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Silvia Novello

Moderator of

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    OA07 - Precision Medicine Involves Biology and Patients (ID 132)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 9
    • Now Available
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      OA07.01 - Osimertinib Plus Platinum/Pemetrexed in Newly-Diagnosed Advanced EGFRm-Positive NSCLC; The Phase 3 FLAURA2 Study (Now Available) (ID 2383)

      11:00 - 12:30  |  Presenting Author(s): Pasi A Jänne  |  Author(s): David Planchard, Paul Howarth, Alexander Todd, Kunihiko Kobayashi

      • Abstract
      • Presentation
      • Slides

      Background

      Osimertinib is a third-generation, CNS-active EGFR-TKI that potently and selectively inhibits both sensitizing EGFR and T790M mutations. Osimertinib is considered the standard of care for patients with newly-diagnosed advanced/metastatic NSCLC harbouring EGFR-activating mutations, based on results of the phase 3 FLAURA trial, which demonstrated a statistically and clinically significant progression-free survival (PFS) benefit for osimertinib over erlotinib or gefitinib. Evidence indicates that adding chemotherapy to gefitinib improves efficacy outcomes versus EGFR TKI monotherapy in newly-diagnosed patients with EGFRm NSCLC (Nakamura et al JCO 2018;36:9005). Adding platinum/pemetrexed to osimertinib could further improve outcomes for newly-diagnosed patients with EGFRm-positive NSCLC.

      Method

      The phase 3, open-label, FLAURA2 study aims to assess the efficacy and safety of osimertinib plus cisplatin/carboplatin plus pemetrexed in adults with locally-advanced/metastatic EGFRm-positive (Ex19del and/or L858R) NSCLC who have not received prior therapy for advanced disease. Patients are required to have a WHO performance status (PS) 0-1, life expectancy >12 weeks and not be amenable to curative surgery or radiotherapy. An initial non-randomised run-in phase (n=30) will assess the safety and tolerability of osimertinib 80 mg once daily (QD) with either cisplatin or carboplatin, and pemetrexed, both administered every 3 weeks (Q3W) for 4 cycles, followed by osimertinib 80 mg QD plus pemetrexed maintenance Q3W until progression or discontinuation. Based on evaluation of safety data from the run-in after ≥12 patients from each group have received ≥3 cycles of study treatment or discontinued therapy, the second phase will randomise approximately 556 patients 1:1 to receive osimertinib 80 mg QD with pemetrexed and cisplatin/carboplatin for 4 cycles followed by osimertinib plus pemetrexed maintenance Q3W or osimertinib alone (80 mg QD), to be continued until progression or discontinuation. Randomisation will be stratified by race (Chinese/Asian vs. non-Chinese/Asian vs. non-Asian), WHO PS (0 vs. 1), and tissue EGFR mutation test at enrolment (cobas® EGFR Mutation Test vs local assessment). A futility analysis of the randomized phase is planned for when approximately 83 PFS events have occurred. The primary endpoint is PFS based on investigator assessment of response using RECIST 1.1 criteria (blinded central assessment is included as a sensitivity analysis). Secondary endpoints include overall survival, objective response rate, duration of response, PFS2, health-related quality of life and safety. Effects on CNS metastases in patients with lesions at baseline will be included as an exploratory endpoint. Enrolment is planned for Q3 2019 for the safety run-in and Q1 2020 for the randomized phase.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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      OA07.02 - LKB1 Mutations in Metastatic Non-Small Cell Lung Cancer (mNSCLC): Prognostic Value in the Real World (Now Available) (ID 902)

      11:00 - 12:30  |  Presenting Author(s): Norah Shire  |  Author(s): Asieh Golozar, Jenna Collins, Kathy Fraeman, Beth Nordstrom, Robert McEwen, Brandon Higgs

      • Abstract
      • Presentation
      • Slides

      Background

      Despite recent advances in treating mNSCLC, many patients fail to respond. Identifying genetic markers may help maximize clinical benefit and avoid unnecessary toxicity. LKB1/STK11 alterations (LKB1m) and co-occurring KRAS mutations/LKB1 loss (KRAS/LKB1) have been associated with poor outcomes in patients treated with immunotherapy (IO). Among chemotherapy-treated patients, however, the prognostic value is less understood. This retrospective study examined LKB1m, KRAS/LKB1 and outcomes in patients with mNSCLC receiving IO (as monotherapy or in combination) or chemotherapy in the real-world setting.

      Method

      Adult patients with mNSCLC who initiated first line (1L) treatment between Jan 2013 and Jun 2017 and had been profiled with the FoundationOne assay in routine care were enrolled from the Flatiron Health Oncology electronic medical record database. Associations between LKB1m, LKB1/KRAS and overall survival (OS) or progression-free survival (PFS) were evaluated by line of therapy (1L and second line [2L]) according to histology (non-squamous/squamous and non-squamous only) using multivariate Cox proportional hazards models. All analyses were stratified by IO or chemotherapy.

      Result

      2407 patients (1847 non-squamous) were included; average age was 66.1 years at 1L initiation. 328 (13.6%) patients harbored LKB1m and 157 (6.5%) harbored KRAS/LKB1. Among IO-treated patients in the 2L setting, LKB1m was associated with shorter OS and PFS versus wild type. A similar association was observed in the 1L setting and in the non-squamous only subgroup. In patients receiving chemotherapy, LKB1m was associated with worse outcomes only in the 1L setting. All associations were generally more pronounced among KRAS/LKB1 compared with LKB1m patients.

      Table. Association between LKB1m and OS or PFS in mNSCLC stratified by IO or chemotherapy and lines of therapy
      Mutation group
      LKB1m
      All mNSCLC Non-Squamous
      Outcome IO Chemotherapy IO Chemotherapy
      1L (n = 270) 2L (n = 670) 1L (n =2,137) 2L (n = 863) 1L (n = 187) 2L (n = 498) 1L (n = 1,687) 2L (n = 683)
      LKB1m, N (%) 40 (14.8) 111 (16.6) 288 (13.5) 83 (9.6) 38 (20.3) 97 (19.5) 257 (15.2) 75 (11.0)
      OS
      Median 341 192 340 350 431 201 356 400
      (IQR) (221 – NA) (72 – 523) (284 – 405) (307 – 451) (221 – NA) (73 – 613) (287 – 415) (307 – 453)
      HR 1.43 1.59 1.40 1.07 1.40 1.67 1.43 1.05
      (95% CI) (0.90 – 2.27) (1.25 – 2.03) (1.21 – 1.63) (0.81 – 1.41) (0.84 – 2.32) (1.27 – 2.19) (1.22 – 1.68) (0.78 – 1.42)
      PFS
      Median 122 67 136 122 125 68 136 128
      (IQR) (83 – 295) (46 – 118) (119 – 146) (97 – 147) (81 – 299) (46 – 114) (122 – 149) (98 – 153)
      HR 1.43 1.59 1.40 1.07 1.36 1.55 1.38 1.07
      (95% CI) (0.90 – 2.27) (1.25 – 2.03) (1.21 – 1.63) (0.81 – 1.41) (0.92 – 2.03) (1.22 1.97) (1.20 – 1.59) (0.82 – 1.39)
      KRAS/LKB1
      All mNSCLC Non-squamous
      IO Chemotherapy IO Chemotherapy
      1L (n = 270) 2L (n = 670) 1L (n =2,137) 2L (n = 863) 1L (n = 187) 2L (n = 498) 1L (n = 1,687) 2L (n = 683)
      KRAS/LKB1, N (%) 17 (6.3) 56 (8.4) 140 (6.6) 42 (4.9) 16 (8.6) 52 (10.4) 133 (7.9) 40 (5.9)
      OS
      Median 303 209 356 343 341 230 363 350
      (IQR) (222 – NA) (72 – 666) (272 – 450) (254 – 554) (130 – NA) (72 – 666) (284 – 462) (254 – 554)
      HR 1.46 1.63 1.55 1.27 1.44 1.78 1.61 1.28
      (95% CI) (0.74 – 2.86) (1.16 2.29) (1.26 – 1.90) (0.87 – 1.84) (0.68 – 3.05) (1.22 – 2.59) (1.29 – 2.00) (0.86 – 1.90)
      PFS
      Median 126 67 136 133 174 68 136 133
      (IQR) (77 – 291) (46 – 91) (112 – 160) (91 – 190) (72 – 295) (47 – 91) (112 – 160) (91 – 190)
      HR 1.34 1.81 1.40 1.08 1.34 1.86 1.44 1.05
      (95% CI) (0.80 – 2.24) (1.35 2.44) (1.16 – 1.68) (0.77 – 1.51) (0.76 – 2.36) (1.35 2.57) (1.19 1.75) (0.74 – 1.50)
      Note: Bold text indicates significant results; reference group for LKB1m is LKB1wt; reference group for KRAS/LKB1 is KRASwt/LKB1wt
      Median OS and PFS and IQRs are expressed in days
      Abbreviations: KRAS mutation/LKB1 loss (KRAS/LKB1), Hazard ratio (HR), Interquartile range (IQR), Confidence interval (CI), Immunotherapy (IO), Overall Survival (OS), Progression-free survival (PFS), Wild type (wt)
      Conclusion

      LKB1m and LKB1/KRAS were associated with numerically worse OS and PFS in the 1L setting, irrespective of treatment, and in IO-treated patients in the 2L setting. Results of this real-world study support previous clinical findings and suggest unique relevance of these mutations in 1L chemotherapy and for 1L and 2L IO.

