLC patients do not benefit of ICIs treatment. We showed that a plasma microRNA signature classifier (MSC), reflecting the switch towards an immunosuppressive profile of immune cells, identifies NSCLC patients with worse prognosis after ICIs, irrespective from PD-L1 expression. Aim of this trial is to prospectively define the MSC role as biomarker of primary or secondary resistance in PD-L1≥50% NSCLC treated with ICIs.

      Method

      Fifty consecutive advanced NSCLC patients with PD-L1≥50% treated with ICI as first (n=32) or further line were enrolled. Plasma samples, as well as demographics information, smoking history and ECOG PS were collected before starting ICI treatment. The MSC test identified patients at high (H) risk vs intermediate/low (I/L) risk levels. According to RECIST 1.1 criteria, patients were classified as responders (R), patients with stable disease (SD), and progressors (P). Objective Response Rate (ORR), Progression Free Survival (PFS) and Overall Survival (OS) in MSC risk level strata at the baseline were considered as endpoints. For 26 R or SD patients with extended follow-up, additive, not mandatory plasma samples were collected and analyzed at the time of revaluations. To determine changes in the risk level during follow-up, we evaluated changes in the probability of having progressive disease after two consecutive MSC tests, considering all possible combinations.

      Result

      Overall 17 (34%) R, 17 (34%) patients with SD, 11 (22%) P and 5 (10%) not evaluable patients were identified. Considering the baseline blood samples 11 (22%) NSCLC patients were MSC H. ORR was 0% in MSC H vs 45% for other patients (p=0.0090). Median PFS was 2.3 months for MSC H vs 10.9 months for other patients (HR=0.38; 95%CI=0.17-0.84; p=0.0174). Median OS was 2.9 months for MSC H vs 22.0 months for other patients (HR=0.18; 95%CI=0.07-0.47; p=0.0004). Data remained significant adjusting for age, sex, pack-years and ECOG performance status: PFS HR=0.31 (95%CI=0.13-0.73; p=0.0072) and OS HR=0.13 (95%CI=0.04-0.39; p=0.0003). Among the 26 patients with longitudinal evaluation of MSC risk level, all the 12 patients reaching progression during treatment showed an increase in the risk level (Sign-test p-value=0.0039). Conversely, when considering the 14 NSCLC patients still maintaining SD or responding to ICIs at the time of the analysis, the risk level decreased for 9 (64%) of them (Sign-test p-value=0.1655).

      Conclusion

      These preliminary results suggest that MSC risk level at the baseline and during treatment could help to identify primary or secondary resistance in PD-L1≥50% NSCLC patients treated with ICIs. Ongoing clinical trials are validating these results.

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      MA07.04 - Discussant - MA07.01, MA07.02, MA07.03 (Now Available) (ID 3739)

      13:30 - 15:00  |  Presenting Author(s): Sara Pilotto

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      • Abstract
      • Presentation
      • Slides

      Background

      Anti-PD1/PDL1 deeply changed the NSCLC therapeutic algorithm in the past few years. Unfortunately, a majority of patients experiences disease progression. ICPis re-challenge could be an attractive option but no data supporting this strategy are available. Here we report outcomes of a large cohort of NSCLC patients treated with anti-PD1/PDL1 re-challenge.

      Method

      We retrospectively collected data about 144 advanced NSCLC patients (diagnosis between 2010 and 2018) from 26 French centers. Patients were re-challenged with ICPis after at least 12 weeks of discontinuation for toxicity, disease progression or clinical decision. Progression Free Survival (PFS) and Overall Survival (OS) were calculated from the start of first or second ICPi to disease progression (PFS1;PFSR) and death or last follow-up (OS1;OS2) respectively.

      Result

      Median age was 63 year [39 –83], most of patients were male (67%), smokers (87%), adenocarcinomas (62%) and stage IV at diagnosis (66%). Most of patients received the first ICPi round in first or second line (66%) and the second ICPi round in third line or later (79%). In both settings patients received preferentially an anti-PD1 (87%) and no differences were detected regarding brain metastasis or ECOG PS (P = 1.10-1 and P = 1.10-1 respectively). The Best Response during the re-challenge was not associated to that one achieved to the first ICPi (P = 1.10-1). The median PFS1 and PFSR were 13 months [95% CI 10-16.5] and 4.4 months [95% CI 3-6.5] respectively. PFSR was longer in patients discontinued because of clinical decision (6.5 months [95% CI 2.5-11.9]) or toxicity (5.8 months [95%CI 3.5-18]) compared to disease progression (2.9 months [95% CI 2.0-4.4]) (P = 2.10-2) and in those not receiving chemotherapy between the two ICPis (5.8 months [95%CI 4.1-10.5]) compared to those who did (3.0 months [95% CI 2.0-4.4])(P = 2.10-3). Median OS1 was 3.3 years [95% CI 2.9-3.9] without differences according to the discontinuation reason (P =2.10-1). Median OS2 was 1.5 y [95%CI 1.0-2.1] and was longer in patients discontinuing the first ICPi due to toxicity (2.1y [95%CI 1.4-NR]) compared to disease progression (1.0y [95%CI 0.4-1.5]) or clinical decision (1.5y [95%CI 0.4-NR]) (P = 3.10-2). Neither OS1 nor OS2 were affected by treatments received between the two ICPis (P = 3.10-1 and P = 1.10-1 respectively).

      Conclusion

      ICPis re-challenge might be a useful option mainly in patients discontinuing the first ICPi because of toxicity or clinical decision and in those able to keep a treatment-free period between the two ICPis.

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      MA07.06 - Immunotherapy Re-Challenge After Nivolumab Treatment in Advanced Non-Small Cell Lung Cancer in French Real-World Setting (Now Available) (ID 1281)

      13:30 - 15:00  |  Presenting Author(s): Matteo Giaj Levra  |  Author(s): François-Emery Cotté, Romain Corre, Christophe Calvet, Baptiste Jouaneton, Ronan Jolivel, Anne-Françoise Gaudin, Valentine Grumberg, Jean-Baptiste Assié, Christos Chouaid

      • Abstract
      • Presentation
      • Slides

      Background

      Real‐world evidence of nivolumab as treatment for advanced non-small cell lung cancer (aNSCLC) can complement evidence from clinical trials to optimize routine usage and personalization of care. Further, little is known about treatment options and outcomes after discontinuation of nivolumab.

      Method

      Based on the National hospitals database (PMSI), we built a retrospective cohort of all NSCLC patients (ICD code: C34*) starting nivolumab in 2015-2016 and followed them until Dec 2017. Information on patients’ baseline characteristics (demographics, comorbidities, treatment history) was retrieved. Nivolumab treatment was considered discontinued if ≥3 infusions were missed. Time to treatment discontinuation (TTD) and overall survival (OS) were estimated with Kaplan-Meier methodology. Re-challenged patients were analyzed according to their first nivolumab treatment duration i.e. <3; 3-6; ≥6 months.

