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Diego Signorelli

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    MA14 - The Adequate MTarget Is Still the Issue (ID 140)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 12
    • Now Available
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      MA14.01 - Clinical and Genomic Features of Chinese Lung Cancer Patients with Germline Mutations (Now Available) (ID 682)

      15:45 - 17:15  |  Presenting Author(s): Wenying Peng  |  Author(s): Jin Li, Lian-peng Chang, Jing Bai, Yanyan Zhang, Yan-Fang Guan, Xingxiang Pu, Meilin Jiang, Jun Cao, Bolin Chen, Xuefeng Xia, Xin Yi, Jianjun Zhang, Lin Wu

      • Abstract
      • Presentation
      • Slides

      Background

      Recent studies on next generation sequencing (NGS) data from cancer patients have demonstrated that germline mutations in genetic predisposition genes were more common than previous known in many cancer types including lung cancer. However, most previous studies have focused on western patient population and the germline mutation landscape in Asian lung cancer patients and the clinical and genomic features in these patients are largely unknown.

      Method

      NGS data from a targeted panel of 1,021 known cancer genes from paired cancer and germline DNA of 1,797 Chinese lung cancer patients was analyzed to identify pathogenic or likely pathogenic (P/LP) germline variants in predisposition genes based on American College of Medical Genetics and Genomics (ACMG) 2015 guideline.

      Result

      Totally, 5.95% of lung patients were found to harbor germline variants in 35 cancer predisposition genes. The prevalence of germline mutations was higher in patients under 40 compared to older counterparts (10.1% vs 5.74%, p=0.103, Chi-Square test ) although it did not reach statistical significance. However, germline BRCA1/2 mutations were associated with earlier age of onset (median 52.5 vs 60 years-old, p=0.0080 by Mann-Whitney test). Furthermore, patients with P/LP germline mutations had significantly more somatic mutations in KRAS (p=0.012, fisher’s exact test) and c-MET (p=0.018, fisher’s exact test) oncogenes, but less in tumor suppressor gene TP53 (p=0.019, fisher’s exact test). Compared to western lung cancer patients enrolled in TCGA, P/LP germline mutations in BRCA2, FANCA, ATM, MUTYH, BLM, TP53, BRCA1, CHEK2, PMS2, NBN and FANCC were identified in both current Chinese cohort and TCGA cohort with BRCA2 germline mutations significantly more common in Chinese cohort than TCGA cohort (p=0.015, Fisher’s exact test). In addition, RAD51D, FANCD2, BRIP1, MSH6, PMS1, PALB2, RAD51C, SDHA, TSC2, BAP1, CDH1, FLCN, NF1 and RUNX1) were exclusively identified in Chinese patients, while RET, ERCC3, FANCG and VHL were only detected in TCGA cohort.

      Conclusion

      These results implied that there might be both common and unique cancer predisposition germline mutations for lung cancer between Asian and Western patient populations.

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      MA14.02 - Entrectinib in Patients with ROS1-Positive NSCLC or NTRK Fusion-Positive Solid Tumors with CNS Metastases (Now Available) (ID 1631)

      15:45 - 17:15  |  Presenting Author(s): Luis Paz-Ares  |  Author(s): Rafal Dziadziuszko, Alexander Drilon, Tom John, Matthew G Krebs, George Demetri, Alice T. Shaw, Salvatore Siena, Juergen Wolf, Anna F Farago, Brian Simmons, Chenglin Ye, Xinhui Huang, Robert C. Doebele

      • Abstract
      • Presentation
      • Slides

      Background

      Entrectinib potently inhibits kinases encoded by NTRK and ROS1 genes. It achieves therapeutic levels in the CNS with antitumor activity in intracranial tumor models. We report integrated analysis data (31 May 2018 data cut-off) from three Phase 1/2 entrectinib trials (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]) for a large cohort of adult patients with NTRK fusion-positive solid tumors (NTRK+) or ROS1 fusion-positive NSCLC (ROS1+), with baseline CNS metastases.

      Method

      Patients had locally advanced/metastatic NTRK+ solid tumors or ROS1+ NSCLC by nucleic acid-based assays confirmation. Baseline CNS metastases were identified by CT/MRI. Tumor assessments were performed at baseline, week 4, and then every 8 weeks by blinded independent central review (RECIST v1.1). Primary endpoints were overall response rate (ORR), duration of response (DOR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), intracranial efficacy in patients with CNS metastases, safety.

      Result

      Most patients were treated first-line or after one line of prior therapy; baseline characteristics relating to measurable CNS metastases for patients with NTRK+ solid tumors and ROS1+ NSCLC are presented (Table). Intracranial outcomes for the NTRK+ solid tumors (n=54; 18% NSCLC) and ROS1+ NSCLC (n=53) efficacy evaluable populations are reported (Table). Durability of treatment effect and potential delayed progression in the CNS was observed; time to CNS progression was 17.0 months (95% CI: 14.3–NE) for NTRK+ solid tumor patients and NE (95% CI: 15.1–NE) for ROS1+ NSCLC. In the subset of patients with NTRK+ NSCLC (n=10), 6 patients had CNS metastases at baseline (by BICR); IC-ORR was 66.7% (4/6), 2 CR; IC-DOR was NE. In both the NTRK+ and ROS1+ populations, entrectinib was tolerable with a manageable safety profile; most treatment-related AEs were grade 1–2.

      Conclusion

      Entrectinib induced clinically meaningful durable responses in patients with NTRK+ solid tumors or ROS1+ NSCLC with CNS disease at baseline.

