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Santiago Viteri



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    OA13 - Ideal Approach to Lung Resection and Novel Perioperative Therapy (ID 146)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
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      OA13.05 - NADIM Study: Updated Clinical Research and Outcomes (Now Available) (ID 1670)

      11:30 - 13:00  |  Author(s): Santiago Viteri

      • Abstract
      • Presentation
      • Slides

      Background

      Patients with stage IIIA (N2 or T4N0) are potentially curable but median overall survival is only around 15 months

      Method

      A Phase II, single-arm, open-label multicenter study of resectable stage IIIA N2-NSCLC in adult patients with CT plus IO as neoadjuvant treatment: 3 cycles of nivolumab (NV) 360 mg IV Q3W + paclitaxel 200 mg/m2 + carboplatin AUC 6 IV Q3W followed by adjuvant NV treatment for 1 year. After completing neoadjuvant therapy, all patients underwent tumor assessment prior to surgery. Surgery was performed during the 3rd or 4th week after day 21 of the 3rd neoadjuvant treatment cycle. The study aimed to recruit 46 patients. The primary endpoint was Progression-Free Survival (PFS) at 24 months. Efficacy was explored using objective pathologic response criteria. Here we present the final data on all study patients that underwent surgical assessment.

      Result

      At the time of submission, the 46 patients had been included. None of the patients were withdrawn from the study preoperatively due to progression or toxicity. 41 patients had undergone surgery and all tumors were deemed resectable with R0 resection in all cases. Intention to treat analysis shows 35 patients (85%; 95% CI, 71; 94%) achieved major pathologic response (MPR) of which 25 (71%; 95% CI, 54; 85%) were complete pathologic responses (CPR). Downstaging was seen in 38 (93%; 95% CI, 80; 98%) of cases. The median follow-up was 13.8 months (P25; P75: 11.7; 16.6 months) for both the whole series and resected patients, and 12 month PFS was 95.7% (95% CI, 84; 99%).

      Conclusion

      This is the first multicentric study to test CT-IO in the neoadjuvant setting in stage IIIA. Neoadjuvant CT-IO with nivolumab in resectable IIIA NSCLC yields a complete pathologic response rate that is higher than ever seen previously, together with a promising PFS which may translate into increased overall survival. EudraCT Number: 2016-003732-20. Clinical trial information: NCT 03081689.

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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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      P1.01-56 - Increased ROS1 and RET Transcripts in Fusion-Negative NSCLC Patients (ID 2477)

      09:45 - 18:00  |  Author(s): Santiago Viteri

      • Abstract

      Background

      Fusion involving anaplastic lymphoma kinase (ALK), RET proto-oncogene (RET) or v-ros UR2 sarcoma virus oncogene homolog 1 (ROS1) occur in non-small cell lung cancers (NSCLC) and are important biomarkers for targeted therapies. However, little is known about the RNA expression levels of these genes regardless of fusions.

      Method

      We used a custom nCounter panel (NanoString Technologies) designed to detect several genetic alterations, including fusions and mRNA expression levels of ALK, ROS1 and RET in formalin-fixed paraffin embedded (FFPE) samples. RNA was purified from NSCLC tumor samples and analyzed with the custom panel. The counts corresponding to the 3’ probes were normalized using the geometrical mean of the housekeeping genes and then added to evaluate total mRNA expression levels. Cut-off values for overexpression were established as the average counts for each gene plus two times the standard deviation.

      Result

      A total of 400 stage III-IV NSCLC patients (p) from two different institutions were retrospectively analyzed. Overexpression of ALK was found in 55 p (13.8%). Of them, 48 (87%) were also positive for EML4-ALK fusions. One ALK-translocated patient with low levels of ALK mRNA expression did not respond to therapy. Fifteen p (3.8%) showed ROS1 overexpression. In contrast with ALK, only three of them (15%) had a concomitant ROS1 fusion. Among the remaining 12 patients overexpressing ROS1, four were ALK positive, five harbored mutations in EGFR and three were non-smoker females with no known drivers. Regarding RET, high expression levels were found in 14 p (3.5%) and only one of them showed a RET fusion (7%). Among the remaining 13 p, three presented neuroendocrine features and seven were smoker or ex-smoker without other known drivers.

