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Roy S. Herbst



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    ES02 - Pro-Con: Do We Need Biomarkers to Guide the Choice of Immunotherapy Treatment? (ID 157)

    • Event: WCLC 2020
    • Type: Educational Session
    • Track: Immunotherapy (Phase II/III Trials)
    • Presentations: 1
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      ES02.03 - We Should Use IO Alone as Maintenance (ID 3972)

      10:30 - 11:30  |  Presenting Author(s): Roy S. Herbst

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    FP13 - Immunotherapy (Phase II/III Trials) (ID 247)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Immunotherapy (Phase II/III Trials)
    • Presentations: 2
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP13.01 - 5-Year Survival Update From KEYNOTE-010: Pembrolizumab Versus Docetaxel in Previously Treated, PD-L1–Positive Advanced NSCLC (ID 1371)

      00:00 - 00:00  |  Presenting Author(s): Roy S. Herbst

      • Abstract
      • Slides

      Introduction

      The KEYNOTE-010 study (NCT01905657) showed significantly improved OS with pembrolizumab 2 or 10 mg/kg Q3W versus docetaxel in patients with previously treated advanced NSCLC with PD-L1 TPS ≥50% and ≥1%. We provide long-term follow-up for KEYNOTE-010 including updated efficacy outcomes in patients who completed 35 cycles (2 years) of pembrolizumab and those who received second-course pembrolizumab.

      Methods

      Patients had previously treated advanced NSCLC with PD-L1 TPS ≥1% and were randomized 1:1:1 to receive pembrolizumab 2 or 10 mg/kg Q3W or docetaxel 75 mg/m2 Q3W. Pembrolizumab treatment continued for 35 cycles (~2 years) or until disease progression/unacceptable toxicity. Eligible patients who completed pembrolizumab treatment or stopped pembrolizumab after achieving CR and receiving ≥6 months of treatment could receive second-course of pembrolizumab for up to 17 cycles (1 year) following disease progression after stopping pembrolizumab. Response was assessed Q9W. Survival was assessed every 2 months after treatment ended. Primary endpoints were OS and PFS in patients with PD-L1 TPS ≥50% and in those with PD-L1 TPS ≥1% (total population). Pembrolizumab in the pembrolizumab dose groups were pooled for this analysis.

      Results

      1033 patients were included in these analyses (pembrolizumab, 690; docetaxel, 343). As of April 8, 2020, median (range) time from randomization to data cutoff was 67.4 (60.0‒77.9) months. OS and PFS favored pembrolizumab in patients with PD-L1 TPS ≥50% and ≥1% (Table). Seventy-nine patients in the pembrolizumab group completed 35 cycles or 2 years of treatment with ORR of 98.7% (15 CR, 63 PR) in this group. Among those who completed 35 cycles or 2 years of pembrolizumab, 61 patients (77.2%) were alive (38 of whom were alive without PD). The 3-year OS rate after completing 35 cycles or 2 years (ie, at approximately 5 years) was 83.0%. Twenty-one patients received second-course pembrolizumab; 15 (71.4%) were alive at data cutoff. ORR after starting second-course was 52.4% (1 CR, 10 PR) and 6 had SD. Eight patients with CR/PR/SD after starting second-course subsequently had PD.

      Table.

      Patients with PD-L1 TPS ≥50%

      Patients With PD-L1 TPS ≥1%

      Pembrolizumab

      (N = 290)

      Docetaxel

      (N = 152)

      Pembrolizumab

      (N = 690)

      Docetaxel

      (N = 343)

      Median OS,a mo (95% CI)

      16.9 (12.3‒21.4)

      8.2 (6.4‒9.8)

      11.8 (10.4‒13.1)

      8.4 (7.6‒9.5)

      HR (95% CI)

      0.55 (0.44‒0.69)

      0.70 (0.61‒0.80)

      5-year OS rate,a %

      25.0

      8.2

      15.6

      6.5

      Median PFS,a,b mo (95% CI)

      5.3 (4.2‒6.5)

      4.2 (3.8‒5.1)

      4.0 (3.1‒4.1)

      4.1 (3.8‒4.5)

      HR (95% CI)

      0.57 (0.46‒0.71)

      0.84 (0.73‒0.96)

      5-year PFS rate,a %

      18.2

      Not reached

      9.4

      0.7

      aKaplan-Meier estimate.

      bAssessed by independent central review per RECIST version 1.1.