      Funding: This study was funded by F. Hoffmann-La Roche

      table.jpg

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      MA14.03 - EGFR M+ Subgroup of Phase 1b Study of Telisotuzumab Vedotin (Teliso-V) Plus Erlotinib in c-Met+ Non-Small Cell Lung Cancer (Now Available) (ID 1622)

      15:45 - 17:15  |  Presenting Author(s): D. Ross Camidge  |  Author(s): Fabrice Barlesi, Jonathan Goldman, Daniel Morgensztern, Rebecca S Heist, Everett E. Vokes, Alex Spira, Eric Angevin, Wu-Chou Su, David S. Hong, John H. Strickler, Monica Motwani, Zhaowen Sun, Apurvasena Parikh, Philip Komarnitsky, Jun Wu, Karen Kelly

      • Abstract
      • Presentation
      • Slides

      Background

      Telisotuzumab vedotin (ABBV-399; teliso-v) is an anti-c-Met antibody conjugated with monomethyl auristatin E, a tubulin polymerization inhibitor. Preliminary activity was reported for the teliso-v + erlotinib combination in c-Met overexpressing (c-MET+) non-small cell lung cancer (NSCLC) patients, with an activating EGFR mutation and for whom prior EGFR TKI failed. We present mature data from the EGFR M+ subgroup of the teliso-v + erlotinib cohort of a phase 1b study (NCT02099058).

      Method

      Teliso-v was administered at 2.4 mg/kg (dose-escalation phase) or 2.7 mg/kg intravenously once every 3 weeks, and erlotinib at 150 mg orally once a day/prior tolerated dose in adult patients with advanced NSCLC. For efficacy analysis, c-Met+ was defined as central lab IHC H-score ≥150 or local lab MET amplification (MET/CEN7 ≥2); EGFR M+ was defined as del19 or L858R by local lab. Pharmacokinetics were assessed. All patients who received teliso-v + erlotinib were evaluated for safety.

      Result

      As of Dec 2018, 42 NSCLC patients received teliso-v + erlotinib; 37 were c-MET+ (36 evaluable: 35 H-score≥150, 1 MET amplified). Median age was 65 years, 25 patients (69%) had ECOG PS 1, 29 (81%) were EGFR M+ (of these: 48% had T790M, 10% had MET amplification, 3% had polysomy, 97% had prior EGFR TKI, 55% 3rd-generation TKI, 69% TKI as last prior therapy, and 62% platinum doublet). All-grade (≥20%) adverse events (AEs) were dermatitis acneiform (38%), diarrhea (36%), peripheral motor/sensory neuropathy (52%; 7% Grade 3), dyspnea, fatigue, hypoalbuminemia (31% each), decreased appetite, nausea (24% each), asthenia, vomiting (21% each). Grade ≥3 (≥10%) AE: pulmonary embolism (14%). Pharmacokinetics of teliso-v for the combination were similar to single-agent teliso-v. The table presents efficacy data.

      Patients with EGFR mutation
      (n=29)

      Objective response rate*, % (95% CI)
      Complete response, n

      34.5 (17.9, 54.3)
      1

      Median duration of response, months
      (95% CI)

      NR
      (2.8, NE)

      Median PFS, months (95% CI)

      NR
      (2.8, NE)

      Median follow-up, months 4
      6-month PFS rate, % (95% CI)

      51 (30, 69)

      Median treatment duration, month (range)
      Teliso-v
      Erlotinib


      3.5 (0.71–10.4)
      5.3 (0.71–25.4)

      Objective response rate by subgroup of interest, n (%)
      Received prior 3rd generation EGFR TKI
      C-met amplified, copy number gain, or polysomy
      EGFR TKI-containing regimen as last-line therapies


      6/16 (37.5)
      5/7 (71.4)
      8/20 (40.0)

      *RECIST version 1.1.

      EGFR, epidermal growth factor receptor; NE, not estimable; NR, not reached; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; TKI, tyrosine kinase inhibitor;

      Conclusion

      These data suggest acceptable safety and promising activity of teliso-v + erlotinib in patients with c-Met+ NSCLC with an activating EGFR mutation and for whom EGFR TKI has failed.

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      MA14.04 - Discussant - MA14.01, MA14.02, MA14.03 (Now Available) (ID 3777)

      15:45 - 17:15  |  Presenting Author(s): Yuichiro Ohe

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      • Abstract
      • Presentation
      • Slides

      Background

      Fruquintinib, an orally active kinase inhibitor that selectively targets vascular endothelial growth factor (VEGF) receptor, demonstrated significant benefit in progression-free survival and disease control in a randomized Phase II study in patients with non-small-cell lung cancer (NSCLC) who had failed two lines of chemotherapy. This Phase III FALUCA trial is a randomized, double-blind, placebo-controlled, multicenter trial designed to confirm the efficacy in the same patient population (NCT02691299).

      Method

      From December 2015 to February 2018, 45 clinical centers across China participated in the trial. A total of 730 patients aged 18-75 with advanced NSCLC who had failed two lines of chemotherapy were screened and 527 who met the eligibility criteria were enrolled into the study. Patients were stratified based on epidermal growth factor receptor mutation status and prior use of VEGF inhibitor therapy, and were randomized in a 2:1 ratio to receive fruquintinib (n=354) or placebo (n=173) once daily in a 3 weeks on/1 week off 4-week cycle. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response. The final data cutoff was on September 21, 2018.

      Result

      Median OS was 8.94 months for fruquintinib and 10.38 months for placebo (hazard ratio, 1.02; 95% CI, 0.816 to 1.283; p=0.841). Median PFS was 3.68 months for fruquintinib comparing to 0.99 months for placebo, respectively (hazard ratio, 0.34; 95%CI, 0.279 to 0.425; p<0.001). The ORR and DCR were 13.8% and 66.7% for fruquintinib, compared with 0.6% and 24.9% for placebo (both p<0.001), respectively. The most frequent treatment-emergent adverse events with fruquintinib (≥grade 3) were hypertension (20.7%), hand-foot syndrome (11.0%), and proteinuria (1.4%). A sensitivity analysis revealed that median OS was significantly prolonged with fruquintinib compared with placebo in patients who received no subsequent systemic anti-tumor therapies (7.00 months versus 5.06 months ; hazard ratio, 0.64; 95%CI, 0.453 to 0.903; p=0.010).