      Conclusion

      Overexpression of ALK mRNA in NSCLC is associated with EML4-ALK translocations. In contrast, a significant number of fusion negative patients show high ROS1 or RET mRNA levels. Further research is warranted to determine the clinical relevance of this finding.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-12 - A Phase I/II Trial of IO102 and Pembrolizumab With/Without Chemotherapy as First-line Treatment of Metastatic NSCLC (ID 706)

      10:15 - 18:15  |  Author(s): Santiago Viteri

      • Abstract
      • Slides

      Background

      Immunotherapy has significantly changed the treatment landscape of non-small cell lung cancer (NSCLC) with no driver mutations. However, despite the addition of anti-PD-1/PD-L1 therapies to the clinical armamentarium only a subset of patients derives durable benefit. IO102 is a novel, second generation, HLA-A unrestricted immune modulating T-win® vaccine targeting IDO. IO102 has a dual mode of action; remodulation of the tumour micro-environment through elimination of immune suppressive cells, and induction of CD8 T-cell mediated killing of IDO-expressing tumor cells. Our first-generation IDO vaccine (IO101) has shown promising antitumor activity and a favorable safety in heavily pretreated NSCLC patients (Iversen, CCR 2013).

      Method

      Phase I/II, international, multicenter, open-label, randomized trial with two parallel cohorts. Cohort A: IO102 (100µg s.c.) and pembrolizumab (200 mg) (PD-L1 ≥ 50%); Cohort B: IO102, pembrolizumab and carboplatin plus pemetrexed (PD-L1 < 50%). The maximum treatment duration is 35 cycles (app. 2 years). Key eligibility criteria include metastatic NSCLC or non-squamous NSCLC (cohort B) with no prior treatment for metastatic NSCLC and no driver mutations.

      Phase I is a non-randomized safety run-in with 6 patients per cohort investigating one dose level of the experimental arms. Only one DLT is allowed in each cohort. Phase II is following Sargent’s two-stage, three-outcome optimum design (Sargent, ClinTrial2001) with a 2:1 randomization in the cohorts. Cohort A: IO102 and pembrolizumab versus pembrolizumab alone; Cohort B: IO102, pembrolizumab and chemotherapy vs. pembrolizumab and chemotherapy. Provision of blood and tumour tissue is required for biomarker studies.

      The primary endpoint is safety and objective response rate (ORR) per RECIST 1.1 in Phases I and II, respectively. Secondary endpoints include ORR per iRECIST, duration of response, progression free survival, overall survival, and biomarkers including immunoscore in tissue, tumour mutational burden and immunomonitoring in blood.

      The study is enrolling in Europe. First patient was entered in September 2018 and recruitment is expected to continue throughout 2019: EudraCT Number 2018-000139-28 / IND Number: 018081.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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      P2.01-56 - Copy Number Gains (CNGs) of Clinically Relevant Genes in Advanced NSCLC Patients (ID 2519)

      10:15 - 18:15  |  Author(s): Santiago Viteri

      • Abstract

      Background

      Somatic copy number variations (CNV; i.e. amplifications and deletions) have been implicated in the origin and development of multiple cancers and some of these aberrations are designated targets for therapies, such as amplified ERBB2 in breast cancer. In the case of NSCLC patients, MET alterations are receiving increasing attention as targets in precision medicine, and several clinical trials of anti-MET agents are ongoing. Routine testing for these potential targets on formalin-fixed paraffin embedded (FFPE) samples is mainly carried out by in-situ hybridization (FISH) approaches covering only a single gene of interest. Although this methodology is still the gold standard of CNV detection, it presents several drawbacks. Here we aimed to determine the potential of next generation sequencing (NGS) to simultaneously determine CNGs across many in FFPE samples

