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Sherin Rouhani



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    P14 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Immuno-Biology (ID 153)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P14.27 - Pathogenic Genomic Alterations of CDKN2A Predict Immunotherapy Resistance in NSCLC (ID 2353)

      00:00 - 00:00  |  Author(s): Sherin Rouhani

      • Abstract
      • Slides

      Introduction

      Immune checkpoint blockade (ICB) has improved outcomes for patients with non-small cell lung cancer (NSCLC). However, most patients experience disease progression. There are limited data regarding molecular predictors of progression, particularly in those patients predicted to respond most favorably. We used a next-generation sequencing (NGS) platform to identify genomic aberrations associated with clinical outcomes following ICB in NSCLC.

      Methods

      We retrospectively reviewed NSCLC patients who received ICB at our institution and underwent NGS with “OncoPlus”, a proprietary 1212-gene hybrid capture genomic sequencing assay. We characterized tumor mutations and copy number variations and investigated their associations with clinical outcome.

      Results

      139 patients with advanced treatment-naïve or recurrent NSCLC received ICB from 2016-2020 and underwent “OncoPlus” testing. Median age was 66, 87% had adenocarcinoma, and 88% had a smoking history. AJCC 8th edition initial staging: IA/IIB (n=6), IIIA/B/C (n=38), IVA (n=25), and IVB (n=70). 53% of patients (n=73) received ICB in the treatment-naïve, metastatic setting. 82% had PD-L1 staining: unavailable in 25 patients (18%), 0% in 31 (22%), 1-49% in 36 (26%), and ≥50% in 47 (34%).

      64% of patients received ICB monotherapy (n=89), 28% of patients received concurrent chemo-ICB (n=39), and the remaining 7% of patients received some combination of molecularly targeted therapies + ICB +/- cytotoxic chemotherapy. ICB included pembrolizumab (n=85, 58%), nivolumab +/- ipilimumab (n=19 monotherapy, n=18 dual blockade, 27%), atezolizumab (n=17, 12%), and durvalumab (n=11, 8%). The majority received radiotherapy to at least 1 lesion (n=104, 75%). Median follow-up after ICB initiation was 11 months (range 0-44); 2-yr PFS and OS for the overall cohort were 21% and 41%, respectively.

      The most frequent pathogenic genomic alterations affected TP53 (67%, n=93), KRAS (38%, n=51), STK11 (27%, n=38), and CDKN2A (22%, n=31). We found that tumors with alterations in CDKN2A (mutation/deletion 48%/52%) were associated with inferior median progression-free survival (PFS; 3.4 vs. 7.4 mo., p=0.043) and more markedly median overall survival (OS; 11.6 vs. 22.1 mo., p=0.020) compared to wild-type tumors. On multivariate Cox proportional hazards analysis including age, gender, BMI, ECOG, TMB, PD-L1 status, and ICB indication, CDKN2A loss/mutation was independently associated with a 2.1-fold risk of progression (p=0.015) and a 3.0-fold risk of death (p=0.001). In high TMB NSCLCs (≥ 10 mutations/megabase, n=66), CDKN2A alteration was associated with a trend to worsened OS (median OS 9.4 vs. 16.6 mo., p=0.055). In high PD-L1 NSCLCs (≥50%; n=47), CDKN2A alteration remained negatively associated with OS (median OS 10.4 vs. 22.2 mo., p=0.020). Using RECIST 1.1 criteria, CDKN2A loss-of-function tumors were twice as likely to exhibit progressive disease as their best response to ICB when compared to CDKN2A wild-type tumors (48% vs. 22%, p=0.02).

      Conclusion

      In a large cohort of NSCLC patients treated with ICB, NGS identified CDKN2A mutation/deletion as a predictor of poor clinical outcomes. In the context of recent evidence for sensitivity to CDK4/6 inhibition of CDKN2A-deficient tumors, our findings raise the possibility of utilizing currently available targeted agents in the treatment of CDKN2A-deficient NSCLCs receiving ICB.

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    P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P76.30 - The Neutrophil-to-Lymphocyte Ratio is a Prognostic Biomarker in Patients with EGFR Mutated Advanced NSCLC (ID 1644)

      00:00 - 00:00  |  Presenting Author(s): Sherin Rouhani

      • Abstract
      • Slides

      Introduction

      An elevated neutrophil-to-lymphocyte ratio (NLR) indicates a poor prognosis across multiple cancers, including non-small cell lung cancer (NSCLC) and is associated with cancer cachexia. EGFR tyrosine kinase inhibitors (TKI) are typically associated with brisk responses and prolonged PFS benefit. This study evaluates baseline NLR and serial values in EGFR-mutated NSCLC patients receiving TKI therapy. Preliminary findings from a smaller cohort were submitted to ASCO 2020.

      Methods

      We retrospectively analyzed 137 patients with advanced EGFR-mutated NSCLC treated with TKIs at Rush University Medical Center and University of Chicago Medical Center from August 2011 to July 2019. The prognostic value of NLR was assessed at the start of therapy, and after 6 and 12 weeks of treatment. Progression free survival (PFS) and overall survival (OS) were calculated by the Kaplan-Meier method and compared between groups with the log-rank test. Cox proportional hazards models were used to calculate the association between number of disease sites and survival outcomes. Spearman rank correlations were used to correlate number of disease sites with NLR at diagnosis. T-tests were used to compare mean NLR between patients with high or low grade toxicities. Changes in NLR and BMI were calculated by subtracting the value at treatment start from the values at 6 or 12 weeks, and the relationship between the change in NLR vs BMI were analyzed using Pearson correlation.

      Results

      At therapy start, patients with NLR <5 (n=88) had median PFS (mPFS) of 17.2 months and median OS (mOS) of 58.0 months, while those with NLR ≥5 (n=40) had mPFS of 14.0 months (p=0.0029) and mOS of 27.6 months (p=0.0024). After 6 weeks of treatment, patients with NLR <5 (n=104) had mPFS of 17.4 months and mOS of 59.7 months, while those with NLR ≥5 (n=27) had mPFS of 12.1 months (p=0.037) and mOS of 39.1 months (p=0.015). After 12 weeks of treatment, patients with NLR <5 (n=89) had mPFS of 18.4 months and mOS of 59.7 months, while those with NLR ≥5 (n=21) had mPFS of 5.8 months (p=0.0003) and mOS of 25.2 months (p=0.00083).

      There was a modest association between baseline number of disease sites and NLR at diagnosis (Spearman’s ρ=0.272, p=0.002), OS (HR=1.423, p<0.001), and PFS (HR=1.330, p<0.001). mPFS and mOS was not significantly different in patients whose NLR increased or decreased at 6 weeks (p=0.29) or 12 weeks (p=0.52). The change in BMI and change in NLR at 12 weeks was weakly correlated (r= -0.21, p=0.03), but changes in BMI did not correlate with OS (p=0.174) or PFS (p=0.439) at 12 weeks. There was no significant difference in NLR between patients with high grade (≥3) versus no or low grade (0-2) drug toxicities at 6 weeks (p=0.28) or 12 weeks (p=0.30), and development of grade 3-5 toxicities did not affect OS (p=0.8) or PFS (p=0.09).

      Conclusion

      NLR is a prognostic factor which can predict which EGFR mutated NSCLC patients on TKIs may have worse PFS and OS. Potential therapeutic escalation may be beneficial in patients with elevated NLR≥5 on treatment and is worthy of study.

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