      Conclusion

      The FALUCA trial failed to meet the primary end point of OS while confirming significant benefit in secondary end points including PFS, ORR and DCR. The safety profile of fruquintinib in this patient population was acceptable and consistent with that identified in the Phase II study. A post-hoc sensitivity analysis revealed that the anti-tumor therapies that patients received post disease progression probably contributed to the failure of this study on the primary end point.

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      MA14.06 - Nintedanib-Docetaxel in 2nd Line Treatment in No Squamous Non-Small Cell Lung Cancer Patients, Refractory to First Line Treatment (GFPC02-15) (Now Available) (ID 558)

      15:45 - 17:15  |  Presenting Author(s): Alain Vergnenegre  |  Author(s): Jean Bernard Auliac, Isabelle Monnet, acya Bizieux, Laurent Greillier, Lionel Falchero, Gilles Robinet, Regien Lamy, Pierre-Alexandre Hauss, Florian Guisier, Hervé Lena, Christos Chouaid

      • Abstract
      • Presentation
      • Slides

      Background

      Second line chemotherapy used in advanced Non Small Cell Lung Cancer (NSCLC) have demonstrated a slight survival benefit in patient refractory to a first line platinum based doublet chemotherapy. In exploratory analysis, Nintedanib in combination with docetaxel have shown interesting result in second line setting for refractory NSCLC patients.

      Objective: To assess the efficacy in terms of progression-free survival (PFS) of the nintedanib - docetaxel combination in second-line treatment in refractory no squamous NSCLC (NsqNSCL) patients

      Method

      This prospective, multicentric open-label phase II trial, included patients with advanced Nsq NSCLC (EGFR, ALK wild-type), PS 0-1, progressing during the first four cycles of cisplatin-based induction chemotherapy. Patients received Nintedanib (200 mg X2 /d d2-d20)- Docetaxel (75 mg/m2 d1-d21) combination until progressive disease or unacceptable toxicity.

      The primary endpoint was the PFS rate at 12 weeks. Secondary endpoints included median PFS, median overall survival (OS), overall response rate (ORR) and tolerability. Based on a A’Hern’s single-stage phase II design trial (sample size determination is based on exact binomial distribution), the Nintedanib-Docetaxel strategy will be rejected if the primary endpoint was below 22/53 patients at the end of study.

      Result

      The analysis included 53 evaluable patients managed in 21 centers; last patient included at the end of January 2019. Mean age 58.4 years, male 73 %, adenocarcinoma 97.5%, current/former smokers: 42/50 %, PS 0/1: 25%/75%; weight loss >5% : 19%, stage IV: 100% (38% with brain metastasis, median metastasis 2). All patients received for induction chemotherapy, a platin doublet (22% with bevacizumab), number of cycle 1-2/ 3-4: 57%/ 43%.

      Interim analysis reviewed by the independent committee conducted as planned, after the 27 first inclusions concluded that there was no sign of unexpected toxicity (adverse events grade 3-4 :22%, grade 5 :0%) or futility (9 patients meet primary end point on 25 evaluable). The results of the final analysis on the whole population (PFS at 12 weeks (primary end point), median PFS, median OS and toxicity) will be presented at the meeting

      Academic grant from Boehringer Ingelheim

      Conclusion

      Section not applicable

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      MA14.07 - Phase I Expansion Cohort of Ramucirumab Plus Pembrolizumab in Advanced Treatment-Naïve Non-Small Cell Lung Cancer (JVDF) (Now Available) (ID 209)

      15:45 - 17:15  |  Presenting Author(s): Roy S. Herbst  |  Author(s): Hendrik Tobias Arkenau, Johanna Bendell, Edward Arrowsmith, Martin Wermke, Andres Soriano, Nicolas Penel, Rafael Santana-Davila, Helge Bischoff, Ian Chau, Bo Chao, David Ferry, Gu Mi, Luis Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Background

      Emerging data suggest blockade of vascular endothelial growth factor receptor 2 (VEGFR-2) with ramucirumab (R) and programmed cell death 1 protein (PD-1) with pembrolizumab (P) has anti-tumor activity. The JVDF study (NCT02443324) evaluated the safety and efficacy of R+P in locally advanced and unresectable or metastatic gastric/gastroesophageal junction adenocarcinoma, non-small cell lung cancer (NSCLC), urothelial carcinoma, and biliary tract cancer. Data from NSCLC patients receiving R+P as first-line therapy are reported.

      Method

      Eligible patients had treatment-naïve, PD-L1 positive, histopathologically confirmed nonsquamous or squamous NSCLC and received R 10 mg/kg and P 200 mg on Day 1 every 21 days for up to 35 cycles until confirmed disease progression or discontinuation for other reasons. Response and progression were assessed using RECIST 1.1 with confirmatory scans. PD-L1 was assessed using the PD-L1 IHC 22C3 pharmDx assay; PD-L1 positivity was defined as a tumor proportion score (TPS) ≥1%.

      Result

      As of August 31, 2018, 26 patients were treated. Baseline characteristics were as expected for an advanced, treatment-naïve population. Median follow-up was 17.4 (13.4, 20.1) months. Adverse events were consistent with R+P, with no additive toxicities. Eleven (42.3%) patients experienced Grade ≥3 treatment-related adverse events (TRAEs), most commonly hypertension (15.4%) and myocardial infarction (7.7%). No patients discontinued because of TRAEs; the two on-study deaths were due to disease progression. Efficacy results are shown in the table.

      table.jpg

      Conclusion

      In previously untreated NSCLC, R+P has a manageable safety profile and is active in patients with PD-L1 expression. Updated results will be presented at the meeting. Randomized trials in this population are warranted.

