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Jarushka Naidoo



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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): Jarushka Naidoo

      • 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.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MA05 - Improving Outcomes in Locoregional NSCLC II (ID 901)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 105
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      MA05.02 - PACIFIC Subgroup Analysis: Pneumonitis in Stage III, Unresectable NSCLC Patients Treated with Durvalumab vs. Placebo After CRT (ID 13876)

      13:35 - 13:40  |  Author(s): Jarushka Naidoo

      • Abstract
      • Presentation
      • Slides

      Background

      In the Phase 3 PACIFIC study of durvalumab versus placebo in patients with stage III, unresectable non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (cCRT), on-treatment pneumonitis or radiation pneumonitis (‘pneumonitis’) occurred in both arms with similar rates of grade 3/4 pneumonitis (durvalumab, 3.4%; placebo, 2.6%). We performed exploratory analyses to further characterize time to onset and duration of pneumonitis and examine its relationship with underlying risk factors, including patient characteristics and prior CRT.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      PACIFIC (NCT02125461) was a randomized, double-blind study of patients with WHO PS 0/1 without progression after ≥2 cycles of platinum-based cCRT. Patients were stratified by age, sex, and smoking history and randomized (2:1) 1–42 days after completing cCRT to durvalumab 10 mg/kg IV Q2W or placebo up to 12 months. Potential associations between the presence of the AE pneumonitis (investigator assessed with review/adjudication by study sponsor) and baseline characteristics or patient disposition were investigated.

      4c3880bb027f159e801041b1021e88e8 Result

      As of Feb 13, 2017, 709 patients had received treatment; 33.6% on durvalumab and 24.9% on placebo had any-grade pneumonitis. Treatment exposure was similar in patients with or without pneumonitis across both arms. Median time to onset of pneumonitis from treatment start was the same for both durvalumab and placebo, 55.0 days (73.0 and 76.5 days from RT completion). Pneumonitis was self-limited, with median durations of 64.0 and 57.0 days, respectively. Patients with pneumonitis were more likely to be Asian (47.9% vs 17.6%) or have EGFR mutations (11.0% vs 3.8%); however, the proportions of patients with pneumonitis and these risk factors were numerically lower with durvalumab than with placebo (Asian: 44.4% [71/160] vs 57.6% [34/59]; EGFRm: 10.6% [17/160] vs 11.9% [7/59]), suggesting no apparent interaction with treatment. There were no apparent associations of pneumonitis with baseline respiratory disorders, prior RT dose, or prior cisplatin or carboplatin use. Previous induction CT was more commonly associated with the absence of pneumonitis in both treatment arms (durvalumab: 30.1% vs 17.5%; placebo: 31.5% vs 20.3%). The presence of pneumonitis was associated with greater discontinuation due to AEs (durvalumab: 25.6% vs 10.2%; placebo: 18.6% vs 6.8%) regardless of treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Rates of pneumonitis were higher in Asian patients and those with EGFRm, as previously reported. Durvalumab did not increase pneumonitis in patients with these risk factors. There were no differences in treatment exposure in patients based on the presence/absence of pneumonitis. Multivariate analyses may further assist in the discernment of etiologic risks.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MTE26 - New Paradigms in Symptom Management in Lung Cancer (Ticketed Session) (ID 836)

    • Event: WCLC 2018
    • Type: Meet the Expert Session
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 07:00 - 08:00, Room 206 AC
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      MTE26.02 - Symptoms and IO Toxicity Management (ID 11593)

      07:30 - 08:00  |  Presenting Author(s): Jarushka Naidoo

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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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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      P2.01-103 - Neutrophil-to-Lymphocyte Ratio as a Predictor of Immunotherapy Treatment Outcomes in Advanced Non-Small Lung Cancer (ID 12633)

      16:45 - 18:00  |  Author(s): Jarushka Naidoo

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitors (ICIs) are a new class of therapy for patients with non-small cell lung cancer (NSCLC). Immunologic markers, such as serum neutrophil-to-lymphocyte ratio (NLR), are prognostic in patients with a variety of malignancies, with preliminary findings in patients on immunotherapy. In this study, we evaluate the association between NLR and ICI outcomes in NSCLC, including the development of immune-related adverse events (irAEs).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We conducted a retrospective analysis of advanced or recurrent NSCLC patients receiving ICI from 2011 to 2017. Demographics, disease and treatment history, and pretreatment labs were recorded. An NLR³5 was defined as high and <5 as low, based on meta-analyses. Cox proportional hazards models and univariate and multivariate regressions were used to assess the association between NLR and overall survival (OS), progression-free survival (PFS), disease control rate at 10 weeks (DCR), and irAEs.

      4c3880bb027f159e801041b1021e88e8 Result

      183 patients were identified: 55.2% male, 76.5% Caucasian, mean age 65.3 years (range 38–90 years). Male sex, smoking history, prior radiotherapy, and pretreatment albumin were significantly associated with high versus low NLR (p < 0.05). In univariate analyses, pretreatment NLR was a significant predictor of OS (HR 1.47, p < 0.05, Fig. 1), PFS (HR 1.44,, p < 0.05), and DCR (OR 0.49, p < 0.05), but not irAEs (OR 1.37, p = 0.33). These findings persisted with multivariate analyses (OS HR 1.76, PFS HR 1.64, DCR OR 0.24, all p < 0.01; irAE OR 1.52, p = 0.33).nlr survival.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      High NLR was positively associated with OS, PFS, and DCR but not irAEs in NSCLC patients receiving ICI. Our results support the use of NLR as a biomarker for clinical outcomes. Prospective studies are needed to study this measure in patients undergoing ICI therapy, and further studies to identify predictive biomarkers of irAEs are warranted.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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