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David Kozono



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    MA08 - Advances in Biomarkers for Immune Checkpoint Blockade and Targeted Therapy in Non Small Cell Lung Carcinoma (ID 166)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
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      MA08.10 - LUNGMAP Master Protocol (LUNGMAP): Concordance Between Plasma ctDNA and Tissue Molecular Analysis (ID 3146)

      16:45 - 17:45  |  Author(s): David Kozono

      • Abstract
      • Slides

      Introduction

      The national LUNGMAP clinical trial is predicated on molecular screening enabling patient enrollment to biomarker-matched sub-studies for rapid evaluation of new precision medicine concepts in advanced NSCLC. To date, LUNGMAP has used a tissue-based Next-Generation Sequencing (NGS) approach for biomarker assessment. Given the utility of circulating tumor DNA (ctDNA) for biomarker identification, LUNGMAP investigators are evaluating the feasibility of plasma ctDNA as a screening approach.

      Methods

      Plasma samples for ctDNA testing were required for patients submitting fresh tissue biopsies for LUNGMAP screening. Tissue and plasma ctDNA were analyzed using the FoundationONE CDx and FoundationACT platforms at Foundation Medicine, Inc., respectively. Alterations detectable in both platforms were evaluated. Using tissue-detected driver alterations (referred to as drivers) as the gold standard, sensitivity was calculated as the proportion of patients with drivers also detected in ctDNA in addition to tissue, and specificity was calculated as the proportion of patients without drivers in ctDNA among those without drivers in tissue. Proportions and 95% exact confidence interval (CI) estimates were calculated.

      Results

      From January 2019 to June 2020, 129 patients had paired data and 54 (42%) had recognized oncogene drivers detected (EGFR [n=7], KRAS [n=37], MET [n=7], RET [n=2], BRAF [n=1], Table 1). Fifty-two patients had drivers detected in tissue; of these 43 were also observed in ctDNA, with 9 found in tissue only, for a ctDNA driver sensitivity of 83% (43/52, 95% CI: 74-93%). Of the 77 patients with no drivers in tissue, 2 drivers were detected in ctDNA (EGFR Ex20ins, MET amp) for a ctDNA specificity of 97% (75/77, 95% CI: 91-100%). For drivers, median variant allele frequency (VAF) in ctDNA was 2.22% (range: 0.13%-46.27%). For all single nucleotide variants (SNVs) and rearrangements detectable on both platforms, 386 variants were detected. Short variants (point mutations and small in/dels) showed the most fidelity, with 54% detected in both platforms (Table 1). Copy number alterations using an earlier platform version were least reproduced, with 8% identified by both.

      Conclusion

      In the LUNGMAP population, ctDNA (FoundationAct) had an 83% sensitivity and 97% specificity for NSCLC drivers detected in tissue. For non-driver alterations, additional variants were detected exclusively in plasma or tissue, likely reflecting differential sensitivity and/or non-shedding and tissue heterogeneity. These results, consistant with other recent studies, support the planned use of ctDNA for enrollment onto LUNGMAP sub-studies, with a positive finding meriting inclusion in study but a negative finding, considered inconclusive, requiring use of tissue results.

      Table 1

      N (%)

      Total Alterations Detected

      Number of Patients

      ................... In ctDNA ................

      ...................... In Tissue ................

      Overall

      In Tissue

      Not in Tissue

      Overall

      In ctDNA

      Not in ctDNA

      Driver Alterations

      54

      54

      45

      43 (96%)

      2 (4%)

      52

      43 (83%)

      9 (17%)

      Non-driver Alterations

      439

      75

      294

      169 (57%)

      125 (43%)

      314

      169 (54%)

      145 (46%)

      Short Variants

      316

      273

      158 (58%)

      115 (42%)

      201

      158 (79%)

      43 (21%)

      Copy Number Alts

      104

      10

      8 (80%)

      2 (20%)

      102

      8 (8%)

      94 (92%)

      Rearrangements

      19

      11

      3 (27%)

      8 (73%)

      11

      3 (27%)

      8 (73%)

