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Emilio Bria



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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
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-69 - Blood Serum Amyloid A as Potential Predictor of Response to First-Line Pembrolizumab in Patients with Advanced Non-Small-Cell Lung Cancer (ID 1128)

      09:45 - 18:00  |  Author(s): Emilio Bria

      • Abstract

      Background

      The selection of patients (pts) deriving clinical benefit from immune checkpoint agents represents the modern challenge for clinicians. Tumor-derived Serum Amyloid A (SAA) inhibits the immune response through the expansion of IL-10-secreting neutrophils in pts with melanoma. We investigated the predictive value of blood SAA monitoring in a cohort of Advanced Non-Small-Cell Lung Cancer (ANSCLC) pts receiving up-front Pembrolizumab (P).

      Method

      Pts with ANSCLC (PD-L1≥50%) receiving upfront P, were prospectively evaluated for blood SAA and radiological response at baseline and every 9 weeks during the treatment. The primary endpoint was response rate (RR) according Immune-related Response Evaluation Criteria in Solid Tumors (IrRECIST); the secondary endpoints were progression-free survival (PFS) and overall survival (OS). The most accurate SAA cut-off to predict response was established with a ROC-analysis.

      Result

      Forty-two patients were enrolled. Pts characteristics: male/female (71/29%), number of sites 1/2/3/≥ 4 (5/38/40/17%), ECOG PS 0/≥ 1 (38/62%); never or former/current smokers (12/78%); median age 70.5 (range 35-86) years. The overall RR was 38% (95%CI 25-53%). After a median follow-up of 13.5 months (m), baseline SAA ≤ the ROC-derived cut-off (29.9 mg/L, AUC 0.74, 95% CI 0.59-0.87, p=0.002; 14 [33%] pts) was significantly associated with a higher RR (53.6vs 7.1%, OR 15, 95% CI 1.72-130.7, p<0.01), longer PFS (17.4 vs 2.1 m, HR 0.18, 95%CI 0.06-0.51, p<0.0001) and OS (not reached [NR]vs7.2 m, HR 0.08, 95%CI 0.02-0.39, p<0.0001) compared with SAA >29.9 mg/L. Multivariate analysis confirmed pre-treatment low SAA as independent predictor of longer PFS (p=0.029) and OS (p=0.018). Considering SAA at baseline and the dynamic monitoring (pts=40), the median PFS was 17.4 m (95% CI 10.7-14.7) when SAA remained low (n=14) compared with 2.1 m (95%CI 1.3-5.6) when SAA remained high (n=12) (p<0.0001).The SAA monitoring was also significantly associated with OS (p=0.0002), with a median OS of 7.2 m (95% CI 5.6-13.4) in pts maintaining high SAA versus NR median at 18-m for pts with SAA remained low or changed. No deaths occurred in the permanently low-SAA group at the current data-lock.

      Conclusion

      Baseline low SAA predicts good outcomes of 1stline P and the SAA monitoring throught simple blood test could help to easily identify patients who derived the greatest benefit from immunotherapy. The strong relationship with RR and the known immunosuppressive activity support a potential predictive value of this serum marker. A multi-institutional validation set is currently ongoing to confirm the role of SAA in this setting.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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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): Emilio Bria

      • 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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    P1.16 - 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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      P1.16-43 - Prevalence of Clinical and Sub-Clinical Malnutrition in Advanced Non-Small-Cell Lung Cancer Patients and Association with Outcome (ID 1757)

      09:45 - 18:00  |  Author(s): Emilio Bria

      • Abstract
      • Slides

      Background

      While weight loss and lean body mass wasting are common hallmarks of non-small-cell lung cancer (NSCLC), their early detection and management are usually overlooked in clinical routine. The present study aimed to explore the prevalence of malnutrition and its correlation with outcome in advance (A)-NSCLC pts.

      Method

      A-NSCLC pts treated at AOUI of Verona (2016-2018) received nutritional counseling by a qualified dietitian. Prevalence of malnutrition was assessed by nutritional screening score (NRS). Bilateral psoas major muscles were measured at L3 vertebrae level with routine staging-computed tomography (CT). Changes in psoas muscles observed in subsequent scans were evaluated using Wilcoxon signed-rank test. Clinical, pathological and nutritional data were correlated to progression-free/overall survival (PFS/OS) and response rate (ORR) using a Cox and logistic regression model. Kaplan-Meier curves were compared with Log-Rank.

