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Vassiliki A Papadimitrakopoulou



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    MA03 - Clinomics and Genomics (ID 119)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA03.05 - BRAF Mutations Are Associated with Increased Benefit from PD1/PDL1 Blockade Compared with Other Oncogenic Drivers in Non-Small Cell Lung Cancer (Now Available) (ID 1472)

      10:30 - 12:00  |  Author(s): Vassiliki A Papadimitrakopoulou

      • Abstract
      • Presentation
      • Slides

      Background

      PD-1/PD-L1 immune checkpoint blockade (ICB) has revolutionized the treatment of non-small cell lung cancer (NSCLC), but only a minority of patients achieve durable clinical benefit. Although classic EGFR/ALK alterations are correlated with ICB resistance, it is unknown if patients with other molecular subtypes of NSCLC also derive poorer outcomes from ICB. We investigated if there are oncogene-driven NSCLC associated with higher response rates (RR) and progression-free survival (PFS) to ICB.

      Method

      Two independent retrospective cohorts of oncogene-driven NSCLC treated with ICB monotherapy were analyzed for clinical outcome: MD Anderson (MDACC) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (FH-CGDB). PD-L1 expression (Dako 22C3 - FoundationCore) and tumor mutational burden (TMB - FoundationCore; TCGA and MSK-IMPACT – cbioportal.org) were compared across distinct molecular subtypes of NSCLC to determine differences in clinical outcome.

      Result

      Among five oncogene defined groups from the MDACC cohort, BRAF-mutant NSCLC had the highest response rate (RR) (RECIST 1.1) (P<0.01) and PFS (P<0.01) when treated with ICB (Table). These differences remained significant after adjusting for PD-L1 expression. Classic EGFR and HER-2 mutant NSCLC had the lowest RR and PFS (Table). Similar results were observed in the independent FH-CGDB cohort where BRAF-mutant NSCLC had longer real-world (rw) PFS and OS to ICB monotherapy (Table). PD-L1 expression (tumor score ≥1% and ≥50%) and TMB were higher in BRAF-mutant NSCLC compared to EGFR and HER-2 (P<0.01). BRAF V600E NSCLC had lower TMB compared to non-V600E (5.9 vs 13.7 mut/Mb, P<0.01), but both had high PD-L1 expression (≥1%: 72% vs 61%; ≥50%: 42% vs 32%).

      KRAS

      BRAF

      Classic EGFR

      EGFR exon 20

      HER2

      MDACC cohort

      Patients – N

      87

      10 (V600E 3 / non-V600E 7)

      28

      25

      15

      RR – %

      24.3

      62.5

      4.5b

      10b

      8.3

      Median PFS – mo (95% CI)

      2.76

      (2.23-3.30)

      7.37 (not estimable)a

      1.78 (1.18-2.37)

      2.73 (1.71-3.75)

      1.88 (1.63-2.12)

      FH-CGDB

      Patients – N

      503

      68 (V600E 32 / non-V600E 36)

      52

      42

      25

      Median rwPFS -

      mo (95% CI)

      3.55

      (3.15-4.24)

      6.0

      (2.89-11.6)

      2.17b

      (1.77-2.63)

      2.66b

      (2.23-5.13)

      1.87b (1.31-4.34)

      Median rwOS – mo (95% CI)

      10.28

      (8.51-12.02)

      16.07

      (8.64-NA)

      5.29b

      (3.25-17.68)

      9.89b

      (3.68-20.86)

      10.81

      (4.17-NA)

      FoundationCore cohort – N

      NA

      188 (V600E 74 / non-V600E 114)

      386

      96

      57

      TMB – mean (mut/Mb)

      NA

      10.6a

      3.7

      3.8

      5.8

      PD-L1 TPS ≥ 50% (%)

      NA

      36a

      19

      23

      16

      a: P<0.01 vs all groups; b: P<0.05 for pairwise comparison vs BRAF.

      Conclusion

      NSCLCs with BRAF mutations are associated with increased benefit from ICB when compared to tumors harboring other targetable oncogenic drivers. Oncogene driver mutations are associated with distinct patterns of TMB and PD-L1 expression. These findings highlight the importance of developing mutation-specific clinical trials in NSCLC.

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    MA09 - EGFR & MET (ID 128)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA09.03 - Identification of Mechanisms of Acquired Resistance to Poziotinib in EGFR Exon 20 Mutant Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 2904)

      15:15 - 16:45  |  Author(s): Vassiliki A Papadimitrakopoulou

      • Abstract
      • Presentation
      • Slides

      Background

      Insertions/mutations in exon 20 of EGFR occur in ~2% Insertions/mutations in exon 20 of EGFR occur in ~2% of all lung adenocarcinomas. These alterations are characterized by primary resistance to approved tyrosine kinase inhibitors (TKIs) with response rates of <12%. We have shown that exon 20 insertions restrict the size of the drug-binding pocket, limiting binding of large inhibitors. However, poziotinib can circumvent these steric changes and is a potent inhibitor of EGFR exon 20 mutants. In our investigator-initiated phase 2 trial of EGFR exon 20 mutant NSCLC, poziotinib was associated with a best objective response rate of 55% (Heymach et al, 19th WCLC). Herein, we use preclinical models and clinical samples from our phase 2 study to identify mechanisms of acquired poziotinib resistance (NCT03066206).

