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Normand Blais



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    MA08 - Clinical Trials in Brain Metastases (ID 906)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 203 BD
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      MA08.11 - Early Safety Data of a Phase I/II Combining Nivolumab and Stereotactic Brain Radiosurgery for Treatment of Brain Metastases in Patients with NSCLC (ID 14064)

      16:20 - 16:25  |  Author(s): Normand Blais

      • Abstract
      • Presentation
      • Slides

      Background

      Radiotherapy can stimulate the immune system through various means. Highly cytotoxic stereotactic radiosurgery (SRS) doses (>10Gy per fraction) may synergize with anti-PD1 to reduce intracranial disease progression or recurrence.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Within a phase I/II trial evaluating the combination of nivolumab with SRS in the treatment of brain metastases from NSCLC and RCC (NCT02978404), 8 patients were enrolled (1 RCC and 7 NSCLC) in the first trial cohort. Herein, only the NSCLC cases are reviewed. Patients were eligible if their KPS ≥70, were minimally symptomatic (RTOG neurological function <2), and had ≤10cc of untreated brain metastases. Prophylactic corticosteroids were not given. Nivolumab (240mg IV q2 weeks) was started 2 weeks prior to SRS, and administered until RECIST progression. SRS (15-20Gy in 1 fraction) was given to each brain metastasis. The aim of the first patient cohort is to estimate the tolerability of the combined treatment strategy.

      4c3880bb027f159e801041b1021e88e8 Result

      The median follow-up of the three male and four female patients was 2 months. Median age was 63 years (55-84 years). Five NSCLC patients completed ≥1 cycle of nivolumab and SRS, and were evaluated for tolerability of the combination. One patient elected to withdraw before the first nivolumab dose and 1 patient died prior to SRS. Median baseline brain edema and total brain metastases volumes were 0.5cc (0-46.97cc) and 1.25 cc (0.1-3.46cc), respectively. To date, the median number of nivolumab cycles administered is 4.5 (1-15). Intracranial adverse effects were limited to apraxia and paresthesias in the patient who had the largest volume of peri-tumoral brain edema at baseline (46.97cc). Nivolumab was held and dexamethasone was given for 74 days at doses >1mg/day until neurological symptoms resolved. Systemic adverse events included one patient with grade 2 arthritis necessitating a 6-week treatment delay and 51 days of prednisone ≥10mg. At last follow-up, three patients had died of extracranial disease progression, including the two patients who did not receive protocol SRS. Among the three patients evaluable for intracranial response, there was one partial response and two stable diseases. All three patients had stable extracranial disease.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Combining SRS and immunotherapy is safe in regards to acute toxicity with a manageable side effect profile. Close monitoring may be required for patients with significant baseline brain edema. Evaluation for efficacy awaits further follow-up and completion of recruitment in the phase 2 component of the trial.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    OA13 - Therapeutics and Radiation for Small Cell Lung Cancer (ID 927)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 203 BD
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      OA13.04 - Discussant - OA 13.01, OA 13.02, OA 13.03 (ID 14570)

      11:00 - 11:15  |  Presenting Author(s): Normand Blais

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.13-19 - Treatment Cessation for Improved Detection of EGFR-Mutated Circulating Tumor DNA in Advanced Non-Small Cell Lung Cancer (aNSCLC) (ID 11329)

      16:45 - 18:00  |  Author(s): Normand Blais

      • Abstract
      • Slides

      Background

      First/second generation EGFR-tyrosine kinase inhibitors (EGFR-TKI) are eventually met with therapeutic failure in EGFR-mutated (EGFRm) aNSCLC, but post-progression continuation of therapy can delay the need for second line therapy by a median of ~ 3 months. In this context, osimertinib was shown to be effective in T790M mutated EGFR, which occurs in > 50% of cases. T790M detection within circulating tumor DNA (ctDNA) is convenient but has suboptimal sensitivity. The goal of this study is to determine whether temporary cessation of the TKI - beyond initial progression - would allow for increased plasma detection of EGFR mutations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      EGFRm aNSCLC patients who were still on first/second generation EGFR-TKI beyond initial progression were enrolled. TKI was withheld on day 0. Blood samples were drawn and the NCCN-FACT FLSI-17 questionnaire v2 was administered on days 0 and 6±1. Semi quantitative measurements of EGFR mutations within plasma samples were obtained using the cobas® EGFR Mutation Test v2. Descriptive statistics were reported and paired t-test was used to compare differences in ctDNA yield and quality of life after TKI cessation.