      Conclusion

      With more than 5 years of follow-up, pembrolizumab continued to provide clinically meaningful improvement in OS and PFS versus docetaxel in patients with previously treated, PD-L1–positive advanced NSCLC; 5-year OS rates were more than doubled in pembrolizumab-treated patients. Patients who completed 35 cycles or 2 years of pembrolizumab had durable clinical benefit. Second-course pembrolizumab provided meaningful disease control in the majority of patients who had disease progression after 2 years of pembrolizumab treatment.

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      FP13.03 - IMpower110: Updated OS Analysis of Atezolizumab vs Platinum-Based Chemotherapy as First-Line Treatment in PD-L1–Selected NSCLC (ID 3143)

      00:00 - 00:00  |  Presenting Author(s): Roy S. Herbst

      • Abstract
      • Slides

      Introduction

      The Phase III IMpower110 study (NCT02409342) evaluated first-line atezolizumab (anti–PD-L1) in PD-L1–selected squamous or non-squamous NSCLC. At the OS interim analysis (IA; data cutoff: 10 September 2018), IMpower110 met its primary endpoint of significant OS improvement in the atezolizumab vs chemotherapy arm in PD-L1–high (≥50% tumour cell [TC] or ≥10% tumour-infiltrating immune cell [IC; TC3 or IC3]) wild-type (WT; EGFR/ALK-negative) patients (HR, 0.59 [95% CI: 0.40, 0.89]; P = 0.0106). Here we report final OS analysis results in TC2/3 or IC2/3-WT and TC1/2/3 or IC1/2/3-WT patients.

      Methods

      Patients had PD-L1–selected (≥1% PD-L1 on TC or IC [TC1/2/3 or IC1/2/3]; VENTANA SP142 IHC assay), chemotherapy-naive, stage IV NSCLC and an ECOG PS of 0-1. Patients were randomised 1:1 to Arm A (atezolizumab 1200 mg IV q3w) or Arm B (platinum-based chemotherapy; 4 or 6 21-day cycles). In Arm B, patients with non-squamous disease received cisplatin 75 mg/m2 or carboplatin AUC 6 + pemetrexed 500 mg/m2 IV q3w and patients with squamous disease received cisplatin 75 mg/m2 + gemcitabine 1250 mg/m2 or carboplatin AUC 5 + gemcitabine 1000 mg/m2 IV q3w. The primary OS endpoint was tested hierarchically by PD-L1 expression status in WT patients: TC3 or IC3 (≥50% TC or ≥10% IC), then TC2/3 or IC2/3 (≥5% TC or IC) and then TC1/2/3 or IC1/2/3. Because the pre-specified OS statistical boundary in TC3 or IC3-WT patients was crossed at the OS IA, updated OS analyses in this population are exploratory in nature.

      Results

      With an additional 17 months of follow-up (data cutoff: 4 February 2020), OS in TC2/3 or IC2/3-WT patients showed numerical benefit in Arm A vs B but was not statistically significant (Table). Thus, OS could not be formally tested in TC1/2/3 or IC1/2/3-WT patients. In TC3 or IC3-WT patients, exploratory OS analysis showed continued clinically meaningful improvement in Arm A vs B. Treatment-related AEs (TRAEs) and Grade 3-4 TRAEs occurred in 62.9% (Arm A) and 85.2% (Arm B), and 14.3% (Arm A) and 44.9% (Arm B), respectively.

      Conclusion

      At the final OS analysis, IMpower110 did not show statistical significance in TC2/3 or IC2/3-WT patients. Exploratory updated analysis in TC3 or IC3-WT patients showed continued clinically meaningful OS benefit in the atezolizumab vs chemotherapy arm. The overall safety profile of atezolizumab in IMpower110 was consistent with the data from the OS IA and prior experience with atezolizumab monotherapy across indications.