      Method

      EGFR exon 20 insertion (D770insNPG) genetically engineered mice (GEM) were treated with poziotinib until progression. Upon progression, tumor DNA and protein were analyzed using whole exome sequencing (WES) and reverse phase protein assay (RPPA). Mandatory and optional biopsies were obtained at baseline and progression, respectively, from patients treated in our phase 2 trial of poziotinib in EGFR exon 20 mutant NSCLC. Serial cfDNA was collected at baseline, 8 weeks of therapy, and on progression. Patient samples were analyzed using targeted next generation sequencing or WES.

      Result

      Poziotinib acquired-resistance GEM tumors acquired mutations in ErbB4, KRAS, and other genes which represent potential targetable bypass pathways. Resistant GEM tumors displayed increased activation of MAPK, AKT, ERK and MEK compared to sensitive tumors, suggesting that poziotinib acquired resistance is associated with reactivation of the MAPK/PI3K pathways. We enrolled 50 EGFR exon 20 mutant patients in our phase 2 trial. Analysis of matched pre-poziotinib and on-progression samples from 20 responding patients revealed acquired EGFR tyrosine kinase domain point mutations in 4 patients (T790M (2), V774A (1), D770A, (1)). Ba/F3 cells co-expressing EGFR exon 20 insertion (S768supSVD) and T790M were resistant to poziotinib, suggesting that T790M is a poziotinib resistance driver. Potential acquired EGFR-independent resistance mechanisms identified in patients to date include PIK3CA E545K (1), MAP2K2 S94L (1), MET amplification (1), EGFR amplification (2), and CDK6 amplification (2).

      Conclusion

      Parallel to acquired resistance mechanisms seen in classical EGFR mutation, acquired resistance to poziotinib can be mediated through EGFR-dependent mechanisms, notably T790M and other EGFR tyrosine kinase domain point mutations. EGFR-independent resistance mechanisms include activation of bypass pathways. Preclinical validation of resistance mechanisms and additional analysis of patient samples will be presented at the meeting.

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    MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MA11.11 - STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (Now Available) (ID 2898)

      14:00 - 15:30  |  Author(s): Vassiliki A Papadimitrakopoulou

      • Abstract
      • Presentation
      • Slides

      Background

      Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread use of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we present updated data on the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy from a large retrospective multi-institution international study.

      Method

      620 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 21 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 468 pts treated with first-line CPP (or >1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 152 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP.

      Result

      Among 468 CPP-treated pts, STK11/LKB1 genomic alterations (N=118) were associated with significantly shorter PFS (mPFS 5.0m vs 6.8m, HR 1.45, 95% CI 1.11 to 1.91; P=0.007) and shorter OS (mOS 10.6m vs 16.7m, HR 1.46, 95% CI 1.04 to 2.07; P=0.031) compared with STK11/LKB1-wt tumors (N=350). The likelihood of disease progression as BOR to CPP differed significantly between the two groups (29.5% vs 17%, P= 0.006). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N=435) (mPFS 5.0m vs 6.9m, HR 1.48, 95% CI 1.12-1.95, P=0.006 and mOS 10.6m vs 16.7m, HR 1.45, 95% CI 1.02-2.05, P=0.036). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not result in significant improvement of PFS (mPFS 5.0m vs 3.9m, HR 0.82, 95% CI 0.63 to 1.07, P=0.14) or OS (mOS 10.6m vs 9.1m, HR 0.93, 95% CI 0.67 to 1.30, P=0.69) compared to CP alone.

      Conclusion

      In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.

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    MA14 - The Adequate MTarget Is Still the Issue (ID 140)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA14.10 - Clinical Outcomes in Metastatic Squamous Lung Cancer with Targetable Driver Alterations (Now Available) (ID 527)

      15:45 - 17:15  |  Author(s): Vassiliki A Papadimitrakopoulou

      • Abstract
      • Presentation
      • Slides

      Background

      Genomic profiling is not routinely performed for metastatic squamous (SCC) and adenosquamous (ASC) NSCLC. However molecular profiling may be ordered if demographic features suggest a higher likelihood of a targetable driver alteration (e.g. never or remote smoking history). Response and survival data are scant in pts with actionable alterations treated with targeted therapy.

      Method

      We reviewed the clinical data and molecular profiling (FISH, PCR, tissue NGS, ctDNA) of metastatic SCC and ASC pts treated at our institution from Feb 2010-Dec 2018. Pts with typical sensitizing mutations in EGFR or BRAF V600E or fusions in ALK or ROS1 treated with matched targeted therapy for ≥ 2 months were included in this analysis. Response assessment was based on RECIST v1.1.

      Result

      Among 261 metastatic SCC or ASC pts with available molecular profiling, 16 total pts (6%) were found to have actionable targets, consisting of 13 SCC and 2 ASC (median age 53, 81% female, 88% never-smoker). The distribution of driver alterations in this cohort was 56% (9/16) EGFR ex19del/L858R/G719A, 38% (6/16) ALK fusion, and 6% (1/16) BRAF. The overall objective response rate (ORR) and median progression free survival (PFS) to targeted therapy was 69% and 5.2 months respectively. By mutational subgroup, ORR was 67% (6/9) for EGFR, 67% (4/6) for ALK, and 100% (1/1) for BRAF. Median PFS was only 4.5 months (95% CI 3.0 – 6.0) for EGFR pts and 2.8 months (95% CI 0 – 6.4) for ALK pts, and the lone BRAF pt had a PFS of 8.5 months. In EGFR pts with available NGS, co-mutations in TP53 (75% [6/8]) and PIK3CA (38% [3/8]) were seen at rates higher than previously reported in EGFR+ ADC (TP53 55%, PIK3CA 12%; Blakely et al, Nat Gen 2017). In ALK pts with available NGS, co-mutations in TP53 (80% [4/5]) were also higher than recently reported in ALK+ ADC (24%; Kron et al, Ann Oncol 2018).