      Method

      FFPE biopsies from 140 stage IIIb-IV NSCLC patients (p) of our institution were prospective tested. Of them, 110 corresponded to samples at diagnostic and 30 after progression to targeted therapies. DNA was purified submitted to NGS using the 16-gene QIAact Lung Panel (Genereader®, Qiagen). Coverages for the genes analyzed were normalized using the total coverage of the panel. Cut-off values for CNVs were established as the average normalized coverage for each gene plus two times the standard deviation. Representative samples were analyzed by FISH

      Result

      Validation analyses in 8 cell lines showed 100% concordance between FISH and NGS for detection of EGFR, MET and ERBB2 amplifications. Among the 140 NSCLC p, MET was the gene showing a higher frequency of CNGs, followed by PIK3CA, NRAS, EGFR and KRAS (Table 1). In contrast, only one p was found to harbor a ROS1 CNG. Among the 17 samples with MET CNG (12%), 6 corresponded to p progressing to targeted therapies. In addition, 8 of the 17 samples with MET CNGs were submitted to FISH, 6 of them were positive and the remaining 2 samples had copy numbers higher than 3.5 by this technique. In the case of EGFR, CNGs were associated with sensitizing mutations, with 5 samples showing both alterations concomitantly. In contrast, PIK3CA, NRAS, ALK, BRAF, HER2, PDGFRA, KIT and MET CNGs were not associated with mutations (Table 1).

      n CNG

      %

      n MUTANT

      MET

      17

      12.1

      0

      PIK3CA

      12

      8.6

      0

      NRAS

      10

      7.1

      0

      EGFR

      10

      7.1

      5

      KRAS

      10

      7.1

      2

      ALK

      8

      5.7

      0

      BRAF

      8

      5.7

      0

      ERBB2

      8

      5.7

      0

      PDGFRA

      6

      4.3

      0

      KIT

      6

      4.3

      0

      ROS1

      1

      0.7

      0

      Conclusion

      CNGs in clinically relevant genes are present in a significant percentage of advanced NSCLC patients and, except in the case of EGFR, are not associated with driver mutations. Further research is warranted to determine the clinical implications of this finding.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-16 - Agreement Between Different Methodologies for Non-Invasive p.T790M and EGFR Sensitizing Mutation Testing (ID 1965)

      10:15 - 18:15  |  Author(s): Santiago Viteri

      • Abstract
      • Slides

      Background

      Tyrosine kinase inhibitors (TKIs) are the current standard of care for patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, most patients progressed within 1 to 2 years. The EGFR p.T790M mutation is the most common resistance mechanism to first and second generation EGFR TKIs. The identification of p.T790M mutation is of considerable clinical relevance as osimertinib has demonstrated clinical efficacy in this setting. Guidelines recommend testing for the p.T790M mutation in blood at relapse to TKIs, and re-biopsy only in case of a negative result. Several blood based methodologies for detection of EGFR mutations have been developed in the recent years. However, the number of comparison studies between platforms is very limited.

      Method

      This is a multicenter, cross-sectional study (ClinicalTrials.gov Identifier: NCT03363139) performed by the Spanish Lung Cancer Group. Samples from 75 consecutive EGFR mutant NSCLC patients were collected at disease progression to first line TKI treatment. The presence of EGFR mutations in the cfDNA was evaluated in 39 samples by 7 methodologies, namely: Cobas® EGFR Mutation Test v2 (Roche Diagnostics), Therascreen EGFR Plasma RGQ PCR Kit (Qiagen), QuantStudio® 3D Digital PCR System (Thermofisher), a 5′-nuclease real-time PCR (TaqMan®) assay in presence of PNA, OncoBEAM EGFR (Sysmex Inostics), NGS with two different gene panels: Oncomine® (Thermofisher) and Lung Cancer Panel (Qiagen). The agreement between methodologies was assessed using the kappa coefficient (K) and its corresponding 95% confidence intervals (95% CI). For quantitative variables the concordance correlation coefficient (ccc) was used.

