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Brian Alexander



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    EP1.01 - Advanced NSCLC (ID 150)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.01-108 - EGFR Exon 18 Mutations in NSCLC: Frequent Co-Occurrence of Multiple EGFR Mutations and Assessment of Cis/Trans Status (ID 2747)

      08:00 - 18:00  |  Author(s): Brian Alexander

      • Abstract

      Background

      A subset of EGFR exon 18 (ex18) mutations including G719X are known drivers in NSCLC. However, the sensitivity profile of other ex18 mutations and frequently occurring dual ex18/ex18 and ex18/non-ex18 combinations has not been well described.

      Method

      Hybrid-capture based comprehensive genomic profiling was performed on 46,296 FFPE tissue samples from patients with NSCLC. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA and reported as mut/Mb. Configuration was determined by analyzing sequencing reads that spanned both loci. The number of reads that harbored mutations at one or both positions was tabulated and used to infer cis or trans status. Patient ancestry was determined by single nucleotide polymorphism (SNP) microarray data, ancestry informative markers, and principal component analysis (PCA)..

      Result

      EGFR ex18 mutations (point mutations and indels) were identified in 1.1% (522/46,296) of NSCLCs. The median patient age was 67 years (range 30-96) and 67% of patients were female. This subset was also enriched for patients of East Asian descent when compared to EGFR wildtype NSCLC (17% v 3.9%; p < 0.001), similar to ex19del and L858R populations (19% and 24%, respectively). Median TMB was 4.35 mut/mb (range 0-70). Co-occurring EGFR mutations were identified in 69% (362/522) of cases, including most commonly S768I (20%, 103/522) and L858R (12%,61/522). T790M was detected in 6.1% (32/522) of ex18 cases. Multiple EGFR ex18 mutations occurred in 15% (76/522) of cases including 2 cases with 3 and a single case with 4 such mutations. The most commonly observed missense pairs were E709A/G719S (17/76) and E709A/G719A (16/76). Other combinations of E709X/G719X made up an additional 42% (32/76), with the remaining 14% of cases consisting of rare combinations (n<4 for all). All ex18 mutations in all cases (76/76) were in cis. Preliminary evidence from paired cases and assessment of mutant allele frequencies suggests that ex18 mutations found together in cis arise de novo. Results of in vitro studies to determine the sensitivity of single ex18 mutations as well as common pairs to all generations of EGFR inhibitors will be presented.

      Conclusion
      EGFR ex18 mutations co-occur at a high frequency with both ex18 and non-ex18 EGFR mutations, unlike classic EGFR mutations (L858R, ex19del). Female gender, East Asian ancestry, and low TMB were common in ex18 cases, similar to populations with classic EGFR mutations. In all cases with multiple EGFR ex18 mutations these mutations were always found to occur in cis. Further work to understand the evolution of these co-occurring EGFR mutations and to determine the best therapeutic strategy or strategies for this NSCLC patient population is warranted

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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): Brian Alexander

      • 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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    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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      P1.01-23 - Retrospective Analysis of Real-World Clinico-Genomic Data for Clinical Impact of Genomic Profiling of ctDNA in NSCLC (ID 1883)

      09:45 - 18:00  |  Author(s): Brian Alexander

      • Abstract
      • Slides

      Background

      Liquid biopsy (LBx) and comprehensive genomic profiling (CGP) of circulating tumor DNA (ctDNA) is a minimally-invasive approach that is increasingly used for detection of targetable genomic alterations (GA) in patients with NSCLC. To determine the clinical utility of LBx-based CGP in routine clinical practice, we evaluated responses to targeted therapy post-LBx in the real-world setting.

      Method

      The Flatiron Health-Foundation Medicine Clinico-Genomic Database included 475 NSCLC patients with LBx CGP results (FoundationACT): clinical characteristics and real-world tumor response (rwTR) were obtained via technology-enabled abstraction of clinician notes and radiology/pathology reports and linked to CGP data. Targetable GAs were defined as genomic alterations with a matched FDA-approved targeted therapy or in NCCN guidelines (Table). Patients with a targetable GA were evaluated for rwTR to matched targeted therapy. Real-world overall response rates (rwORR: fraction of patients with partial or complete response) to matched targeted therapy after LBx versus tissue-based CGP (TBx, [FoundationOne/FoundationOneCDx, N=3,956]) were compared.