      Result

      We identified 10,452 NSCLC patients initiating nivolumab during the inclusion period (male: 71%; mean age; 63.8±9.6 years; squamous histology: 44%; cerebral metastasis: 17.4%; median aNSCLC history: 12.5 months; previous curative surgery: 15.6%; median time since first chemotherapy: 10.5 months; mean dose of nivolumab: 213±54mg). Median TTD and OS were 2.8 months and 11.6 months. One-year and 2-year OS rates were 48.8% and 27.4%. Overall, 5118 (53.4%) patients received subsequent systemic therapy after nivolumab discontinuation. Among them, 1517 patients (29.6%) were re-treated with anti-PD1 agents (nivolumab: 98.8%) either after a therapeutic break (‘immunotherapy resumption group’: n=1127; mTTD: 4.1 months; mOS: 14.9 months from second initiation) or after chemotherapy (‘immunotherapy re-challenge group’: n=390; mTTD: 3.0 months; mOS: 18.2 months from second initiation). The Figure presents OS curves of the ‘re-challenge group’ according to first nivolumab treatment duration.

      graph os re-challenge according to ttd 1st nivo.jpg

      Conclusion

      After nivolumab discontinuation, around 30% of patients received immunotherapy again, either as a resumption or as a re-challenge following non-immunotherapy treatment. The influence of the first nivolumab treatment duration on re-challenged patients' OS should be further investigated.

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      MA07.07 - Discussant - MA07.05, MA07.06 (Now Available) (ID 3740)

      13:30 - 15:00  |  Presenting Author(s): Helena Linardou

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA07.08 - The Role of a Cachexia Grading System in Patients with NSCLC Treated with Immunotherapy: Implications for Response and Survival (Now Available) (ID 2046)

      13:30 - 15:00  |  Presenting Author(s): Jenny Georgina Turcott  |  Author(s): Andrés Felipe Cardona, Laura Alejandra Ramírez-Tirado, Zyanya Lucia Zatarain Barrón, Feliciano Barrón, Luis Corrales, Claudio Martin, Pablo Alan Barragán Castillo, Diana Flores-Estrada, Alejandro Ruiz-Patiño, Oscar Gerardo Arrieta

      • Abstract
      • Presentation
      • Slides

      Background

      The association between cancer-induced weight-loss (CIWL) and poor clinical outcomes is well established. However, many of these studies were performed in the chemotherapy era. Meanwhile, current standard of care for NSCLC patients has shifted towards the more efficacious immunotherapy agents (IO). IO has improved survival outcomes, nonetheless clinicians face the challenge of identifying who will derive substantial clinical benefit from these more costly agents. Response to IO is influenced by several patient-related factors, including microbiome, medications, and nutritional status.

      Method

      In this study we sought to evaluate the effect of cachexia in survival of NSCLC patients undergoing treatment with IO. Included patients had advanced NSCLC (IIIB, IV), who received IO agents in any line of therapy, and had a good performance status. All the patients were evaluated by the nutritionist specialist and were graded according to a previously documented cachexia scale which takes into consideration body mass index (BMI) and weight loss in order to stratify patients into 5 risk categories (0 [pre-cachexia] - 4 [refractory cachexia]). Primary endpoint was overall survival (OS), secondary endpoints included objective response rate (ORR) and progression-free survival.

      Result

      A total of 181 patients met the inclusion criteria and were included in the analysis. Among these 82 (45%) were classified in the first category (risk grade 0-1 [low risk]), 83 (46%) were classified in the second category (risk grade 2-3[intermediate risk]) and 9% were in the third category (risk grade 4 [high risk]). Patients classified as low-risk had a significantly longer OS compared to those with intermediate or high risk (22.4 months [95%CI: 18.7-26.1] vs. 15.7 [95%CI: 10.8-20.7] vs. 3.9 [0.0-7.8]; p<0.001; Hazard ratio: 1.81 [1.29-2.53]; p<0.001). In the multivariate analysis ORR, hemoglobin and risk category were independent factors associated with OS. Grade of cachexia was also significantly associated with ORR, with low-risk patients having a significantly higher ORR compared to intermediate and high-risk patients (36.6% vs. 17.3% vs. 25%; p=0.021). PFS was also influenced by risk category, with low risk patients having a longer PFS compared with intermediate and high-risk patients. diapositiva1.jpg

      Conclusion

      Cachexia is independently associated with worse OS in NSCLC patients who receive IO, while better nutritional status is related to higher ORR, highlighting a potential role for nutritional assessment in the selection of patients who are candidates for IO. Early assessment of nutritional status in these patients is imperative in order to timely diagnose and treat anorexia-cachexia and improve outcomes.

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      MA07.09 - Impact of Body Mass Index on Clinical Outcomes of Immune Checkpoint Blockers in Advanced Non-Small Cell Lung Cancer (Now Available) (ID 653)

      13:30 - 15:00  |  Presenting Author(s): Amit Arun Kulkarni  |  Author(s): Shijia Zhang, Todd De For, Manish Patel

      • Abstract
      • Presentation
      • Slides

      Background

      Studies have suggested that obesity may have a paradoxical effect on the efficacy of immune check-point blockers (ICB). Higher Body Mass Index (BMI) has been associated with favorable outcomes with ICB. There is limited data on the impact of BMI on ICB efficacy in real-world patients with advanced non-small-cell lung cancer (NSCLC). We evaluated whether BMI is associated with survival outcomes in metastatic NSCLC patients treated with ICB.

      Method

      We identified advanced NSCLC patients treated with anti-PD1/PD-L1 at our institution between 5/2015 to 1/2019. Data regarding BMI at the beginning of ICB treatment were collected. Patients with BMI > 25 (overweight and obese) were assigned to high-BMI group and patients with BMI < 25 were assigned to low-BMI group. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Cox proportional hazards model were used for statistical analysis.

      Result

      148 patients with NSCLC were eligible for inclusion. The median follow-up time was 12 months. Median age was 66 years. Majority of patients were female (52.1%), Caucasian (93%), had adenocarcinoma histology (66%), current or previous smokers (88%) and received Nivolumab (88%) in the 2nd or later line setting. The median number of treatment doses were 7. Median BMI of the patient population was 25.4 kg/m2. 64/148 (43%) of patients were in the low-BMI group (BMI < 25) and 84/148 (57%) patients were included in the high-BMI group (BMI > 25). Patients in high-BMI group had superior OS (HR=0.64, 95% CI 0.45-0.90; p=0.01) that was statistically significant. 1-year OS was 46.4% and 39.0% in the high-BMI and low-BMI group respectively. PFS was also greater in high-BMI group with a trend towards statistical significance (HR=0.73, 95% CI 0.51-1.03; p=0.07). 1-year PFS was 25.0% and 15.6% in the high-BMI and low-BMI group respectively. In multivariate analysis, OS benefit remained statistically significant after adjustment for clinical covariates (age, sex, performance status, number of previous lines of therapy, smoking status and brain metastasis).

      Conclusion

      Our study provides independent validation of previously published results demonstrating an association of BMI with survival outcomes in NSCLC patients treated with ICB. The OS benefit in the high-BMI group is independent of classical prognostic factors. While the reasons underlying this relationship remains unknown, prospective studies are needed to confirm this association. Future clinical trials with ICB should consider stratification of patients based on BMI.figure 1.png

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      MA07.10 - The Influence of Sex on Immunotherapy Efficacy in Non-Small Cell Lung Cancer (Now Available) (ID 712)

      13:30 - 15:00  |  Presenting Author(s): Stephanie Tuminello  |  Author(s): Rajwanth Veluswamy, Naomi Alpert, John Lazar, Raja Flores, Maaike Van Gerwen

      • Abstract
      • Presentation
      • Slides

      Background

      Patient’s sex impacts clinical outcomes for multiple cancers, including non-small cell lung cancer (NSCLC). A recent meta-analysis demonstrated sex may also impact response to novel immunotherapeutic agents, where men appear to derive greater benefit than women. However, the role of important clinical confounders of immunotherapy response that differ according to sex was not accounted for. The aim of this project was to investigate the effect of sex on immunotherapy benefit for NSCLC patients using a large, nationally representative database while adjusting for important clinical confounders.