      Median OS

      HRa
      95% CI

      P Valuea

      Arm A (atezolizumab)

      Arm B (chemotherapy)

      n

      Months

      n

      Months

      TC3 or IC3-WT

      107

      20.2

      98

      14.7

      0.764
      (0.536, 1.087)

      NAb

      TC2/3 or IC2/3-WT

      166

      19.9

      162

      16.1

      0.868
      (0.661, 1.140)

      0.3091

      TC1/2/3 or IC1/2/3-WT

      277

      18.9

      277

      14.7

      0.845
      (0.688, 1.037)

      0.1070c

      PD-L1 expression was centrally evaluated with the VENTANA SP142 IHC assay. TC3 or IC3 = TC ≥50% or IC ≥10% PD-L1+; TC2/3 or IC2/3 = TC ≥5% or IC ≥5% PD-L1+; TC1/2/3 or IC1/2/3 = TC ≥1% or IC ≥1% PD-L1+. a Stratified. b Since OS was statistically significant at the IA, the updated OS analysis in this population was exploratory and not formally tested. c For descriptive purposes only.

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    IS05 - Industry Symposium Sponsored by MSD: Redefining Survival Expectations in Lung Cancer (ID 282)

    • Event: WCLC 2020
    • Type: Industry Symposium
    • Track:
    • Presentations: 2
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      IS05.03 - Predictive Biomarkers of Response to Immune Checkpoint Inhibitors in Lung Cancer (ID 4329)

      14:15 - 15:15  |  Presenting Author(s): Roy S. Herbst

      • Abstract

      Abstract not provided

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      IS05.05 - Q&A and Closing Remarks (ID 4331)

      14:15 - 15:15  |  Presenting Author(s): Roy S. Herbst

      • Abstract

      Abstract not provided

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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): Roy S. Herbst

      • 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  |  Author(s): Roy S. Herbst

      • 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): Roy S. Herbst

      • 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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    OA06 - Updates on EGFR Targeted Perioperative Therapy and Precision Adjuvant Chemotherapy (ID 118)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Early Stage/Localized Disease
    • Presentations: 2
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      OA06.03 - Patient-Reported Outcomes from ADAURA: Osimertinib as Adjuvant Therapy in Patients with Resected EGFR Mutated (EGFRm) NSCLC (ID 3505)

      16:45 - 17:45  |  Author(s): Roy S. Herbst

      • Abstract
      • Presentation
      • Slides

      Introduction

      Osimertinib is a third-generation, irreversible, central-nervous system-active, EGFR-tyrosine kinase inhibitor. The Phase III, double‑blind, randomized ADAURA study (NCT02511106) of completely resected stage IB–IIIA EGFRm non-small cell lung cancer (NSCLC), with/without adjuvant chemotherapy, reported a highly statistically significant and clinically meaningful disease-free survival (DFS) benefit with adjuvant osimertinib vs placebo (HR: 0.20 [99.12% CI: 0.14, 0.30]; p<0.0001). The effect of adjuvant treatment on health-related quality of life (HRQoL) is an important clinical consideration for patients who, following surgery with curative intent, are disease-free and require long-term treatment to reduce the risk of disease recurrence. We report patient-reported outcomes from ADAURA.

      Methods

      Adult patients with completely resected stage IB/II/IIIA (AJCC 7th edition; pathologic stage) EGFRm NSCLC (postoperative chemotherapy allowed, per physician and patient choice) were randomized 1:1 to osimertinib 80 mg once daily or placebo for three years (treatment completion)/until discontinuation. Per protocol, HRQoL was measured by the Short Form-36 (SF-36) health survey. Patients completed the SF‑36 health survey (eight domains and two aggregated summary scores: physical [PCS] and mental [MCS] component summary) at baseline, 12 and 24 weeks, then every 24 weeks until treatment completion/discontinuation. SF-36 was scored using norm-based scoring relative to the 2009 US general population (mean ± standard deviation, 50±10), resulting in T‑scores (higher T‑scores indicate better health). Here we report an exploratory post-hoc analysis of HRQoL in the overall patient population (N=682; stage IB–IIIA). A mixed model of repeated measures (MMRM) was used to analyze changes in SF-36 scores from baseline until Week 96 (to ensure balanced comparison between arms, due to earlier disease recurrence with placebo). Time to deterioration (TTD) was defined as time from randomization to first confirmed clinically important worsening/death. Clinically meaningful changes at the individual (PCS ±3.8 points, MCS ±4.6 points; TTD analyses) and group (PCS ±2 points, MCS ±3 points; MMRM analyses) level were assigned based on pre‑specified definitions from the SF-36 manual, 3rd edition. Data cut‑off: 17/01/2020.

