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John Victor Heymach



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    GR01 - Whether and How to Adapt Treatment of NSCLC Oligometastatic Disease to… (ID 29)

    • Event: WCLC 2019
    • Type: Grand Rounds Session
    • Track: Oligometastatic NSCLC
    • Presentations: 1
    • Now Available
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      GR01.04 - The Rationale for Local Consolidative Therapy in Oncogene-driven, Oligo-and Poly-metastatic NSCLC (Now Available) (ID 3301)

      13:30 - 15:00  |  Presenting Author(s): John Victor Heymach

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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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): John Victor Heymach

      • 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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    MA06 - Challenges in the Treatment of Early Stage NSCLC (ID 124)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
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      MA06.10 - Stereotactic Ablative Radiotherapy in the Management of Synchronous Early Stage Non-Small Cell Lung Cancers (Now Available) (ID 1924)

      13:30 - 15:00  |  Author(s): John Victor Heymach

      • Abstract
      • Presentation
      • Slides

      Background

      The aim of the study is to evaluate the efficacy and patterns of failure of early stage synchronous non-small cell lung cancer (NSCLC) treated with stereotactic ablative radiotherapy (SABR).

      Method

      Patients with synchronous NSCLC who received SABR (50 grays in 4 fractions or 70 grays in 10 fractions) to at least one lesion were reviewed. Synchronous lesions were defined as multiple ipsilateral or contralateral intrapulmonary lesions diagnosed within 6 months.

      Result

      Out of a total of 912 patients treated with SABR for early stage NSCLC between 2005 and 2015, 82 (9%) had synchronous disease. The median age was 70 years and 34 (41.5 %) patients were males. The median diameter was 2.1 cm (Interquartile range (IQR) 1.6-3 cm) for index lesions and 1.5 cm (IQR 1.1-2.2 cm) for second lesions. At a median follow-up time of 58 months, the 1, 3 and 5-year progression-free survival (PFS) rates were 85.4%, 47.3% and 28.5%, respectively; the corresponding overall survival rates were 95.1%, 66.9% and 52.4% and the 1, 3 and 5-year local recurrence (LR)-free survival rates were 97.3%, 79.6% and 70.8%, respectively. Among the 39 (47.6%) patients with disease progression, intralobal LR was the first site of failure in 15 (18.3%) patients, with a total of 19 local recurrences out of 169 (11.2%) thoracic lesions. Isolated regional recurrence occurred in 3 (3.7%) patients, and distant failure in 221 (25.6%) patients. On multivariate analysis, factors associated with improved PFS were an improved ECOG PS score (HR 10.786; 95% CI 2.845-40.902; p-value <0.001), DLCO (HR 0.947; 95% CI 0.903-0.994; p-value 0.026) and an index lesion pathology of adenocarcinoma (HR 0.167; 95% CI 0.033-0.841; p-value 0.030). Only the ECOG PS score maintained significance (HR 6.165; 95% CI 2.081-18.263; p-value 0.001) on multivariate analysis for OS. No association was found between the use of chemotherapy as part of the initial management strategy and survival outcomes. Similarly, no difference in outcomes was observed whether all lesions were treated with SABR compared to SABR and other modalities.

      Conclusion

      SABR achieves promising long-term survival and tumor control rates and may be a potential curative treatment for synchronous early stage NSCLC. Our data indicates that patients presenting with synchronous NSCLC lesions can be approached as having two separate primary lung tumors, and be offered definitive local therapy with aims of cure.

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    MA08 - Pawing the Way to Improve Outcomes in Stage III NSCLC (ID 127)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
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      MA08.01 - Analysis of PD-L1 Expression on Circulating Stromal and Tumor Cells in Lung Cancer Patients Treated with Chemoradiation Therapy and Atezolizumab (Now Available) (ID 2965)

      15:15 - 16:45  |  Author(s): John Victor Heymach

      • Abstract
      • Presentation
      • Slides

      Background

      We have previously shown dynamic changes to PD-L1 expression during chemoradiotherapy (CRT) could be tracked by evaluating PD-L1 expression on circulating cells. How these changes relate to immunotherapy response is unknown. We prospectively monitored PD-L1 expression in 2 cell types found in circulation (Circulating tumor cells [CTCs] and Cancer Associated Macrophage-like Cells [CAMLs]) in locally advanced non-small cell lung cancer (LA-NSCLC) patients (pts) treated with atezolizumab and CRT.

      Method

      Samples were taken from a completed phase II DETERRED trial (NCT02525757) where atezolizumab was added for one year after completing CRT (N=10) or concurrently and after CRT (N=30). Samples from 39 pts from the study were available for analysis. Baseline blood sample (7.5 ml) were drawn prior to start of CRT (T0), and a second sample was drawn ~1 month after completing CRT (T1), and a 3rd sample was drawn ~2 months after completing CRT (T2). Blood was processed by CellSieve™ microfilters; stained for cytokeratin/PDL1/CD45 to identify CTCs and CAMLs. PD-L1 intensity was measured and grouped by 4 scores: 0-negative, 1-low, 2-medium, & 3-high. Tumor IHC for PD-L1 levels from core biopsies was done with Dako 22c3 and was compared to T0 samples. PD-L1 levels from tumor and in circulating cells were used to evaluate PFS and OS. Significance was assessed by log-rank testing.