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      MA14.08 - Discussant - MA14.05, MA14.06, MA14.07 (Now Available) (ID 3778)

      15:45 - 17:15  |  Presenting Author(s): Mirjana Rajer

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA14.09 - Real-World Survival of Relapsed Compared to De-Novo Stage IV Diagnosis of Advanced Non-Small Cell Lung Cancer (Now Available) (ID 529)

      15:45 - 17:15  |  Presenting Author(s): Katie Kerrigan  |  Author(s): Benjamin Haaland, Blythe Adamson, Shiven Patel, Wallace Akerley

      • Abstract
      • Presentation
      • Slides

      Background

      Differences in tumor biology and cancer therapy in early stage lung cancer may affect overall survival (OS) of patients with relapsed stage IV disease compared to others with de-novo stage IV disease. This study aimed to compare real-world survival of these patients.

      Method

      We selected patients with advanced NSCLC diagnosed between 2011 and 2017, who received at least one line of therapy, from the US Flatiron Health electronic health record-derived database. Patient data was collected through June 2018, providing at least 6 months of follow-up.

      OS was defined as time from advanced or metastatic diagnosis to the event of death, censored at last clinic visit or end of oral therapy. The unadjusted OS of patients was estimated using the Kaplan-Meier method. We fit multivariable Cox proportional hazards models to compare the hazard of death between groups.

      Result

      de-novo vs relapsed image final.jpg

      The study included 30,310 patients with median age of 68.8 years, 46.7% female, and 76.8% non-Hispanic white. We observed 22.8% had relapsed and 77.2% were de-novo stage IV. Relapsed patients had median OS of 15.5 months (95% CI: 14.9-16.2). Patients with de-novo stage IV had median overall survival of 12.0 months (95% CI: 11.7-12.2). The force of mortality among relapsed stage IV patients was 24% lower than the rate of death among de-novo stage IV patients (Hazard Ratio [HR]: 0.76; 95% CI 0.73-0.79; p <0.001), adjusting for age, gender, state, histology, smoking, race/ethnicity, and stratifying by year of diagnosis. Sensitivity analyses of an unadjusted model (HR 0.79, p <0.001) and a sub-group analysis of patients with advanced diagnoses in 2016-2017 (HR 0.74, p <0.001) suggested the results were robust.

      Conclusion

      Among patients with stage IV NSCLC that received at least one treatment, those who relapsed had better OS than those who presented with de-novo stage IV disease. These findings have implications for future clinical trial design.

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      MA14.10 - Clinical Outcomes in Metastatic Squamous Lung Cancer with Targetable Driver Alterations (Now Available) (ID 527)

      15:45 - 17:15  |  Presenting Author(s): Whitney Elizabeth Lewis  |  Author(s): George R Simon, Frank E Mott, Vassiliki A Papadimitrakopoulou, Waree Rinsurongkawong, Jeff Lewis, Jack Lee, Jack Roth, Stephen Swisher, John Victor Heymach, Jianjun Zhang, Vincent Lam

      • Abstract
      • Presentation
      • Slides

      Background

      Genomic profiling is not routinely performed for metastatic squamous (SCC) and adenosquamous (ASC) NSCLC. However molecular profiling may be ordered if demographic features suggest a higher likelihood of a targetable driver alteration (e.g. never or remote smoking history). Response and survival data are scant in pts with actionable alterations treated with targeted therapy.

      Method

      We reviewed the clinical data and molecular profiling (FISH, PCR, tissue NGS, ctDNA) of metastatic SCC and ASC pts treated at our institution from Feb 2010-Dec 2018. Pts with typical sensitizing mutations in EGFR or BRAF V600E or fusions in ALK or ROS1 treated with matched targeted therapy for ≥ 2 months were included in this analysis. Response assessment was based on RECIST v1.1.

      Result

      Among 261 metastatic SCC or ASC pts with available molecular profiling, 16 total pts (6%) were found to have actionable targets, consisting of 13 SCC and 2 ASC (median age 53, 81% female, 88% never-smoker). The distribution of driver alterations in this cohort was 56% (9/16) EGFR ex19del/L858R/G719A, 38% (6/16) ALK fusion, and 6% (1/16) BRAF. The overall objective response rate (ORR) and median progression free survival (PFS) to targeted therapy was 69% and 5.2 months respectively. By mutational subgroup, ORR was 67% (6/9) for EGFR, 67% (4/6) for ALK, and 100% (1/1) for BRAF. Median PFS was only 4.5 months (95% CI 3.0 – 6.0) for EGFR pts and 2.8 months (95% CI 0 – 6.4) for ALK pts, and the lone BRAF pt had a PFS of 8.5 months. In EGFR pts with available NGS, co-mutations in TP53 (75% [6/8]) and PIK3CA (38% [3/8]) were seen at rates higher than previously reported in EGFR+ ADC (TP53 55%, PIK3CA 12%; Blakely et al, Nat Gen 2017). In ALK pts with available NGS, co-mutations in TP53 (80% [4/5]) were also higher than recently reported in ALK+ ADC (24%; Kron et al, Ann Oncol 2018).

      Conclusion

      Despite initial responses comparable to those previously reported in ADC, matched targeted therapy in pts with SCC and ASC histology is associated with shorter PFS. A higher prevalence of adverse co-mutations such as TP53 and PIK3CA may contribute to early targeted therapy resistance in these histologies. These findings may have implications for the use of targeted therapy in squamous lung cancer.

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      MA14.11 - CareTrack: An Application-Based Method of Documentation for Improving Patient Communication in Cancer Care (Now Available) (ID 1933)

      15:45 - 17:15  |  Presenting Author(s): Jawaid Younus  |  Author(s): Jacques Raphael, Phillip Blanchette, Fahad Khan, Vineet Sharma, Morgan Black, Mark Vincent, Sara Kuruvilla, Michael Sanatani

      • Abstract
      • Presentation
      • Slides

      Background

      Patients being able to accurately understand and recall medical information correctly has been shown to improve outcomes, however, most studies suggest that patient information understanding in oncology tends to be poor with as much as 40-80% of information being relayed by healthcare professionals being forgotten (Kessels, 2003).