      Conclusion

      Despite initial responses comparable to those previously reported in ADC, matched targeted therapy in pts with SCC and ASC histology is associated with shorter PFS. A higher prevalence of adverse co-mutations such as TP53 and PIK3CA may contribute to early targeted therapy resistance in these histologies. These findings may have implications for the use of targeted therapy in squamous lung cancer.

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    MA25 - Precision Medicine in Advanced NSCLC (ID 352)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA25.01 - Pembrolizumab Plus Chemotherapy for Advanced NSCLC Without Tumor PD-L1 Expression: Pooled Analysis of KN021G, KN189 and KN407 (Now Available) (ID 1399)

      14:30 - 16:00  |  Author(s): Vassiliki A Papadimitrakopoulou

      • Abstract
      • Presentation
      • Slides

      Background

      Randomized studies have demonstrated that pembrolizumab plus chemotherapy improves OS, PFS, and ORR compared with chemotherapy alone in patients with advanced NSCLC regardless of tumor PD-L1 expression level. We present a post hoc pooled analysis of pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced NSCLC and no PD-L1 expression (ie, TPS <1%), representing an area of unmet need.

      Method

      Patients enrolled in KEYNOTE-021 cohort G (nonsquamous; NCT02039674), KEYNOTE-189 (nonsquamous; NCT02578680), and KEYNOTE-407 (squamous; NCT02775435) were included. Patients with nonsquamous NSCLC were randomized to pemetrexed-platinum with or without pembrolizumab; those with squamous NSCLC were randomized to carboplatin-paclitaxel/nab-paclitaxel with or without pembrolizumab. OS, PFS, and ORR were evaluated for the pooled intent-to-treat population. Response was assessed per RECIST v1.1 by blinded independent central review. Across studies, PD-L1 expression was assessed centrally using PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Carpinteria, CA). Analyses were descriptive.

      Result

      Of 1298 patients enrolled across the 3 trials, 428 (33%) had PD-L1 TPS <1% (pembrolizumab plus chemotherapy, n=243; chemotherapy alone, n=185) and were included in this analysis. 52% had nonsquamous histology, 63% had ECOG PS of 1. Median (range) follow-up at data cutoff was 10.2 (0.1‒34.9) months. OS, PFS, and ORR were improved with pembrolizumab plus chemotherapy versus chemotherapy alone (Table). Grade ≥3 AEs (all-cause) occurred in 68% of patients receiving pembrolizumab plus chemotherapy versus 72% receiving chemotherapy alone. Immune-mediated AEs and infusion reactions occurred in 26% who received pembrolizumab plus chemotherapy versus 12% who received chemotherapy alone.

      Pembrolizumab + Chemotherapy

      n=243

      Chemotherapy
      Alone

      n=185

      Median (95% CI) OS, mo

      19.0 (15.2–24.0)

      11.0 (9.2–13.5)

      Hazard ratio (95% CI)

      0.56 (0.43–0.73)

      Median (95% CI) PFS, mo

      6.5 (6.2–8.5)

      5.4 (4.7–6.2)

      Hazard ratio (95% CI)

      0.67 (0.54–0.84)

      ORR, % (95% CI)

      46.9% (40.5%–53.4%)

      28.6% (22.3%–35.7%)

      Difference (95% CI)

      18.3% (9.0%–27.1%)

      Conclusion

      Our results highlight the clinically meaningful efficacy benefit and acceptable safety profile of pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced NSCLC and no PD-L1 expression. Benefit was consistent with that observed in the overall study populations, suggesting pembrolizumab plus chemotherapy should be considered standard-of-care first-line therapy for all patients with NSCLC, irrespective of PD-L1 expression.

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    OA04 - Immuno Combinations and the Role of TMB (ID 126)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 3
    • Now Available
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      OA04.01 - A Phase III Randomized Study of Nivolumab/Ipilimumab vs Nivolumab for Previously Treated Stage IV Squamous Cell Lung Cancer (Now Available) (ID 872)

      15:15 - 16:45  |  Author(s): Vassiliki A Papadimitrakopoulou

      • Abstract
      • Presentation
      • Slides

      Background

      Lung-MAP is a master protocol for patients (pts) with stage IV previously treated SqNSCLC. S1400I enrolled pts who were not eligible for a biomarker-matched sub-study. (Lung-MAP Sub-Study S1400I, NCT02785952)

      Method

      S1400I is phase III randomized trial for immunotherapy-naïve patients with ECOG 0-1 not selected by PD-L1 expression. Pts were assigned 1:1 to nivolumab and ipilimumab (N+I) vs nivolumab (N). N was given at 3 mg/kg q 2w, I was given at 1 mg/kg q 6w. The primary endpoint was overall survival (OS). Secondary endpoints: investigator-assessed progression-free survival (IA-PFS), response by RECIST 1.1, and toxicity.

      Result

      From December 18, 2015 to April 23, 2018, 275 pts enrolled and 252 determined eligible (125 N+I and 127 N). Median follow up for patients still alive was 17.4 months. The study was closed for futility at an interim analysis. Baseline characteristics were similar across arms. mOS was 10.0 m (8.0-12.8) and 11.0 m (8.2-13.5) for N+I and N. HR 0.97 (0.71-1.31), p 0.82. mPFS was 3.8 m (2.3-4.2) and 2.9 m (1.8-3.9) for N+I and N. HR 0.84 (0.64-1.09), p 0.19. The response rate was 18% (12-25) in N+I and 17 % (11, 24) in N. Outcomes were similar across TMB subgroups and PD-L1 expression levels. Most AE were low grade. There were 5 grade 5 AE in N+I arm and 1 in N arm. Grade ≥3 treatment-related AEs occurred in 48(39%) of pts on N+I vs 38(31%) on N. irAE reported in 39% of pts on N+I and 34% of patients on N. Drug-related AEs led to discontinuation in 25% of pts on N+I and 16% of pts on N.

