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Apar Kishor Ganti



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    FP12 - Tumor Biology and Systems Biology - Basic and Translational Science (ID 188)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Tumor Biology and Systems Biology - Basic and Translational Science
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP12.10 - IGF-1R Inhibition in Small Cell Lung Cancer: Role of Brigatinib (ID 1953)

      00:00 - 00:00  |  Presenting Author(s): Apar Kishor Ganti

      • Abstract
      • Slides

      Introduction

      Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor characterized by early distant spread and chemoresistance. The overall 5-year survival rate has remained a dismal 7% over the last 25 years, and systemic treatment options for patients with relapsed SCLC have remained unchanged. Even though patients often initially respond to chemotherapy, they routinely relapse. Relapsed SCLC is often chemorefractory, resulting in poor survival. Brigatinib (AP26113) is a selective anaplastic lymphoma kinase-positive (ALK) inhibitor; however, besides ALK inhibition, brigatinib inhibits IGF-1R signaling. IGF-1R is thought to be a key target in SCLC. The objective of this project is to identify the mechanism and therapeutic efficacy of brigatinib along with currently available chemotherapeutic drugs in SCLC.

      Methods

      We used various SCLC cell lines and normal human bronchial epithelial cells (NHBE) for the screening of IGF-1R by quantitative real-time PCR and western blotting. MTT assays were performed to identify the inhibitory role of brigatinib on IGF-1R positive and negative SCLC cells. We have also performed apoptosis and cell cycle experiments to identify the effect of brigatinib on apoptosis and cell growth, respectively. Further, we have formed CRISPR-Cas9 based IGF-1R, and IGF-1 knockout. These isogenic cells were used to identify the chemoresistance mechanisms.

      Results

      We chose five SCLC cell lines based on IGF-1R level (SBC-5 high, H82high, H526basal, SBC-3 basal and H69basal). The IC50 of brigatinib ranged from 50 nM to 100 nM in H526 and H69 cells lines and from 750 nM to 1 µM in SBC-3, SBC-5, and H82 cell lines. IGF-1R knockdown SCLC cells showed enhanced sensitivity to cisplatin and etoposide, as compared to control clone cells. We observed that combination of brigatinib and etoposide increased apoptosis. SBC-3 and SBC-5 cells ware treated with brigatinib alone, etoposide alone and combination of brigatinib and etoposide. The percentage of apoptotic cells was significantly higher in cells treated with combination etoposide and brigatinib (SBC-3 - 54.1 %; SBC-5 - 37.5%) compared to brigatinib alone (12.9%; 37.8%), etoposide alone (31.2%; 14.9%) and untreated controls (3.7%; 8.1%).

      Conclusion

      Brigatinib induced IGF-1R inhibition may have therapeutic implications in SCLC. Targeting IGF-1R signaling and identifying possible mechanisms of IGF-1R mediated chemoresistance in SCLC can potentially reduce the SCLC associated mortality. Clinical trials of brigatinib in patients with SCLC and high IGF-1R expression are warranted.

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    P50 - Small Cell Lung Cancer/NET - Real World Outcomes (ID 232)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P50.09 - Estimates of First-Line Extensive Stage Small Cell Lung Cancer Treatment Rates from a U.S. Claims Database (ID 3306)

      00:00 - 00:00  |  Presenting Author(s): Apar Kishor Ganti

      • Abstract
      • Slides

      Introduction

      Immunotherapy (IO) plus chemotherapy (CT) has been an NCCN-recommended first-line (1L) treatment for extensive stage small cell lung cancer (ES-SCLC) since 2018. Estimates of treated ES-SCLC rates (treated patients per year/real-world population size) are useful in assessing the clinical and economic effects of improved treatments.