      Method

      Our study aimed to implement the use of ‘CareTrack’, an easy-to-use iPad application, as a simple yet complete app-based information package that provides an appointment summary sheet with no identifying information for patients to take home. An iPad pre-loaded with the CareTrack application was provided to oncologists and they filled in the form for their patients at the end of the initial consultation for lung cancer. A hard printout copy was provided to the patient to take home and the option of an email copy was sent as well. Approximately one-week later a patient satisfaction questionnaire was administered over the phone to patients who participated in the study.

      Result

      Six oncologists were recruited to the study with 35 patients consented to the study and 25 of these patients completing the follow-up surveys. Our primary objective was to assess feasibility of the CareTrack application. The average physician time to complete the CareTrack form for each patient was 1 minute and 29 seconds thus demonstrating that this is a quick and easy tool for physician use. Our secondary objective was to assess patient satisfaction with a brief survey. Ninety-six percent (24/25) of patients found the CareTrack information provided useful and 100% (25/25) of patients found the information easy to understand. Most patients did not require frequent review of the CareTrack form (28%, 7/25) nor needed the form to remember the information (56%, 14/25) or when discussing diagnosis/stage/treatment at home (44%, 11/25). Importantly, 96% (24/25) of patients were comfortable seeing their cancer information and treatment plan displayed on the CareTrack tool and 84% (21/25) of patients would like to receive additional CareTrack information in the future if their staging and/or treatment planned is changed/updated.

      Conclusion

      To conclude, the CareTrack application was found to be easy to use and was able to effectively provide new lung cancer patients with a comprehensive yet easy-to-understand summary of their initial consult. In the future, we envision this project expanding province- and nation-wide as well as expanding to other disease sites (e.g. breast, colorectal etc.).

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      MA14.12 - Discussant - MA14.09, MA14.10, MA14.11 (Now Available) (ID 3779)

      15:45 - 17:15  |  Presenting Author(s): Virginie Westeel

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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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: 8
    • Now Available
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      OA14.01 - KEYNOTE-024 3-Year Survival Update: Pembrolizumab vs Platinum-Based Chemotherapy for Advanced Non–Small-Cell Lung Cancer (ID 1465)

      11:30 - 13:00  |  Presenting Author(s): Martin Reck  |  Author(s): Delvys Rodríguez-Abreu, Andrew G. Robinson, Rina Hui, Tibor Csőszi, Andrea Fülöp, Maya Gottfried, Nir Peled, Ali Tafreshi, Sinead Cuffe, Mary O'Brien, Suman Rao, Katsuyuki Hotta, Tara Garay, Erin Jensen, Victoria Ebiana, Julie R. Brahmer

      • Abstract
      • Slides

      Background

      In the phase 3 KEYNOTE-024 trial (NCT02142738), first-line pembrolizumab significantly improved PFS (hazard ratio [HR] 0.50, P<0.001) and OS (HR 0.60, P=0.005) vs platinum-based chemotherapy in patients with advanced NSCLC, PD-L1 tumor proportion score (TPS) ≥50%, and no targetable EGFR/ALK alterations (median follow-up, 11.2 months). We present data with 3-years minimum follow-up.

      Method

      Patients were randomized to pembrolizumab 200 mg Q3W for 2 years or platinum doublet (investigator’s choice) for 4‒6 cycles plus optional maintenance (nonsquamous), with stratification by ECOG PS (0/1), tumor histology (squamous/nonsquamous), and region (East Asia/non‒East Asia). Patients in the chemotherapy arm could cross over to pembrolizumab upon disease progression if they met eligibility criteria. The primary endpoint was PFS; OS was a key secondary endpoint. Response per investigator by RECIST version 1.1 is reported.

      Result

      305 patients were randomized (pembrolizumab, n=154; chemotherapy, n=151). At data cutoff (February 15, 2019), median (range) follow-up was 44.4 (39.6‒52.9) months. 210 patients had died (pembrolizumab, n=97; chemotherapy, n=113). 98 (64.9%) patients crossed over from chemotherapy to anti‒PD-(L)1 therapy during/outside of the study. Median (95% CI) OS in the pembrolizumab arm was 26.3 (18.3‒40.4) months vs 14.2 (9.8‒18.3) months in the chemotherapy arm (HR, 0.65; 95% CI, 0.50‒0.86). 36-month OS rate was 43.7% in the pembrolizumab arm vs 24.9% in the chemotherapy arm. Despite longer mean treatment duration in the pembrolizumab arm (11.1 vs 4.4 months), grade 3‒5 treatment-related adverse events (AEs) were less frequent with pembrolizumab vs chemotherapy: 31.2% vs 53.3%. 38 patients in the pembrolizumab arm completed 2 years (35 cycles) of therapy. Among these, 34 were alive, 31 (81.6%) had an objective response (including 3 with complete response), and median duration of response was not reached (range, 4.2‒46.7+ months). OS rate 12 months after completing pembrolizumab treatment (ie, ~36 months after initiating treatment) was 97.4% (95% CI, 82.8‒99.6). Among the 38 patients who completed 2 years, 5 (13.2%) had treatment-related grade 3-4 AEs; no fatal treatment-related AEs occurred. 10 patients who completed 2 years (1 completed 34 cycles) and subsequently progressed received second-course pembrolizumab; 7 had an objective response, 8 remain alive.

      Conclusion

      With >3 years’ follow-up, first-line pembrolizumab monotherapy continued to provide durable long-term OS benefit vs chemotherapy despite a majority of patients assigned to chemotherapy crossing over to pembrolizumab. Pembrolizumab was associated with less toxicity than chemotherapy. Patients who completed 35 cycles of pembrolizumab had durable clinical benefit and most were alive at data cutoff.