      Results

      Compliance rates for completion of the SF-36 health survey were high (≥85%) across all visits in both arms. Baseline PCS and MCS scores were comparable in the osimertinib and placebo arms (range 46–47); scores in both arms were only slightly lower than the mean scores in the general population (0.3–0.4 SD below the normative mean [50]). PCS/MCS scores increased from baseline to Week 96 by 1.13/1.34 for osimertinib and 2.31/2.68 for placebo, with no clinically meaningful differences between arms (PCS -1.18 [95% CI: -2.02, -0.34]; MCS -1.34 [95% CI: ‑2.40, ‑0.28]. There were no differences in TTD of PCS (HR: 1.17 [95% CI: 0.82, 1.67]) or MCS (HR: 0.98 [95% CI: 0.70, 1.39]) between osimertinib and placebo.

      Conclusion

      In ADAURA, adjuvant osimertinib demonstrated a highly statistically significant improvement in DFS vs placebo in patients with resected stage IB–IIIA EGFRm NSCLC. HRQoL was maintained during osimertinib treatment with no clinically meaningful differences observed between arms. Collectively, these data further support adjuvant osimertinib as a new treatment strategy in this setting, with significant DFS benefit and maintained HRQoL.

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      OA06.04 - Postoperative Chemotherapy Use and Outcomes from ADAURA: Osimertinib as Adjuvant Therapy for Resected EGFR Mutated NSCLC (ID 3464)

      16:45 - 17:45  |  Author(s): Roy S. Herbst

      • Abstract
      • Presentation
      • Slides

      Introduction

      Approximately 30% of patients with non-small cell lung cancer (NSCLC) present with resectable disease. Adjuvant chemotherapy is recommended in patients with resected stage IIꟷIIIA NSCLC, and selected stage IB patients; however, recurrence rates are high. In the Phase III, double-blind, randomized ADAURA study (NCT02511106), osimertinib (a third-generation, irreversible, CNS-active EGFR-tyrosine kinase inhibitor) demonstrated a highly statistically significant and clinically meaningful improvement in disease-free survival (DFS; hazard ratio [HR]: 0.20 [99.12% CI 0.14, 0.30]; p<0.001) in patients with completely resected stage IBꟷIIIA EGFR mutation-positive (EGFRm) NSCLC following adjuvant chemotherapy, when indicated. We report an exploratory analysis of adjuvant chemotherapy use and outcomes in ADAURA.

      Methods

      Patients with resected stage IB–IIIA (AJCC 7th edition; pathologic stage) EGFRm NSCLC were randomized 1:1 to receive osimertinib 80 mg once daily or placebo for three years (study completion) or until disease recurrence. Disease staging was based on electronic case report forms for baseline characteristics data, and interactive voice response system (IVRS) for efficacy data (per statistical analysis plan). Delivery of standard postoperative adjuvant chemotherapy prior to randomization was allowed, per physician and patient choice, but not mandatory. Assessment of adjuvant chemotherapy use was exploratory. DFS analysis in the overall population of patients (stage IB–IIIA disease) with/without adjuvant chemotherapy was a predefined subgroup analysis, performed using a Cox proportional hazards model. Data cutoff: 17/01/20.

      Results

      In ADAURA, 60% (410/682) of all patients randomized received adjuvant chemotherapy for a median duration of 4.0 (Q1: 4.0, Q3: 4.0) cycles, balanced across treatment arms. Overall, 409 patients received platinum-based chemotherapy, most with stage IIꟷIIIA (II: 71% [165/231]; IIIA: 80% [187/235]), and fewer with stage IB (26% [57/216]), disease. Across disease stages, the overall proportion of patients who received chemotherapy was 66% in patients aged <70 years (338/509), compared with 42% (72/173) in patients aged ≥70 years, reducing to 27% (21/78) in patients aged ≥75 years. WHO performance status (PS) did not impact chemotherapy use. The table reports DFS analysis with/without chemotherapy in the overall population and by disease stage, according to IVRS.