      Method

      Advanced metastatic NSCLC patients diagnosed between 2013-2015 were identified in the National Cancer Database (NCDB). A Cox Proportional Hazards model was used to assess the interaction between sex and immunotherapy treatment for overall survival. This model was also adjusted for histology, stage, age, race, tumor size, comorbidities and other treatment (i.e. chemotherapy, radiation).

      Result

      Of 103,525 advanced NSCLC patients, 69,120 (67%) had adequate follow-up information for survival analysis. Of these, 37,423 (54.1%) were males and 31,697 (45.9%) females; 4,012 patients received immunotherapy as first-course treatment. In the adjusted model, both males (Hazard Ratio [HR]adj: 0.77, 95% Confidence Interval [CI] 0.73-0.81) and females (HRadj: 0.80, 95% CI 0.76-0.85) receiving immunotherapy had improved survival compared to those not receiving immunotherapy. The interaction between sex and immunotherapy was not significant (p=0.2539) after adjusting for clinical variables. Among the covariates, younger age, adenocarcinoma histology, Black race, smaller tumor size, lower comorbidity score and additional cancer treatment (either chemotherapy or radiation) were independently associated with better survival (p<0.0001 for all comparisons).

      Conclusion

      Patient sex does not appear to affect the benefit of immunotherapy in advanced NSCLC patients after adjusting for potential clinical confounders. Other clinical factors may play a role in immunotherapy response and should be explored in future research.

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      MA07.11 - Survival Outcomes Based on Gender of Advanced Nonsmall Cell Lung Cancer Patients Treated with Pembrolizumab or Nivolumab in Everyday Clinical Practice (Now Available) (ID 841)

      13:30 - 15:00  |  Presenting Author(s): Doran Ksienski  |  Author(s): Elaine S Wai, Nicole Croteau, Ashley T. Freeman, Leathia Fiorino, Angela Chan, Dave Fenton, Georgia Geller, Edward Brooks, Zia Poonja, Sarah Irons, Mary Lesperance

      • Abstract
      • Presentation
      • Slides

      Background

      Women are underrepresented in clinical trials of PD1 Ab. We investigated the relationship between gender and overall survival (OS) in aNSCLC patients (pts) treated with PD1 Ab in a large Canadian provincial cohort.

      Method

      All aNSCLC pts treated with nivolumab (NIV) or pembrolizumab (PEM) between 06/2015 and 11/2018 at BC Cancer were identified. Demographic, tumor, treatment details, and survival status were collected from chart review. Kaplan-Meier (KM) curves of OS from initiation of PD1 Ab were generated and compared by the log-rank test.

      Result

      Of 527 pts analyzed (58.9% NIV, 36.1% PEM), 50.5% were female. Women were more likely to have Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0/1 at PD1 Ab initiation (72.9% vs. 64.8%, p=0.05), lower median Charlson Comorbidity Index score (CCI, 2.0 vs. 3.0, p=0.006), and tumors with non-squamous histology (83.5% vs. 69.7%, p<0.001) or Epidermal Growth Factor Receptor (EGFR) mutation (9.8% vs. 3.4%, p=0.006). No significant gender variation in age at diagnosis, smoking status, and programmed death ligand 1 tumor proportion score (PD-L1 TPS) was observed. In addition, there were no differences in type of PD1 Ab, line of treatment, duration of treatment, or treatment discontinuation due to immune related adverse events. With a median follow-up of 16.3 months by reverse KM method, 65% of pts had died. In the entire cohort, women had a longer median OS than men (10.2 vs. 8.1 months, p=0.029). In the subgroup of ECOG PS 2/3 pts, men had worse OS (3.9 vs. 6.5 months, p=0.034). Women ≥60 years of age at initiation of PD1 Ab demonstrated superior median OS to men (12.2 vs. 6.1 months, p=0.006). On multivariable analysis of NIV pts, male gender (HR=1.3, 95% CI 1.0-1.7, p=0.02), baseline ECOG PS 2/3 (HR=2.5, 95% CI=1.9-3.2 p<0.001), CCI score≥3 (HR=1.6, 95% CI=1.3-2.1, p<0.001), and EGFR/ALK aberration (HR=2.3, 95% CI 1.4-3.9, p<0.001) predicted for worse survival; for PEM pts, only ECOG PS 2/3 (HR=2.5, 95% CI 1.6-3.9, p<0.001) was associated with OS.

      Conclusion

      In this large series with a significant proportion of women, females treated with PD1 Ab for aNSCLC lived longer than men (especially if ECOG PS 2/3 or age≥ 60 years.) Despite similarities in smoking status and PD-L1 TPS, gender divergence in outcome could be attributed to more favorable histology and baseline ECOG PS in females. Increased enrollment of women in PD1 Ab trials would facilitate evaluation of gender as a predictive variable.

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      MA07.12 - Discussant - MA07.08, MA07.09, MA07.10, MA07.11 (Now Available) (ID 3741)

      13:30 - 15:00  |  Presenting Author(s): Sonja Loges

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS13 - Immunotherapy for Mesothelioma (ID 76)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Mesothelioma
    • Presentations: 6
    • Now Available
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      MS13.01 - Immunotherapy and Mesothelioma: Rationale and Strategies (Now Available) (ID 3514)

      11:30 - 13:00  |  Presenting Author(s): Jan P Van Meerbeeck

      • Abstract
      • Presentation
      • Slides

      Abstract

      Unresectable malignant pleural mesothelioma (MPM) is a uniformly fatal rare cancer with increasing incidence worldwide. Combination chemotherapy with platinum/antifolate –either pemetrexed or raltitrexed- is the only standard of care 1st line treatment with proven improvement of survival, which varies according to series and patient selection between 12-16 months median overall survival (mOS), with corresponding 1 year survival rate of 50-60%. After a median progression-free survival of ~ 3 months, patients relapse and few if any drugs have any proven efficacy at this stage. Survival after progression varies from 3-18 months according to tumors’ biological behavior and patient’s prognostic factors. Therefore, innovative drugs are urgently needed.

      Although called ‘immunologically cold tumours’ and presenting with a low mutational burden, MPM express distinct targetable antigens (WT1, mesothelin), contain tumour-infiltrating lymphocytes (TILs) and PDL-1 expression is variably present, mostly on the sarcomatoid subtype. Experimental models have demonstrated chronic inflammation and local tumor suppression as crucial to MPM pathogenesis. This led to the investigation of immunotherapy in MPM.

      Monoclonal antibodies against immune check point inhibition (ICI-) molecules have been evaluated as salvage therapy after first-line chemotherapy in several phase 2 trials, either as single agent or in combination. The randomized DETERMINE trial evaluated in 564 patients the anti–CTLA-4 antibody tremelimumab versus placebo in second or third line and found no benefit in outcome (hazard ratio 0.92; p = 0.408). Results from the anti–PD-1 or anti–PD-L1 trials with nivolumab, pembrolizumab and durvalumab are fairly consistent with a response rate of 19-30%, a median PFS of 3.5 – 6.0 months and mOS of 12-18 m, all uncontrolled in selected patients with good prognostic features. Addition of CTLA-4 inhibitors to PD(L)-1 seem to increase efficacy and prolong the time-to-event endpoints. Preliminary results suggest that PD-L1 tumour proportional score (TPS) is both a predictive and prognostic biomarker.