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      OA14.02 - IMpower131: Final OS Results of Carboplatin + Nab-Paclitaxel ± Atezolizumab in Advanced Squamous NSCLC (ID 1915)

      11:30 - 13:00  |  Presenting Author(s): Federico Cappuzzo  |  Author(s): Robert Jotte, Ihor Vynnychenko, Daniil Stroyakovskiy, Delvys Rodriguez Abreu, Maen Hussein, Ross Soo, Henry J Conter, Toshiyuki Kozuki, KC Huang, Vilma Graupner, Shawn Sun, Tien Hoang, Helen Jessop, Mark McCleland, Marcus Ballinger, Alan Sandler, Mark A Socinski

      • Abstract
      • Slides

      Background

      IMpower131 (NCT02367794) is a randomised Phase III trial of atezolizumab + chemotherapy vs chemotherapy alone as first-line therapy in Stage IV squamous NSCLC. Here we report the final OS results (Arm B vs Arm C).

      Method

      Enrolled patients were randomised 1:1:1 to Arm A (atezolizumab 1200 mg q3w + carboplatin AUC 6 q3w + paclitaxel 200 mg/m2 q3w), Arm B (atezolizumab + carboplatin + nab-paclitaxel 100 mg/m2 qw) or Arm C (carboplatin + nab-paclitaxel) for 4 or 6 cycles followed by atezolizumab maintenance therapy (Arms A and B) until loss of clinical benefit or progressive disease. Coprimary endpoints were investigator-assessed PFS and OS in the ITT population. Data cutoff: October 3, 2018.

      Result

      1021 patients were enrolled, with 343 in Arm B and 340 in Arm C. Median age was 65 years (range, 23-83 [Arm B] and 38-86 [Arm C]) and ≈80% of patients were male. The proportion of patients with high (14% vs 13%), positive (39% vs 37%) or negative (47% vs 50%) PD-L1 expression was similar between arms. Median OS in the ITT population was 14.2 months in Arm B vs 13.5 months in Arm C (HR, 0.88 [95% CI: 0.73, 1.05]; P = 0.158; Table), not crossing the boundary for statistical significance. In the PD-L1–high subgroup, median OS was 23.4 vs 10.2 months, respectively (HR, 0.48 [95% CI: 0.29, 0.81]; not formally tested). Treatment-related Grade 3-4 AEs and treatment-related SAEs occurred in 68.0% and 21.0% (Arm B) and 57.5% and 10.5% (Arm C) of patients; no new safety signals were identified, consistent with previous analyses.

      Conclusion

      Final OS in Arm B vs C did not cross the boundary for statistical significance. Clinically meaningful OS improvement was observed in the PD-L1–high subgroup, despite not being formally tested. No new or unexpected safety signals were reported.

      Arm B

      Atezolizumab + Carboplatin
      + Nab-Paclitaxel

      (n = 343)

      Arm C

      Carboplatin +
      Nab-Paclitaxel

      (n = 340)

      HR (95% CI)

      Median OS, mo

      ITT

      14.2

      13.5

      0.88 (0.73, 1.05); P = 0.16

      PD-L1 high (TC3 or IC3)

      23.4

      10.2

      0.48 (0.29, 0.81)

      PD-L1 positive (TC1/2/3 or IC1/2/3)

      14.8

      15.0

      0.86 (0.67, 1.11)

      PD-L1 negative (TC0 or IC0)

      14.0

      12.5

      0.87 (0.67, 1.13)

      Median PFS, mo

      6.5

      5.6

      0.75 (0.64, 0.88)

      Confirmed ORR, n/N (%)a

      170/342 (49.7)

      139/339 (41.0)

      a Patients were classified as missing or unevaluable when no post-baseline response assessments were available or all post-baseline response assessments were unevaluable.

      CI, confidence interval; HR, hazard ratio; IC, tumour-infiltrating immune cell; ITT, intention-to-treat; OS, overall survival; ORR, objective response rate; PD-L1, programmed death-ligand 1; PFS, progression-free survival; TC, tumour cell.
      TC3 or IC3: PD-L1 expression on ≥50% of TC or ≥10% of IC; TC1/2/3 or IC1/2/3: PD-L1 expression on ≥1% of TC or IC; TC0 and IC0: PD-L1 expression on <1% of TC and IC.

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      OA14.03 - Clinical Rationale and Preclinical Evidence for Chimeric Antigen Receptor (CAR) T Cell Therapy Clinical Trial in KRAS-Mutant Lung Cancer (ID 3075)

      11:30 - 13:00  |  Presenting Author(s): Janna Claire Minehart  |  Author(s): Takashi Eguchi, Aurore Morello, Prasad S Adusumilli

      • Abstract
      • Slides

      Background

      Chimeric antigen receptor (CAR) T cells are engineered to express a synthetic receptor that redirects specificity to a tumor-associated antigen (TAA). Mesothelin (MSLN) is a TAA expressed by solid tumors, notably in mesothelioma and lung adenocarcinoma (ADC). Our group clinical trial of MSLN-targeted CAR T cells in mesothelioma demonstrated a favorable safety profile and evidence of antitumor activity. In this study, we evaluated the feasibility and utility of MSLN-targeted CAR T cell therapy in advanced, KRAS-mutant lung ADC.

      Method

      Tissue microarray from stage I-III lung ADC tumors (n=1438) were reviewed by two pathologists, then stained for MSLN expression on cell-surface and cytoplasm. Of 327 patients with distant recurrences, adequate tissue was available from 34 autologous metastatic sites for MSLN expression evaluation. Healthy donor T cells were retrovirally transduced with a MSLN-targeted CAR. In vitro function against lung ADC cell lines with heterogenous MSLN expression resembling human tumors was assessed via chromium release assay, ELISA, and flow cytometry. In vivo antitumor efficacy (n=30) was evaluated by median survival and tumor bioluminescence in mice bearing lung ADC tumors.

