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Pilar Garrido



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    MA 02 - Emerging Targets (ID 656)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Clinical Design, Statistics and Clinical Trials
    • Presentations: 1
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      MA 02.02 - Phase 2 Study of Pembrolizumab Plus CC-486 vs Pembrolizumab Plus Placebo in Previously Treated Patients with Advanced NSCLC (ID 8581)

      11:00 - 12:30  |  Author(s): Pilar Garrido

      • Abstract
      • Presentation
      • Slides

      Background:
      Studies have demonstrated that epigenetic modifiers, such as azacitidine, may sensitize tumor cells to treatment with checkpoint inhibitors, such as pembrolizumab (pembro). Efficacy and safety results from a phase 2, randomized, double-blind study of pembro in combination with CC-486, an oral formulation of azacitidine, vs pembro+placebo (PBO) for 2L treatment of advanced NSCLC are reported.

      Method:
      Patients aged ≥ 18 years with stage IIIB/IV NSCLC with only 1 prior platinum-based chemotherapy were randomized 1:1 (stratified by histology) to pembro 200 mg day 1 plus either CC-486 300 mg or placebo days 1-14 of a 21-day cycle. Primary endpoint was PFS. Key secondary endpoints included OS, ORR and safety.

      Result:
      51 and 49 patients were randomized to the pembro+CC-486 and pembro+PBO arms. Baseline characteristics were generally balanced between treatment groups. Efficacy results are shown in Table 1. Median duration of treatment for pembro+CC-486 vs pembro+PBO was 14 vs 24 weeks, and median number of cycles was 5 vs 7. The most common grade 3/4 TEAEs associated with pembro+CC-486 were nausea (14%), vomiting (12%), asthenia (10%), and diarrhea (8%), vs diarrhea (6%), asthenia (6%) and pneumonia (6%) with pembro+PBO. Patients treated with pembro+CC-486 vs pembro+PBO experienced a higher rate of pembro dose interruptions (29% vs 16%) and discontinuations (20% vs 10%), and a higher rate of CC-486 or PBO dose interruptions (61% vs 24%) and discontinuations (33% vs 12%). Gastrointestinal events, asthenia/fatigue, and elevated transaminase levels were the most common TEAEs leading to discontinuations.

      Conclusion:
      The addition of CC-486 to pembro did not improve the primary endpoint of PFS compared with pembro+PBO. PD-L1 expression did not appear to be predictive of CC-486 treatment efficacy. The increase in TEAEs in the combination arm, particularly gastrointestinal (nausea and vomiting), which are known to be associated with CC-486, may have influenced treatment exposure.

      Efficacy Endpoints Pembro + CC-486 n = 51 Pembro + PBO n = 49
      Overall
      PFS, median, months 3.1 4.0
      ORR, n (%) 10 (19.6) 7 (14.3)
      By PD-L1 Level at Baseline n = 45 n = 44
      PFS, median, months ≥ 50% ≥ 1%-49% 0% 5.5 1.6 3.6 8.0 1.4 3.9
      ORR, % ≥ 50% ≥ 1%-49% 0% 37.5 20.0 18.5 37.5 0.0 7.1


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    MA 15 - Lung Cancer Biology II (ID 670)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Biology/Pathology
    • Presentations: 1
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      MA 15.01 - LungBEAM: A Prospective Multicenter Trial to Monitor EGFR Mutations Using BEAMing Technology in Stage IV NSCLC Patients (ID 10145)

      15:45 - 17:30  |  Presenting Author(s): Pilar Garrido

      • Abstract
      • Presentation
      • Slides

      Background:
      Liquid biopsy is a promising approach to improve the management of NSCLC patients, offering a minimally-invasive alternative to tumor tissue testing and enabling timely monitoring of patients on-therapy. The goal of the present study was to evaluate the performance of the OncoBEAM EGFR plasma vs EGFR tissue testing across 19 Spanish hospitals and to examine the timing of T790M mutation emergence in patients during first-line EGFR TKI therapy with respect to radiological progression.

      Method:
      Blood samples from 112 therapy-naïve advanced NSCLC patients were collected at baseline and throughout EGFR TKI therapy. Results from OncoBEAM EGFR mutation were performed by Sysmex in Hamburg, Germany and then compared to those obtained by the initial EGFR tissue testing obtained at the referring hospital. In addition, the time at which T790M was first detected was compared to the date of progression determined by radiological imaging.