      Stage IB

      Stage II

      Stage IIIA

      Overall population
      (stage IB–IIIA)

      With chemotherapy

      OSI
      n=28

      PBO
      n=30

      OSI
      n=81

      PBO
      n=85

      OSI
      n=94

      PBO
      n=92

      OSI
      n=203

      PBO
      n=207

      DFS events, patients (%)

      4 (14)

      11 (37)

      6 (7)

      36 (42)

      12 (13)

      56 (61)

      22 (11)

      103 (50)

      DFS HR
      (95% CI)

      NC (NC, NC)

      0.15 (0.06, 0.32)

      0.13 (0.06, 0.23)

      0.16 (0.10, 0.26)

      Without chemotherapy

      OSI
      n=78

      PBO
      n=76

      OSI
      n=37

      PBO
      n=33

      OSI
      n=21

      PBO
      n=27

      OSI
      n=136

      PBO
      n=136

      DFS events, patients (%)

      7 (9)

      18 (24)

      5 (14)

      16 (48)

      3 (14)

      22 (81)

      15 (11)

      56 (41)

      DFS HR
      (95% CI)

      0.38 (0.15, 0.88)

      0.20 (0.07, 0.52)

      0.10 (0.02, 0.29)

      0.23 (0.13, 0.40)

      CI, confidence interval; DFS, disease-free survival; HR, hazard ratio; NC, not calculable; OSI, osimertinib; PBO, placebo

      Disease stage recorded by interactive voice response system.
      Subgroup categories with less than 20 events were excluded from the analysis. A hazard ratio of less than 1 favors osimertinib.

      Conclusion

      Adjuvant chemotherapy use in ADAURA was in line with uptake observed in previous studies and clinical practice. As expected, younger age and higher disease stage were associated with increased chemotherapy use, whereas use did not vary according to PS. DFS benefit with osimertinib vs placebo in patients who received prior chemotherapy was similar to that in patients who had not received prior chemotherapy, regardless of disease stage.

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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
    • +

      P01.21 - ANSELMA: Antiangiogenic Second Line Lung Cancer Meta-Analysis on Individual Patient Data in Non-Small Cell Lung Cancer, Again Relevant in ICI Era (ID 721)

      00:00 - 00:00  |  Author(s): Roy S. Herbst

      • Abstract
      • Slides

      Introduction

      There is renewed interest in the efficacy of 2nd line treatments (2LT) with anti-angiogenics (AA), now that immunotherapy plus chemotherapy (CT) is one of the standard options in 1st line treatment of advanced non-small cell lung cancer (NSCLC). Antibodies (mAb) against VEGF, VEGFR2, or AA tyrosine kinase inhibitors (TKI) have inconsistently shown benefit in combination with CT or erlotinib (E). We performed an individual patient data (IPD) meta-analysis to validate efficacy of these combinations as 2LT.

      Methods

      Randomized trials of AA plus standard 2LT (CT or TKI) compared to 2LT alone that ended accrual before 2015 were identified from publication databases, abstract proceedings and trial registers. Fixed-effect models were used to compute pooled hazard ratios (HRs) for overall survival (OS, primary endpoint), progression-free survival (PFS) and subgroup analyses. Peto method was used to estimate survival benefit.

      Results

      IPD were available for 15 out of 17 eligible trials (only via remote access for 9 trials). Out of 8,502 patients (pts) enrolled, 35% were female and 64% had adenocarcinoma. At 3 years, 10.5% were alive. Addition of AA significantly prolonged OS (HR=0.93 [95% confidence interval (CI): 0.89-0.98], p=0.005) and PFS (0.80 [0.77-0.84], p<0.0001) compared with 2LT alone. Absolute 1-year OS and PFS benefit for AA were +1.9% [95% CI: -0.3%;+4.1%] and +3.6% [+2.0%;+5.2%] respectively. According to the 3 types of combinations (mAb AA + CT, TKI AA + CT, AA + E), there was no significant interaction for OS. Interaction was significant for PFS (p=0.004): HR=0.78 [0.72-0.85], 0.86 [0.80-0.91] and 0.70 [0.63-0.77] respectively. There was a significant reduction of AA benefit on OS when age increased: 0.86 [0.75-0.99], 0.89 [0.81-0.97], 0.94 [0.87-1.02] and 1.04 [0.93-1.17] for pts <50, 50-59, 60-69 and ≥70 respectively (interaction p=0.009). Effect of AA was independent of sex (p=0.98) and performance status (0, ≥1; p=0.78) and ethnicity (Asian, non-Asian, p=0.38). Subgroup results were similar for PFS.

      Conclusion

      In the 2LT of advanced NSCLC, adding AA modestly but significantly prolongs OS and PFS. This appears independent of type of AA drugs, but the observed benefit may be higher in younger pts.