      Result

      Complete results are available for 39 patients. Overall, the agreement between all methodologies for the detection of p.T790M mutation as well as the original EGFR sensitizing mutation was good (K=0.669; 95CI: 0.504-0.835 and K=0.750 95CI: 0.599-0.899 respectively). Remarkably, the agreement between FDA-approved methodologies for p.T790M detection was almost perfect (K=0.926; 95CI: 0.712-1) and good for the EGFR sensitizing mutations (K=0.657; 95CI: 0.417-0.902). Similarly, the agreement between NGS-based methodologies for the detection of p.T790M and the EGFR activating mutations was very high (K=0.843; 95CI: 0.567-1 and K=0.872 95CI: 0.595-1 respectively). Moreover, concordance between both technologies for p.T790M and EGFR sensitizing mutation mutant allele frequency was excellent (ccc=0.956; 95CI: 0.906-1 and ccc=0.980 95CI: 0.950-1 respectively). The proportion of samples that were positive for p.T790M detection varied from 28% (PCR based technologies) to 37% depending on the methodology.

      Conclusion

      NGS and PCR-based methodologies show a good to excellent agreement for the detection of EGFR mutations, including the p.T790M. Our results support the use of liquid biopsies for non-invasive testing of clinically relevant mutations (Data from the whole cohort will be presented at the meeting).

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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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      P2.04-10 - Biomarkers of Pathological Response on Neo-Adjuvant Chemo-Immunotherapy Treatment for Resectable Stage IIIA NSCLC Patients (ID 1466)

      10:15 - 18:15  |  Author(s): Santiago Viteri

      • Abstract
      • Slides

      Background

      PD1/PDL1 treatments have become the main therapy in advanced stages of NSCLC due to its significant increase in overall survival (OS), but recently, combination with chemotherapy in locally advanced stages is showing promising results. Many studies have described peripheral blood immune cells parameters as biomarkers of response to immunotherapy. In our study, we described the effect of neo-adjuvant chemo-immunotherapy treatment in Complete Blood Count (CBC) and Peripheral Blood Mononuclear Cells (PBMCs) phenotype, as well as, the association of these parameters with the degree of pathological response.

      Method

      Immune cell populations of 46 resectable stage IIIA NSCLC patients treated with neo-adjuvant chemo-immunotherapy from NADIM clinical trial were analysed. Samples were extracted before initiating the neo-adjuvant treatment with nivolumab plus carboplatin and at the third cycle before patients underwent surgery. We classified patients in 3 subgroups of pathological response assessed in the resection specimen: complete response (pCR), major response (<10% viable tumour) and incomplete response (>10% viable tumour, pIR). Wilcoxon and Mann-Whitney U statistic test were used to evaluate differences between pre and post treatment and between pathological responses groups respectively.

      Result

      From 46 patients, 5 patients did not undergo surgery, so they were excluded from the analysis. Absolute numbers of Leucocytes, Eosinophil, Monocytes, Neutrophils, Haemoglobin and Platelets from hemograms were significantly reduced after neo-adjuvant treatment. However, no changes were observed for Lymphocytes, Basophils, LDH levels or the Lung Immune Prognostic Index (LIPI). Additionally, post-treatment Neutrophil-to-Lymphocyte (NLR), Myeloid-to-Lymphoid lineage (M:L) and Platelets-to-Lymphocytes (PLR) ratios were decreased. Remarkably, from all the CBC absolute numbers and ratios, only PLR variation showed differences between pCR and pIR.

      On the other hand, percentages of PBMCs (T cells, B cells, NK cells and macrophages) did not vary after neo-adjuvant treatment, however activation of CD4 T cells and NK cells as well as PD-1 receptor expression on immune cells were downregulated after neo-adjuvant chemo-immunotherapy. Interestingly, these variations correlate with pCR.