      Result:
      112 stage IV NSCLC patients (p) were enrolled between Nov 2016 and May 2017. Clinical characteristics: median age 65 y. , 81 female. Smoking pattern: never 70 p (62,5%), former 33 p (29.4%) and active 9 (8%). M1a 28 p (25%), M1b only brain 10 p (8.9%), only bone 17 p (15%). Baseline tissue samples: Exon 19 deletion 74 p (66%) , L858R 38 p (34%). Initial positive percent agreement (PPA) in 69 out of 112 p was 52/69 or 75.4%. Interestingly, the agreement between plasma and tissue EGFR mutation results for patients diagnosed at M0 was 56%, versus 81% with patients diagnosed at M1. In addition, the average number of days between tissue biopsy and blood collection for concordant cases was 128 days, versus 358 days for discordant cases. Currently, the tissue EGFR mutation status of all discordant cases is being re-examined using BEAMing. Preliminary results from serial T790M plasma analyses revealed cases where detection by OncoBEAM was observed several weeks prior to documented progression by imaging. More mature results will be available at the time of the meeting

      Conclusion:
      Overall, these initial results show high PPA of plasma and tissue EGFR mutation status at baseline. Moreover, early detection of T790M in blood may assist in anticipating resistance to first-line EGFR TKI therapy.

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    P1.01 - Advanced NSCLC (ID 757)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P1.01-040 - Clinical Utility of Plasma-Based NGS for Advanced-Stage NSCLC Patients with Insufficient or Unavailable Tumor Tissue (ID 10215)

      09:30 - 16:00  |  Presenting Author(s): Pilar Garrido

      • Abstract
      • Slides

      Background:
      The failure rate of tissue-based NGS in newly diagnosed NSCLCs is approximately 20-25 %, reaching 40 % in the case of tumor biopsy samples collected at disease progression. In this study, we are analyzing the clinical utility of plasma-based NGS using cell-free circulating tumor DNA (ctDNA) for advanced-stage lung adenocarcinoma patients, as a complement or alternative to tissue-based molecular profiling.

      Method:
      Eight Academic Spanish Institutions are participating in patient recruitment. We are stratifying patients in three cohorts: 1) Patients with advanced-stage lung adenocarcinomas with insufficient tumor tissue for EGFR, ALK or ROS1 analysis; 2) Patients with EGFR, ALK or ROS1 altered tumors with acquired TKI resistance; 3) Patients with EGFR T790M positive cancers progressing on third generation EGFR TKIs. Next-generation ctDNA sequencing is being performed using GUARDANT360 73-gene panel at a CLIA certified central laboratory facility (Redwood City, California). We are stratifying gene variant actionability into four levels according to the OncoKB website criteria.

      Result:
      We have currently included 97 patients (January-June 2017). Complete clinical and molecular data are available at present for the first 37 patients. Twelve, 19 and 6 patients have been enrolled in cohorts 1, 2 and 3 respectively. Never smoker patients were overrepresented (n = 21, 56 %), predominantly at cohorts 2 and 3. A total of 30 cases (81 %) had detectable ctDNA. We have detected potentially actionable genetic alterations involved in mitogenic pathways in 16 patients (43 %). Level 1 alterations (variants with matched approved drugs) were found in three patients’ tumors (25 %) from cohort 1 (two EGFR sensitizing mutations and one ROS1 rearrangement). Nine patients (36 %) from cohort 2 and 3 had tumors with potentially targetable acquired genetic alterations, including three cases with EGFR T790M mutations and one case with a ROS1 kinase domain mutation. Six patients (16 %) received matched targeted therapies, four (11 %) in genotype-driven clinical trials. Reasons for not receiving matched targeted therapies in patients with actionable tumors were clinical deterioration or death (n = 2), unavailability of matched clinical trials (n = 6), treatment with non-genotype-tailored therapies (n =1) or no disease progression to ongoing therapies (n =1). Final clinical and molecular data of the whole cohort will be provided at the meeting.

      Conclusion:
      On the basis of our preliminary data, next-generation ctDNA sequencing (GUARDANT 360) appears to detect actionable genetic alterations when tissue is unavailable, avoiding multiple biopsies and enabling rapid patient selection for genotype-tailored therapies.