      Methods

      The IBM Watson Health MarketScan Commercial and Medicare Supplemental healthcare claims databases covering years 2013-2018 were used for the analyses. These data lack tumor histology and staging. We therefore estimated the number of treated ES-SCLC patients using a treatment driven algorithm that incorporates diagnosis, medication, and procedure codes from the databases. Each year’s newly treated patients had a new lung cancer diagnosis in the year, no evidence of non-small cell lung cancer (NSCLC) treatment or resection, 6 months of continuous enrollment in their health plan, and an NCCN recommended 1L treatment for ES-SCLC [etoposide (3 days)+cisplatin or carboplatin; irinotecan+cisplatin or carboplatin; atezolizumab+ etoposide (≤3 days)+carboplatin]. The overall number of treated patients per year equaled the number of newly treated patients in a year plus the number of treated patients from previous years with ongoing follow-up. Treatment rates (number treated per year per 100,000 people) were obtained by dividing the number of newly and overall treated patients per year by the number of adult enrollees in MarketScan with ≥6 months of continuous healthcare plan enrollment during the year. Age-adjusted rates and crude (unadjusted) rates for three age categories (18+, 18-64, 65+) and are reported.

      Results

      Newly treated crude rates declined from 2.7/100,000 people in 2013 to 1.9/100,000 people in 2018 in the 18-64 age group and from 18.2/100,000 people in 2013 to 11.8/100,000 people in 2018 in the 65+ age group (Table 1). Overall treated rates were largely stable from 2014-2017 and declined in 2018. Age-adjusted newly treated and overall treated rates (based on the age distribution of the US population in 2015) were greater than the crude treated rates for each year.

      table 1. first-line es-sclc treatment rates, 2013-2018.png

      Conclusion

      Yearly [overall treated rate/newly treated rate] ratios for the 18-64 and 65+ age categories generally rose from 2013-2018, possibly reflecting greater survival in each year’s newly treated ES-SCLC population (since they are counted in the next year’s overall treated number of patients). These estimates of newly treated and overall treated ES-SCLC rates may be useful in calculating the overall clinical and economic effects of different treatment options for ES-SCLC patients.

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    P60 - Tumor Biology and Systems Biology - Basic and Translational Science - Immune Bio (ID 198)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Tumor Biology and Systems Biology - Basic and Translational Science
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P60.10 - Tumor Neoantigen Burden and Immune Environment in Driver Alteration-Positive Lung Adenocarcinoma. (ID 3344)

      00:00 - 00:00  |  Author(s): Apar Kishor Ganti

      • Abstract
      • Slides

      Introduction

      Immune checkpoint inhibitors (ICI) provide limited benefit in patients with EGFR-, ALK- or ROS1-positive lung adenocarcinoma (LUAD), while patients with BRAF- and KRAS-positive LUAD demonstrate better responses. To understand the differential response to ICI in driver gene-altered LUAD, we performed a comparative analysis of their tumor neoepitope load and immune environment.

      Methods

      De-identified molecular data from 2,740 LUAD patients previously sequenced with Tempus|xT, a 648-gene DNA panel (Tempus Labs, Chicago, IL) were analyzed. Whole-exome capture RNAseq was performed on 1,454 of these samples. Driver mutational status was correlated with neoepitope load and immune infiltration enrichment. Neoantigen prediction was performed on all non-silent mutations using tumor only or tumor/normal matched samples, and immune infiltration scores were predicted using a machine-learning model trained on mRNA expression and pathologist-scored IHC data (PMID:31570899). Distributions of predicted neoantigens and immune infiltration, including CD8+/CD4+ T-cells, B-cells, NK cells, and macrophages, between driver-gene altered LUAD (defined as patients with alterations in KRAS, EGFR, ALK, BRAF, MET, PIK3CA, ROS1, RET, or ERBB2) and driver-gene wild type (WT) LUAD were compared using two-sided Wilcoxon tests.