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      OA07.03 - Clinical Outcome of Non-Small Cell Lung Cancer with EGFR/HER2 Exon 20 Insertions Identified in the LC-SCRUM-Japan (Now Available) (ID 629)

      11:00 - 12:30  |  Presenting Author(s): Hibiki Udagawa  |  Author(s): Shingo Matsumoto, Yuichiro Ohe, Miyako Satouchi, Naoki Furuya, Young Hak Kim, Takashi Seto, Kenzo Soejima, Daisuke Hayakawa, Terufumi Kato, Shingo Miyamoto, Kadoaki Ohashi, Sho Saeki, Hiromitsu Ohta, Daichi Fujimoto, Akimasa Sekine, Kiyotaka Yoh, Koichi Goto

      • Abstract
      • Presentation
      • Slides

      Background

      In-frame insertions in exon 20 (Ex20ins) of EGFR/HER2 occur in 2-5 % of non-small cell lung cancer (NSCLC). There is no approved targeted therapy for patients with these mutations. Historical control data would be valuable for the development of novel targeted therapies for these rare cancers.

      Method

      A nationwide genome screening project in Japan (LC-SCRUM-Japan) has been established for the development of molecular-targeted therapies for lung cancers. In this project, 161 cancer-related genes have been analyzed by a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay. The therapeutic efficacy and survival of the patients with non-squamous (non-sq) NSCLC harboring EGFR/HER2 Ex20ins were evaluated using a large-scale clinico-genomic database in the LC-SCRUM-Japan.

      Result

      A total of 3441 advanced non-sq NSCLC patients were successfully analyzed from 2015 to 2018. EGFR Ex20ins were detected in 73 patients (2%; M766_A767insASV/A767_S768insSVD/H773_V774insH/D770_N771insNPH/N771_P772insPH/others=22/17/5/4/4/21) and HER2 Ex20ins were detected in 128 patients (4%; A775_G776insYVMA/G776delinsVC/P780_Y781insGSP/others=95/16/10/7). The median age of the patients was 62 (range, 33-90) years. Eighty-one patients (40%) were male and 114 (57%) were never smoker. Two-hundred patients (99%) were diagnosed as adenocarcinoma and 1 as adenosquamous-cell carcinoma. Based on our database, the median overall survivals in patients with EGFR Ex20ins were 22.4 (95%CI, 15.3-36.8) months, and those with HER2 Ex20ins were 18.8 (13.6-30.3) months. In the patients with EGFR/HER2 Ex20ins, the objective response rate (ORR) and median progression-free survivals (mPFS) of 1st-line platinum-containing chemotherapies were 32% and 6.0 (5.7-7.0) months, respectively. The ORR and mPFS of docetaxel with or without ramucirumab were 26% and 5.1 (3.8-5.9) months, respectively. The ORR and mPFS of PD-1 inhibitor were 0% and 2.0 (1.6-2.6) months, respectively. No significant difference in the therapeutic efficacy of these drugs was observed between the patients with EGFR Ex20ins and HER2 Ex20ins. In 19 patients with EGFR Ex20ins treated with 1st/2nd generation EGFR-TKIs, the ORR was 5% (a M766_A767insASV-positive tumor responded to afatinib) and the mPFS was 2.1 (1.3-4.2) months.

      Conclusion

      The patients with EGFR/HER2 Ex20ins-positive NSCLC showed poor responses to PD-1 inhibitors and 1st/2nd generation EGFR-TKIs. These historical data are highly informative in evaluating the efficacy of novel targeted therapies for EGFR/HER2 Ex20ins-positive NSCLC.

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      OA07.04 - Discussant - OA07.01, OA07.02, OA07.03 (Now Available) (ID 3758)

      11:00 - 12:30  |  Presenting Author(s): Vladmir Cláudio Cordeiro De Lima

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA07.05 - High-Grade Chemotherapy-Induced Peripheral Neuropathy (CIPN):  An Analysis of ECOG-ACRIN Lung Cancer Clinical Trials (Now Available) (ID 1431)

      11:00 - 12:30  |  Presenting Author(s): Sawsan Rashdan  |  Author(s): Suzanne E Dahlberg, David E. Gerber, Alan Sandler, Joan H Schiller, David Johnson, Suresh S Ramalingam

      • Abstract
      • Presentation
      • Slides

      Background

      High-grade (CTCAE grade ≥3) CIPN implies severe symptoms and limitation of self-care activities of daily living (ADL). To date, studies characterizing the incidence of and factors associated with CIPN have been conducted almost exclusively in breast cancer populations. As such, they generally evaluate only women and lack assessment of platinum-based chemotherapy. We therefore examined the incidence and factors associated with high-grade CIPN among patients treated on ECOG-ACRIN advanced non-small cell lung cancer (NSCLC) clinical trials.

      Method

      We included two completed trials in the analysis: E1594 (comparison of 4 chemotherapy regimens: cisplatin-paclitaxel, cisplatin-gemcitabine, cisplatin-docetaxel, carboplatin-paclitaxel) and E4599 (carboplatin-paclitaxel ± bevacizumab). We identified patients who developed treatment-related grade ≥3 CIPN. Multivariable logistic regression modeling was performed to estimate adjusted odds ratios. For the treatment variable, the reference group ended up combining the cisplatin+paclitaxel and cisplatin+docetaxel arms since their results were not significantly different from one another. Body-mass index (BMI) was categorized by median value (25.2 kg/m2).

      Result

      Among 1,989 total patients, 167 (8.4%) developed grade ≥3 CIPN. Incidence was highest for the carboplatin-paclitaxel regimen (9.9%) and lowest for cisplatin-paclitaxel (4.5%) (P=0.006). Grade ≥3 CIPN was associated with BMI (9.9% for ≥25.2 kg/m2 vs 6.9% for <25.2 kg/m2; P=0.02) and sex (6.9% for men vs 10.4% for women; P=0.006). There was a non-significant trend toward association with age (10.4% for ≥70 years versus 7.8% for <70 years; P=0.08). In multivariate analysis, chemotherapy regimen, sex, and BMI remained independently associated with grade ≥3 CIPN.

      Conclusion

      Carboplatin-paclitaxel chemotherapy, female sex, and high BMI are associated with the development of high-grade CIPN. Given the clinical severity of this condition and the potential for long-term persistence, consideration of risk-based monitoring and treatment selection may be warranted.

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      OA07.06 - Patient Knowledge and Expectations Related to Return of Genomic Results in the Lung-MAP (SWOG 1400) Biomarker-Driven Clinical Trial (Now Available) (ID 730)

      11:00 - 12:30  |  Presenting Author(s): Joshua A Roth  |  Author(s): Meghna S Trivedi, Stacy Gray, Donald Patrick, Wylie Burke, Debbie Delaney, Kate Watabayashi, Paul Litwin, Parth Shah, Katherine D. Crew, Monica Yee, Mary Redman, Vassiliki A Papadimitrakopoulou, Karen Kelly, David R Gandara, Dawn L Hershman, Scott D Ramsey

      • Abstract
      • Presentation
      • Slides

      Background

      Biomarker-driven clinical trials (BDCTs)--where participants qualify for targeted therapy sub-studies based on tumor genomic testing results--represent a new paradigm in oncology clinical trials. However, BDCTs’ complex designs are difficult to communicate to patients considering participation, and deficits in knowledge and expectations have implications for shared decision-making and informed consent. The objective of this pilot study was to evaluate patient knowledge and expectations related to return of genomic results in the Lung-MAP (SWOG 1400) BDCT.

      Method

      From 8/2017 to 4/2019, we recruited a subset of participants with advanced non-small cell lung cancer (NSCLC) from among patients enrolled in the Lung-MAP genomic screening study (SWOG 1400). Participants completed a 38-item telephone survey conducted by trained staff within 30 days of consent. Survey questions assessed patient knowledge about the benefits and risks of study participation and expectations about return of genomic results in the study. The survey was structured as 5-level scale responses (‘strongly disagree’ [1] to ‘strongly agree’ [5]) and true/false/don’t know. Survey questions were adapted from prior studies that evaluated knowledge and expectations about return of genomic results. Descriptive statistics (means, medians, proportions) were assessed in this preliminary analysis.