      OS and PFS based on TMB and PD-L1

      N+I

      Median in months

      N

      Median in months
      HR p
      OS PD-L1 ≥5 14.1 (5.8-17.5) 12.0 (8.2-19.8) 1.06 (0.58-1.92) 0.86
      OS PD-L1 <5 8.3 (6.0-10.7) 10.3 (6.3-13.5) 1.01 (0.62-1.65) 0.97
      OS TMB ≥10 13.1 (9.3-17.0) 11.4 (8.2-16.1) 0.86 (0.56-1.32) 0.48
      OS TMB <10 7.6 (5.7-10.2) 10.0 (6.3-15.2) 1.08 (0.68-1.71) 0.74
      PFS PD-L1 ≥ 5 3.9 (1.7-7.1) 2.9 (1.8-4.7) 0.65 (0.38-1.08) 0.10
      PFS PD-L1 <5 4.4 (2.1-6.0) 1.6 (1.5-3.0) 0.64 (0.41-1.01) 0.06
      PFS TMB ≥ 10 4.2 (3.4-5.9) 3.4 (1.8-5.3) 0.75 (0.52-1.10) 0.15
      PFS TMB < 10 1.9 (1.5-4.1) 2.7 (1.6-3.3) 0.92 (0.62-1.39) 0.70

      Conclusion

      S1400I failed to show improvement in outcomes with N+I. Study was closed for futility at interim analysis. Toxicities were not different between two arms. Molecular correlates will be presented at the meeting.

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      OA04.05 - KEYNOTE-021: TMB and Outcomes for Carboplatin and Pemetrexed With or Without Pembrolizumab for Nonsquamous NSCLC (Now Available) (ID 2630)

      15:15 - 16:45  |  Author(s): Vassiliki A Papadimitrakopoulou

      • Abstract
      • Presentation
      • Slides

      Background

      KEYNOTE-021 cohort C was the first study to show antitumor activity for pembrolizumab plus platinum-based chemotherapy in previously untreated advanced nonsquamous NSCLC; the combination significantly improved efficacy vs platinum-based chemotherapy alone in cohort G. We explored the relationship between TMB and outcomes in KEYNOTE-021 cohorts C and G.

      Method

      All patients in cohort C received pembrolizumab plus carboplatin and pemetrexed. Patients in cohort G were randomized 1:1 to pembrolizumab plus carboplatin and pemetrexed or carboplatin and pemetrexed alone. TMB was determined by whole-exome sequencing of tumor and matched normal DNA. Association of TMB (continuous, log10 transformed) with outcomes for pembrolizumab plus chemotherapy and chemotherapy alone were assessed using logistic regression for ORR and Cox proportional hazards models for PFS and OS adjusted for ECOG PS; statistical significance was determined at the 0.05 level without multiplicity adjustment. The correlation of TMB (continuous, log10­ transformed) with PD-L1 TPS (square root scale) was assessed in the combined population. The clinical utility of TMB for ORR using a prespecified TMB cutpoint of 175 Mut/exome (~13 Mut/Mb by FoundationOne CDx) was assessed for pembrolizumab + chemotherapy.

      Result

      TMB data were evaluable for 70 patients: 12/24 (50.0%) in cohort C, 32/60 (53.3%) in the cohort G pembrolizumab plus chemotherapy arm, and 26/63 (41.3%) in the cohort G chemotherapy only arm; median age was 65 years (IQR, 57-70) and 61% were female. Baseline characteristics were generally similar in the TMB-evaluable and total populations. TMB as a continuous variable was not significantly associated with ORR, PFS, or OS for pembrolizumab plus chemotherapy (one-sided P = 0.180, 0.187 and 0.081, respectively) or chemotherapy alone (one-sided P = 0.861, 0.795 and 0.763, respectively). There was no significant correlation between TMB and TPS (r=0.12, P=0.34). ORR (95% CI) in patients treated with pembrolizumab plus chemotherapy was 60.8% (38.5-80.3) in the 23 patients with TMB <175 and 71.4% (47.8-88.7) in the 21 patients with TMB ≥175.

      Conclusion

      In this exploratory analysis, TMB was not significantly associated with efficacy of pembrolizumab plus carboplatin and pemetrexed or carboplatin and pemetrexed alone as first-line therapy for metastatic nonsquamous NSCLC. TMB was not significantly correlated with PD-L1 expression. Among pembrolizumab plus chemotherapy-treated patients, ORR was high in both the TMB low and high subgroups. Sample size is a limitation of this study; exploration in larger datasets is required to understand any differential efficacy of pembrolizumab plus chemotherapy vs chemotherapy alone based on TMB status.