      Result

      The incidence of cell-surface MSLN expression was higher in metastases than matched primary tumors (65% vs 38%) and higher in KRAS-mutant than wild type tumors (42% vs 32%). CAR T cells secrete cytokines and lyse lung ADC cell lines in proportion to their cell-surface MSLN expression. No activity against MSLN-very low mesothelial or MSLN-negative lung ADC cell lines was observed. In vivo, a single dose of CAR T cells eradicates established primary and metastatic MSLN-high tumors without evidence of on-target off-tumor toxicity.

      Conclusion

      Therapeutically-relevant cell surface MSLN expression is enriched in a population of KRAS-mutant lung ADC patients with poor prognosis and limited treatment options. MSLN-targeted CAR T cells exhibit antigen-specific and antigen density-dependent cytotoxicity against lung ADC cells in vitro and in vivo with no on-target, off-tumor toxicity to normal tissues. These results provide strong rationale for our upcoming MSLN-targeted CAR T cell therapy clinical trial in metastatic, KRAS-mutant lung ADC patients.

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      • Abstract
      • Slides

      Background

      Historically, outcomes for advanced non-small cell lung cancer (NSCLC) have been poor, with 5-year survival rates < 5% with conventional chemotherapy. Nivolumab, a programmed death-1 (PD-1) inhibitor, was approved in 2015 for patients with previously treated advanced NSCLC based on two randomized phase 3 trials, CheckMate 017 (NCT01642004; squamous) and CheckMate 057 (NCT01673867; non-squamous), which demonstrated improved overall survival (OS) vs docetaxel. We report 5-year pooled efficacy and safety from these trials, representing the longest survival follow-up for randomized phase 3 trials of an immune checkpoint inhibitor in advanced NSCLC.

      Method

      Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG performance status (PS) ≤ 1, and progression during or after first-line platinum-based chemotherapy, were randomized 1:1 to nivolumab 3 mg/kg Q2W or docetaxel 75 mg/m2 Q3W until progression or unacceptable toxicity. After completion of the primary analyses, patients in the docetaxel arm no longer receiving benefit could cross over to receive nivolumab. OS was the primary endpoint for both studies.

      Result

      At 5-year follow-up, 50 nivolumab patients and 9 docetaxel patients were alive. Baseline characteristics of 5-year survivors in both arms were similar to the overall population and patients who survived < 1 year, except for a higher percentage of patients with ECOG PS 0 or tumor programmed death ligand-1 (PD-L1) expression ≥ 1% on nivolumab and ECOG PS 0 and Stage IIIB NSCLC on docetaxel. Nivolumab continued to show long-term OS and progression-free survival (PFS) benefit vs docetaxel with 5-year OS rates 13% vs 3% (HR, 0.68 [95% CI, 0.59–0.78]) and PFS rates 8% vs 0% (0.79 [0.68–0.92]). OS benefit with nivolumab vs docetaxel was observed across subgroups including patients with tumor PD-L1 expression < 1%, baseline liver and adrenal metastases, neutrophil-to-lymphocyte ratio < median, lactate dehydrogenase ≥ upper limit of normal or no baseline proton-pump inhibitor use. Among patients with an objective response to nivolumab (20%) or docetaxel (11%), 32% remained in response at 5 years vs none on docetaxel, with a median duration of response of 19.9 vs 5.6 months, respectively. Of the 5-year nivolumab vs docetaxel survivors, 36% vs 0% were on study drug, 20% vs 67% received subsequent immunotherapy (on or off study), and 10% vs 0% were off study drug, progression free, with no subsequent therapy. No new safety signals were observed with longer follow-up. Between 3 and 5 years’ follow-up, 8 of the 31 (26%) nivolumab-treated patients reported a treatment-related adverse event, 1 (3%) grade 3–4. The most common select adverse events (events with a potential immunological cause) were related to skin, in 4 (13%) patients, none of which were grade 3–4.

      Conclusion

      CheckMate 017 and 057 are the first phase 3 trials to report 5-year outcomes for a PD-1 inhibitor in previously treated advanced NSCLC, demonstrating a greater than 4-fold increase in 5-year OS rates with nivolumab (13%) over docetaxel (3%). Nivolumab remained well tolerated with no new safety signals.

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      OA14.05 - Discussant - OA14.01, OA14.02, OA14.03, OA14.04 (Now Available) (ID 3799)

      11:30 - 13:00  |  Presenting Author(s): Jay M Lee

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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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  |  Presenting Author(s): Giuseppe Lo Russo  |  Author(s): Diego Signorelli, Claudia Proto, Giulia Galli, Arsela Prelaj, Roberto Ferrara, Michele Sommariva, Massimo Moro, Valeria Cancila, Monica Ganzinelli, Silvia Brich, Sabina Sangaletti, Giancarlo Pruneri, Claudio Tripodo, Mario Paolo Colombo, Licia Rivoltini, Andrea Balsari, Gabriella Sozzi, Mattia Boeri, Marina Chiara Garassino

      • 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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      OA14.07 - Clinical and Genetic Characterization of Hyperprogression Based on Volumetry in Advanced NSCLC Treated with Immunotherapy (Now Available) (ID 1067)

      11:30 - 13:00  |  Presenting Author(s): Youjin Kim  |  Author(s): Chu Hyun Kim, Se-Hoon Lee, Ho Yun Lee, Hong Sook Kim, Kyunga Kim, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park

      • Abstract
      • Presentation
      • Slides

      Background

      Hyperprogressive disease (HPD), characterized by accelerated tumor progression, has been proposed as a new pattern of progression following immune checkpoint inhibitor (ICI) treatment. The aim of this study was to describe the characteristics of HPD and investigate its predictive markers.

      Method

      Clinical and radiological findings of 335 advanced non-small cell lung cancer (NSCLC) patients treated with ICI monotherapy were retrospectively analyzed. Radiological data were quantitatively and longitudinally analyzed for tumor size and volume by comparing baseline and follow-up computerized tomography results. The findings were matched to individual genomic profiles generated by deep sequencing of 380 genes.