      4c3880bb027f159e801041b1021e88e8 Result

      33 patients were enrolled in 2017. Baseline characteristics and relevant study results are summarized in Table 1. Temporary TKI cessation was safe with no tumor flares reported - questionnaire scores indicate a trend towards improved quality of life one week after TKI cessation. The yield of detection was significantly higher after TKI cessation, but only for the baseline sensitizing mutation.

      Table 1
      Age, Median - years (range) 71(46 - 87)
      Gender, female n (%) 25 (75.8)
      Median time to progression on first/second generation TKI, months (range) 9.76 (0.3 - 46)
      Median time from initial progression to study enrollment, months (range) 1.03 (0.25 - 7.57)
      NCCN-FACT FLSI-17 questionnaire
      - Questionnaire score day 1
      - Questionnaire Score day 6/7

      - 45.81±10.78
      - 48.41±9.91 (p=0.08)
      Baseline EGFR sensitizing mutation
      - Overall detection of ctDNA, n (%)
      - Detection within ctDNA on only one of the two test dates, n (%)

      Semi quantitative index of detected ctDNA
      - Day 1
      - Day 6/7

      - 21 (63.6)
      - 6 (28.5)


      - 5.2±6.2
      - 6.1±6.4 (p=0.04)
      T790M EGFR mutation
      - Overall detection of ctDNA, n (%)
      - Detection within ctDNA on only one of the two test dates, n (%)

      Semi quantitative index of detected ctDNA
      - Day 1
      - Day 6/7

      - 21 (63.6)
      - 6 (28.5)


      - 5.2±6.2
      - 6.1±6.4 (p=0.04)

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our data suggest that TKI cessation can lead to increased shedding of ctDNA in sensitive cells. However, drug withdrawal may not impact the shedding of ctDNA in resistant clones. Irrespective of drug withdrawal, a strategy of repeat testing appears to increase the sensitivity of ctDNA detection and would likely produce more clinically relevant outcomes in comparison with one-time testing.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.01-23 - Baseline Plasma Biomarkers Predict Long-Term Responses to ALK-TKIs in ALK+ Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 13458)

      16:45 - 18:00  |  Author(s): Normand Blais

      • Abstract
      • Slides

      Background

      Median progression free survival (PFS) for ALK tyrosine kinase inhibitors (ALK-TKIs) range from 10.9-25.7 months (mos)[1],[2],[3],[4]. While most ALK+ NSCLC patients develop resistance to ALK-TKIs within 1-2 years, a subset of patients experience a response >2 years. Given the lack of proteogenomic markers predicting long-term responses to ALK-TKIs, we conducted whole-exome sequencing (WES) and proteomic profiling to define molecular determinants that could predict a long-term ALK-TKI response, help guide the sequentiality of therapies and optimize treatment strategies.

      [1]Soria, J.C. et al. Lancet389,917–929 (2017)

      [2]Peters, S. et al. N. Engl. J. Med.377, 829-838(2017)

      [3]Kim, D.-W. et al.J. Clin. Oncol.35,2490–2498 (2017)

      [4]Solomon, B. J. et al.N. Engl. J. Med.371,2167–2177 (2014).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Twenty-four patients with advanced ALK+ NSCLC were enrolled in our study. WES was performed on primary and post-treatment metastatic tissue to identify genomic aberrations and ALK fusions. MRM-MS was used to analyze 327 protein candidates in plasma collected from patients at baseline.

