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Julie R. Brahmer



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    MA04 - Novel Approaches with IO (ID 900)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 107
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      MA04.11 - Neoantigen Targeting and T Cell Reshaping in Resectable NSCLC Patients Treated with Neoadjuvant PD-1 Blockade (ID 12605)

      14:40 - 14:45  |  Author(s): Julie R. Brahmer

      • Abstract
      • Presentation
      • Slides

      Background

      PD-1 blockade is now standard treatment for advanced non-small cell lung cancer (NSCLC) and has recently shown impressive efficacy in promoting major pathologic response (MPR) and delaying relapse in the neoadjuvant setting. The role of tumor mutational burden, and specifically T cells targeting neoantigens derived from these mutations, in facilitating tumor clearance has been demonstrated in advanced NSCLC. However, it is unknown how neoadjuvant PD-1 blockade impacts the frequency and function of tumor specific T cells and their ability to promote major pathologic response, or how these factors may synergize to prevent or delay relapse after surgical resection.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Whole exome sequencing and neoantigen prediction was performed on pre-treatment tumor biopsies and matched normal tissue from 11 patients with resectable NSCLC treated with neoadjuvant nivolumab as part of a clinical trial (NCT02259621). T cell recognition of peptides representing candidate neoantigens was evaluated using the MANAFEST assay, which identifies T cell receptor clonotypes corresponding to antigen specificities. T cell receptor sequencing was additionally performed on serial peripheral blood T cells, pre-treatment tumor biopsies, and resected post-treatment tissues. A bioinformatic platform was developed to evaluate the dynamics of intratumoral T cell clonotypes, and more specifically neoantigen-specific clonotypes detected before, during, and after treatment and during long-term follow-up.

      4c3880bb027f159e801041b1021e88e8 Result

      High-magnitude, polyclonal neoantigen-specific T cell responses were detected in the peripheral blood and persisted for many months after surgical resection and cessation of treatment. Binding to and stability with cognate HLA I molecules was validated for reactive neoantigens. Significant treatment-induced systemic perturbations in the tumor-specific T cell repertoire and an influx of peripheral T cell clonotypes into tumor tissue and lymph nodes was observed in patients regardless of pathologic response, whereas peripheral clonotypic reshaping of the anti-tumor repertoire and intratumoral T cell clonality were associated with MPR status.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We show significant and systemic alterations in the peripheral anti-tumor T cell repertoire in NSCLC patients treated with neoadjuvant anti-PD-1 regardless of MPR status. Notwithstanding, the impaired restructuring of the anti-tumor T cell repertoire in patients without MPR highlights a potential immunological deficiency to overcome in future therapeutic approaches aiming to increase the MPR rate in NSCLC patients treated with neoadjuvant PD-1 blockade.

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    MS14 - IO in Early Stage NSCLC (ID 793)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Immunooncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 107
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      MS14.02 - Adjuvant / Neoadjuvant IO Therapy (ID 11459)

      10:45 - 11:00  |  Presenting Author(s): Julie R. Brahmer

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA05 - Clinical Trials in IO (ID 899)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 106
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      OA05.06 - CheckMate 227: Patient-Reported Outcomes of First-Line Nivolumab + Ipilimumab in High Tumor Mutational Burden Advanced NSCLC (ID 13450)

      14:25 - 14:35  |  Presenting Author(s): Julie R. Brahmer

      • Abstract
      • Presentation
      • Slides

      Background

      The randomized, open-label, multipart phase 3 study CheckMate 227 (NCT02477826) demonstrated a significant progression-free survival benefit (co-primary endpoint) with first-line nivolumab+ipilimumab versus histology-based, platinum-doublet chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and high tumor mutational burden (TMB; ≥10 mutations/Mb). Patient-reported outcomes (PROs) for this population within CheckMate 227 are presented.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible chemotherapy-naïve patients had stage IV or recurrent NSCLC, ECOG performance status 0−1, and no known sensitizing EGFR/ALK alterations. PROs were assessed as an exploratory endpoint; this analysis included patients with high TMB randomized to nivolumab+ipilimumab or chemotherapy; specific outcomes included proportion of patients with disease-related symptom deterioration by 12 weeks and time to deterioration in symptoms (by Lung Cancer Symptom Scale [LCSS] Average Symptom Burden Index [ASBI]), and assessment of quality of life and overall health status (by EuroQoL-5 Dimension [EQ-5D] utility index [UI] and visual analog scale [VAS]). PROs were evaluated each cycle (Q2W, nivolumab+ipilimumab; Q3W, chemotherapy) for the first 6 months, every 6 weeks thereafter during treatment, and at follow-up visits 1/2. EQ-5D was also assessed during survival follow-up.