      Result

      Among 123 participants, median age was 67, 61.0% were male, 95.1% were white, 22.0% had a 4-year college education or more, and 28.5% had a household income of <$25,000/year. In the overall sample, 82.9% ‘strongly/somewhat agreed’ with the statement ‘I received enough information about the testing in Lung-MAP to understand the benefits of enrolling’ and 73.2% ‘strongly/somewhat agreed’ with the statement ‘I received enough information…to understand the risks of enrolling’. Among the sub-group that ‘strongly/somewhat agreed’ with understanding trial benefits: 89.2% correctly believed that it was ‘true’ that test results would help to select their cancer treatment (8.8% responded ‘don’t know’), 8.8% correctly believed it was ‘false’ that the somatic testing in the study would provide information to find out if family members had increased risk of cancer (40.2% responded ‘don’t know’), and 11.8% correctly believed it was ‘false’ that results would tell them about their risk of developing diseases besides cancer (38.2% responded ‘don’t know’).

      Conclusion

      Among participants in a large BDCT, a majority of participants had serious deficits about the reporting of genomic results despite reporting to have enough information to understand benefits and risks. Our findings suggest that further research is needed to identify effective approaches to communicating information about BDCTs to improve patient knowledge about return of genomic results.

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      OA07.07 - Quality of Life (QoL) Analysis in Lung Cancer: A Systematic Review of Phase III Trials Published Between 2012 and 2018 (Now Available) (ID 1958)

      11:00 - 12:30  |  Presenting Author(s): Maria Lucia Reale  |  Author(s): Emmanuele De Luca, Pasquale Lombardi, Laura Marandino, Clizia Zichi, Daniele Pignataro, Eleonora Ghisoni, Rosario Francesco Di Stefano, Annapaola Mariniello, Elena Trevisi, Gianmarco Leone, Leonardo Muratori, Anna La Salvia, Cristina Sonetto, Paolo Bironzo, Massimo Aglietta, Silvia Novello, Giorgio Vittorio Scagliotti, Francesco Perrone, Massimo Di Maio

      • Abstract
      • Presentation
      • Slides

      Background

      We previously reported that QoL is not included among endpoints and QoL results are underreported in a high proportion of phase III trials in oncology. Here we describe QoL prevalence and heterogeneity in QoL reporting in lung cancer phase III trials.

      Method

      We selected all primary publications of lung cancer phase III trials evaluating anticancer drugs published between 2012 and 2018 by 11 major journals. We analyzed QoL inclusion among endpoints, presence of QoL results and methodology of QoL analysis.

      Result

      122 publications were identified. In 39 (32.0%) publications, QoL was not listed among endpoints: 10/17 (58.8%) early stage/locally advanced NSCLC, 15/54 (27.8%) first-line of advanced NSCLC; 10/41 (24.4%) second and further lines of advanced NSCLC, 4/10 (40.0%) SCLC. Proportion of trials not including QoL was similar over time: 32.9% publications in 2012-2015 vs. 30.6% in 2016-2018. QoL was not listed among endpoints in primary publication in 16/80 (20.0%) for-profit trials vs. 23/42 (54.8%) no-profit trials. Out of 83 trials including QoL among endpoints, QoL results were not reported in 36 primary publications (43.4%). Proportion of trials not reporting QoL results in primary publication significantly increased over time (30.6% 2012-2015 vs. 61.8% 2016-2018, p=0.005). Overall, QoL data were not available in 65/122 (61.5%) primary publications, due to the absence as endpoint or unpublished results. QoL data were not available in primary publication in 48/80 (60.0%) for-profit trials vs. 27/42 (64.3%) no-profit trials. QoL data were lacking in 48/78 (70.6%) publications of trials with overall survival as primary endpoint, 27/54 (50.0%) with other primary endpoints and 28/54 (51.9%) publications with a positive result. For trials including QoL among endpoints but lacking QoL results in primary publication, probability of secondary publication was 6.3%, 30.1% and 49.8% after 1, 2 and 3 years respectively, without evidence of improvement in time to publication comparing 2012-2015 vs. 2016-2018. Out of 83 trials including QoL, most common tools were EORTC QLQ-C30 (42, 50.6%); EORTC LC13 (39, 47.0%); EQ-5D (37, 44.6%); LCSS (19, 22.9%); FACT-L (15, 18.1%). Out of 58 trials with available results, common methods of analysis were mean scores or changes (45, 77.6%), time to deterioration (31, 53.4%) and proportion of responders (19, 32.8%). Availability of a secondary QoL publication allowed a higher number of methods of QoL analysis (p<0.001).

      Conclusion

      QoL is not assessed in a high proportion of phase III trials evaluating lung cancer patients, a setting where attention to QoL should be particularly high, due to symptoms and limited life expectancy. Furthermore, the timely inclusion of QoL results in primary publications is worsening in recent years. Secondary publications allow a more complete description of QoL results, but imply a delay in their availability.

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      OA07.08 - Discussant - OA07.05, OA07.06, OA07.07 (Now Available) (ID 3759)

      11:00 - 12:30  |  Presenting Author(s): Mary O'Brien

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA07.09 - Daniel C. Idhe Lectureship Award for Medical Oncology (Now Available) (ID 3904)

      11:00 - 12:30  |  Presenting Author(s): Shao Weng Daniel Tan

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    EP1.09 - Pathology (ID 199)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.09-13 - Clinic-Pathological and Molecular Features of PD-L1 Analyses in Advanced NSCLC: A Real Life Single Center Experience (Now Available) (ID 2559)

      08:00 - 18:00  |  Author(s): Silvia Novello

      • Abstract
      • Slides

      Background

      Programmed death ligand 1 (PD-L1) immunohistochemistry (IHC) is the most rapid, less expensive and routinely applied predictive assay for treatment with immune checkpoint inhibitors (ICI) in advanced non small cell lung cancer (NSCLC). We analyzed a real-life single center activity of PD-L1 characterization together with pathological features, molecular status determination and patients’ clinical response to ICI.

      Method

      From January 2017 to July 2018 all advanced NSCLC tumor tissue analyzed for PD-L1 expression and molecular status determination in the Pathology Unit of San Luigi Hospital, Orbassano (Turin) were selected. PD-L1 analysis was performed using 22C3 PharmDX on Dako Autostainer, while ALK rearrangement was assessed by FISH and EGFR mutations by direct pyrosequencing. Furthermore in a majority of cases (60%) a 22-gene panel was evaluated by Ion Torrent PGMTM Next Generation Sequencing (NGS). The PD-L1 IHC assay results were analyzed with cut-off values of >50% (strong positive), 1-49% (weak positive), and <1% (negative). Clinical data of response to ICI were acquired for 65 patients.

      Result

      510/532 (96%) cases were adequate for PD-L1 determination and molecular analyses; 169 (33%) were histological, 269 (53%) core biopsies and 72 (14%) cytological samples; 375 (74%) were from primitive lesion, while 135 (26%) were from metastatic sites. Of the 22 inadequate samples for PD-L1 analysis half of them were cytological specimens. PD-L1 was strong positive in 91 (18%) cases, weak positive in 137 (27%) cases and negative in 285 (56%) cases. Specimens with higher expression (>50%) derived preferentially from histological samples (e.g. surgical specimens) and from external hospitals referred to our Central Hub. EGFR and ALK positive cases were more frequently PD-L1 negative or weak positive (13% and 2%, respectively), although not reaching statistical significance. Instead, KRAS and TP53 mutated cases were significantly associated with negative or weak positive PD-L1 expression (14% and 22%, chi-square p=0.0006 and p=0.01, respectively). Among the 65 patients with clinical data of response to ICI, 37/65 (57%) were responders (partial response + stable disease) while 28/65 (43%) had progressive disease. No significant differences in terms of clinic-pathological or molecular features were found between these two groups, maybe due to the limited number of cases.

      Conclusion

      Our analyses suggest that integration of PD-L1 testing in the pathological and molecular characterization of advanced NSCLC is feasible with a very high adequacy, enabling a wide ICI administration to these patients.

