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Shirish Madhav Gadgeel



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    IS07 - Industry Symposium Sponsored by Roche: Expert Perspectives on the Management of Lung Cancer (ID 284)

    • Event: WCLC 2020
    • Type: Industry Symposium
    • Track:
    • Presentations: 1
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      IS07.01 - The Past, Present and Future of Biomarker-Driven Advanced NSCLC (ID 4339)

      16:45 - 17:45  |  Presenting Author(s): Shirish Madhav Gadgeel

      • Abstract

      Abstract not provided

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    MA04 - Health Policy and the Real World (ID 217)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Health Services Research/Health Economics
    • Presentations: 1
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      MA04.07 - Comparative Clinical Outcomes for Patients with NSCLC Harboring EGFR Exon 20 Insertion Mutations and Common EGFR Mutations (ID 3390)

      16:45 - 17:45  |  Author(s): Shirish Madhav Gadgeel

      • Abstract
      • Slides

      Introduction

      Approximately 85–90% of the mutations seen in EGFR-mutant non-small cell lung cancers (NSCLCs) are common mutations (cEGFR), Exon 19 deletions and Exon 21 L858R. Up to 10% of EGFR-mutant NSCLC harbors Exon 20 insertion mutations (Exon20ins). We conducted a retrospective cohort study using real-world data to compare clinical outcomes between patients harboring Exon20ins and cEGFR.

      Methods

      This retrospective cohort study included patients from the Flatiron Health database (1 January 2011 through 31 May 2020) who had advanced NSCLC. The objectives of the study were to assess the prognostic value of Exon20ins compared with cEGFR (start date of first-line therapy as the index date) and the effect of tyrosine kinase inhibitor (TKI) treatment between the groups (start date of first TKI line as the index date). Analysis was stratified by line of TKI use. Endpoints included real-world overall survival (rwOS), progression-free survival (rwPFS), and time to next therapy (rwTTNT) and were analyzed using multivariable Cox proportional hazards model and summarized by Kaplan-Meier method.

      Results

      Among 62,464 patients with advanced NSCLC, 181 with Exon20ins and 2833 with cEGFR met eligibility criteria. Population demographics between the groups were comparable with minor exceptions. With median 34-month follow-up, Exon20ins was associated with a 75% increased risk of death (adjusted hazard ratio [adjHR] of 1.75 [95%CI, 1.45–2.13]; p˂0.0001); median rwOS was 16.23 (95%CI, 11.04–19.38) for Exon20ins and 25.49 months (95%CI, 24.48–27.04) for cEGFR (Table). The estimated 5-year survival rate for Exon20ins is 8% compared with 19% for cEGFR.

      The predictive value of TKI treatment, stratified by line, was assessed in 76 Exon20ins and 2749 cEGFR patients who were treated with TKIs. With median 20.6-month follow-up, there was a 170% increase in risk of progression or death associated with Exon20ins (adjHR of 2.7 [95% CI, 2.06–3.55]; p˂0.0001); median rwPFS was 2.86 months (95%CI, 2.14–3.91) compared with 10.45 months (95%CI: 10.05–10.94) for cEGFR. Furthermore, there was a 170% increased risk of death (adjHR of 2.70 [95% CI, 2.04–3.57]; p˂0.0001) associated with Exon20ins; median rwOS was 7.46 months (95%CI, 5.45–13.34) for Exon20ins and 25.49 months (95%CI, 24.28–26.81) for cEGFR (Table).

      Conclusion

      Patients with Exon20ins have a worse prognosis compared with patients with cEGFR. Furthermore, EGFR TKI treatment was substantially less effective for patients with Exon20ins, as the risk of disease progression and mortality was higher compared with patients with cEGFR. These findings highlight the need for new treatment options for Exon20ins.

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    MA11 - Expanding Targetable Genetic Alterations in NSCLC (ID 251)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
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      MA11.01 - Chair (ID 4177)

      14:15 - 15:15  |  Presenting Author(s): Shirish Madhav Gadgeel

      • Abstract

      Abstract not provided

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    OA04 - New Data from Rare EGFR Alterations (ID 223)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
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      OA04.05 - Trastuzumab Deruxtecan in HER2-Overexpressing Metastatic Non-Small Cell Lung Cancer: Interim Results of DESTINY-Lung01 (ID 1419)

      11:45 - 12:45  |  Author(s): Shirish Madhav Gadgeel

      • Abstract
      • Slides

      Introduction

      Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor payload. DESTINY-Lung01 (NCT03505710) is an ongoing, multicenter, phase 2 study evaluating T-DXd in 2 separate cohorts of patients with unresectable and/or metastatic nonsquamous non-small cell lung cancer (NSCLC): overexpressing HER2 (centrally confirmed, IHC 2+ or 3+) or containing a HER2-activating mutation. We have previously shown promising activity of T-DXd in patients with HER2-mutated NSCLC (confirmed objective response rate [cORR] by independent central review [ICR], 61.9%; Smit ASCO 2020). Here we report data from an interim analysis of the HER2-overexpressing cohort.

      Methods

      Patients with HER2-overexpressing metastatic NSCLC were treated with T-DXd 6.4 mg/kg every 3 weeks. The primary endpoint was ORR (CR + PR) by ICR. Additional endpoints were disease control rate (DCR; CR + PR + stable disease), duration of response (DOR), progression-free survival (PFS), and safety.