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    P1.04 - Clinical Design, Statistics and Clinical Trials (ID 690)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Clinical Design, Statistics and Clinical Trials
    • Presentations: 1
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      P1.04-001 - Osimertinib with Ramucirumab or Necitumumab in Advanced T790M-positive EGFR-Mutant NSCLC: Preliminary Ph1 Study Results (ID 7940)

      09:30 - 16:00  |  Author(s): Pilar Garrido

      • Abstract
      • Slides

      Background:
      Combination studies of a first- or second-generation EGFR tyrosine kinase inhibitor (TKI) and either a VEGF or EGFR-targeting monoclonal antibody have recently shown promising clinical results in EGFR-mutant non-small cell lung cancer (NSCLC) patients. The preliminary safety results from the phase 1 study JVDL (NCT02789345), combining third-generation EGFR TKI osimertinib (Osi) with human IgG1 monoclonal antibodies ramucirumab (Ram) or necitumumab (Neci), are reported.

      Method:
      Eligible pts naïve to third-generation EGFR TKI therapy with advanced EGFR T790M-positive NSCLC who progressed after initial EGFR TKI therapy were enrolled. In the dose-finding portion, following a dose de-escalation 3+3 design, patients received daily oral Osi (80 mg) and either 10 mg/kg intravenous (IV) Ram on day 1 (D1) every two weeks (Q2W), or 800 mg (IV) Neci on D1 and D8 Q3W. Primary objective of the study is to assess the safety and tolerability of Ram or Neci combined with Osi, and secondary objectives include preliminary evaluation of efficacy.

      Result:
      As of data cutoff on 09-May-2017, 7 pts were treated in the completed dose-finding portion: 3 pts with Ram+Osi (Arm A) and 4 pts (1 non-evaluable and replaced) with Neci+Osi (Arm B). No DLTs were observed in either arm, and the initial dose level became the recommended dose for expansion cohort. After the DLT observation period was complete, the only Grade ≥3 (Gr≥3) treatment-related adverse event (TRAE) was dermatitis acneiform (Arm B), with one unrelated Gr≥3 treatment-emergent AE (TEAE) of increased lipase (Arm B) and one serious AE of Gr2 diverticulitis (unrelated to study treatment) (Arm A). Expansion cohort A of Ram+Osi is fully enrolled with 22 pts. Safety data were available for 18 out of 22 cohort A patients. Gr≥3 TEAEs were reported in 4 patients, including dyspnea (unrelated [n=1]), decreased appetite (unrelated [n=1]), and hypertension (related [n=2]). Three patients reported serious adverse events (none related to study treatment): Gr3 dyspnea and Gr2 pyrexia, Gr2 dyspnea, and Gr2 urinary tract infection. No death was reported in patients in the dose-finding portion, and one death unrelated to study treatment was reported in the expansion cohort.

      Conclusion:
      No DLTs were observed and no unexpected safety signals were seen to date. The recommended dose for expansion cohort was the initial dose level of 10 mg/kg ramucirumab IV Q2W with oral 80 mg osimertinib. Additional safety and efficacy observation for the combination of Ram+Osi is ongoing, and will be presented at the meeting.

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    P2.07 - Immunology and Immunotherapy (ID 708)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      P2.07-060 - Response Assessment and Subgroups Analysis According to the Lung Immune Prognostic Index (LIPI) for Immunotherapy in Advanced NSCLC Patients (ID 10179)

      09:30 - 16:00  |  Author(s): Pilar Garrido

      • Abstract

      Background:
      LIPI is a score that combine dNLR (neutrophils/(leucocytes-neutrophils) and lactate dehydrogenase (LDH) and correlate with prognosis of NSCLC patients treated with immune checkpoint inhibitors (ICI). We report the predictive role of LIPI on response and in various subgroups of patients.

      Method:
      Baseline dNLR and LDH were retrospectively collected in 431 patients treated with ICI from Nov. 2012 to Jan. 2017, from 8 European centers. LIPI delineates 3 groups: good (dNLR<3+LDH3 or LDH>ULN), poor (dNLR>3+LDH>ULN). Response rate (RR) and disease control rate (DCR) were assessed according to the investigator’s criteria. The subgroup analysis was performed according to the age, histology, performance status (PS) and PD-L1 status by immunohistochemistry (positivity if ≥ 1% on tumor cells).