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

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

      13:30 - 15:00  |  Author(s): Silvia Novello

      • 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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    MA08 - Pawing the Way to Improve Outcomes in Stage III NSCLC (ID 127)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
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      MA08.02 - Durvalumab Impact in the Treatment Strategy of Stage III Non-Small Cell Lung Cancer (NSCLC): An EORTC Young Investigator Lung Cancer Group Survey (Now Available) (ID 608)

      15:15 - 16:45  |  Author(s): Silvia Novello

      • Abstract
      • Presentation
      • Slides

      Background

      Stage III NSCLC represents a very heterogeneous population with extremely different treatment modalities including surgery, chemotherapy (CT) and radiotherapy (RT), mostly in combination. The results of the PACIFIC trial have now been reported in full including an overall survival (OS) benefit with durvalumab in addition to concomitant CT-RT. An electronic European survey was circulated to evaluate the impact of durvalumab in the staging and treatment strategy of stage III disease.

      Method

      A Young Investigator EORTC Lung Cancer Group survey containing 31 questions, was distributed between 31/01/18 and 31/03/19 to EORTC LCG and several European thoracic oncology societies’ members

      Result

      206 responses were analyzed (radiation oncologist: 50% [n=103], pulmonologist: 26.7% [n=55], medical oncologist: 22.3% [n=46]; 81.5% with >5 years experience in treating NSCLC). Italy (27.7%, n=57), Netherlands (22.8%, n=47), France (13.6%, n=28), and Spain (11.6%, n=24) contributed most. 83.5% (n=172) confirmed that they had access to durvalumab at the time of the survey. 97.6% (n=201) report that treatment decision is made by a multidisciplinary board. Regarding staging, 76.7% (n=158) support the need of a mediastinal pathological staging in case of suspect lymph-nodes, with a preference for EBUS/EUS (61.2%, n=126). 81.6% (n=168) treated more than half of patients with a concomitant CT-RT with the 1st cycle of chemotherapy in 39.7% (n=81). 95.1% consider durvalumab as practice changing, especially given the OS results (77.9%, n=152/195). 30% (n=119/395) will give patients concomitant CT-RT if PD-L1 >1%, and in borderline resectable cases 17.7% (n=70/395) will propose concomitant CT-RT instead of surgery. Durvalumab administration will be given regardless of PDL1 status in 13.1% (n=27) and 28.6% (n=59) would consider the possibility of a rebiopsy after CT-RT in case of negative PD-L1. 38.8% (n=80) foresee some problems with PD-L1 testing in this population due to availability of cytologic or small histologic samples. About 53.8% (n=105/195) normally will start durvalumab within 6 weeks after CT-RT and 48.5% (n=100) would also use durvalumab after sequential CT-RT

      Conclusion

      Durvalumab results are changing the treatment approach to stage III unresectable (and maybe resectable) NSCLC and planned strict adherence to the patient population as recruited to the PACIFIC study, was not demonstrated. This survey was released after the EMA approval of durvalumab and PD-L1 status seems to play a role in the treatment strategies, but surprisingly almost half of the clinicians will use durvalumab after sequential CT-RT without safety or efficacy data.

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    MS13 - Immunotherapy for Mesothelioma (ID 76)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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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

      • 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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    OA02 - A New Vision of Targets and Strategies (ID 120)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      OA02.07 - Phase 3 ALUR Study of Alectinib in Pretreated ALK+ NSCLC: Final Efficacy, Safety and Targeted Genomic Sequencing Analyses (Now Available) (ID 2267)

      10:30 - 12:00  |  Author(s): Silvia Novello

      • Abstract
      • Presentation
      • Slides

      Background

      The ALUR (NCT02604342) primary analysis (cut-off January 2017) demonstrated improved efficacy and safety with alectinib versus chemotherapy in patients with ALK+ NSCLC previously treated with chemotherapy and crizotinib. These patients can develop crizotinib resistance through ALK secondary mutations, but limited data exist regarding alectinib’s efficacy in patients with different post-crizotinib genetic profiles. We report final data from ALUR including treatment outcomes according to genetic profile.

      Method

      Overall, 119 patients with locally determined ALK+ NSCLC were randomised 2:1 to receive alectinib 600mg bid or chemotherapy (pemetrexed 500mg/m2 or docetaxel 75mg/m2 q3w). The primary endpoint was PFS by investigator. Targeted genomic sequencing (FoundationONE® [tissue; 315 genes] and FoundationACT® [plasma; 62 genes]) was performed retrospectively using tumour tissue (n=33) and baseline plasma (n=59).

      Result

      Final efficacy data confirmed those of the primary analysis (table). Grade ≥3 treatment-emergent adverse events were lower with alectinib (37.7%) than with chemotherapy (43.2%); adverse events causing treatment discontinuation were lower with alectinib (5.2% versus 10.8% chemotherapy), despite alectinib’s longer treatment duration. ALK fusions were confirmed retrospectively in 26/33 (78.8%) tissue and 41/59 (69.5%) plasma (post-crizotinib) samples. ORR in alectinib-treated patients with ALK fusions was 72.2% (13/18, tissue) and 63.0% (17/27, plasma) versus 0% for chemotherapy (tissue [0/8], plasma [0/14]). ALK secondary mutations were detected in 16/59 (27.1%) patients (plasma, both arms). ORR in the alectinib arm (plasma) was similar in patients with ALK fusions with (60.0%, 6/10) or without (64.7%, 11/17) ALK secondary mutations, but lower in patients with gene mutations other than ALK (23.1%, 3/13).

      Conclusion

      Final data from ALUR confirm the primary analysis, demonstrating improved efficacy and safety with alectinib versus chemotherapy in post-crizotinib ALK+ NSCLC. The role of reconfirming ALK status upon sequential ALK inhibitor treatment requires further investigation, due to the limited data and known technical challenges of plasma testing.

      Funding: F. Hoffmann-La Roche Ltd.

      table.jpg

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    OA07 - Precision Medicine Involves Biology and Patients (ID 132)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      OA07.07 - Quality of Life (QoL) Analysis in Lung Cancer: A Systematic Review of Phase III Trials Published Between 2012 and 2018 (Now Available) (ID 1958)

      11:00 - 12:30  |  Author(s): Silvia Novello

      • Abstract
      • Presentation
      • Slides

      Background

      We previously reported that QoL is not included among endpoints and QoL results are underreported in a high proportion of phase III trials in oncology. Here we describe QoL prevalence and heterogeneity in QoL reporting in lung cancer phase III trials.

      Method

      We selected all primary publications of lung cancer phase III trials evaluating anticancer drugs published between 2012 and 2018 by 11 major journals. We analyzed QoL inclusion among endpoints, presence of QoL results and methodology of QoL analysis.

      Result

      122 publications were identified. In 39 (32.0%) publications, QoL was not listed among endpoints: 10/17 (58.8%) early stage/locally advanced NSCLC, 15/54 (27.8%) first-line of advanced NSCLC; 10/41 (24.4%) second and further lines of advanced NSCLC, 4/10 (40.0%) SCLC. Proportion of trials not including QoL was similar over time: 32.9% publications in 2012-2015 vs. 30.6% in 2016-2018. QoL was not listed among endpoints in primary publication in 16/80 (20.0%) for-profit trials vs. 23/42 (54.8%) no-profit trials. Out of 83 trials including QoL among endpoints, QoL results were not reported in 36 primary publications (43.4%). Proportion of trials not reporting QoL results in primary publication significantly increased over time (30.6% 2012-2015 vs. 61.8% 2016-2018, p=0.005). Overall, QoL data were not available in 65/122 (61.5%) primary publications, due to the absence as endpoint or unpublished results. QoL data were not available in primary publication in 48/80 (60.0%) for-profit trials vs. 27/42 (64.3%) no-profit trials. QoL data were lacking in 48/78 (70.6%) publications of trials with overall survival as primary endpoint, 27/54 (50.0%) with other primary endpoints and 28/54 (51.9%) publications with a positive result. For trials including QoL among endpoints but lacking QoL results in primary publication, probability of secondary publication was 6.3%, 30.1% and 49.8% after 1, 2 and 3 years respectively, without evidence of improvement in time to publication comparing 2012-2015 vs. 2016-2018. Out of 83 trials including QoL, most common tools were EORTC QLQ-C30 (42, 50.6%); EORTC LC13 (39, 47.0%); EQ-5D (37, 44.6%); LCSS (19, 22.9%); FACT-L (15, 18.1%). Out of 58 trials with available results, common methods of analysis were mean scores or changes (45, 77.6%), time to deterioration (31, 53.4%) and proportion of responders (19, 32.8%). Availability of a secondary QoL publication allowed a higher number of methods of QoL analysis (p<0.001).

      Conclusion

      QoL is not assessed in a high proportion of phase III trials evaluating lung cancer patients, a setting where attention to QoL should be particularly high, due to symptoms and limited life expectancy. Furthermore, the timely inclusion of QoL results in primary publications is worsening in recent years. Secondary publications allow a more complete description of QoL results, but imply a delay in their availability.