      Result

      Data from 38 pts (20 males [52.6%], 18 females [47.4%]) were gathered (median age 59 years [range 42-82], with a median follow-up of 21 months (range 1-197). At baseline, 18.4% were underweight, 18.4% normal weight, 34.2% overweight and 31.6% obese. The majority (65.8%) were at risk of malnutrition (NRS≥3). At multivariate analysis, stage (HR 4.99, 95% CI 1.05-27.74, p = 0.04), performance status (HR 4.99, 95% CI 1.55-16.03, p = 0.007) and NRS (HR 7.61, 95% CI 1.52-38.11, p = 0.01), were significant independent predictors for PFS. Pts with baseline NRS≤3 had significantly longer 1-year PFS (58.6% vs 16.7%, p = 0.04) and 2-year OS (90.6% vs 68.3%, p = 0.03) and a better ORR than those with NRS > 3 (66.7% vs 21.4%). Conversely, BMI did not affect PFS/OS. A significant loss in psoas muscle mass was detected in pts treated with both immunotherapy and other therapies (p = 0.01 and p=0.002, respectively). Of interest, in immunotherapy-treated pts (n = 16) loss in psoas muscle mass correlated with worse ORR, PFS and OS, although differences did not reach a statistical significance due to the limited sample.

      Conclusion

      Our analysis suggests that malnutrition has a detrimental impact on ORR, PFS and OS in A-NSCLC. Particularly, in pts treated with immunotherapy, muscle mass wasting seems to impact on efficacy outcome, suggesting a potential interaction between immunological and nutritional parameters. Therefore, the introduction in the clinical routine of a comprehensive nutritional profiling and monitoring, beyond body weight and BMI, is highly recommended in A-NSCLC. A comparison between NSCLC pts who underwent a personalized nutritional intervention during therapy and who did not is ongoing, together with a series of biomolecular analysis.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-51 - A 6-Gene Immune Genomic Signature (IGS) Predicts Resistance to Nivolumab [NIV] in Advanced Pretreated NSCLC: Results of PRINCiPe Trial (ID 1885)

      10:15 - 18:15  |  Author(s): Emilio Bria

      • Abstract
      • Slides

      Background

      Genomic abnormalities detected in immune-escape/editing-related genes may promote immunotherapy resistance. In the light of this hypothesis, we designed the PRINCiPe (Predictors of Resistance to Immunotherapy with NIV) study in APNSCLC.

      Method

      FFPE-tumor blocks of APNSCLC pts undergone NIV were retrospectively sequenced for Somatic Mutations/Copy Number Variations (SM/CNV) (Ampliseq 17-genes customized panel: APLNR, B2M, IFNAR1, IFNAR2, IFNGR1, IFNGR2, IRF9, JAK1, JAK2, JAK3, PIAS4, PTPN2, SOCS1, STAT1, STAT2, STAT3, TYK2). End-points of the PRINCiPe study were overall-, progression-free-survival (OS/PFS) and objective response rate (ORR).

      Result

      Forty-four APNSCLC pts were gathered (median age 69.5 yrs, median number of previous lines 3 [2-5], 2nd line NIV [75.0%], male/female 77.3/22.7%, squamous/non-squamous 31.8/68.2%, EGFR mutant 5 [11.4%], median follow-up 6.8 months [range 1-23], deaths 24 [54.5%]). JAK3/JAK2 (7/3 pts, 15.9/6.8%) CNV and IFNAR2 SM (4 pts, 9.1%) were the most frequent (>1 pts) abnormalities. Pts (n=15) with JAK3, PIAS4, PTPN2, STAT3, IFNAR2 SM and/or JAK2/3 CNV (IGS+) had a significantly lower PFS than those without (IGS-) (median PFS 2.8 vs. 6.6 months; p=0.006), while a trend towards significance was observed in terms of OS (median OS 5.1 vs. 13.0 months for IGS+ and IGS-, respectively; p=0.06 log-rank, p=0.05 Tarone-Ware). At multivariate analysis, IGS+ was independently associated with a shorter PFS (HR 2.64, 95% CI 1.3-5.4, p=0.008). IGS+ pts were significantly more probable to be affected by liver metastases than those without (p=0.01).

      Conclusion

      The identified IGS appears to select APNSCLC pts with a significant lower chance to benefit from NIV, supporting intrinsic resistance. A prospective larger and external validation is ongoing, as well as the comprehensive transcriptome analysis.

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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): Emilio Bria

      • 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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