      Several trials are underway investigating ICI alone or in combination with SOC-chemotherapy as frontline treatment. The DREAM trial, a single-arm, open-label phase II trial of durvalumab with cisplatin/pemetrexed, followed by durvalumab maintenance therapy for 1 year. The primary endpoint was PFS at 6months. Interim results in the first 54 patients show a mPFS of 6.2 months, with 48% achieved a partial response based on immune-modified RECIST. The -immature- 1-year OS estimate is 65% at a median follow-up of 14.4 months.

      Other randomized studies of triplet combinations are ongoing, including SOC-chemotherapy w/wo pembrolizumab (NCT02784171) or durvalumab (NCT02899195). The phase III CheckMate743 (NCT02899299) trial randomly selected 600 patients with treatment-naïve MPM to nivolumab plus ipilimumab -until progression or unacceptable toxicity- versus up to six cycles of SOC-chemotherapy.

      Surgical management in resectable MPM represents an excellent opportunity for window-of-opportunity trials when treating patients with neo-adjuvant immunotherapies to improve resectability, fight residual disease and improve patient outcome. Several studies are ongoing with anti–PD(L)-1 with or without CTLA-4 inhibitors or chemotherapy in the neo-adjuvant setting, but results have not yet been published.

      Immunotherapy beyond ICI have been also tested in MPM but with discordant results. Several randomized phase II trials have targeted mesothelin, including amatuximab, an antimesothelin chimeric monoclonal antibody, anetumab-ravtansine, an antibody drug conjugate, and CRS-207, a vaccine targeting mesothelin: these have not yet shown any efficacy in MPM (unpublished data). Cell therapies in phase I trials are being investigated in MPM, including chimeric antigen receptor (CAR) T cells targeting surface antigens such as mesothelin, given both intravenously (NCT02159716) and intrapleuraly (NCT02414269).

      Vaccines targeting the Wilms tumor-1 (WT-1) antigen have also been tested in MPM with variable results. Dendritic cell vaccination was found to be efficacious in small trials of MPM, providing the rationale for ongoing trials, such as the large randomized phase II trial (DENIM) with dendritic cell therapy as maintenance after P/P frontline chemotherapy or a phase I/II trial testing autologous dendritic cells loaded with WT-1 tumor antigen following standard first-line chemotherapy. Autologous tumor infiltrating lymphocytes and interleukin-2 (IL-2) infusion after lympho-depletion are also currently under investigation in a phase I/II trial in MPM. Immune-gene therapy using intrapleural delivery of adenovirus-expressing interferon-α combined with celecoxib and chemotherapy was well tolerated and provided a remarkable mOS of 21.5 months as second-line treatment. Finally, oncoviral therapy is being assessed in a phase I trial with intrapleural injection of measles virus (NCT01503177), or with an oncolytic adenovirus coding for GM-CSF combined with chemotherapy and cyclophosphamide versus chemotherapy alone in a randomized phase II trial (NCT02879669).

      In conclusion, immunotherapies are being investigated in different settings of MPM. Regulatory approval is anticipated soon for ICI (anti–PD-1 with or without anti–CTLA-4) as salvage treatment in MPM. However, state of the art phase III trials comparing ICI with SOC-chemotherapy are needed to firmly establish immunotherapy, either alone or in combination with standard treatment, and to validate biomarkers for patient selection.

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      MS13.02 - Pro - Hedy Kindler Is Right (Immuno Works for Mesothelioma) (Now Available) (ID 3512)

      11:30 - 13:00  |  Presenting Author(s): Hedy Lee Kindler

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS13.03 - Con - Raphael Bueno Is Right (It Does Not Work) (Now Available) (ID 3513)

      11:30 - 13:00  |  Presenting Author(s): Raphael Bueno

      • Abstract
      • Presentation
      • Slides

      Abstract

      Mesothelioma is a heterogeneous cancer and it is not always correctly staged in the absence of surgical extirpation. While some clinical trials utilizing a remarkably small number of patients showed some response to immunotherapy in mesothelioma, the response rate is relatively low (in the 10% rate) and it is unclear how durable. The heterogeneity of the tumor makes interpretation of such small number difficults leading to the conclusion that at this time immunotherapy remains experimental in mesothelioma

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      MS13.04 - Biomarkers of Anti-PD1 Therapy in Mesothelioma (Now Available) (ID 3515)

      11:30 - 13:00  |  Presenting Author(s): Paul Baas

      • Abstract
      • Presentation
      • Slides

      Abstract

      Biomarkers of Anti-PD1 Therapy in Mesothelioma.

      Biomarkers have attracted attention for their usefulness in selecting the right treatment for the right patient. There are different types of biomakers; blood based, clinical markers and histological markers. Most of the biomarker studies have focused on the prognosis of patients while only a limited number examined the predictive value of a marker; to correctly predict the outcome of a certain treatment.

      After the reported successes of check-point inhibitors in melanoma and NSCLC (1-4), the use of these agents have found its way to mesothelioma(5-8).
      Since 2015 many studies have been initiated whit a comparable efficacy compared to NSCLC outcomes. Around 20-25% of cases do respond favorably to this approach. This is considered to be of great importance since there is a limited 2 years survival rate (8) and no standard second line therapy has yet been defined. There are a number of factors that have to be considered before embarking on Immuno-Oncology (IO) therapies as single agent or in combination. The choice of the drug or combination; the expected outcome in short time; the toxicity profile and the costs. Because of the lack of registration, there is a limited availability and patients can only join in studies or be part of a compassionate use program. When registration is a fact we merely have to deal with the questions; who will benefit, who will experience toxicity and is the treatment cost effective?

      In a series of studies we performed in patients with pleural mesothelioma we have collected samples to be used as biomarkers (6,7). Currently we are analyzing the predictive value of these biomarkers.
      1. Histological biopsies: It is well known that the expression PD-L1 can be predictive in NSCLC of a success while in melanoma there is a better correlation with tumor mutational burden. For mesothelioma the expression of PD-L1 varies between the different subtypes of mesothelioma (with sarcomatoid type expressing higher PD-L1 levels) (9). In general the high expression correlates with a worse survival. In addition, the expression of PD-L1 on tumor stroma also influences the outcome of IO treatment. In our study of 34 patients (7), we observed a clinical benefit of 18% in PD-L1 tumor negative patients compared with 15% in the (TIL+) stroma and 32% versus 35% in stroma for any PD-L1 expression. When analyzed for PD-L1 > 50% the stromal T+ cells showed a factor of 2 higher clinical benefit. This implies that a single analysis of the PD-L1 of the tumor cells might underestimate the effect of IO therapy.

      2. eNose analyses. The use of exhaled air has attracted clinical interest since early data indicate that the Volatile Organic Compounds (VOCs) can predict an outcome of IO therapy (11). These VOCs probably represent a complex combination of tumor and immune cell interactions. Ongoing studies focus on the use of these electronic noses to select only patients for whom a treatment has a high chance of success.

      3. Blood based biomarkers have been tested in many studies in mesothelioma. For well-known markers such as mesothelin, cyfra 21-1, osteopontin and fibulin-3 no positive outcomes have been reported in prediction studies.