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      OA04.07 - Mutations Associated with Sensitivity or Resistance to Immunotherapy in mNSCLC: Analysis from the MYSTIC Trial (Now Available) (ID 901)

      15:15 - 16:45  |  Author(s): Vassiliki A Papadimitrakopoulou

      • Abstract
      • Presentation
      • Slides

      Background

      In the Phase 3 MYSTIC study (NCT02453282), blood tumour mutational burden, at various thresholds from ≥12 to ≥20 mut/Mb (bTMB≥20), has been associated with improved OS and PFS with first-line durvalumab (D; anti-PD-L1) +/- tremelimumab (T; anti-CTLA-4) versus platinum-based chemotherapy (CT). Specific gene mutations have been associated with resistance (STK11 and KEAP1) or sensitisation (ARID1A) to anti-PD-(L)1 monotherapy. However, the relationship between gene alterations and response to anti-PD-(L)1 ± anti-CTLA-4 are not well characterised. Here we explore associations between mutations and survival outcomes in the MYSTIC patient population.

      Method

      Circulating tumour DNA from baseline blood specimens was profiled using the GuardantOMNI platform. Samples were available from 1003 patients (89.7% of ITT; 943 mutation-evaluable). Survival outcomes were analysed in patients with (m) or without (wt) non-synonymous somatic mutations in STK11, KEAP1, or ARID1A.

      Result

      In the mutation-evaluable population, STK11m, KEAP1m, and ARID1Am frequencies were 16%, 18% and 12%, respectively (19%, 20%, and 11% [nonsquamous]; 7%, 13%, and 15% [squamous]). Across treatment arms, patients with STK11m or KEAP1m had a shorter median OS (mOS) than patients with STK11wt (D, 10.3 vs 13.3 mo; D+T, 4.4 vs 11.3 mo; CT, 6.7 vs 13.1 mo) or KEAP1wt (D, 7.6 vs 14.6 mo; D+T, 9.2 vs 11.3 mo; CT, 6.3 vs 13.3 mo) mNSCLC. In the D+T arm, patients with ARID1Am had a longer mOS than patients with ARID1Awt mNSCLC (D, 8.6 vs 13.7 mo; D+T, 23.2 vs 9.8 mo; CT, 10.6 vs 12.4 mo). Additional mutational analyses will be presented.

      Conclusion

      In these analyses from the MYSTIC study, poorer outcomes were observed across treatment arms in patients with mNSCLC and mutations in STK11 or KEAP1 compared with those without the corresponding mutations. In patients receiving D+T, ARID1Am was associated with survival benefits compared with ARID1wt. These data are exploratory and require further validation.

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    OA07 - Precision Medicine Involves Biology and Patients (ID 132)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      OA07.06 - Patient Knowledge and Expectations Related to Return of Genomic Results in the Lung-MAP (SWOG 1400) Biomarker-Driven Clinical Trial (Now Available) (ID 730)

      11:00 - 12:30  |  Author(s): Vassiliki A Papadimitrakopoulou

      • Abstract
      • Presentation
      • Slides

      Background

      Biomarker-driven clinical trials (BDCTs)--where participants qualify for targeted therapy sub-studies based on tumor genomic testing results--represent a new paradigm in oncology clinical trials. However, BDCTs’ complex designs are difficult to communicate to patients considering participation, and deficits in knowledge and expectations have implications for shared decision-making and informed consent. The objective of this pilot study was to evaluate patient knowledge and expectations related to return of genomic results in the Lung-MAP (SWOG 1400) BDCT.

      Method

      From 8/2017 to 4/2019, we recruited a subset of participants with advanced non-small cell lung cancer (NSCLC) from among patients enrolled in the Lung-MAP genomic screening study (SWOG 1400). Participants completed a 38-item telephone survey conducted by trained staff within 30 days of consent. Survey questions assessed patient knowledge about the benefits and risks of study participation and expectations about return of genomic results in the study. The survey was structured as 5-level scale responses (‘strongly disagree’ [1] to ‘strongly agree’ [5]) and true/false/don’t know. Survey questions were adapted from prior studies that evaluated knowledge and expectations about return of genomic results. Descriptive statistics (means, medians, proportions) were assessed in this preliminary analysis.

      Result

      Among 123 participants, median age was 67, 61.0% were male, 95.1% were white, 22.0% had a 4-year college education or more, and 28.5% had a household income of <$25,000/year. In the overall sample, 82.9% ‘strongly/somewhat agreed’ with the statement ‘I received enough information about the testing in Lung-MAP to understand the benefits of enrolling’ and 73.2% ‘strongly/somewhat agreed’ with the statement ‘I received enough information…to understand the risks of enrolling’. Among the sub-group that ‘strongly/somewhat agreed’ with understanding trial benefits: 89.2% correctly believed that it was ‘true’ that test results would help to select their cancer treatment (8.8% responded ‘don’t know’), 8.8% correctly believed it was ‘false’ that the somatic testing in the study would provide information to find out if family members had increased risk of cancer (40.2% responded ‘don’t know’), and 11.8% correctly believed it was ‘false’ that results would tell them about their risk of developing diseases besides cancer (38.2% responded ‘don’t know’).

      Conclusion

      Among participants in a large BDCT, a majority of participants had serious deficits about the reporting of genomic results despite reporting to have enough information to understand benefits and risks. Our findings suggest that further research is needed to identify effective approaches to communicating information about BDCTs to improve patient knowledge about return of genomic results.

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    OA13 - Ideal Approach to Lung Resection and Novel Perioperative Therapy (ID 146)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
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      OA13.06 - Surgical Outcomes Following Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in Non-Small Cell Lung Cancer - NEOSTAR Study (Now Available) (ID 2041)

      11:30 - 13:00  |  Author(s): Vassiliki A Papadimitrakopoulou

      • Abstract
      • Presentation
      • Slides

      Background

      Surgical outcomes following neoadjuvant immune checkpoint inhibitors (ICIs) are limited. We report 90-day perioperative results of the NEOSTAR phase II trial of neoadjuvant nivolumab or nivolumab/ipilimumab in resectable non-small cell lung cancers (NSCLCs).