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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
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-45 - Immune-Oncology Gene Expression Profiles Allow Lung Cancer Patients’ Stratification and Identification of Responders to Immunotherapy (ID 2339)

      09:45 - 18:00  |  Author(s): Silvia Novello

      • Abstract
      • Slides

      Background

      Immune-checkpoint inhibitors (ICI) represent a new standard of care for Non-Small Cell Lung Cancer (NSCLC) patients. Beyond tumor PD-L1 protein expression, other biological parameters are emerging as potential predictive biomarkers. We evaluated high-throughput immune-related Gene Expression Profiles (GEP) in tumor tissue from ICI-treated patients, correlating immune activation data with clinical response to immunotherapy.

      Method

      RNA was isolated from tumor tissues of 44 metastatic NSCLC patients treated with Nivolumab (as 2nd or 3rd line therapy) and collected from different Italian centers. The nCounter® PanCancer IO360™ Panel was applied on NanoString platform to analyze 770 genes involved in key immuno-oncology pathways. Clinical-pathological data, as well as best response to ICI treatment, have been collected.

      Result

      Patients were dichotomized as responders (7 Partial Response and 19 Stable Disease) and non-responders (18 Progressive Disease). A pre-identified T-cell inflamed signature was evaluated at single gene level and the expression of CCL5, CD27, CD276, CMKLR1, CXCL9, CXCR6, LAG3, NKG7, PDCD1LG2, PSMB10, TIGIT was higher in the responder group, although not reaching statistical significance. Moreover, higher STING, CGAS and IRF3 genes expression level appeared to be more commonly associated with non-responder patients.

      Considering the disease stage at the time of diagnosis, a different gene panel (CCL5, CD27, CD274, CD8A, CXCL9, CXCR6, HLA-DQA1, HLA-DRB1, HLA-E, IDO1, LAG3, NKG7, PSMB10, TIGIT) resulted to be more expressed in early and locally advanced (16 from stage I to IIIA) compared to metastatic (28 stage IV) tissue samples.

      Conclusion

      A trend in differential expression patterns was observed between responders and non-responders NSCLC patients treated with Nivolumab and additional analyses on this cohort could reveal specific pathways able to predict unresponsiveness to ICI treatment. Different disease stage seems also to influence immune-related GEPs.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 3
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-03 - Molecular Determinants for Lorlatinib Activity in ROS1 Positive NSCLC: Results of the Prospective PFROST Trial (ID 1566)

      09:45 - 18:00  |  Author(s): Silvia Novello

      • Abstract

      Background

      Lorlatinib, an ALK/ROS1 inhibitor, demonstrated activity in ROS1+ NSCLC pretreated with crizotinib. However, molecular events predictive for tumor response during lorlatinib treatment are largely unknown.

      Method

      PFROST was a prospective phase II trial designed to include ROS1+ NSCLC refractory to crizotinib. Eligible patients were treated with lorlatinib at the daily dose of 100 mg until disease progression. Primary end point was response rate (RR). For all included patients pre-lorlatinib tumor tissue or blood sample collection was mandatory. At the time of lorlatinib failure liquid biopsy was recommended. The samples were then run with the NEOliquid assay, specifically designed for liquid biopsies, or NEOselect, a panel optimized for formalin-fixed paraffin-embedded (FFPE) tumor tissue, covering 39 cancer related genes.

      Result

      From June 2017 to April 2019, 22 ROS1+ crizotinib refractory lung adenocarcinoma patients were included in 10 Institutions. Median age was 56 years (range 39-82); male/female: 8/14; ECOG PS 0 (N=8; 36.4%), PS1 (N=14; 63,6%); The majority had brain metastases at baseline (N=15; 68.1%), were never smokers (N=13; 59.1%) and received lorlatinib as third line therapy (N=16; 72.7%). In all cases crizotinib was the last therapy line before lorlatinib. At the time of the present analysis, trial completed its accrual and 13 patients are still receiving therapy. A total of 18 patients were evaluable for response and 7 had confirmed complete (N=1) or partial (N=6) responses for an overall RR of 38.8%. In 4 patients, response to therapy was not yet evaluated. A total of 10 tissue biopsies and 20 blood samples obtained after crizotinib and before lorlatinib therapy were collected. For 7 samples analyses are ongoing. Among responders, no patient harbored a secondary ROS1 mutation. Conversely, no response was observed among patients with secondary ROS1 mutations (N= 1 ROS1S1861I, N=1 ROS1 V2054A, N=3 ROS1G2032R). All patients harboring the ROS1G2032R mutation rapidly progressed and maintained this aberration in liquid biopsy at the time of radiological evidence of lorlatinib failure.

      Conclusion

      In our study lorlatinib confirmed its efficacy in crizotinib resistant ROS1+ NSCLC. Molecular profile of refractory patients suggests reduced efficacy in individuals developing secondary ROS1 mutations after crizotinib failure.

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      P1.14-04 - Final Results of the Prospective Genomics of Young Lung Cancer (GYLC), an Addario Lung Cancer Medical Institute Study (ID 427)

      09:45 - 18:00  |  Author(s): Silvia Novello

      • Abstract

      Background

      We hypothesized that young age at lung cancer diagnosis is a clinical characteristic associated with a higher likelihood for having a driver mutation. Our goals were to identify a genomically enriched subtype of lung cancer, facilitate delivery of targeted therapy and lay groundwork for studies of heritable and environmental lung cancer risk factors.

      Method

      Eligible subjects had a diagnosis of bronchogenic lung cancer < 40 years old. We included a website to allow for virtual consenting and remote participation from anywhere in the world. An integrated data and biorepository allowed for completion of study activities and routing of specimens. We defined seven genes of interest based on the Lung Cancer Mutational Consortium (LCMC): EGFR, KRAS, HER2, BRAF, ALK, ROS1, RET. We hypothesized that the prevalence of targetable alterations in these genes would be greater in our population compared to the LCMC and powered our study to detect an increase from 35% to 50%. Subjects with advanced adenocarcinoma who were not tested for all seven genes or who were wild type for all seven underwent additional genomic profiling using Foundation Medicine testing.

      Result

      We accrued 133 participants from July 2014 to June 2017. Notably, 44% entered the trial via the website. The mean age at diagnosis was 34 (range 16 to 39) and 57% were female; 77% were stage 4 at diagnosis and the majority had adenocarcinoma (86%). Of the 115 patients with adenocarcinoma, 83.5% were stage 4 and the focus of the comparison to the LCMC cohort. A targetable mutation was identified in 85.4%, with 76% harboring a combined ALK (38.5%), EGFR (31.3%), or ROS1 (6.3%) mutation. Of 14 patients who underwent on-protocol testing, a targetable driver was identified in eight (57%), including two with a RET rearrangement, two with ERBB2 mutations, two with MET amplification, one with an ALK rearrangement with a prior negative FISH and one with a novel EGFR-RAD fusion previously tested negative for EGFR.

      Conclusion

      We have described a genomically distinct subset of NSCLC in patients < age 40. Those with stage 4 adenocarcinoma must undergo comprehensive genomic testing to identify a targetable driver. The extremely high rate of driver mutations particularly in ALK supports the need for an Epidemiology of YLC study. Additionally, use of remote consenting and the Addario Lung Cancer Foundation's advocacy enabled rapid accrual of this rare cohort (<1%) and has laid the foundation for innovative research partnerships with other rare oncogene-driven patient groups.

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      P1.14-26 - ALK Fusion Variant Detection by Targeted RNA-Seq in TKIs Treated ALK-Positive Lung Adenocarcinoma (ID 1860)

      09:45 - 18:00  |  Author(s): Silvia Novello

      • Abstract
      • Slides

      Background

      Clinical outcomes of ALK positive (ALK+) Non-Small-Cell Lung Cancer (NSCLC) and the identification of the most effective anaplastic lymphoma kinase inhibitor (ALKi) according to the specific ALK fusion variants are not well assessed. We retrospectively characterized fusion variant distribution in a cohort of ALK+ lung adenocarcinomas (ADC) with paired clinical data about treatments and outcomes.

      Method

      Diagnostic tumor tissue from advanced ALK+ (by FISH and/or IHC) ADC diagnosed from 2010 to 2018 and treated with single or multiple ALKis were collected (expanded cohort from Gobbini et al. Lung Cancer, 2017). The OncomineTM Solid Tumor Fusion Transcript Kit on an Ion PGM™ system and the Ion Reporter™ software were used to identify targeted ALK fusion gene products (ThermoFisher).