      4. MicroRNAs. These short, non-coding RNA sequences have attracted attention because of their prognostic capability in mesothelioma and other cancers. The huge number of miR’s identified and the lack of comparative studies to date indicate that these markers can only be used for diagnostic and perhaps treatment purposes. (12)

      5. BAP1 is a nuclear deubiquitinase which regulates the ubiquitination of selected histones and other translational factors. This mutation is occurring both in germline or, more frequently, as a somatic mutation in mesothelioma. It has different functions and can influence the inflammation status of the microenvironment. Although not tested in a proper study setting this marker may well have a predictive potential(13).

      6. Other biomarkers. Finally there are a number of interesting biomarkers including chemokines like IL-6 which acts as a pro-inflammatory cytokine and is closely related to T cell function. Ongoing studies will try to elucidate the predictive effect of this and other markers.

      To date there is a lot of activity ongoing in mesothelioma and the introduction of the IO drugs have been welcomed full-heartedly. Although we have identified an abundant number of prognostic factors in cancer, the high costs of IO therapies presses us to find solid predictive markers. The combination therapies of IO drugs now proposed do increase the toxicity profile and we must not lose precious time of patients and doctors spend on ineffective and costly therapies.

      References are available at the author at request

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      MS13.05 - CaR T Cell in Mesothelioma (Now Available) (ID 3516)

      11:30 - 13:00  |  Presenting Author(s): Prasad S Adusumilli

      • Abstract
      • Presentation
      • Slides

      Abstract

      Chimeric antigen receptor (CAR) T-cell therapy has shown great promise in hematological malignancies and was approved by FDA for the treatment of leukemia and lymphoma patients. Adotpive cell therapy by use of CARs involves transducing patient's own T lymphocytes with antigen-specific CAR by retro or lenti virus, and infusing back to the patient following Cyclophosphamide preconditioning. This presentation will dicuss the challenges in developing CAR T-cell therapy, progress to date in translation of CAR T-cell therapy for thoracic cancers.

      Advances in understanding thoracic cancers tumor immune microenvironment and successes with checkpoint blockade agents has opened doors to devlop combiantion immunotherapy for thoracic cancer patients. Our laboratory has shown that in the presence of high tumor burden as in patients with metastases, a low-dose of CAR T cells adminsitered in phase I clinical trials can be exhausted. Addition of anti-PD-1 agents can rescue functionally exhausted CAR T cells and prolong their anti-tumor efficacy. Based on this strong rationale, our laboratory has translated mesothelin-targeted CAR T-cell therapy for patients with malignant pleural mesothelioma and demonstrated anti-tumor efficacy in addition to safety in combination with anti-PD-1 agents. The results of the ongoing trials will be discussed.

      While extrinsic anti-PD-1 agent administration requires multiple doses and potential off-tumor side effects, we have developed T-cell intrinsic anti-PD-1 strategies which are in translation. The preclinical and clinical data supporting this upcoming clinical trial will be presented.

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      MS13.06 - Role of Second Line Chemotherapy and New Target Treatment in Recurrent Mesothelioma (Now Available) (ID 3517)

      11:30 - 13:00  |  Presenting Author(s): Silvia Novello  |  Author(s): Paolo Bironzo

      • Abstract
      • Presentation
      • Slides

      Abstract

      Malignant pleural mesothelioma (MPM) is a highly lethal disease, with a median overall survival (OS) between 12 and 18 months. Following first-line treatment, neither chemotherapy nor target treatments have clearly shown to increase overall survival (OS), to date. Historically, second-line cytoxic drugs, such as gemcitabine and vinorelbine have been the backbone in pre-treated patients, with response rates ranging from 7% to 16% [Zucali PA, Perrino M, Lorenzi E, et al. Vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma. Lung Cancer 2014; 84:265-270; Stebbing J, Powles T, McPherson K, et al. The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma. Lung Cancer 2009; 63:94-97; van Meerbeck JP, Baas P, Debruyne C, et al. A phase II study of gemcitabine in patients with malignant pleural mesothelioma. European Organisation for Research and Treatment of Cancer Lung Cancer Cooperative Group. Cancer 1999;85(12):2577-2582]. Pemetrexed rechallenge was assessed in small retrospective studies, suggesting its role, especially when combined with platinum compounds, in selected patients with a pemetrexed-free interval of at least 3 to 6 months [Zucali PA, Simonelli M, Michetti G, et al. Second-line chemotherapy in malignant pleural mesothelioma: results of a retrospective multicenter survey. Lung cancer 2012; 75: 360-367]. “Omics” studies have enlarged our knowledge of MPM, describing high prevalence of TP53, NF2, BAP1 and cyclin dependent kinase inhibitor 2A (CDKN2A) mutations, along with the lack of tyrosine receptor kinase (TRK) activating mutations [Lo Iacono M, Monica V, Righi L, et al. Targeted next-generation sequencing of cancer genes in advanced malignant pleural mesothelioma: a retrospective study.J Thorac Oncol 2015;10(3):492-9]. For this reason, the development of target treatment approaches in MPM has been more difficult and slower as compared to non-small-cell lung cancer (NSCLC), for example. However, many drugs have been tested, while others are currently under evaluation. Among the first studied agents, mTOR inhibitors failed to show activity in pre-treated MPM patients [Ou SH, Moon J, Garland LL, et al.SWOG S0722: phase II study of mTOR inhibitor everolimus (RAD001) in advanced malignant pleural mesothelioma (MPM). J Thorac Oncol 2015;10(2):387-91]. Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) is upregulated in MPM with BAP1 inactivation and its inhibition showed to be syntethic lethal in BAP1-negative tumors. The EZH2 inhibitor tazemetostat demonstrated a 51% disease control rate (DCR) in 74 MPM patients (95% with BAP1 inactivation) enrolled in a phase 2 study [Zauderer MG, Szlosarek P, Le Moulec S, et al. Phase 2, multicenter study of the EZH2 inhibitor tazemetostat as monotherapy in adults with relapsed or refrectory (R/R) malignant mesothelioma (MM) with BAP1 inactivation. J Clin Oncol 36, 2018 (suppl.abstr 8515)]. As BAP1 loss leads to homologous repair deficiency, PARP inhibitors are currently being tested in this subgroup [NCT03531840; NCT03207347; NCT03654833]. Neurofibromin 2 (NF2) inactivation, which encodes for merlin, has been proposed to be synthetic lethal to focal adhesion kinase (FAK) inhibition. However, the COMMAND trial, exploring the use of the FAK inhibitor defactinib as a maintenance treatment after first-line chemotherapy in MPM patients stratified for merlin expression, failed to show any improvement as compared to placebo [Fennell DA, Baas P, Taylor P, et al. Maintenance defactinib versus placebo after first-line chemotherapy in patients with merlin-stratified pleural mesothelioma: COMMAND-a double-blind, randomized, phase II study. J Clin Oncol 2019;37(10):790-798]. Defactinib is currently under investigation in combination with anti programmed-death 1 (PD-1) monoclonal antibody pembrolizumab in a phase I/IIA clinical trial enrolling pretreated MPM patients along with pancreatic cancer and NSCLC ones [NCT02758587]. The identification of argininosuccinate synthetase 1 (ASS1) loss in MPM, leading to arginine auxotrophy, paved the way to the use of the arginine depletor pegylated adenosine deiminase ADI-PEG20 in a phase 2 randomized trial in 70 ASS1-deficient patients [Szlosarek PW, Steele JP, Nolan L, et al. Arginine deprivation with pegylated arginine deiminase in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma: a randomized clinical trial. JAMA Oncol 2017;3(1):58-66]. Among the 68 treated patients, the drug improved progression free survival (PFS) as compared to best supportive care (BSC) (HR 0.56, 95% CI, 0-33-0.96), although by only 1.2 months (median PFS 3.2 vs 2.0 months for ADI-PEG20 and BSC, respectively; p=0.03). Currently, ADA-PEG20 is being explored in combination with first-line chemotherapy in biphasic and sarcomatous MPM only [NCT02709512]. Recent studies described novel prognostic MPM subsets with specific genomic characteristics that could further shape personalized treatment approaches, especially when looking at immunotherapic approaches [Hmljak J, Sanchez-Vega F, Hoadley KA, et al. Integrative molecular characterization of malignant pleural mesothelioma. Cancer Discov 2018;8(12):1548-1565]. Indeed, the high expression of V-domain immunoglobulin suppressor of T-cell activation (VISTA) negative immune-checkpoint in epithelioid MPM reported in this study, suggests a possible of role of specific inhibitors alone or in combination with other agents in advanced MPM.