      Conclusion

      In our study, PLR, PD-1 expression, CD4 T cells and NK cells activation are predictive biomarkers of response to treatment. Thus, a higher decrease on PLR post neo-adjuvant treatment is associated to pCR. Moreover, a decrease of PD-1 expression in CD4, CD8 and NK cells, as well as, a reduction of CD4 T cells and NK cells activation after neo-adjuvant treatment, are associated to pCR.

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      P2.04-79 - High Rate of Immune Related Pneumonitis in Lung Cancer Patients Treated with Anti PD-1 Antibodies (ID 1061)

      10:15 - 18:15  |  Author(s): Santiago Viteri

      • Abstract
      • Slides

      Background

      Treatment with anti PD-1/PD-L1 antibodies has demonstrated survival improvement in several malignancies, including non small cell lung cancer (NSCLC), but these therapies are not exempt from risks. Meta-analysis and clinical trials have reported immune related (ir) pneumonitis of any grade in 3-5% of patients treated with anti PD-1/PD-L1 antibodies, including grade 3 or higher in 0.8% to 1.8% of patients.

      Method

      We have retrospectively reviewed clinical reports from 125 cancer patients treated at our center with anti PD-1/PD-L1 antibodies (55 were treated with nivolumab, 27 with pembrolizumab, 33 with atezolizumab, 6 with avelumab, and 4 with durvalumab) from January 2016 to January 2019.

      Result

      Nineteen patients (15.2%) developed ir pneumonitis. Four (21%) patients had recurrent pneumonitis during tapering corticoesteroid dose after an initial improvement and finally died. Patient characteristics are summarized in Table 1. Median time to pneumonitis was 4 months (m) (range 1m to 9m). Twelve patients (9.6% %) had grade 3-5 and 7 patients (5.6 %) grade 1-2 pneumonitis. Nine (7.2 %) patients died from ir pneumonitis, including 4 patients with no tumor progression (1 had received only one cycle, and 3 patients had ongoing tumor response at 10m+, 12m+ and 30m+). Ir pneumonitis was more frequent with nivolumab (any grade 21.8 %, grade 3 or higher 18.2 %, including 7 fatal cases-12.7%-), while no patient treated with atezolizumab developed pneumonitis (Table 2).

      Table 1
      Total 19

      Gender

      Women, n (%)

      7 (36,8%)

      Age

      Median (range)

      63,4 (51-82)

      Cancer type, n (rate)

      NSCLC Adenoca

      NSCLC Squamous

      SCLC

      Mesothelioma

      13 (68,4 %)

      4 (21%)

      1 (5,3%)

      1 (5,3%)

      Line of therapy, n (rate)

      Adjuvant

      First line

      Second or further line

      1 (5,2 %)

      8 (42,1%)

      10 (52,6%)

      Tumor Response, n (rate)

      CR

      PR

      SD

      PD

      NE

      2 (10,5%)

      8 (42,1%)

      5 (26,3%)

      3 (15,8%)

      1 (5,2%)

      table 2
      Drug,n patients treated Any Grade, n (%) Grade 3-5, n (%) Grade 5, n (%)
      Nivolumab, 55 12 (21,8%) 10 (18,2%) 7 (12,7%)
      Pembrolizumab, 27 3 (11,1%) 1 (3,7%) 1 (3,7%)
      Atezolizumab, 33 0 0 0
      Durvalumab, 4 2 (50%) 0 0
      Avelumab, 6 2 (33,3%) 1 (16,7%) 1 (16,7%)
      Total, 125 19 (15,2%) 12 (9,6%) 9 (7,2%)

      Conclusion

      In our experience, ir pneumonitis rate with anti PD-1/PD-L1 antibodies in lung cancer patients was 15.2%, including 7.2% of fatal complications. It suggests that previous clinical trials could have under diagnosed this serious complication. Further studies must be performed in order to specifically assess the rate of pneumonitis in patients treated with anti PD-1 and anti PD-L1 antibodies in lung cancer patients.

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