      Overall

      493

      129

      339

      212 (63%)

      127 (37%)

      366

      212 (58%)

      154 (42%)

      Short Variants

      365

      314

      198 (63%)

      116 (37%)

      249

      198 (80%)

      51 (20%)

      Copy Number Alts

      107

      12

      9 (75%)

      3 (25%)

      104

      9 (9%)

      95 (91%)

      Rearrangements

      21

      13

      5 (38%)

      8 (62%)

      13

      5 (38%)

      8 (62%)

      TP53

      150

      128

      77 (60%)

      51 (40%)

      99

      77 (78%)

      22 (22%)

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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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      MA11.10 - Lung Master Protocol (Lung-MAP) Next Generation Sequencing Analysis of Advanced Squamous Cell Cancers (SWOG S1400) (ID 3055)

      14:15 - 15:15  |  Presenting Author(s): David Kozono

      • Abstract
      • Slides

      Introduction

      SWOG S1400, the original screening protocol of Lung-MAP, enrolled patients with Stage IV or recurrent squamous cell lung cancer previously treated with at least one line of systemic therapy. Tumors were profiled by NGS using Foundation Medicine’s FoundationOne T5 research platform, which sequenced the exons and/or introns of 313 cancer-related genes. Here, we report the results of a comprehensive analysis of the S1400 NGS data compared to The Cancer Genome Atlas (TCGA) data, including identification of novel sets of mutually exclusive and co-occurring genetic alterations.

      Methods

      Analyses included all patients with successful NGS testing enrolled on S1400. Mutually Exclusive Gene Set Analysis (MEGSA) was used to identify sets across genetic alterations with mutated prevalence > 6%. Selected Events Linked by Evolutionary Conditions across human Tumors (SELECT) was used to identify pairwise gene interactions. Comparisons were performed using mutation profiles of 495 squamous cell lung cancers downloaded from the TCGA data portal. Cox proportional hazards models adjusted for clinical covariates including age, sex, smoking history and AJCC TNM categories were used to examine the association between each genetic variant and survival. The Benjamini-Hochberg method was used to adjust significance values for multiple comparisons.

      Results

      Between June 16, 2014 and January 29, 2019, 1864 patients were enrolled to be screened, of whom NGS was available for 1672. 73% of the sequenced tumor samples were archival and 27% were fresh biopsies; there were no significant differences in prevalence of genetic alterations between these. MEGSA identified two non-overlapping sets of mutually exclusive gene alterations with a false discovery rate (FDR) < 15%: NFE2L2, KEAP1 and PARP4 (FDR = 4.1%) and CDKN2A and RB1 (FDR = 13.1%). Mutual exclusivity of NFE2L2 and KEAP1 alterations has been previously observed, e.g., in TCGA, however mutual exclusivity of PARP4 and NFE2L2 or KEAP1 alterations is a novel finding. SELECT identified 41 pairs of mutually exclusive and 95 pairs of co-occurring gene alterations. Top significant co-occurring pairs that appeared in this dataset but not TCGA include CDKN2A and TP53, KRAS and STK11, HGF and MLL2, PDGFRB and SMARCA4, NFE2L2 and TP53, ATRX and RUNX1T1, GRIN2A and NCOR1, and MCL1 and MYCN. Male sex and smoking history were associated with poorer survival. When these and other clinical covariates were incorporated in Cox proportional hazards models, there were no individual genetic variants that were associated with survival; however, NFE2L2 and KEAP1 alterations when taken together were associated with poorer survival.

      Conclusion

      This analysis of the Lung-MAP S1400 NGS data features a substantially larger sample size than any previously published dataset of squamous cell lung cancers, although it is limited to genes sequenced on the FoundationOne T5 platform. Compared to TCGA, this dataset features a homogeneous set of subjects all with previously treated advanced disease and enrolled on a clinical trial. Novel findings, including mutual exclusivity of PARP4 and NFE2L2 or KEAP1 alterations, suggest that PARP4 may have a hitherto undiscovered role in a key pathway known to impact responses to oxidative stress and treatment resistance.