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    MA03 - Clinomics and Genomics (ID 119)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA03.10 - Prospective Evaluation of a Prognostic Clinico-Molecular Score (DEMo) to Predict Outcome of Advanced NSCLC Patients Treated with Immunotherapy (Now Available) (ID 1378)

      10:30 - 12:00  |  Author(s): Roberto Ferrara

      • Abstract
      • Presentation
      • Slides

      Background

      We have already reported three different molecular (MSC: plasma miRNA-signature classifier, Boeri, Clin Cancer Res 2019) and clinico-biochemical scores (DiMaio: Di Maio, EJC 2010; EPSILoN: Ann.Onco 2018 supp) able to differently predict prognosis in advanced non-small cell lung cancer (aNSCLC) patients treated with immunotherapy (IO). Exploiting the ability of each test we developed a combined clinico-biological composite score called DEMo (DiMaio EPSILoN MSC). Objective of the study is to prospectively evaluate the prognostic value of DEMo in aNSCLC patients treated with IO.

      Method

      We enrolled 127 consecutive aNSCLC patients treated with IO in first (n=37) and further-lines (n=90) at Istituto Nazionale dei Tumori, Milan. All patients had complete clinico-laboratoristic data necessary for both scores: DiMaio (ECOG-PS, sex, histology, stage, uses of platinum-based therapy at first-line and response to first-line) and EPSILoN (ECOG-PS, Smoke, Liver, LDH, NLRatio). MSC was prospectively evaluated in plasma samples collected prior starting IO and the risk level were assessed. Progression-free survival (PFS) and overall survival (OS) in strata of MSC/DiMaio/EPSILoN alone or DEMo and overall response rate (ORR), were considered as endpoints. Kaplan Meier were used to generate survival curves and Cox hazard model were employed to perform multivariate analyses.

      Result

      In multivariate analyses, adjusted for age, sex, pack/year and ECOG-PS, patients with high MSC and high DiMaio and EPSILoN scores reported a lower PFS (MSC: HR 1.72 CI95% 1.06 – 2.77, p=0.027; DiMaio: HR 2.63 CI95% 1.40 – 5.00, p=0.002; EPSILoN: HR 2.17 CI95% 1.16 – 4.16, p=0.014) and OS (MSC: HR 2.17 CI95% 1.29 – 3.70, p=0.003; DiMaio: HR 3.57 CI95% 1.66 – 7.69, p=0.001; EPSILoN: HR 2.50 CI95% 1.15 – 5.26, p=0.020). DEMo stratified patients into four risk groups according to the presence of 3–2–1–0 bad markers (High MSC/DiMaio/EPSILoN or none). Groups had 0%–0%–32.2%–53.3% 1-year PFS (p<0.0001) and 4.4%– 19.4% – 66.9% – 75.4% 1-year OS (p<0.0001). We further compared 0/1 to 2/3 combined groups. At the multivariate Cox model group 2/3 had a mPFS 1.9 vs 9.4 mo compared to group 0/1 (HR 3.70 CI95% 2.08 – 6.67, p<0.0001) and mOS 4.1 vs 22.4 mo (HR 4.76 CI95% 2.56 – 9.10, p<0.0001). Regarding ORR, DEMo group 0/1 had a 3.86 (CI95% 1.76-8.47) fold higher probability to respond compare to 2/3 group (p=0.0007).

      Conclusion

      DEMo composite biomarker is able to predict better prognosis compared to each single score and can be a useful tool for guiding IO treatment choices. In particular, DEMo allowed a good selection for those patients who are less likely to benefit from IO.

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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): Roberto Ferrara

      • 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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      MA07.03 - A Circulating MicroRNAs-Based Test as Biomarker of Primary and Secondary Resistance in PD-L1 ≥50% NSCLC Treated with Immunotherapy (Now Available) (ID 2495)

      13:30 - 15:00  |  Author(s): Roberto Ferrara

      • Abstract
      • Presentation
      • Slides

      Background

      PD-L1 represents the only clinically approved biomarker to select patients for immunotherapy. However, about 20-25% of PD-L1≥50% NSCLC patients do not benefit of ICIs treatment. We showed that a plasma microRNA signature classifier (MSC), reflecting the switch towards an immunosuppressive profile of immune cells, identifies NSCLC patients with worse prognosis after ICIs, irrespective from PD-L1 expression. Aim of this trial is to prospectively define the MSC role as biomarker of primary or secondary resistance in PD-L1≥50% NSCLC treated with ICIs.

      Method

      Fifty consecutive advanced NSCLC patients with PD-L1≥50% treated with ICI as first (n=32) or further line were enrolled. Plasma samples, as well as demographics information, smoking history and ECOG PS were collected before starting ICI treatment. The MSC test identified patients at high (H) risk vs intermediate/low (I/L) risk levels. According to RECIST 1.1 criteria, patients were classified as responders (R), patients with stable disease (SD), and progressors (P). Objective Response Rate (ORR), Progression Free Survival (PFS) and Overall Survival (OS) in MSC risk level strata at the baseline were considered as endpoints. For 26 R or SD patients with extended follow-up, additive, not mandatory plasma samples were collected and analyzed at the time of revaluations. To determine changes in the risk level during follow-up, we evaluated changes in the probability of having progressive disease after two consecutive MSC tests, considering all possible combinations.

      Result

      Overall 17 (34%) R, 17 (34%) patients with SD, 11 (22%) P and 5 (10%) not evaluable patients were identified. Considering the baseline blood samples 11 (22%) NSCLC patients were MSC H. ORR was 0% in MSC H vs 45% for other patients (p=0.0090). Median PFS was 2.3 months for MSC H vs 10.9 months for other patients (HR=0.38; 95%CI=0.17-0.84; p=0.0174). Median OS was 2.9 months for MSC H vs 22.0 months for other patients (HR=0.18; 95%CI=0.07-0.47; p=0.0004). Data remained significant adjusting for age, sex, pack-years and ECOG performance status: PFS HR=0.31 (95%CI=0.13-0.73; p=0.0072) and OS HR=0.13 (95%CI=0.04-0.39; p=0.0003). Among the 26 patients with longitudinal evaluation of MSC risk level, all the 12 patients reaching progression during treatment showed an increase in the risk level (Sign-test p-value=0.0039). Conversely, when considering the 14 NSCLC patients still maintaining SD or responding to ICIs at the time of the analysis, the risk level decreased for 9 (64%) of them (Sign-test p-value=0.1655).