      Result:
      With a median follow-up of 12.8 months (m.) [95%CI 11.9-14], 431 patients were included. Baseline characteristics are summarized in table 1. The median overall survival (OS) and progression-free survival (PFS) were 10.5m. [95%CI 9.5-13] and 3.9m. [3-4.4], respectively. The median OS was 4.8m. vs. 10 m. vs. 16.5m., and median PFS was 2m. vs. 3.1m. vs. 5m. for the poor, intermediate and good LIPI groups, respectively (both p<0.0001). LIPI was correlated with response rate (p<0.0001). In multivariate analysis, the intermediate and poor group were associated with progressive disease, with an OR of 2.20 [CI95% 1.26-3.84] p=0.005) and an OR of 3.04 [CI95% 1.46-6.36] p=0.003), respectively. LIPI was correlated with OS, regardless the age (<70 years (p<0.0001) vs. older (p=0.0006) and the histology non-squamous (p<0.0001) vs. squamous (p=0.02). In PS 0-1 and in smoker population, LIPI correlated with OS (both p<0.0001), but not in PS ≥2 (12%) and non-smokers (8%). LIPI was correlated with OS for positivity (p=0.01) and unknown PD-L1 (p=0.0001), but not negativity.

      LIPI 0 Good (N=162, 37%) LIPI 1 Intermediate (N=206, 48%) LIPI 2 Poor (N= 63, 15%) All population cohort N = 431 (%)
      Sex
      Male 102 (63) 131 (64) 42 (67) 275 (64)
      Age at diagnosis
      Median (years, range) 62 (36;86) 63 (29;86) 62 (39;84) 62 (29;86)
      Smoking status
      Non-smoker 13 (8) 18 (9) 5 (8) 36 (8)
      Former 80 (49) 115 (56) 46 (73) 241 (56)
      Current 67 (42) 69 (33) 11 (17) 147 (34)
      Unknown 2 4 1 7
      Histology
      Non-squamous 111 (69) 132 (64) 41 (65) 284 (66)
      Squamous 51 (31) 74 (36) 22 (35) 147 (34)
      Molecular alteration
      EGFR mutation 3 (2) 13 (6) 3 (5) 19 (4)
      ALK rearrangement 2 (1) 2 (1) 1 (2) 5 (1)
      KRAS mutation 34 (21) 31 (15) 8 (13) 73 (17)
      PDL1 status
      Negative 16 (36) 14 (25) 1 (5) 31 (25)
      Positive 28 (64) 43 (75) 20 (95) 91 (75)
      Unknown 118 149 42 337
      Performance Status
      0 51 (32) 45 (22) 10 (16) 106 (25)
      1 96 (60) 132 (64) 42 (67) 270 (63)
      ≥ 2 12 (8) 28 (14) 11 (17) 51 (12)
      Stage at diagnosis
      IIIb 18 (11) 33 (16) 14 (22) 65 (15)
      IV 101 (62) 135 (66) 38 (60) 274 (64)
      Metastases sites
      Median (Range) 2 (0;6) 2 (0;7) 2 (1;7) 2 (0-7)
      Bone 43 (27) 58 (28) 20 (32) 121 (28)
      Liver 28 (17) 39 (19) 16 (25) 83 (19)
      Brain 22 (14) 19 (9) 9 (14) 50 (12)
      Immunotherapy
      PD1 inhibitor 133 (82) 167 (81) 48 (76) 348 (81)
      PDL1 inhibitor 19 (12) 34 (17) 12 (19) 65 (15)
      PDL1 inhibitor- CTLA4 inhibitor 10 (6) 5 (2) 3 (5) 18 (4)
      Immunotherapy line
      Median (Range) 2 (1;11) 2 (1;12) 2 (1;8) 2 (1-12)
      Response rate
      Complete response (CR) 6 (4) 3 (1) 0 (0) 8 (2)
      Partial response (PR) 42 (26) 53 (26) 18 (28) 113 (26)
      Stable disease (SD) 66 (41) 59 (29) 8 (13) 133 (31)
      Progression 40 (25) 81 (39) 33 (52) 154 (36)
      NA 8 10 4 25
      Dissociated response 14 (9) 15 (7) 2 (3) 31 (7)


      Conclusion:
      Baseline LIPI predicts response to ICI, and was correlated with OS regardless of age and histology.