      4c3880bb027f159e801041b1021e88e8 Result

      PRO completion rates were ~90% at baseline and >80% for nearly all on-treatment assessments. Among patients with high TMB, fewer patients in the nivolumab+ipilimumab (n=139) versus chemotherapy (n=160) groups reported symptom deterioration by week 12, irrespective of whether they were still on therapy or had discontinued (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% CI: 2.4–22.5]). Time to first deterioration (TTD) using common assessment time points (on/off treatment) was delayed with nivolumab+ipilimumab versus chemotherapy for the LCSS ASBI (hazard ratio [HR]: 0.40; 95% CI: 0.26–0.63) and 3-Item Global Index (3-IGI; HR: 0.56; 95% CI: 0.38–0.82). The estimated benefit in TTD generally favored nivolumab+ipilimumab for individual symptoms in the ASBI and each item in the 3-IGI (HRs: 0.48–0.74), except for hemoptysis (HR: 1.20), which exhibited very low burden; an advantage for nivolumab+ipilimumab was also seen in the EQ-5D VAS (HR: 0.62; 95% CI: 0.42–0.92) and UI (HR: 0.50; 95% CI: 0.34–0.73). Mean changes from baseline with nivolumab+ipilimumab showed early and clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; for patients treated with chemotherapy, symptoms and quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following completion of chemotherapy (EQ-5D VAS).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Nivolumab+ipilimumab demonstrated early and sustained improvements in health-related quality of life versus chemotherapy in patients with advanced NSCLC and high TMB.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • 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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      P1.01-02 - Long-Term Outcomes with First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 3-Year Follow-Up from CheckMate 012 (ID 12380)

      16:45 - 18:00  |  Author(s): Julie R. Brahmer

      • Abstract

      Background

      CheckMate 012 (NCT01454102) is a phase 1 study evaluating several nivolumab monotherapy/combination regimens as first-line treatment for advanced non-small cell lung cancer (NSCLC). CheckMate 012 was the first study to suggest the benefit of nivolumab plus ipilimumab in NSCLC. In the phase 3 study CheckMate 227, nivolumab plus ipilimumab recently demonstrated significantly improved progression-free survival (PFS) as well as more frequent, deeper, and more durable responses versus chemotherapy in patients with chemotherapy-naive advanced NSCLC and high tumor mutational burden (TMB). Here, we provide 2-year follow-up results for nivolumab plus ipilimumab from CheckMate 012. Three-year results, the longest follow-up to date for an immuno-oncology combination in NSCLC, will be presented.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible patients had recurrent stage IIIb or stage IV chemotherapy-naive NSCLC and Eastern Cooperative Oncology Group performance status 0–1. Patients received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 12 weeks (n=38) or every 6 weeks (n=39) until disease progression, unacceptable toxicity, or consent withdrawal; pooled results of these two cohorts are presented. Endpoints included safety/tolerability (primary); objective response rate and PFS (secondary); and overall survival (OS), chemotherapy-free survival (CFS), and efficacy by TMB status (exploratory).

      4c3880bb027f159e801041b1021e88e8 Result

      With 2 years of follow-up, no new safety signals were observed. Thirty-three of 77 patients (43%) achieved objective responses, including six investigator-assessed complete responses (8%), three of which were complete pathological responses. Responses were durable (median duration of response, not reached; range, 1.4+ to 27.9+ months). The 2-year PFS rate was 29%. At the time of database lock, 32 of 34 patients (94%) with OS ≥2 years were alive, with four (12%) remaining on treatment and progression-free; 14 (41%) were off treatment and progression-free without subsequent therapy. Three-year follow-up results to be presented include OS, PFS, and select data on CFS, efficacy by TMB status, and characteristics of long-term survivors.

      8eea62084ca7e541d918e823422bd82e Conclusion

      With long-term follow-up, nivolumab plus ipilimumab continued to demonstrate durable clinical benefit and a consistent safety profile as first-line treatment for patients with advanced NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 965)

    • 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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      P2.16-03 - CheckMate 816: A Phase 3 Trial of Neoadjuvant Nivolumab Plus Ipilimumab or Chemotherapy vs Chemotherapy in Early-Stage NSCLC (ID 12599)