      Results

      nsclc abstract table_final_082820_400dpi.pngNon-synonymous antigenic mutations were predicted for all DNA-sequenced tumors. The median neoepitope load was 13 (range 1-406) and WT tumors had the highest median neoepitope load (Table). EGFR-, MET-, RET-, ALK-, ROS1- and BRAF-positive tumors had significantly lower neoepitope load than WT, with BRAF-positive LUAD having the highest neoepitope load in this group (Table). Neoepitope loads of KRAS-, ERBB2- and PIK3CA-positive tumors were not significantly different from WT. PD-L1 status was not associated with neoantigen load after controlling for driver mutation status. Overall immune infiltration was higher in MET- and BRAF-positive LUAD compared to WT (Table). Relative to WT, KRAS- and PIK3CA-positive tumors had higher CD4+ T-cell infiltration, while EGFR-positive had significantly lower CD8+ T-cell infiltration (P<0.001, P=0.03 and P<0.0001, respectively).

      Conclusion

      The high neoepitope load and unique immune composition in KRAS- and BRAF-positive LUAD may be associated with better response to ICI typically observed in these tumors. High immune infiltration in MET-positive LUAD suggests that ICI may be more beneficial in these tumors. Cumulatively, our findings suggest that the significant variability in neoepitope load and immune environment of driver-gene altered LUAD might explain their differential sensitivity to ICI. Ongoing studies are evaluating the impact of neoepitope load on clinical characteristics and outcomes.

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    P77 - Immunotherapy (Phase II/III Trials) - Combining Different Immunotherapeutic Approaches (ID 254)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Immunotherapy (Phase II/III Trials)
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P77.04 - PROPEL: A Phase 1/2 Trial of Bempegaldesleukin (NKTR-214) Plus Pembrolizumab in Lung Cancer and other Advanced Solid Tumors (ID 1548)

      00:00 - 00:00  |  Author(s): Apar Kishor Ganti

      • Abstract
      • Slides

      Introduction

      Checkpoint inhibitors (CPIs), are now part of standard treatment in many advanced solid tumors, including metastatic non-small cell lung cancer (NSCLC). However, novel, more effective CPI combinations are needed to broaden, deepen, and prolong responses, especially for patients with poor prognostic features or negative predictive clinical factors for CPI benefit, including programmed death-ligand 1-negative (PD-L1[-]) status. Bempegaldesleukin (BEMPEG; NKTR-214) is a first-in-class CD122-preferential interleukin-2 pathway agonist that directly activates and expands effector T cells and natural killer cells over immunosuppressive regulatory T cells. BEMPEG plus CPI combination has demonstrated promising efficacy and can convert PD-L1(-) tumors to PD-L1(+) in patients with various solid tumors.(1,2) Given the early efficacy data and favorable safety profile of BEMPEG plus nivolumab, PROPEL will evaluate the clinical benefit, safety and tolerability of BEMPEG combined with another CPI, pembrolizumab (PEMBRO). Here, we present the updated methodology and protocol for the enrolling PROPEL study.(3)

      Methods

      This phase 1/2 multinational trial evaluates BEMPEG plus PEMBRO in patients with locally advanced or metastatic solid tumors. During dose escalation (US only), ~40 patients with various advanced solid tumors (first- and second-line melanoma, NSCLC, urothelial carcinoma, head and neck squamous cell carcinoma, and hepatocellular carcinoma; regardless of PD-L1 status) will be treated with escalating doses of BEMPEG plus PEMBRO according to a 3+3 or step-up design. During dose expansion (global), ~58 patients with previously untreated advanced or metastatic NSCLC will be enrolled, and stratified based on PD-L1 status (<1%, 1-49%, and >50% staining on tumor cells by immunohistochemistry [for France only, patients with PD-L1 ≤49% will be excluded]). The primary objectives of the dose escalation are to evaluate safety and tolerability and determine the maximum tolerated dose/recommended phase 2 dose for BEMPEG in combination with PEMBRO. The primary objective of the dose expansion is objective response rate (by RECIST 1.1) in first-line metastatic NSCLC. Enrollment is ongoing (NCT03138889).

      References: 1. Diab A, et al. J Immunotherapy Canc 2019;7(1 suppl):3006; 2. Siefker-Radtke A, et al. J Clin Oncol 2019;37(7 suppl):388; 3. Reck M, et al. Poster presented at ESMO 2019; Poster 127TiP.

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