      Result

      Specific fusion variant transcripts were found in 34/55 (62%) of collected samples. As expected, EML4-ALK fusion transcripts were the most common (31/34 samples, 91%), but HIP-ALK transcripts were also detected (3/34 - 9%). Among EML4-ALK fusions the following variants were detected: V1 (n=11); V2 (n=2); V3a/b (n=12 ) V5a/b (n=5 ) and E6A19 (n=1). Patient median age was 60 year [range 36-85], 22 were male and 12 female. Three patients were current, 11 former and 20 never smokers. Crizotinib, alectinib, ceritinib, brigatinib and lorlatinib were the ALKis used. Independently of the therapy line, 12 patients received crizotinib only, while 22 patients received crizotinib followed by one or two other ALKis. Regardless of the type of transcript, those patients who received more than one ALKi had a better median overall survival compared to those receiving crizotinib only, as expected (74 vs 21 months, HR: 5.31; 95%CI: 1.464-19.26, log rank p=0.0006). Furthermore, a significant difference in the mean duration of the different ALKi treatment was found according to the ALK variants (Chi-square p<0.0001), suggesting a private ALKi efficacy profile for specific fusion variants. Finally, the 3 HIP-ALK cases showed a better outcome with respect the EML4-ALK variants (not reached vs 51 months).

      Conclusion

      Our analysis suggests that different ALK fusion variant might affect ALKi treatment duration in ALK+ lung ADC.

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    P1.18 - Treatment of Locoregional Disease - NSCLC (ID 190)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.18-01 - RELAY EU/US Subset: Ramucirumab Plus Erlotinib Improves Progression-Free Survival in First-Line EGFR Mutation-Positive NSCLC (Now Available) (ID 356)

      09:45 - 18:00  |  Author(s): Silvia Novello

      • Abstract
      • Slides

      Background

      Dual blockade of EGFR and VEGFR pathways in EGFR mutation-positive NSCLC augments anti-tumor efficacy versus EGFR inhibition alone. The RELAY (NCT02411448) phase 3 study demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for erlotinib plus ramucirumab versus erlotinib plus placebo in patients with previously untreated EGFR mutation-positive metastatic NSCLC (median PFS 19.4 vs 12.4mo, HR 0.591 (95% CI 0.461–0.760), p<0.0001). Here we report efficacy and safety data of the EU/US subset.

      Method

      Eligible patients (untreated, metastatic NSCLC with an EGFR exon 19 deletion or exon 21 (L858R) substitution mutation and no CNS metastasis) were randomized (1:1) to receive 150 mg daily oral erlotinib plus 10 mg/kg intravenous ramucirumab (RAM+ERL) or placebo (PL+ERL) Q2W until progressive disease or unacceptable toxicity. Patients were stratified by geographic region (East Asia vs ‘other’, i.e. EU/US). Primary endpoint was investigator-assessed PFS. Other key objectives included safety, ORR, DoR, PFS2, and OS.

      Result

      In the EU/US, 113 (25.2%) of 449 total patients (58 RAM+ERL, 55 PL+ERL) were randomized between Feb 2016-Feb 2018. Baseline characteristics were balanced between treatment arms: ~60% female, ~52% never-smokers and ~66% Ex19del. RAM+ERL improved PFS and had a longer DoR (Table). PFS2 and OS data were immature. Grade≥3 TEAEs occurring in >5% of patients included (RAM+ERL vs PL+ERL): hypertension (29.8% vs 7.3%), diarrhea (12.3% vs 1.8%), AST increased (7.0% vs 3.6%), ALT increased (7.0% vs 1.8%), dermatitis acneiform (5.3% vs 9.1%), fatigue (5.3% vs 0%), and rash (0% vs 5.5%).

      Abbreviations: CI=confidence interval; DoR=duration of response; ERL=erlotinib; HR=hazard ratio; N=total population; n=total responders; NR=no response; ORR=overall response rate; OS=overall survival; PFS=progression-free survival; PL=placebo; RAM=ramucirumab
      RAM + ERL (N=58) PL + ERL (N=55) Unstratified HR (95% CI) p-value
      PFS
      Median, months (95% CI) 20.6 (14.7-26.0)
      10.9 (8.3-19.4)
      0.605 (0.362-1.010) 0.0523

      Censoring rate

      52% 38%

      ORR, % (95% CI)

      74.1 (62.9-85.4) 76.4 (65.1-87.6) NA 0.8319
      DoR, for responders only n=43 n=42
      Median, months (95% CI) 18.0 (12.7-22.0) 10.0 (7.1-17.7) 0.527 (0.296-0.939) 0.0274

      Censoring rate

      54% 33%
      PFS2
      Median, months (95% CI) NR NR 0.632 (0.304-1.313) 0.2143
      Censoring rate 79% 67%
      OS
      Median, months (95% CI) NR NR 1.096 (0.465-2.582) 0.8344
      Censoring rate 81% 82%

      Conclusion

      The EU/US subset analysis was consistent with the full ITT population where RAM+ERL demonstrated a statistically significant improvement in PFS over PL+ERL. Efficacy and tolerability were similar to that of the overall RELAY study population. Ramucirumab is an effective and safe addition to standard-of-care EGFR-TKI for treating EGFR mutation-positive metastatic NSCLC.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-74 - Clinical-Pathological Features and Outcome of Patients with Oral Metastases from Lung Cancer: A Multicenter Retrospective Study (ID 2701)

      10:15 - 18:15  |  Author(s): Silvia Novello

      • Abstract
      • Slides

      Background

      Oral metastases are a rare event, accounting to less than 1% of all oral malignancies, sometimes being the first manifestation of a wide-spread disease. Regardless of the site of the primary tumor, patients with oral metastases have a poor prognosis, with a reported median overall survival (mOS) of 6 months. Lung cancer, particularly small cell lung cancer (SCLC) and poorly differentiated carcinoma, represents the main source of oral metastases, even if large datasets still lack. We conducted a multicenter retrospective study investigating incidence, clinical-pathological features and outcome of patients with oral metastases from lung cancer.

      Method

      Between January 2014 and December 2018 we collected data from all consecutive patients diagnosed with lung cancer in four oncological Italian centers. Clinical-pathological features of those patients with oral metastases involving jaw or/and soft tissues were described.

      Result

      Among 4,082 consecutive lung cancer patients, the incidence of oral cavity metastases was 0.15% (6 out of 4,082 patients,). Patients were more frequently male (5 out of 6, 83%), current or former smokers (5 out of 6, 83%), with a median age at diagnosis of 61 years (range 53-69) [table 1]. Four different histotypes of lung cancer were detected. Five patients (83%) were stage IV ab initio, with synchronous histologically confirmed oral metastases. All these patients had distant metastases other than in the oral cavity (median of 5 different metastatic sites). The mOS since the diagnosis of oral metastases was 67 days (range 36-166).

      Table 1. Patient characteristics

      Gender

      Age (years)

      Smoke

      Histotype

      N° metastatic sites

      Site of oral lesion

      Time between stage IV diagnosis and oral lesion occurrence

      Local radiotherapy

      Median OS from oral lesion occurrence (days)

      M

      69

      Current

      Poorly differentiated

      4

      Jaw

      Syncronous

      Yes

      57

      M

      61

      Current

      Sarcomatoid

      5

      Jaw

      Syncronous

      Yes

      107

      M

      61

      Former

      Adenocarcinoma

      3

      Gum

      11 months

      Yes

      77

      M

      53

      Former

      Poorly differentiated

      4

      Gum

      Syncronous

      No

      44

      M

      59

      Current

      SCLC

      5

      Gum

      Syncronous

      No

      36

      F

      66

      Unknown

      Squamous (mut ex 19 EGFR)

      5

      Gum

      Syncronous

      No

      166

      Conclusion

      To our knowledge, this is the largest study assessing the incidence of oral metastases in lung cancer patients. Oral involvement, usually diagnosed at an advanced stage, seems to be associated with a very poor prognosis, with a mOS of about 2 months. Further confirmatory datasets are warranted.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 3
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-14 - NLR, dNLR and PLR as Possible Predictive Markers in Patients with NSCLC Treated with ICI (ID 1063)

      10:15 - 18:15  |  Author(s): Silvia Novello

      • Abstract
      • Slides

      Background

      Clinical evidence suggests a possible predictive role of Neutrophil-to-Lymphocyte ratio (NLR), derived Neutrophils/(leukocytes minus neutrophils) ratio (dNLR) and Platelet-to-Lymphocyte ratio (PLR) in different tumors, including non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI).

      Method

      In this Italian multicenter retrospective trial NLR, dLNR, PRL fluctuations were analyzed in patients with stage IV NSCLC treated with ICI. Those rates were assessed at baseline, before the second, third and fifth cycles. In patients still on treatment, samples were collected also at 1 and at 2 years from ICI start. The primary objective was the relationship between baseline ratios and response to ICI, through the identification of different cut-offs estimated using ROC curves.