      16:45 - 18:00  |  Author(s): Julie R. Brahmer

      • Abstract
      • Slides

      Background

      Approximately 20–25% of patients with NSCLC are diagnosed with early or localized disease, which has a relapse rate of 30–80% with surgery. Although neoadjuvant chemotherapy can reduce the risk of relapse, it only provides a pathological complete response (pCR; no viable tumor cells) rate of 4%. The neoadjuvant setting presents abundant tumor-associated neoantigens derived from the primary tumor that may allow immunotherapy to prime a long-lasting immune response. Clinical trial results support the use of immuno-oncology agents as neoadjuvant treatment for early-stage NSCLC. In a pilot study in patients with untreated, surgically resectable early-stage (stage I–IIIA) NSCLC, nivolumab (a fully human PD-1 immune checkpoint inhibitor antibody) administered as neoadjuvant treatment (3 mg/kg for 2 cycles during the 4 weeks prior to surgery) induced a pCR in 10% of patients and a major pathological response (MPR; ≤10% residual viable tumor cells in resected primary tumor) in 45% of patients, did not delay surgery, and was associated with an acceptable safety profile. Combining immuno-oncology agents with distinct mechanisms of action, such as PD-1 and CTLA-4 inhibitors, offers the possibility of a synergistic response and may improve antitumor activity compared with either agent alone. The combination of an immuno-oncology agent and chemotherapy may also offer synergistic activity, given that chemotherapy results in tumor cell death and subsequent antigen release that can activate an immune response. Promising results have been noted with nivolumab plus ipilimumab (a CTLA-4 immune checkpoint inhibitor antibody) and nivolumab plus chemotherapy in patients with treatment-naïve stage IIIB/IV NSCLC in the multicohort phase 1 CheckMate 012 study. CheckMate 816 (NCT02998528) is a phase 3 study evaluating nivolumab plus ipilimumab, nivolumab plus platinum-doublet chemotherapy, and platinum-doublet chemotherapy as neoadjuvant treatment for early-stage NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Approximately 642 patients aged ≥18 years with early-stage (stages IB–IIIA) resectable NSCLC, ECOG performance status 0–1, pulmonary function capable of tolerating lung resection, and available lung tumor tissue will be enrolled in North America, South America, Europe, Asia, and Africa. Patients are ineligible if they have active autoimmune disease or had received prior treatment with immune checkpoint inhibitors. Patients will be randomized (1:1:1) to receive neoadjuvant nivolumab plus ipilimumab, nivolumab plus platinum-doublet chemotherapy, or platinum-doublet chemotherapy. Primary endpoints are event-free survival and pCR. Key secondary endpoints are overall survival and MPR (<10% residual tumor in lung and lymph nodes). The start date was January 2017. The estimated primary completion date is May 2023.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)

    • 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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      P3.01-70 - Meta-Analysis of Metformin in Combination with Platinum Chemotherapy in Advanced Non-Squamous Non-Small Cell Lung Cancer (ID 12602)

      12:00 - 13:30  |  Author(s): Julie R. Brahmer

      • Abstract
      • Slides

      Background

      Metformin has been shown to have a variety of insulin-dependent and –independent antitumor effects, primarily through cellular growth inhibition via the AMP-activated protein kinase (AMPK) pathway and the IGF1-insulin axis. Two prospective trials evaluating metformin with platinum doublet chemotherapy +/- bevacizumab have demonstrated competitive outcomes in non-diabetic, chemotherapy-naïve advanced non-small cell lung cancer (NSCLC) patients. Outcomes in KRAS-mutated NSCLC, an area of interest due to potential co-occurring LKB1 mutations, an AMPK pathway upstream kinase, is currently unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This meta-analysis is of two phase II study treatment arms (NCT02019979, NCT01578551), evaluating the use of concurrent metformin and platinum-based doublet chemotherapy +/- bevacizumab. Patient’s demographic, molecular and adverse event (AE) profiles were summarized with descriptive statistics. Kaplan-Meier curves for progression free survival (PFS) and overall survival (OS) were generated for all patients, as well as known KRAS and EGFR mutation subsets.

      4c3880bb027f159e801041b1021e88e8 Result

      33 non-squamous NSCLC patients were treated; 60% were female and the median age was 64 (Range: 37-77). The most common AE was neutropenia (Grade 3-4: 30%). No patients required study treatment cessation due to metformin-related toxicity. Across all patients, mPFS was 6 months (95% CI: 1.36-7.96); mOS was 14.83 months (95% CI: 8.25-19.99). In KRAS-mutated patients (n=13), mPFS was 7.21 months; mOS was 17.46 months. In EGFR-mutated patients (n=7), mPFS was 6.57 months; mOS was 13.25 months.overall survival.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Combination metformin and chemotherapy +/- bevacizumab was safe and well-tolerated in advanced, chemotherapy-naïve non-squamous NSCLC across two phase II clinical trials. Metformin appeared particularly effective in KRAS-mutated NSCLC. Data for LKB1 status was unknown for a majority of patients, but may be an important co-mechanism for benefit. Metformin appeared to underperform in the EGFR subset, perhaps due to lack of TKI use. Given the tolerability, low cost and activity observed in NSCLC, further investigation into metformin’s antitumor effects in molecularly defined subsets is needed.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    PL03 - Call to Action - Challenges Ahead (ID 851)

    • Event: WCLC 2018
    • Type: Plenary Session
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 08:15 - 09:45, Plenary Hall
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      PL03.02 - Host Immunity - No Longer a Passive Bystander (ID 11650)

      08:30 - 08:45  |  Presenting Author(s): Julie R. Brahmer

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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