      4c3880bb027f159e801041b1021e88e8 Result

      Patients were categorized into 3 groups based on duration of response: long-term responders [LR; PFS ≥24 mos (n=8)], normal responders [R; 3 < PFS < 24 mos (n=10)] and non-responders [NR;PFS <3 mos (n=6)]. At data cutoff (30 April 2018), median PFS was 1.6 mos for NR, 11.7 mos for R and 37.1 mos for LR. Two LR remain on treatment and have experienced a PFS > 37.4 mos. Despite detecting novel ALK fusion partners, multiple somatic mutations and copy number aberrations by WES, we could not define a genomic signature predictive of a long-term response to ALK-TKIs from our small cohort. However, MRM-MS identified 15 proteins differentially regulated between LR and NR, including SODE, F13A, LYAM1, FCGBP, PGBM and LUM. Differences in protein levels were further pronounced between LR and NR. To determine whether our protein signature can discriminate according to response groups, we performed principal component and hierarchical clustering analyses. Both analyses successfully segregated LR from R and NR. Moreover, we used our set of 15 proteins to generate single-sample Gene Set Enrichment Analysis scores which distinguished LR from R and NR as distinct groups.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Targeted proteomic profiling of baseline plasma from ALK+ NSCLC patients identified a protein signature that may predict a long-term response or resistance to ALK-TKIs. A collaboration is in development to confirm the validity of this protein signature in a larger cohort, and with next-generation ALK-TKIs.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.08 - Oligometastatic NSCLC (Not CME Accredited Session) (ID 974)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.08-16 - Prognostic Value of PDL-1 Expression and Correlation Between Primary Tissue and Brain Metastases in Oligometastatic NSCLC (ID 13582)

      12:00 - 13:30  |  Author(s): Normand Blais

      • Abstract
      • Slides

      Background

      Immunotherapy with anti-PD-1/PDL-1 agents in first-line metastatic non-small cell lung cancer (NSCLC) is chosen based on tumor cell PDL-1 expression. However, the incidence and prognostic value of PDL-1 expression in NSCLC patients with oligometastatic brain disease has never been characterized.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively analyzed in our SARDO clinical database NSCLC patients with only 1-3 brain metastases (oligometastastic) treated in our University Health Care Center CHUM from 2007-2014. Samples were stained with SP263 (Ventana) antibody against PDL-1. A membranous staining of >25% was considered positive, and scoring was performed by an experienced pathologist. Kaplan-Meier survival curves of all clinical data were performed in SPSS 25.

      4c3880bb027f159e801041b1021e88e8 Result

      In our cohort of 39 oligometastatic NSCLC patients treated before 2014, none received immunotherapy. A total of 49 specimens (biopsy or surgical) from either the primary or metastatic site were adequate and included in the study. In 10 cases, both primary and metastatic tissue were available for correlation. Overall PDL-1 positivity was 40.8% (20/49), with a positivity of 54.5% (12/22) in primary site samples and 29.6% (8/27) in metastatic brain tissue. Correlation of PDL-1 status between primary and metastatic site in a sub-group of 10 patients was 80% (8/10). Median overall survival (mOS) was significantly shorter for PDL-1 positive patients (8 mos) compared to PDL-1 negative patients (20 mos, p=0.05). 59% (23/39) of patients were aggressively treated for the primary tumor, and 86% (31/39) were aggressively treated for metastatic brain disease. When we controlled for treatment aggressivity of the primary tumor, mOS of PDL-1 positive patients treated aggressively was significantly shorter than mOS of PDL-1 negative patients treated aggressively (15 vs 22 mos, p=0.046). When the primary lung tumor was not addressed aggressively, mOS was the same regardless of the PDL-1 status (4 vs 4 mos). Median progression free survival (mPFS) tended to be longer in PDL-1 positive patients (6.0 vs 9.8 mos, p=0.254).

      8eea62084ca7e541d918e823422bd82e Conclusion

      PDL-1 status is concordant between primary and metastatic tissue in 80% of cases. PDL-1 expression is an adverse prognostic factor in NSCLC patients with oligometastatic brain disease, despite treating the patients aggressively for their primary lung cancer and their brain metastasis. In the future, giving early PD1/PDL-1 to oligometastatic PDL-1 positive NSCLC patients could significantly improve their outcome.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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