      Result

      Data of 402 patients receiving ICI (antiPD1 91%, antiPDL1 7% and antiPDL1 plus antiCTLA-4 2%) were analysed: 287 (71%) were males, median age was 65 (39-86 yrs-old), 84 patients (21%) were on first line treatment. The most common histology was adenocarcinoma (62%) and 95% of patients had an ECOG performance status of 0-1. One hundred and eleven (30%) patients were using steroids in permissive doses for ICI. Disease control rate (DCR) was observed in 228 patients (58%) with 95 (24%) reporting an immune objective response. Median progression free survival was 5,3 months and the median overall survival was 9,6 months, after a median follow-up of 9,6 months (range 4,0-13.0). Basal NLR, dNLR and PRL were predictive of response (p=0.0002, p=0.0003 and p=0.0304, respectively). Best response categories were dichotomized in Response (SD + PR + CR) versus no Response (PD). With this classification, the differences were more pronounced and statistically significant for basal NLR and dNLR (p=0,045 and p=0,004, respectively). The cut-off values for basal NLR and dNLR were defined (BLNLR=2,46; BLdNLR=1,61) to identify patients most at risk of “non Response” through the ROC curves. Confounding factors were assessed using logistic regression models (age, gender, smoking). During treatment, an increase in the values was observed at the time of progression, both for NLR (average variation: -1.57) and for dNLR (average variation + 0.32), even if the statistical significance is limited to NLR (p = 0.041).

      Conclusion

      NLR, dNLR and PLR are independent factors of response to ICI. Compared to the present literature data, this study highlights that NLR ratio may predict progressive disease earlier than radiological restaging.

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      P2.04-15 - Association Between Opioids and Outcome of 1st Line Immunotherapy in Advanced NSCLC Patients: A Retrospective Evaluation (Now Available) (ID 2428)

      10:15 - 18:15  |  Author(s): Silvia Novello

      • Abstract
      • Slides

      Background

      Opioids represent the pharmacological backbone of cancer-related pain treatment. However, preclinical studies suggest that opioids can cause immunosuppression. Recently, immune checkpoint inhibitors (ICIs) have become available for treatment of patients with advanced NSCLC. With this study we aimed at retrospectively evaluate the impact of chronic opioid treatment on the outcome of advanced NSCLC (aNSCLC) patients treated with first-line ICIs.

      Method

      We retrospectively reviewed the records of aNSCLC patients treated with anti-programmed-death-1 (PD-1) or its ligand (PD-L1) single-agent ICIs in 2 Italian institutions. We included all patients with enough follow-up to have at least one radiological evaluation during ICIs treatment. Patients with rapid clinical progression were included in the analysis. We analyzed response rate (RR), progression-free survival (PFS), and overall survival (OS). Response was evaluated using RECIST v1.1 criteria.

      Result

      75 patients were found, 64 included in the analysis. Mean age at diagnosis was 66.5 years (range 37-84), 65% were male. Histological type were: 76.5% adenocarcinoma, 14% squamous, 9.5% others, most with high PD-L1 expression (90.5% with ≥50% TPS). 58 patients (90.6%) were stage IV at ICIs start, with mean number of metastatic sites 1.8. Most patients were current/former smokers (87.5%); ECOG performance status (PS) at ICI start was: 0 in 34 pts (53.1%), 1 in 25 (39%), 2 in 5 (7.9%). 20 patients were receiving opioids at ICIs start (31.3%), with a mean daily dose equal to 59 mg of oral controlled-release morphine. With a median follow-up of 10.9 months, the median number of ICIs cycles was 7.5 (range 1-26). RR, mPFS and mOS in the whole series were 40.6%, 9.4 months and 17.1 months, respectively. Compared to the others, patients receiving opioids had numerically lower RR (30% vs 45.5%, p=0.24), a shorter PFS (median 12.7 vs 1.7 months, Hazard Ratio [HR] 4.16, 95%CI 2.15-8.05, p<0.001) and OS (median not reached vs 3.2 months, HR 4.68, 95%CI 2.09-10.52, p<0.001). At the multivariate analysis, opioid use continued to be significantly associated with worst PFS (HR 3.19, 95%CI 1.45-7.01, p=0.004) and OS (HR 4.16, 95%CI 1.61-10.76, p=0.003), even when accounting for PS, disease stage and number of metastatic sites.

      Conclusion

      Our results suggest a possible detrimental effect of opioids in aNSCLC patients treated with first line single-agent ICIs, even when correcting for other prognostic factors. However, due to the short follow-up, the small number of patients, and the lack of a control group, our results should be considered exploratory.

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      P2.04-84 - NSCLC Survival Expectancy for Patients Treated with Docetaxel/Nintedanib in the SENECA Trial and Previous Immunotherapy (ID 807)

      10:15 - 18:15  |  Author(s): Silvia Novello

      • Abstract
      • Slides

      Background

      The phase IIb SENECA trial was an Italian real-world experience recently ended, which demonstrated similar progression free survival (PFS) and overall survival (OS) in non-squamous non-small cell lung cancer (nsNSCLC) patients treated with second-line docetaxel/nintedanib, regardless the relapsing-time from end of first-line chemotherapy and the docetaxel schedule employed (weekly or q3wks), with a slightly higher toxicity-trend in the q3wks arm. During accrual period (January 2016-April 2018), no therapeutic alternative to the use of docetaxel was available for patients with recurrent nsNSCLC until April 2017, when the first immune-checkpoint inhibitor was approved and reimbursed in Italy in this setting. At that point, the study was amended allowing enrolment of patients previously treated with immunotherapy (IT). Because of the lack of data about the optimal therapeutic algorithm in this context, aim of the present evaluation is to investigate if survival expectancy of patients treated with docetaxel/nintedanib could positively influenced when previously treated with IT.

      Method

      In the SENECA trial, 212 nsNSCLC patients, progressing after first-line chemotherapy, were treated with docetaxel plus continuous oral nintedanib, with the possibility of maintenance in case of stabilization or response. This evaluation focus on 16 patients previously treated with IT and compares them to the rest of patient population. Survival analysis is performed using Kaplan Meier curves; Hazard Ratios (HR) with 95% Confidence Interval (95%CI) are reported to compare the two groups.

      Result

      Patients treated with IT (2 combined with first-line chemotherapy, 14 alone) correspond to 7.5% of the entire study population; they were 9 males and 7 females, with a median age of 62.5 years, mainly current or former-smokers, with an ECOG-performance status 0 in 93.7% of cases. At the cut-off date (December 25th, 2018), after a median follow-up of 35.5 months, no significant differences appear between patients previously treated with IT and the other ones in terms of PFS (5.84 vs 4.31 months, respectively; HR 0.564 [95% CI 0.283-1.122], p-value=0.1029), and OS (9.37 vs 9.02 months, respectively; HR 1.108 [95% CI 0.393-3.123], p-value=0.8456). No significant differences have been observed also in disease-control rates (80.0% vs 66.7%, p-value=0.5436).

      Conclusion

      Despite this report does not show a greater survival expectancy for patients treated with docetaxel/nintedanib and previous IT, it's likely that the small sample size may affect this result. The longer PFS and greater disease-control rate are attractive hints for future evaluations with larger sample sizes, supposing a new therapeutic algorithm for recurrent nsNSCLC patients.

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    P2.09 - Pathology (ID 174)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.09-18 - Lymphocyte Infiltration Pattern and STING Expression Identify Different Prognostic Groups in Early Stage NSCLC (ID 2536)

      10:15 - 18:15  |  Author(s): Silvia Novello

      • Abstract
      • Slides

      Background

      Lymphocyte infiltration has been described has a potential biomarker of lung cancer patients’ survival. Different studies de-convoluted immune cell compartment (i.e. stromal CD8 density) trying to identify clinically relevant immune patterns.

      Method

      A series of 178 early-stage (IB-IIIA) NSCLC has been retrospectively collected at Department of Oncology, San Luigi Hospital (Orbassano, Italy). From Formalin-Fixed and Paraffine-Embedeed (FFPE) tumor blocks, Tissue Microarrays (TMA) were constructed (4 cores were selected for each case). Lymphocyte infiltration pattern was determined by light-microscopy on Hemathoxylin-Eosin (HE) whole slides. Immunohistochemistry was performed as follow: CD8 (SP57) and STING (D2P2F) antibodies were tested with Ventana Benchmark and PD-L1 (22C3) with Dako Autostainer. Infiltration pattern has been clustered in 4 different categories: brisk-diffuse, non-brisk multifocal, non-brisk focal and none. CD8 was quantified as positivity percentage, PD-L1 through TPS (<1%, 1-49% and ≥50%) and STING taking advantage of H-score. Overall survival (OS) and Progression Free Survival (PFS) were estimated using the Kaplan-Meier method and compared using log-rank test.