      Conclusion

      These preliminary results suggest that MSC risk level at the baseline and during treatment could help to identify primary or secondary resistance in PD-L1≥50% NSCLC patients treated with ICIs. Ongoing clinical trials are validating these results.

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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
    • Now Available
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      OA14.06 - Hyperprogressive Disease in Advanced Non–Small Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors (Now Available) (ID 1835)

      11:30 - 13:00  |  Author(s): Roberto Ferrara

      • Abstract
      • Presentation
      • Slides

      Background

      Hyperprogressive disease (HPD) is a paradoxical boost in tumour growth described in a subset of cancer patients treated with immune checkpoint inhibitors (ICIs).

      Method

      We retrospectively collected data about all consecutive patients with advanced Non-Small Cell Lung Cancer (aNSCLC) treated with ICIs at our Institution between 04/2013 and 12/2018. Patients were classified according to our previously published clinical/radiological criteria for HPD (Lo Russo G, Clin Canc Res 2018). (Table). All ICIs administered for ≥1 cycle were admitted. Chi-square test was used to compare qualitative variables. Survival was estimated with Kaplan-Meier method. Log-rank test was used to compare curves. Multivariate analyses were performed with Cox hazard model.

      Table HPD definition on the basis of 3 concomitant out of the five possible criteria

      HPD CLINICAL & RADIOLOGICAL CRITERIA

      Time-to-treatment failure < 2 months

      Increase of ≥ 50% in the sum of target lesions major diameters between baseline and first radiological evaluation

      Appearance of at least two new lesions in an organ already involved between baseline and first radiological evaluation

      Spread of the disease to a new organ between baseline and first radiological evaluation

      Clinical deterioration with decrease in ECOG performance status ≥ 2 during the first 2 months of treatment

      Result

      We reviewed 301 cases and 257 were evaluable for response. We identified four categories: responders (R, 57 cases, 22.2%), patients with stable disease as best response (SD, 69 cases, 26.8%), patients with progressive disease as best response (P, 78 cases, 30.4%) and patients with HPD (53 cases, 20.6%). Clinical/pathological variables were uniformly distributed among groups, except for a higher rate of patients with Eastern Cooperative Oncology Group Performance Status (ECOG-PS) >1 in HPD group (p = 0.0141). After a median follow-up of 23.49 months (IQR 10.72–44.21 months), median Progression-Free Survival (mPFS) and median Overall Survival (mOS) were 14,2 vs 6,5 vs 2,3 vs 1,5 months ( p < 0.0001) and 32,5 vs 17,8 vs 7,8 vs 4,1months (p < 0.0001) in R, SD, P and HPD group, respectively. The multivariate analyses, between P and HPD groups, adjusted for ICIs line, number of metastatic sites and ECOG-PS according to PFS (HR 2.448, 95% CI 2.137-2.899, p<0.0001) and OS (HR 2.481, 95%CI 2.092-2.950, p < 0.0001) confirmed the worse outcome of HPD group.

      Conclusion

      Our updated analysis confirmed patients with HPD as a distinct category that performs significantly worse than other groups, including P patients. The incidence of HPD in our cohort is relevant. The ICIs’ detrimental effect has to be taken into account and further investigated.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-120 - Immune Checkpoint Inhibitors Versus Second Line Chemotherapy for Patients with Lung Cancer Refractory to First Line Chemotherapy (Now Available) (ID 2662)

      09:45 - 18:00  |  Author(s): Roberto Ferrara

      • Abstract
      • Slides

      Background

      Anti Programmed Death-ligand (PD1/PD-L1) directed immune-checkpoint-inhibitors (ICI) are widely used to treat patients with advanced non-small cell lung cancer (NSCLC) who progress after first line chemotherapy. The best strategy after early progression under first line has not been specifically studied

      Method

      We conducted a multicenter, retrospective study including all consecutive NSCLC patients progressing within the first 3 months following introduction of first-line chemotherapy and being treated with second line ICI monotherapy or chemotherapy between March 2010 and November 2017. We analysed the clinicopathological data and outcome under second line chemotherapy vs. second line ICI: progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).

      Result

      We identified 176 patients with refractory disease, 99 who received subsequent immunotherapy and 77 undergoing chemotherapy. The 2 populations were comparable regarding the main prognostic criteria, median age was 60, main histology was adenocarcimoma (68,2%). Compared to chemotherapy, ICI treated patients had a superior OS (logrank test, p=0.03) (Median [95% CI] OS 4.6 [2.8-6.7] versus 4.2 months [3.4-5.9] and a non-significant improvement in ORR (17.2% and 7.9%, respectively, p = 0.072). PFS was not significantly different (1.9 [1.8-2.1] versus 1.6 months [1.4- ; 2.0] (p=0.125). Poor performance status (ECOG PS≥2) and a higher number of metastatic sites (≥3) were associated with poorer prognosis. KRAS-mutated patients did not seem to benefit more from ICI than chemotherapy.

      Table 1 Multivariable analysis of characteristics associated

      n= 175

      OS

      PFS

      Variable

      HR [CI 95%]

      p value

      HR [CI 95%]

      p value

      Treatment

      0.045

      0.040

      Chemotherapy (ref)

      1.00

      1.00

      Immunotherapy

      0.70 [0.49 ; 0.99]

      0.71 [0.51 ; 0.98]

      Number of metastatic location before 2nd line

      0.005

      0.011

      0-1-2 (ref)

      1.00

      1.00

      3 or +

      1.64 [1.16 ; 2.31]

      1.52 [1.10 ; 2.10]

      Performance Status

      0.038

      0 -1

      1.00

      2 - 3 - 4

      1.46 [1.02 ; 2.09]

      Figure 1 : Kaplan Meier curves for Overall Survival for ICI group and CT group

      figure.png

      Conclusion

      ICI appears to be the preferred second-line treatment for patients who are refractory to first line chemotherapy

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      P1.01-135 - Salvage Chemotherapy After Immunotherapy Failure in Non-Small-Cell Lung Cancer Patients (Now Available) (ID 2490)

      09:45 - 18:00  |  Author(s): Roberto Ferrara

      • Abstract
      • Slides

      Background

      Objective response rate (ORR) to salvage chemotherapy (sCT) in non-small-cell lung cancer (NSCLC) patients failing upfront platinum-based doublets is limited (≈5-15%). Recently, unexpected favorable outcomes have been reported for sCT upon progression to immune checkpoint inhibitors (ICIs) as compared to historical data, with ORR observed in up to 53% and 27% in Asian and Caucasian patients respectively. Few data are available regarding prior response to ICIs and sCT performance, especially in Caucasian patients.

      Method

      All consecutive patients with advanced NSCLC who started ICIs at our institution from Apr 2013 to Dec 2018 were retrospectively reviewed. Patients who underwent sCT after progression to ICIs and had at least one radiological response assessment were included. ORR was calculated as the percentage of complete or partial responses according to RECIST 1.1 as best response. Survivals were estimated with Kaplan-Meier method. Correlation was assessed using Spearman’s test.