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    OA01 - Established Drugs in Special Populations and New Drugs in Established Populations (ID 226)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Immunotherapy (Phase II/III Trials)
    • Presentations: 1
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      OA01.04 - Tumor Mutation Burden (TMB) by Next Generation Sequencing (NGS) Associates with Survival (OS) in Lung-MAP Immunotherapy Trials S1400I and S1400A (ID 3229)

      09:15 - 10:15  |  Author(s): David Kozono

      • Abstract
      • Presentation
      • Slides

      Introduction

      TMB is an emerging biomarker for efficacy of immune checkpoint inhibitors (ICI). Lung-MAP is a master protocol for biomarker-driven trials in advanced NSCLC. Two sub-studies in previously treated ICI naïve advanced squamous cell lung cancer (sqNSCLC), S1400I, a phase III trial randomizing patients to nivolumab plus ipilimumab (N/I) versus nivolumab (N), and S1400A, a phase II trial evaluating durvalumab (D), provided the opportunity to evaluate TMB and related biomarkers by NGS and to determine associations with clinical outcomes.

      Methods

      NGS was performed on DNA from formalin-fixed paraffin-embedded tumor specimens using the FoundationOne T5 platform. TMB was defined as the total number of nonsynonymous mutations per megabase (Mb) of coding sequence. In S1400I, PD-L1 expression was assessed by the 22C3 antibody. A Cox model was used to evaluate associations between TMB (continuous and dichotomized at 10 Mb/mt), PD-L1 (continuous and dichotomized at 0% versus > 0%), overall survival (OS) and progression-free survival (PFS), summarized by hazard ratios (HRs) and 95% confidence intervals (CI). Associations between TMB and genetic alterations were evaluated by Wald test, with false discovery rate (FDR) ≤ 5% scored as positive. Unsupervised hierarchical clustering was performed using combined data from S1400I+S1400A.

      Results

      3229 figure.jpg252 patients on N/I or N and 68 patients on D were included in the analysis. Higher TMB (per 10-unit difference in TMB value) was significantly associated with better OS and PFS (OS HR(CI): 0.80 (0.67–0.94), P = 0.008 and PFS HR(CI): 0.80 (0.69–0.93), P = 0.004). In S1400I, PD-L1 expression levels were not significantly associated with OS or PFS (N=161, P > 0.05), alone or in combination with TMB. In S1400I+S1400A, no genetic variants were significantly associated with OS or PFS. Genes whose alterations were significantly associated with TMB are shown in the volcano plot. Unsupervised hierarchical clustering suggested a variant-defined subgroup conferred better PFS (HR (CI): 0.41 (0.19–0.88), P = 0.022) but not OS; notably, this subgroup showed 3.8-fold higher TMB and more frequent alterations of genes shown in the plot, compared to other subgroups.

      Conclusion

      Several different methodologies have been employed to measure TMB. TMB by FoundationOne NGS is an analytically and clinically validated assay correlating well with WES and predicted neoantigen load. Here we report that high TMB, but not PD-L1, is associated with improved OS and PFS in patients treated with ICI on S1400I/S1400A. How genetic alterations associated with high TMB may biologically contribute to clinical outcomes from ICI warrants further consideration.

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    P01 - Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics (ID 227)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P01.23 - Veliparib (V) in Combination with Carboplatin/Paclitaxel (C/P)-Based Chemoradiotherapy (CRT) in Patients With Stage III NSCLC (ID 786)

      00:00 - 00:00  |  Presenting Author(s): David Kozono

      • Abstract
      • Slides

      Introduction

      CRT is a standard treatment for patients with stage III NSCLC. V is a potent, orally bioavailable PARP1/2 inhibitor that inhibits DNA repair following chemotherapy- or radiation-induced damage. Here, we report final results of a Phase 1 study (NCT02412371) of V + C/P-based CRT in stage III NSCLC.