      Result

      Most represented patients had following features: male (119-71%), current or previous smokers (145-82%), stage II (94-53%) and adenocarcinoma histology (119-67%). Distribution of lymphocyte infiltration pattern was: 110 cases with brisk-diffuse (62%), 56 with non-brisk (multi-focal and focal) (31%) and 12 with none pattern (7%). CD8 positivity was distributed in 3 categories: high (66 - 37%), intermediate (75 - 42%) and low (37 -21%) density. For PD-L1 TPS analyses 111 cases (62%) had <1%, 39 cases (22%) 1-49% and 28 cases (16%) >50%. STING high-expressors were 88 (49%) and low-expressors 90 cases (51%). Lastly, were identified 81 samples (45%) with STING positivity at high-density on immune cells (IC) and 97 samples (55%) with low-density. As expected, Brisk-infiltrated samples presented an higher CD8 density (p=0.015). At PFS analyses, STING IC resulted associated (p=0.05) with a worse PFS for high-density patients. At OS analyses, brisk lymphocyte infiltration pattern appeared to have a negative impact (p=0.05) and STING higher-expressors on tumor cells had a worse prognosis (p=0.04).

      Conclusion

      NSCLC with wider lymphocyte infiltration and expression of immune activation markers (as STING) appeared to be associated with a worse prognosis (PFS and OS). These date need further validation at multivariate analyses.

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-17 - Correlation Between Clinic-Pathological Data and T790M Detection in EGFR Mutated NSCLC Patients Progressing on 1st/2nd Generation TKIs (Now Available) (ID 2442)

      10:15 - 18:15  |  Author(s): Silvia Novello

      • Abstract
      • Slides

      Background

      Despite osimertinib is moving to the first-line for advanced NSCLC harboring EGFR activating mutations, some patients still receive a frontline first- or second-generation EGFR-TKI. In this setting, factors predicting the emergence of T790M resistance mutation at progression (PD) are lacking. The aim of this retrospective study was to investigate the correlations between clinic-pathological features and T790M positivity (T790M+) in a single-center cohort of EGFR mutated stage IV or recurrent NSCLC patients, who underwent liquid (LB) or tissue biopsy (TB) at PD when treated with first- or second-generation EGFR-TKIs.

      Method

      Data from 122 patients (80 female, 42 male) treated between 2012 and 2019 were considered for the analysis. EGFR mutations were detected with real time-polymerase chain reaction (RT-PCR) on LB and pyrosequencing or next generation sequencing on TB. PD was determined by RECIST 1.1 criteria. Univariate analysis by Fisher exact test was performed to assess any association.

      Result

      At diagnosis, 117 patients carried common EGFR mutations (84 exon 19 deletions; 33 exon 21 mutations), 5 had rare mutations (3 exon 18 mutations; 2 exon 20 mutations other than T790M) . At PD, 29 patients (24%) underwent only LB, 29 only TB (24%), 64 both (52%). The overall T790M+ rate was 67% (82/122). T790M+ was significantly higher among patients with exon 19 deletion than in those with exon 21 mutation (77% vs 51%, p=0.008). T790M+ was significantly more frequent in patients with exclusively intrathoracic PD as compared to extrathoracic PD (81% vs 56%, p=0.007). Patients with pleural involvement (PI), considered as pleural effusion or/and pleural disease, as site of PD (n=45) had a significantly higher frequency of T790M+ than those with stable or absent PI (n=77) (82% vs 58%, p=0.009), irrespectively of the pattern of PD. No correlation with other sites of PD was found.

      Conclusion

      Exon 19 deletion, intrathoracic PD and PI as site of PD are significantly associated with higher frequency of T790M+ in patients progressing to first-or second-generationEGFR-TKIs. These results, if confirmed by an independent validation cohort, may allow the development of a T790M+ predictive score accounting for type of mutation and sites of progression.

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      P2.14-58 - A Phase IIIb, Open-Label Study of Afatinib in Caucasian EGFR TKI-Naïve Patients with EGFRm+ NSCLC: An Interim Analysis (ID 1371)

      10:15 - 18:15  |  Author(s): Silvia Novello

      • Abstract
      • Slides

      Background

      First-line afatinib demonstrated significantly improved median PFS in patients with EGFR mutation-positive (EGFRm+) NSCLC versus chemotherapy in LUX-Lung 3/6 (HR [95% CI]: 0.58 [0.43–0.78]/0.28 [0.20–0.39]), and versus gefitinib in LUX-Lung 7 (0.73 [0.57–0.95]). Since these trials had strict inclusion criteria, it is important to support these findings with real-world studies of broader patient populations. We report interim results of a Phase IIIb study of afatinib treatment for EGFRm+ NSCLC in a patient population similar to real-world practice.

      Method

      EGFR TKI-naïve patients with locally advanced/metastatic EGFRm+ NSCLC, and ECOG PS 0–2, received afatinib 40 mg/day. Dose reduction was permitted (minimum 20 mg/day). Primary endpoint: adverse events (AEs; descriptive fashion). Efficacy was also assessed.

      Result

      At data cut-off (30-April-2018), 479 patients were enrolled and treated (Caucasian/Asian/other: 97%/2%/<1%; ECOG PS 0–1/2: 92%/8%; 1st/2nd/≥3rd-line therapy: 78%/17%/5%; common/uncommon mutations: 87%/13%; brain metastases: 17%). Median time on afatinib: 359 days. Objective response and disease control rates were 46% and 86%, respectively. Other efficacy outcomes are in the Table. The most common grade ≥3 afatinib-related AEs were diarrhoea (16%) and rash (11%). 258 (54%) patients had AEs leading to dose reduction (most frequently diarrhoea [25%]/rash [11%]), and 37 (8%) had TRAEs leading to discontinuation (most frequently diarrhoea [3%]; all others [<1%]). Serious afatinib-related AEs occurred in 39 (8%) patients.

      Median TTSP, months

      (95% CI)

      Median PFS, months

      (95% CI)

      All pts (n=479)

      14.9

      (13.8–17.6)

      13.4

      (11.8–14.5)

      Line of therapy

      1st (n=374)

      15.6

      (14.1–18.5)

      13.8

      (12.6–15.2)

      2nd (n=81)

      14.7

      (11.3–20.6)

      13.2

      (8.3–17.7)

      ≥3rd (n=24)

      8.1

      (3.7–14.4)

      6.6

      (3.2–12.6)

      Baseline brain metastases*

      No (n=395)

      15.8

      (14.1–18.8)

      13.9

      (12.7–15.5)

      Yes (n=83)

      13.7

      (9.7–17.2)

      10.1

      (8.2–13.9)

      Baseline mutation type*

      Common (n=416)

      15.9

      (14.5–19.1)

      14.1

      (13.0–15.7)

      Uncommon (n=62)

      6.7

      (5.4–8.3)

      5.9

      (4.0–7.4)

      Baseline ECOG PS*, including age

      01 (n=442)

      15.8
      (14.4–18.8)

      13.8
      (12.8–15.2)

      <65 years (n=221)

      14.7
      (12.7–17.6)

      13.4
      (11.6–15.5)

      65 years (n=221)

      18.9
      (14.7–21.7)

      14.1
      (12.6–16.4)

      2 (n=36)

      8.9
      (5.7–13.2)

      6.2
      (2.5–11.6)

      <65 years (n=16)

      6.0
      (2.4–13.2)

      3.2
      (1.5–9.1)

      65 years (n=20)

      9.9
      (7.6–13.9)

      7.7
      (5.7–13.9)

      *Missing (n=1); Del 19 and/or L858R with or without uncommon mutation; Includes, n (%, of those with uncommon mutations): ex 20 ins: 37 (60), T790M: 12 (19), G719S/A/C: 12 (19), L861Q: 10 (16), S768I: 9 (15). TTSP, time to symptomatic progression; PFS, progression-free survival

      Conclusion

      This interim analysis indicated predictable and manageable safety, and encouraging efficacy, with afatinib in a broad patient population. The high proportion of patients with tumours harbouring exon 20 insertions may account for the differences in TTSP/PFS by common/uncommon mutation subgroup. Independent of treatment line, median TTSP/PFS in patients with ECOG PS 0–1 (LUX-Lung trials’ inclusion criteria) was 15.8/13.8 months, and, notably, was 18.9/14.1 months in those also aged ≥65 years. These findings by ECOG PS/age are consistent with those of the LUX-Lung trials.

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    WS06 - Women in Thoracic Oncology Networking Event (ID 355)

    • Event: WCLC 2019
    • Type: Workshop
    • Track: Thymoma/Other Thoracic Malignancies
    • Presentations: 1
    • +

      WS06.08 - Networking Table 6: Work-Life Balance (ID 4070)

      07:00 - 08:00  |  Presenting Author(s): Silvia Novello

      • Abstract

      Abstract not provided