      Result

      Out of 283 patients included, 43 received sCT after ICIs. Among them, 29 (67%) had adenocarcinoma and 14 (37%) squamous cell carcinoma. 11 (26%) patients received sCT as second line therapy and 32 (74%) as third or more advanced treatment. sCT regimens included platinum based doublets (14; 32.5%), docetaxel or paclitaxel (20; 46.5%), and other monotherapies such as gemcitabine or vinorelbine (9; 21%). ORR to sCT was 30%. Median progression free survival and overall survival were 3.6 and 8.4 months, respectively. All patients receiving taxanes as sCT had already been treated with platinum based therapy and their ORR to sCT was 40%. ORR to upfront chemotherapy was 50%, while ORR to the last chemotherapeutic regimen prior to ICIs was 35%. ORR to sCT in pretreated patients was non-inferior to that observed in chemo-naïve ones (31% and 27%, respectively). High ORR (25%) was observed even in patients receiving sCT beyond third line. Neither response to ICIs (P=0.36) nor to prior chemotherapeutic regimens (P>0.05) were associated to the likelihood of achieving tumor response to sCT.

      Conclusion

      We provide further evidence that NSCLC patients progressing to ICIs might still benefit from sCT even if heavily pretreated, regardless of sensitivity to ICIs or previous chemotherapy regimens. Further investigations are needed for uncovering bases of increased sensitivity to genotoxic agents in patients with innate or acquired resistance to ICIs and exploiting optimal treatment sequence.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 2
    • 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  |  Presenting Author(s): Roberto Ferrara

      • 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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      P1.04-38 - Efficacy and Safety of Immunotherapy in Elderly Patients with Non-Small Cell Lung Cancer (Now Available) (ID 1383)

      09:45 - 18:00  |  Author(s): Roberto Ferrara

      • Abstract
      • Slides

      Background

      Most trials with Immune Checkpoint Inhibitors (ICIs) for Non-Small Cell Lung Cancer (NSCLC) included only small subgroups of patients (pts) aged ≥65. As NSCLC is often diagnosed in pts aged ≥70, real-world data about efficacy and safety of IO in elderly pts are essential.

      Method

      We retrospectively collected data about all pts with advanced NSCLC treated with IO at our Institution between April 2013 and March 2019. All ICIs administered for ≥1 cycle were admitted. Pts were stratified for age as follows: <70 year-old (yo), 70-79 yo, ≥80 yo. Chi-square test was used to compare qualitative variables. Survival was estimated with Kaplan-Meier method. Log-rank test was used to compare curves. Multivariate analyses were performed with Cox model.

      Result

      We reviewed 290 cases, with a median age of 67 (range: 29-89). Pts aged<70, 70-79 and ≥80 yo were 180, 94 and 16, respectively. Two hundred five pts received an anti-PD1, 77 an anti-PDL1, 8 an anti-CTLA4 or a combo-IO. Clinical/pathological variables were uniformly distributed across age classes, except for a higher rate of males (p 0.0228) and squamous histology (p 0.0071) in the intermediate class. Response Rate (RR) was similar across age groups (21.5% vs 22.3% vs 18.8% for pts aged<70 vs 70-79 vs ≥80 yo, respectively; p 0.9470). Median PFS did not differ according to age (2.8 vs 3.5 vs 2.6 mos for pts aged<70 vs 70-79 vs ≥80 yo, respectively; p 0.2020). Similarly, median OS was similar across age classes (9.1 vs 11.3 vs 9.6 mos for pts aged<70 vs 70-79 vs ≥80 yo, respectively; p 0.9144). These results did not change after stratification for sex (p 0.516 for PFS, p 0.5154 for OS) and histology (p 0.9057 for PFS, p 0.1002 for OS). The incidence of toxicity was comparable across subgroups (grade ≥2 adverse events in 35.8% vs 32.7% vs 37.5% for pts aged<70 vs 70-79 vs ≥80 yo, p 0.6493). The only variables influencing outcome at both univariate and multivariate analyses were performance status (p<0.0001 for PFS, p 0.0192 for OS), number of metastatic sites (p 0.0842 for PFS, p 0.0235 for OS) and IO line (p<0.0001 for both PFS and OS), regardless age group.

      Conclusion

      Advanced age is apparently not associated to a reduced efficacy of IO in our case series. Furthermore, no toxicity concern emerges even among the eldest pts. Therefore, to our opinion ICIs should be considered irrespective of age, provided an optimal PS at baseline. Of note, IO is often the only therapeutic option applicable to these cases considering the toxicity of chemotherapy.

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    P2.09 - Pathology (ID 174)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.09-05 - Clinical and Biological Characterization of Lung Enteric Adenocarcinoma (Now Available) (ID 1650)

      10:15 - 18:15  |  Author(s): Roberto Ferrara

      • Abstract
      • Slides

      Background

      Lung Enteric Adenocarcinoma (LEA) is a rare and poorly characterized variant of Lung Adenocarcinoma (LA), defined by an intestinal differentiation in ≥50% of tumor and ≥1 colorectal biomarker at Immunohistochemistry.

      Method

      We retrospectively identified the cases of LEA diagnosed at Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy between 01/2013 and 12/2018. Next Generation Sequencing was performed with IonTorrent (ThermoFisher Scientific, Life Technologies) by using the commercial Hot Spot Cancer Panel (HCP) on DNA derived from formalin-fixed paraffin-embedded tissues. ALK and ROS-1 status was assessed with fluorescent in situ hybridization. PD-L1 expression was determined with DAKO22C3 assay. Biological data obtained from our cases were compared with those reported in Tumor Cancer Genome Atlas (TCGA) for LA, restricting the comparison only to the genes targeted by HCP.

      Result

      We identified 38 LEA cases. Main clinical and biological characteristics of the two populations are detailed in the table.

      Variable/

      gene mutation

      INT LEA (N=38)

      TCGA LA (N=660)

      %

      %

      Gender

      Female

      34.1

      51.9

      Male

      65.9

      47.9

      Unknown

      0

      0.2

      Smoking status

      Former/current

      76.3

      78.9

      Never

      15.8

      14.1

      Unknown

      7.9

      7.0

      Disease stage

      I

      2.6

      51.6

      II

      2.6

      23.0

      III

      28.9

      16.4

      IV

      65.9

      4.7

      Unknown

      0

      4.3

      TP53

      52.6

      54.1

      KRAS

      34.2

      32.4

      STK11

      23.7

      15.8

      CDKN2A

      15.8

      3.9

      APC

      7.9

      4.8

      CTNNB1

      7.9

      3.8

      EGFR

      7.9

      15.8

      KIT

      5.3

      2.1

      PI3KCA

      5.3

      5.9

      SMAD4

      5.3

      4.1

      ATM

      2.6

      8.9

      BRAF

      2.6

      8.2

      FGFR

      2.6

      0.8

      GNAS

      2.6

      3.8

      NRAS

      2.6

      0.6

      PDGFRA

      2.6

      7.4

      RB1

      2.6

      5.8

      SMO

      2.6

      2.7

      Neither ALK nor ROS-1 rearrangements were detected in our case series. PD-L1 was negative in 23 cases, 1-49% in 9 cases, not evaluable in 6 cases. Microsatellite were stable except for 3 cases with low instability and 3 not evaluable cases.

      Conclusion

      Our series of LEA was small and differed from TCGA LA for a higher proportions of males and metastatic disease. Given these limitations, our LEA genetic profile showed some difference from that of TCGA LA. In particular, LEA showed a higher incidence of STK11, CTNNB1, FGFR, NRAS, KIT and CDKN2A mutations, and a lower incidence of ATM, BRAF, PDGFRA, RB-1 and EGFR mutations. PD-L1 expression, ALK and ROS-1 rearrangements were lower than literature data in LA. Most cases were microsatellite stable. In conclusion, further research is needed to understand the biology of LEA, which seems partially different from common LA.

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