      Methods

      Dose-escalation followed a 3+3 design to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Patients with newly diagnosed unresectable stage III NSCLC received V (escalated sequentially) + C (area under the curve [AUC] 2 mg/mL/min) + P (45 mg/m2 weekly) + 60–63 Gy (total dose over 6–9 weeks), followed by V + consolidation therapy (C AUC 6 mg/mL/min + P 200 mg/m2) for up to two cycles. V was escalated from 60 mg twice daily (BID) to a maximum planned dose of 240 mg BID during CRT and was tested at 120 mg BID (Cohorts 1–5) or 240 mg BID (Cohort 6) during consolidation therapy. Safety was assessed according to NCI CTCAE v4.0. Radiographic assessments were evaluated according to RECIST v1.1.

      Results

      Forty-eight patients (median age 65 years, 40% male) were enrolled into Cohorts 1–6 between May 2015 – February 2018. Three patients experienced dose-limiting toxicities; one in Cohort 4 (V 200/120 mg BID in CRT/consolidation phase) and two in Cohort 6 (V 240/240 mg BID in CRT/consolidation phase). V 240 mg BID + C/P-based CRT/V 120 mg BID + C/P consolidation (Cohort 5; n=12) was determined to be the MTD/RP2D. In Cohort 5, the most common AEs were nausea (83%), neutropenia, thrombocytopenia, and esophagitis (all 75%), leukopenia and fatigue (both 58%). In Cohort 5, 25% of patients experienced serious AEs (Table). Overall, median PFS was 19.6 months (95% CI 9.7, 32.6), median OS was 32.6 months (95% CI 15.0, not evaluable) and median follow-up was 32.6 months. ORR was 63% (95% CI 46.7, 77.0) for the total evaluable population (≥1 post-baseline tumor assessment; N=43) and 73% (95% CI 39.0, 94.0) for Cohort 5 (N=11).

      Conclusion

      The RP2D of V 240 mg BID + C/P-based CRT/V 120 mg BID + C/P consolidation therapy is tolerable in patients with stage III NSCLC. The V dose in the CRT phase is double that reported in the S1206 study (Argiris et al, J Clin Oncol 2019; abstract 8523) and may enhance C/P activity. The regimen demonstrated anti-tumor activity with median PFS 19.6 months.table.jpg

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    P48 - Small Cell Lung Cancer/NET - Chemo - IO (ID 236)

    • 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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      P48.02 - NRG Oncology/Alliance LU005: Chemoradiation vs. Chemoradiation Plus Atezolizumab in Limited Stage Small Cell Lung Cancer  (ID 1267)

      00:00 - 00:00  |  Author(s): David Kozono

      • Abstract
      • Slides

      Introduction

      Limited stage small cell lung cancer (LS-SCLC) is treated with standard of care platinum/etoposide (EP) and thoracic radiation therapy (TRT) with curative intent, however the majority of patients are not cured and median overall survival is approximately 30 months. Addition of atezolizumab to chemotherapy in extensive stage SCLC has improved progression free and overall survival in a non-curative setting leading to hope that addition of an immune checkpoint inhibitor to standard chemoradiotherapy could benefit LS-SCLC patients. LU005 is a randomized phase II/III trial of standard concurrent chemoradiation with or without atezolizumab for patients with LS-SCLC.

      Methods

      Patients are randomly assigned in a 1:1 ratio to standard EP chemotherapy with concurrent TRT (45 Gy BID or 66 Gy QD) with or without atezolizumab beginning concurrently with TRT, and continued every 3 weeks for up to 12 months. Eligible patients have LS-SCLC, PS 0-2, adequate organ function, no concerning comorbidities (including no active autoimmune disease) and are eligible for TRT. Patients are randomized prior to their second cycle of EP and thoracic radiation begins with the second overall cycle of chemotherapy (first cycle of study therapy) in both treatment arms. Prophylactic cranial radiation (PCI) is recommended for patients who respond to treatment. The phase II/III primary endpoints are progression free (PFS) and overall survival (OS) respectively. Secondary endpoints include objective response rates, local and distant disease control, and quality of life/patient reported outcomes assessment. Translational science component includes blood and tissue based immune related assays.

      Results

      This study activated in May 2019. 120 of 506 planned patients have been accrued as of 8/20/2020.

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