      Results

      At data cutoff (May 31, 2020), 49 patients had received T-DXd. Median age was 63 years (range, 37-85 years); 61.2% were male; 34.7% had CNS metastases at enrollment; 32.7% were never-smokers. 79.6% of patients (n=39) had HER2 IHC 2+ and 20.4% (n = 10) had HER2 IHC 3+. 91.8% of patients had received prior platinum-based chemotherapy and 73.5% had received anti−PD-1/PD-L1 treatment; median number of prior regimens was 3 (range, 1-8). Median treatment duration was 18.0 weeks (range, 3.0-57.1 weeks); 22.4% of patients remained on treatment.

      Confirmed ORR by ICR was 24.5% (95% CI, 13.3%-38.9%), including 1 CR and 11 PRs; IHC 2+, 25.6% (95% CI, 13.0%-42.1%); IHC 3+, 20.0% (95% CI, 2.5%-55.6%). Median DOR was 6.0 months (95% CI, 3.2-NE months); DCR was 69.4% (95% CI, 54.6%-81.8%); estimated median PFS was 5.4 months (95% CI, 2.8-7.0 months).

      All patients had ≥ 1 treatment-emergent adverse event (TEAE); the most common any-grade TEAEs were nausea (59.2%), decreased appetite (38.8%), and fatigue (32.7%). Grade ≥ 3 TEAEs were reported in 73.5% of patients (55.1% drug-related); the most common were decreased neutrophil count (20.4%) and fatigue (10.2%). There were 8 cases (16.3%) of drug-related interstitial lung disease (ILD) as adjudicated by an independent committee (grade 1, n = 2; grade 2, n = 3; grade 5, n = 3). TEAEs were associated with dose interruption in 26 patients (53.1%), dose reduction in 17 patients (34.7%), and treatment discontinuation in 11 patients (22.4%).

      Conclusion

      In this interim analysis, T-DXd demonstrated preliminary evidence of antitumor activity in heavily pretreated patients with HER2-overexpressing NSCLC. The safety profile of T-DXd was generally manageable, but ILD remains a known serious risk that requires proactive monitoring and care. An additional cohort to evaluate T-DXd 5.4 mg/kg in patients with HER2-overexpressing NSCLC has opened and started enrollment to further understand and characterize the safety and efficacy profile of T-DXd in this population.

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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): Shirish Madhav Gadgeel

      • 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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    P78 - Immunotherapy (Phase II/III Trials) - Immune Checkpoint Inhibitor Single Agent (ID 255)

    • 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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      P78.05 - Patterns of irAE During First Line Pembrolizumab for NSCLC: Incidence, Risk Factors, and Impact on Clinical Outcome (ID 2974)

      00:00 - 00:00  |  Author(s): Shirish Madhav Gadgeel

      • Abstract
      • Slides

      Introduction

      Pembrolizumab monotherapy is the preferred treatment option for patients with stage IV non-small cell lung cancer (NSCLC) with programmed death-ligand 1 (PD-L1) tumor expression ≥ 50% and no actionable driver mutations. There is little real word data on immune-related adverse events (irAEs) with first-line pembrolizumab. In this study, we aim to better understand irAE incidence, risk factors, and impact on clinical outcome in treatment naïve patients receiving first-line pembrolizumab therapy.

      Methods

      We conducted a multicenter, retrospective study of patients with treatment-naïve NSCLC and a PD-L1 expression of ≥50% treated with first line pembrolizumab monotherapy between June 2016 and January 2020. irAEs were determined by treating physician diagnosis and lack of alternative etiologies. Risk factors for irAE occurrence were determined using a logistic regression model. Overall survival (OS) was measured from the date of therapy initiation to death or the last point of follow-up. Survival was estimated by the Kaplan-Meier method. Cox proportional hazards were used to determine the association between irAE and OS while treating irAE as a time-dependent variable. P < 0.05 was considered significant.

      Results

      In our cohort of 153 patients, the median age was 66 years old (range 41-90); 37% of patients were female, 76.4% of patients had adenocarcinoma, and 21.5% had squamous cell carcinoma. Median follow-up time was 12 months. irAEs occurred in 65 patients (42.4%) with 23 (15.1%) developing irAE CTCAE grade ≥ 3. The most common high grade irAEs were pneumonitis (n=9), colitis (n=6), and hepatitis (n=2). Higher risk for irAE was associated with current tobacco use or cessation of tobacco use <6 months prior to treatment start (odds ratio [OR] 2.27, 95% confidence interval [CI] 1.14-4.52, P=0.02), prior or concurrent radiation therapy (OR 2.03, 95 %CI 1.06-3.90, P=0.03), neutrophil-lymphocyte ratio (NLR) >5 prior to starting therapy (OR 2.33, 95% CI 1.19-4.56, P=0.01), and longer course of pembrolizumab treatment (OR 1.039 per cycle, 95% CI 1.009-1.070, p=0.011). There was no difference in OS between patients who experienced low grade irAEs (<3) and those who did not develop irAEs (HR=0.391, 95% CI 0.124-1.231, p=0.1325) while those who developed high grade irAEs (≥ 3) had worse OS (HR 2.419, 95% CI, 1.117-5.243, p=0.021). Of patients who developed any grade irAEs, those who discontinued pembrolizumab therapy after irAE were found to have worse OS than those who continued therapy (HR 3.178, 95% CI 1.14-8.83, p=0.03).

      Conclusion

      Risk factors for the development of irAEs during first-line pembrolizumab included current or recent smoking status, NLR >5 prior to treatment start, prior or concurrent radiation therapy, and longer exposure to therapy. Higher grade irAEs and those events leading to discontinuation were associated with worse OS, and no OS benefit was observed in patients with lower grade adverse events. Our study identifies patients at high risk for irAEs who may benefit from closer monitoring during therapy. The lack of survival benefit from irAE in NSCLC patients with high PD-L1 expression has not previously been reported and warrants further investigation.

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