      Result

      At the time of LBx, 61% of patients had ≥1 line of prior therapy (vs 49% for TBx). Median ctDNA fraction was 1%. There was evidence of ctDNA in 86% (408/475) of LBx cases; among these 24% (96/408) had a targetable GA (vs 21% for TBx). Post-detection of a targetable GA, 35% (34/96) of LBx patients received matched targeted therapy (vs 38% for TBx). 21 patients with targetable GAs were evaluated for LBx-based rwTR to matched targeted therapy (Figure): rwORR was 76.2% (vs 62.8% for TBx; p=0.25), including 76.5% (13/17) for FDA-approved matched targeted therapy and 75.0% (3/4) for NCCN targeted therapies (Table).

      table_final.jpgattritiondiagram_final.jpg

      Conclusion

      Retrospective analysis of real-world clinico-genomic data from a large series of NSCLC cases demonstrated that the frequency of detected targetable GAs and rwTR to matched targeted therapy was similar for LBx and TBx CGP.

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      P1.01-86 - Occurrence of de Novo Dual HER2/HER3 or HER2/EGFR TMD Mutations: Extending the Spectrum of Targetable Mono-HER2 TMD in NSCLC? (ID 956)

      09:45 - 18:00  |  Author(s): Brian Alexander

      • Abstract

      Background

      HER2 (ERBB2) TMD mutations have recently been described as novel solo actionable drivers in NSCLC responsive to afatinib in small series. However, dual occurrence of de novo EGFR or HER3 (ERBB3) TMD mutations together with HER2 TMD mutations, which may have implications for dimerization patterns and treatment, has not been described.

      Method

      Hybrid-capture based comprehensive genomic profiling was performed on blood-based circulating tumor DNA (n=5,200) or FFPE tissue (n= 45,780) samples collected during clinical care from 50,980 unique NSCLC patients.

      Result

      HER2 TMD mutations were identified in 0.12% (60/50,980) of cases and included V659E (n=33), V659D (n=8), G660D (n=15), V659E+G660R, V659_I661>VVEGI, G660E>R, and S653C (1 each). Within this subset, the median age of patients was 61 years (range 33-91) and 62% were female. No co-occurring known NSCLC driver alterations were detected, except one case with EGFR exon 19 deletion and one case with EGFR L858R and lung co-primary tumors noted. However, co-occurring HER3 (I649R) or EGFR (G652R) TMD mutations were found in 18% (11/60) and 5.0% (3/60) of cases, respectively. Notably, these ERBB3 or EGFR TMD mutations only co-occurred with HER2 TMD V>D (8/9 cases) or G>D (7/15 cases), but not with V>E changes (0/34 cases; p=0.0002). HER2 amplification co-occurred with V659E in 15% (5/34) of cases, and G660D mutation was seen with the oncogenic extracellular domain S310F mutation in one case. Importantly, neither EGFR G652R nor ERBB3 I649R was found in the absence of a HER2 TMD mutation. Preliminary modelling studies suggest formation of a salt-bridge which would increase propensity for HER2/HER3 and HER2/EGFR heterodimerization favoring receptor activation. Two patients in this series with V659E were previously reported to have responded to afatinib and 1 patient with G660D+I649R did not respond to afatinib. Updated clinical data for these patients and others treated with HER2-tageted therapies will be presented.

      Conclusion

      HER2 TMD mutations (V659D/E or G660D/R) are uncommon but targetable driver alterations in NSCLC. In cases with HER2 TMD V>D or G>D, a de novo co-existing EGFR or HER3 TMD mutation was frequently observed (88% and 47%, respectively), which may explain differential dimerization preference and in turn response to ERBB inhibitors. We hypothesize that dual HER2/HER3 or HER2/EGFR TMD mutants may be more aggressive than single HER2 TMD mutants due to the arginine-aspartic acid interaction, and these dual mutants may require combined kinase inhibitor + antibody therapy to block dimerization. Studies utilizing models to further characterization these co-alterations are in progress.