      Method

      44 pts with stage I-IIIA NSCLC (AJCC 7th) were randomized to nivolumab (3 mg/kg IV, days 1, 15, 29, n=23) or nivolumab/ipilimumab (1 mg/kg IV, day 1, n=21) with resection planned between 3-6 weeks after last dose. Surgical approach and extent of resection were at surgeons’ discretion.

      Result

      39 (89%) patients underwent R0 resection, of those 2 (5%) were resected off trial after additional induction chemotherapy (1 nivolumab, 1 nivolumab/ipilimumab). Among 37 patients, 21 underwent surgery following nivolumab and 16 following nivolumab/ipilimumab. Median age 66 (43-83) years, 24 (65%) male, 33 (89%) white, 22 (59%) adenocarcinoma, 22 (59%) stage I, 9 (24%) stage II, 6 (16%) stage IIIA.

      5 (11%) were not resected, 1 (1/23, 4%) after nivolumab (stage II), 4 (4/21, 19%) after nivolumab/ipilimumab (1 stage I, 1 stage II, 2 stage IIIA). Reasons for unresectability were change in surgeon’s judgement (n=2), toxicity (n=1), progression (n=1), and declining pneumonectomy (n=1). Median time to surgery was 31 days (range 21-87). 8 (22%) operations were delayed beyond 42 days, 5 after nivolumab/ipilimumab (5/16, 31%) and 3 after nivolumab (3/21, 14%).

      33 (89%) underwent lobectomy, 2 (5%) pneumonectomy, 1 (3%) segmentectomy and 1 (3%) wedge resection. 27 (73%) had thoracotomy, 7 (19%) thoracoscopy, 3 (8%) robotic approach. 2 (5%) were electively converted from thoracoscopy to thoracotomy. Median operative time was 147 minutes (71-315), median blood loss was 100cc (50-1000), and median length of stay was 4 days (1-18).

      Perioperatively, pulmonary complications occurred in 8 (22%) patients: 8 (22%) prolonged air leak, 2 (5%) pneumonitis/pneumonias, 1 (3%) empyema, and 1 (3%) bronchopleural fistula (BPF). 1 (3%) died from complications of BPF and steroid therapy for pneumonitis. 4 (11%) developed atrial fibrillation, 1 (3%) diarrhea, 1 (3%) ileus, and 1 (3%) transient ischemic attack.

      Surgeons subjectively judged 15/37 (40%) of operations to be more complex than usual with 7/37 (19%) lasting > 4 hours.

      Conclusion

      Following three cycles of neoadjuvant ICIs 89% of patients underwent complete R0 resection, including two patients who received additional induction chemotherapy off trial. Five marginally operable patients who didn’t proceed to resection, and one perioperative mortality highlight the importance of cautious patient selection for neoadjuvant ICIs in the management of operable NSCLC.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-73 - An Explorative Analysis of Pemetrexed +/- Pembrolizumab Maintenance from KEYNOTE-189 Versus PARAMOUNT, PRONOUNCE, and JVBL (ID 756)

      09:45 - 18:00  |  Author(s): Vassiliki A Papadimitrakopoulou

      • Abstract
      • Slides

      Background

      Recently, the phase 3 KEYNOTE-189 study demonstrated improved progression-free survival (PFS) and overall survival (OS) when pemetrexed/platinum doublet was combined with pembrolizumab as first-line treatment in patients with non-squamous NSCLC. The specific benefits of maintaining pemetrexed in combination with pembrolizumab after the triplet with platinum has not been previously assessed.

      Method

      Using patient level data, we selected patients who had ≥5 cycles of pemetrexed (including the induction phase with platinum) from 3 randomized non-pembrolizumab clinical trials (PARAMOUNT, PRONOUNCE, and JVBL; N=486). As such, patients in the KEYNOTE-189 trial who had ≥5 cycles of pemetrexed in both arms (placebo arm; N=135, versus pembrolizumab arm; N=310) were analyzed. PFS and OS were evaluated by Kaplan-Meier estimator and Cox proportional hazard model; treatment emergent adverse events (TEAEs) were compared by descriptive statistics.

      Result

      Baseline characteristics of the selected population with ≥5 cycles of pemetrexed were comparable between the pooled trials and KEYNOTE-189. Median PFS for patients with ≥5 cycles of pemetrexed was 5.6 months (95% CI: 4.6-5.8) from the pooled non-pembrolizumab trials and 6.6 months (95% CI: 5.4-7.1) in the placebo plus pemetrexed/platinum arm in KEYNOTE-189 (un-stratified HR: 1.29; 95% CI: 1.02-1.62). Median PFS in the selected population with ≥5 cycles of pemetrexed in KEYNOTE-189 was 9.3 months (95% CI: 9.0-11.1) in the pembrolizumab plus pemetrexed/platinum arm, and when compared with the placebo plus pemetrexed/platinum arm in KEYNOTE-189, resulted in an un-stratified HR of 0.53 (95% CI: 0.42-0.68). Incidence rates of TEAEs were similar in those 3 selected populations (Table 1).

      table 1_wclc 2019 alimta abstract.jpg

      Conclusion

      In a selected population with pemetrexed maintenance in KEYNOTE-189, the placebo arm showed numerically comparable efficacy with historical data on pemetrexed maintenance. Pemetrexed/platinum in combination with pembrolizumab proved consistent clinical benefit in the same population with ≥5 cycles of pemetrexed, compared to the placebo arm in KEYNOTE-189 and historical controls.