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    P09 - Health Services Research/Health Economics - Real World Outcomes (ID 121)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Health Services Research/Health Economics
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
    • +

      P09.55 - A Platform to Prospectively Link Real-World Clinico-Genomic, Imaging, and Outcomes Data for Patients With Lung Cancer (ID 808)

      00:00 - 00:00  |  Author(s): Roy S. Herbst

      • Abstract
      • Slides

      Introduction

      Developing personalized diagnostics and treatments for patients with cancer requires a comprehensive understanding of the patient journey. Real-world data can help to advance personalized medicine, but retrospective analyses are limited by data quality, bias, and other confounding factors. We present a multi-stakeholder platform to prospectively collect and link real-world clinico-genomic, imaging, and outcomes data to longitudinal blood genomic profiling for lung cancer patients treated in both the community and academic settings.

      Methods

      This study is enrolling approximately 1,000 patients with metastatic non-small cell lung cancer (NSCLC) or extensive-stage small cell lung cancer (SCLC) who will initiate standard-of-care systemic anti-neoplastic treatment, regardless of line of therapy, at ≥20 practices within the Flatiron Health network, predominantly in the community oncology setting. Designated pre-specified clinical data are being collected from electronic health records (EHR) via technology-enabled abstraction, without the need for case report forms. Clinical images will be collected at standard-of-care visits. Circulating tumor DNA (ctDNA) profiling using FoundationOne®Liquid is being evaluated at enrollment, first tumor assessment, and progression or end of treatment. Tumor tissue may also be submitted at baseline for genomic profiling using FoundationOne®CDx and capture of digital pathology images. Patients are followed until death, withdrawal of consent, loss to follow-up, or end of study. With focused efforts to integrate into routine clinic workflows and minimize site burden, this study is leveraging existing infrastructure for ongoing centralized data abstraction and additionally creating a new, prospective data model for linking clinico-genomic data. The objectives of the study are to evaluate 1) the feasibility of building a linked, multi-modal, longitudinal, scalable, prospective research platform and 2) the associations between ctDNA and real-world clinical outcomes.

      Results

      Between December 5, 2019 and June 30, 2020, 14 sites have been activated and 235 patients have been enrolled (233 patients with a confirmed diagnosis [Table]). At baseline, 83% had NSCLC, the median age was 68 years, and 51% were female.

      Table. Baseline demographics and clinical characteristics

      Characteristic

      All Patients

      (N = 233)

      Age, years, median [IQR]

      68 [62, 75]

      Female, n (%)

      118 (51%)

      Smoking status, n (%)

      History of smoking

      216 (93%)

      No history of smoking

      17 (7.3%)

      ECOG PS, n (%)

      0

      73 (31%)

      1

      91 (39%)

      2

      43 (18%)

      3+

      6 (2.6%)

      Not assessed 20 (8.6%)

      Race, n (%)

      Asian

      1 (0.43%)

      Black or African American

      20 (8.6%)

      White

      175 (75%)

      Other

      27 (12%)

      Unknown

      10 (4.3%)

      Therapy type/class, n (%)

      Anti-VEGF + chemotherapy combinations

      11 (4.7%)

      Chemoimmunotherapy

      92 (39%)

      Clinical study drug-based therapies

      2 (0.86%)

      Immunotherapy

      46 (20%)

      Non-platinum-based chemotherapy combinations 2 (0.86%)

      Platinum-based chemotherapy combinations

      24 (10%)

      Single agent chemotherapy

      24 (10%)

      Targeted therapy

      11 (4.7%)

      Study therapy not yet started

      14 (6.0%)

      Not treated 7 (3.0%)

      Non-small cell lung cancer, n (%)

      Total 194 (83%)
      Non-squamous cell carcinoma 141 (73%)
      Squamous cell carcinoma 48 (25%)

      NSCLC NOS

      5 (2.6%)

      Small cell lung cancer, n (%)

      Total 39 (17%)

      AJCC Stage at diagnosis, n (%)

      I

      15 (6.4%)

      II

      4 (1.7%)

      III

      29 (12%)

      IV

      182 (78%)

      Unknown

      3 (1.3%)

      AJCC, American Joint Committee on Cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; IQR, Interquartile Range; NOS, not otherwise specified; VEGF, vascular endothelial growth factor.

      Conclusion

      This novel prospective research platform, anchored to EHR-based centralized data collection infrastructure and an integrated data model, has the potential to scale and incorporate maturing personalized medicine capabilities. This study will deepen our understanding of the lung cancer patient journey across multiple data modalities in the real-world setting. Enrollment is ongoing.

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