      Result

      Among 135 patients with progressive disease (PD), as assessed by RECIST, 48 (14·3% of total and 35·6% among PD) and 44 (13·1% of total and 32·6% among PD) were found to have HPD by volumetric (HPDV) and one-dimensional (HPDR) analysis, respectively. HPDV patients were associated with significantly inferior overall survival (OS) compared with non-HPDV PD patients (median OS (months), 4·7 [95% confidence interval (CI), 3·5–11·9)] vs. 7·9 [95% CI, 6·0–13·5], p=0·004); OS did not differ between HPDR and non-HPDR patients. HPDV status was an independent OS factor. Derived neutrophil-to-lymphocyte ratio (dNLR) greater than 4 and lactate dehydrogenase (LDH) greater than the upper normal limit were significantly associated with HPDV. Moreover, we identified coinciding KRAS and STK11 mutations in the HPDV cohort (3/16), while none were found in the non-HPDV cohort (0/28).

      Conclusion

      Defining HPD treated with ICI based on volumetric measurement is more precise than that based on one-dimensional analysis. Pre-ICI dNLR, LDH, and concurrence of STK11 and KRAS mutations could, thus, be used as potential biomarkers for HPD prediction.

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      OA14.08 - Discussant - OA14.06, OA14.07 (Now Available) (ID 3800)

      11:30 - 13:00  |  Presenting Author(s): Kazuhiko Nakagawa

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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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): Diego Signorelli

      • 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: 1
    • Now Available
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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): Diego Signorelli

      • 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): Diego Signorelli

      • 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: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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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): Diego Signorelli

      • 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: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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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): Diego Signorelli

      • 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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    P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.16-09 - Post-Progression Outcomes After Pembrolizumab in Patients with NSCLC and High PD-L1 Expression: Real-World Data from a European Cohort (ID 2749)

      09:45 - 18:00  |  Author(s): Diego Signorelli

      • Abstract

      Background

      Real-world data regarding treatment patterns and clinical outcomes after progression on first-line pembrolizumab (pembro) monotherapy among NSCLC patients are lacking.

      Method

      A comprehensive clinicopathological database of 173 consecutive patients with NSCLC and PD-L1>50% treated with first-line pembro in 14 centers in Italy, Spain, Greece and Switzerland was retrospectively created and post-progression patterns and outcomes were recorded. Analysis was performed using the SAS 9.3 software.

      Result

      Main clinicopathological features are summarized in Table 1. Median TPS score for PD-L1 expression was 70%. Median duration of pembro treatment was 6.1 months (range: 0.2-20.8). Thirty patients (17.4%) received pembro despite having non-metastatic disease (stage I-IIIC), as deemed medically inoperable or ineligible for definite chemo-radiotherapy. At data cut-off (10th April 2019), 100 patients (58%) had stopped treatment due to disease progression, 9 (5%) due to toxicity, 3 (2%) for other reasons and 61 (35%) were still on treatment. Best response to pembro was CR, PR, SD and PD in 2%, 34%, 20% and 24% respectively, while in 11.6% death occurred in the absence of documented PD. Among patients who progressed (N=100), in 18 cases pembro was continued beyond progression, as considered to confer clinical benefit. Among patients who discontinued pembro (N=94), 47% received any second-line chemotherapy and 53% received no further treatment. Main chemotherapy regimens were carboplatin with either pemetrexed (16%) or gemcitabine (9%) or paclitaxel (7%), cisplatin-pemetrexed (7%) and gemcitabine monotherapy (9%). Best response to chemotherapy was CR, PR, SD and PD in 2%, 30%, 11% and 32% respectively. After a median follow-up of 11.2 months, median OS was 13.5 months (range: 0.16-25.8+).

      Table 1: Main clinicopathological characteristics of the patient cohort.

      N=173

      %

      COUNTRY OF ORIGIN

      Italy

      98

      56.7

      Greece

      32

      18.5

      Switzerland

      27

      15.6

      Spain

      16

      9.2

      SEX

      Male

      112

      64.7

      Female

      61

      35.3

      AGE Median (Range) yrs

      68 (19-86)

      SMOKING STATUS

      Current

      66

      38.2

      Former

      86

      49.7

      Never

      18

      10.4

      Unknown

      3

      1,7

      PERFORMANCE STATUS

      0

      50

      28.9

      1

      80

      46.2

      2

      41

      23.7

      3

      2

      1.2

      HISTOLOGY

      Adeno

      116

      67.1

      Squamous

      37

      21.4

      Large Cell

      2

      1.2

      Pleiomorphic

      3

      1.7

      Sarcomatoid

      7

      4.0

      Poorly differentiated/

      Undifferentiated

      8

      4.6

      SITE OF METASTASIS

      Bone

      74

      49.7

      Intrapulmonary/Contralateral Lung

      72

      48.3

      Adrenal

      43

      28.9

      Brain

      30

      20.1

      Liver

      23

      15.4

      Other

      63

      36.4

      TNM STAGE AT DIAGNOSIS (AJCCC v.8)

      I

      2

      1.2

      II

      2

      1.2

      III

      26

      15.0

      IV

      142

      82.1

      Unknown

      1

      0.5

      STEROID USE

      Yes

      48

      27.7

      No

      105

      60.7

      Unknown

      20

      11.6

      Conclusion

      Real-world data in a large retrospective cohort, indirectly compared to Keynote 024, suggest that: 1) Due to it’s favorable toxicity profile, pembro is also an option in earlier stages in frail (PS=2 or medically inoperable stage I-III) patients, 2) One in five patients continues pembro beyond progression due to clinical benefit and 3) More than half of patients who progress do not receive any second-line treatment, mainly due to clinical deterioration.

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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  |  Presenting Author(s): Diego Signorelli

      • 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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