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      P1.01-98 - Outcomes in Advanced NSCLC Patients Treated with 1st Line EGFR-TKI Based on Mutation Detection from Tissue or cfDNA-Based Genomic Sequencing (ID 1861)

      09:45 - 18:00  |  Author(s): Vassiliki A Papadimitrakopoulou

      • Abstract

      Background

      Tumor genomic information from tissue has been the standard of practice for identifying actionable molecular alterations. The same genomic profiling is also widely available by a non-invasive blood test (cfDNA). We hypothesized that treatment naïve patients with advanced non-small cell lung cancer (NSCLC) and actionable oncogenic driver mutations identified by tumor and cfDNA would have similar clinical outcomes after treatment with targeted therapies.

      Method

      Patients with any EGFR-TKI sensitive mutation and received FDA-approved EGFR-TKI as first line therapy for their advanced NSCLC were included in this retrospective analysis. Consecutive patients were identified from our GEMINI database with therapy initiated that was based solely from either the tissue or cfDNA report were divided into each cohort, respectively. Assessment of PFS was from date of therapy initiation until disease progression. Tissue genomic profiling was performed on our institution’s CLIA-certified hotspot NGS assay covering 40-50 genes. For blood based genomic profiling, blood was sent for NGS of cfDNA with a panel of up to 70 cancer-related genes at a CLIA-certified lab (Guardant360, Guardant Health, Redwood City, CA). Kaplan–Meier methodology was used to calculate median PFS with Log-rank (Mantel-Cox) test assessment at significance level 5%.

      Result

      Forty patients for each group were identified between 2014-2016. The results as summarized in table and PFS graph below:

      table.jpgpfs graph.jpg

      Conclusion

      There was no progression-free survival difference in patients treated with FDA-approved front-line EGFR-TKI directed by genomic profiling from tissue vs blood -based testing. These results indicate that similar treatment outcomes with targeted therapy based on tissue or blood-based NGS profiling are both viable options for patient with newly diagnosed, advanced NSCLC.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-24 - CANOPY-2: Phase 3 Study of Canakinumab Plus Docetaxel as Second/Third Line Therapy in Locally Advanced/Metastatic NSCLC (ID 2539)

      10:15 - 18:15  |  Author(s): Vassiliki A Papadimitrakopoulou

      • Abstract

      Background

      Pembrolizumab, a PD-1 inhibitor combined with platinum-based chemotherapy is standard first-line therapy for eligible patients without a targetable mutation, stage IIIB/IV NSCLC. Currently, there is no data to guide treatment following progression on sequential/concomitant use of platinum-based chemotherapy and PD-1 inhibitors. Activation of inflammation and elevated baseline C-reactive protein (CRP) levels are associated with lower response/resistance to immunotherapies. Canakinumab is a high-affinity anti-IL-1β monoclonal antibody that demonstrated a significant reduction in incidence of fatal and nonfatal lung cancer in patients with increased CRP levels (CANTOS study).

      Method

      CANOPY-2 (NCT03626545) is a multicenter, phase 3 study evaluating safety and efficacy of docetaxel ± canakinumab in patients with squamous/non-squamous, stage IIIB-IV NSCLC. This study includes a safety run-in part (part 1 – open label) to confirm recommended phase 3 regimen (RP3R) to be used in randomized phase 3 part (part 2 – double blind, placebo-controlled). Key inclusion criteria: adult patients pretreated with one prior platinum-based chemotherapy and one prior PD-(L)1 inhibitor therapy for locally advanced/metastatic disease, either together/sequentially and then progressed; ECOG PS 0-1. In part 1, ~9 patients will be enrolled to have at least 6 evaluable patients and ~226 patients will be randomized (1:1, stratified by number of prior lines of therapy and histology) in part 2 to docetaxel ± canakinumab. Primary objectives: to confirm RP3R of canakinumab + docetaxel, as determined by incidence of DLTs in first 42 days of administration (part 1) and overall survival (part 2). Secondary objectives are to assess efficacy (overall response rate, disease control rate, duration of response, time to response, progression-free survival by investigator per RECIST v1.1), safety, pharmacokinetics, immunogenicity of canakinumab, and patient reported outcomes. Enrollment is ongoing.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-24 - An Open-Label Randomized Phase II Study of Combining Osimertinib With and Without Ramucirumab in TKI-Naïve EGFR-Mutant Metastatic NSCLC (ID 851)

      10:15 - 18:15  |  Author(s): Vassiliki A Papadimitrakopoulou

      • Abstract

      Background

      Osimertinib, a third-generation EGFR inhibitor, has become the first-line therapy for patients with metastatic EGFR-mutant NSCLCs since 2018. Osimertinib is well-tolerated, therefore, it opens opportunities to be combined with other therapeutic agents to enhance the treatment outcome. In preclinical models, it has been shown that upregulated VEGF signaling mediates acquired resistance to EGFR therapies. In xenograft models, combination of anti-VEGF medications with EGFR inhibitors were significantly more effective than erlotinib or gefitinib alone. Ramucirumab, a monoclonal antibody targeting VEGF receptor 2, is approved with docetaxel in as second line treatment for NSCLCs. In clinical trial evaluations, the phase 3 RELAY trial (NCT02411448) studying ramucirumab plus erlotinib in patients with metastatic untreated EGFR-mutant NSCLC patients showed a statistically significant improvement in progression-free survival in the combination group compared to erlotinib alone. A phase I study of osimertinib with ramucirumab (NCT02789345) demonstrated safety and feasibility of this combination. With strong preclinical and clinical evidence showing dual inhibition of VEGF/EGFR signaling prolongs progression-free survival for EGFR-mutant lung cancers, and demonstrated safety, we are conducting a phase 2 trial to evaluate the osimertinib ramucirumab combination’s efficacy in treatment-naïve EGFR-mutant NSCLC.

      Method

      The OSI+RAM trial is a randomized phase 2 study with the primary endpoint being progression-free survival in osi+ram group as compared to osimertinib monotherapy group. The major inclusion criteria include patients with metastatic NSCLC harboring EGFR mutations (L858R/Exon 19 del). The major exclusion criteria include prior anti-EGFR or anti-VEGF treatments. Patients with stable CNS metastasis are allowed. Based on the results from erlotinib bevacizumab (NEJ026) study, we expect an improvement of PFS from 18.9 months to 29.7 months, corresponding to a hazard ratio of 0.65. The trial plans to enroll total of 150 patients, with 100 allocating to osi+ram arm and 50 to osimertinib monotherapy. Total of 9 study sites in the USA are planned. Hoosier Cancer Research Network will facilitate the execution of the trial. The trial protocol has received IND exemption from US FDA and has been approved by IRB at MD Anderson Cancer Center. The first subject is expected to be enrolled in May 2019. A planned interim analysis will be performed after the first 75 subjects are enrolled. NCT03909334.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    PC03 - Adjuvant Therapy for Resected NSCLC Harboring EGFR Mutation, Chemotherapy or Targeted Therapy (ID 85)

    • Event: WCLC 2019
    • Type: Pro-Con Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      PC03.03 - Future Strategies in Early Stage EGFR-mut NSCLC (Now Available) (ID 3569)

      15:45 - 17:15  |  Presenting Author(s): Vassiliki A Papadimitrakopoulou

      • Abstract
      • Presentation
      • Slides

      Abstract

      EGFR tyrosine kinase mutations occur in approximately 10% of advanced non-small cell lung cancer (NSCLC) Western patients and in 30% of Asian patients. EGFR tyrosine kinase inhibitors (i.e., gefitinib, erlotinib, afatinib, icotinib, dacomitinib and, recently, osimertinib) are superior to chemotherapy in patients with advanced EGFR+ lung cancers and have become the standard first-line treatment for NSCLC patients harbouring those specific mutations (1-5). Despite this, definitive trials of EGFR-TKIs as adjuvant treatment of EGFR-mutant early stage NSCLC are few and controversial. Improving outcomes with targeted adjuvant therapy and specifically overall survival remains a challenge in the management of radically resected NSCLC. As shown by the addition of the antiangiogenic agent, bevacizumab to adjuvant chemotherapy in the E1505 trial (6).

      The first prospective data to suggest that adjuvant targeted therapy may indeed alter the disease course for early-stage NSCLC were from the SELECT and RADIANT trials (7, 8), in addition retrospective analyses also showed promising results in improving DFS in stage I-III EGFR mut+ NSCLC and a potential OS benefit. The results of the ADJUVANT/CTONG1104 study (9), a randomized open-label phase III trial in completely resected (R0) stage II–IIIA (N1-N2) EGFR-mutant NSCLC (defined as exon 19 deletion or exon 21 Leu858Arg) comparing 4 cycles of standard adjuvant Cisplatin and Vinorelbine or 24 months of the EGFR-tyrosine kinase inhibitor (TKI), gefitinib revealed significantly longer median DFS in the gefitinib arm than in chemotherapy arm, while OS was not mature.

      Several questions remain including: A) the patient subset with early stage disease that may derive the most benefit B) the optimal duration of adjuvant TKI therapy C) the degree of toxicity and associated adherence to therapy over long periods of time and finally D) the cost of therapy. Phase 3 prospective trials remain necessary and several are under way, including the ALCHEMIST study, using erlotinib and the ADAURA study using Osimertinib. Finally use of neoadjuvant targeted therapy (10) and chemotherapy may offer distinct advantages in eliminating micrometastatic disease prior to surgery and clinical trials using this approach are planned or ongoing and will be discussed.

      References

      1.Shi YK, Wang L, Han BH, et al. First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Ann Oncol 2017;28:2443-50.

      2.Yang JC, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol 2015;16:830-8.

      3.Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010;11:121-8.

      4.Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:113-25.

      5.Wu YL, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol 2017;18:1454-66.

      6.Wakelee HA, Dahlberg SE, Keller SM, et al. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol 2017;18:1610-23.

      7.Kelly K, Altorki NK, Eberhardt WE, et al. Adjuvant Erlotinib Versus Placebo in Patients With Stage IB-IIIA Non-Small-Cell Lung Cancer (RADIANT): A Randomized, Double-Blind, Phase III Trial. J Clin Oncol 2015;33:4007-14.

      8.Neal JW, Pennell NA, Govindan R, et al. The SELECT study: a multicenter phase II trial of adjuvant erlotinib in resected epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). J Clin Oncol 2012;30:abstr 7010.

      9. Zhong WZ, Wang Q, Mao WM, et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II–IIIA (N1–N2) EGFR-mutant NSCLC (ADJUVANT/ CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol 2018;19:139-48.

      10.Zhong WZ et al., Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment for stage IIIA-N2 EGFR.-mutation positive non-small-cell lung cancer (EMERGING-CTONG 1103): multicentre phase 2 randomized study. ESMO 2018, abstract LBA48_PR

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