      Result

      PD-L1 IHC was available for 85% of pts, and there was at least one cytokeratin positive cell (CTC or CAML) found in 100% of T0 samples. CTCs were found in 33% of T0, 24% of T1 & 43% T2. CAMLs were found in 92% of T0, 97% of T1, & 97% of T2 samples. No correlation was seen comparing tumor PD-L1 expression percentage and the T0 PD-L1 staining intensity on CTCs/CAMLs. Tumor PD-L1>1% was found in 58% and >50% in 24% of IHC samples, yet there was no correlation between tumor PD-L1 expression and PFS or OS. At T0, PD-L1 expression in CTCs/CAMLs was low (0-1) in 18 pts and high (2-3) in 15, but no relationship to PFS (HR=0.6, 95%CI 0.2-1.7, p=0.48) or OS (HR=1.7, 95%CI 0.5-6.4, p=0.66) was found. However, pts with high PD-L1 at T1 or T2, regardless of levels at T0, had a trend towards improved PFS (HR 2.5, 95%CI 0.7-8.6, p=0.13), and a significantly better OS (HR 14.2, 95%CI 2.4-81.8, p=0.003). Interestingly, of the 15 pts who had low PD-L1 at T0, 7 had induced PD-L1 expression at T1 or T2. All samples with induced PD-L1 expression had better PFS (HR 8.3, 95%CI 1.4-50.2, p=0.02) and OS (HR 8.7, 95%CI 1.2-64.0, p=0.03) compared to those who remained low.

      Conclusion

      While baseline tumor or circulating cellular PD-L1 expression was not correlated with clinical outcomes, sequential monitoring of high PD-L1 expression in CTCs/CAMLs after CRT appeared to be associated with better clinical outcomes in pts who received consolidation atezolizumab after CRT, particularly in pts who had induced expression at follow up during the consolidation phase. Dynamic tracking of PD-L1 may serve as a predictive biomarker for immunotherapy effectiveness in LA-NSCLC after CRT.

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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): John Victor Heymach

      • 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: 2
    • Now Available
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      MA11.09 - Increased Frequency of Bystander T Cells in the Lungs Is Associated with Recurrence in Localized Non-Small Cell Lung Cancer (Now Available) (ID 955)

      14:00 - 15:30  |  Author(s): John Victor Heymach

      • Abstract
      • Presentation
      • Slides

      Background

      Non-small cell lung cancer (NSCLC) exhibits a high mutational burden. As a result, patients afflicted by this tumor type experience greater responses to immune checkpoint blockade. This is largely due to the ability of T cells to destroy tumor cells on the basis of antigens recognized by their T cell receptor (TCR). However, the lungs are exposed to carcinogens and pathogens which can also trigger a T cell response distinct from cancer. Therefore, a better understanding of the T cell repertoire in the lungs is needed to improve upon the success of current immunotherapies in NSCLC.

      Method

      We obtained peripheral blood, tumors, and adjacent uninvolved lungs from a cohort of 236 early stage NSCLC patients. Whole exome sequencing, RNA microarray, immunohistochemistry (CD3, CD4, CD8, CD57, CD68, FoxP3, CD45RO, GzmB, PD-1, and PD-L1) and T cell repertoire sequencing were performed in NSCLC patients and lungs from organ donors and COPD patients. Antigen specificity was predicted using the Grouping of Lymphocyte Interactions by Paratope Hotspot (GLIPH) algorithm. Single cell TCR and RNA sequencing as well as sequencing of the virome are underway.

      Result

      Clonality was associated with CD8 T cells (r=0.31; p=0.0003), GzmB (r=0.29; p=0.001) and IFN-γ (r=0.52; p<0.0001) production as well as with tumor mutational burden (r=0.19; p=0.015), HLA-B (r=0.29; p=0.0005) and β2-m expression (r=0.20; p=0.018). Patients with classical EGFR mutations exhibited lower T cell clonality (p=0.003) even after adjustment for TMB, highlighting the impact of this driver mutation on the T cell response. Surprisingly, clonality was higher in the adjacent uninvolved lung than tumor (p<0.0001), suggesting an active antigenic response outside the tumor. Comparison of the composition of the T cell repertoire between the uninvolved lung and tumor revealed 57% of the top 100 T cells in the tumor were also found in the adjacent normal lung, highlighting certain parallels in the ongoing antigenic responses. Deeper analysis suggested that shared T cells may have been reactive against mutations shared between the normal lung and tumor (r=0.23, p=0.028) or viruses (p<0.0001). Accordingly, patients with a more reactive T cell repertoire outside the tumor (i.e. bystanders) exhibited shorter disease-free survival (p=0.036) suggesting these responses against shared mutations and/or viruses may detract from the anti-tumor T cell response.

      Conclusion

      Our findings highlight the importance of understanding the specificity of the T cell repertoire in the lungs in patients with NSCLC treated with immunotherapy. As a high proportion of bystander T cells appear to reside in the lungs, their reactivation could contribute to the impaired responses and/or increased toxicity observed in certain patients with NSCLC treated with immunotherapy.

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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  |  Presenting Author(s): John Victor Heymach

      • 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): John Victor Heymach

      • 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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    MA17 - Molecular Mechanisms and Therapies (ID 143)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Biology
    • Presentations: 1
    • Now Available
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      MA17.10 - Lactate Transporter Blockade as a Strategy to Overcome VEGF Inhibitor-Resistance in LKB1-Deficient NSCLC (Now Available) (ID 2647)

      15:45 - 17:15  |  Presenting Author(s): John Victor Heymach

      • Abstract
      • Presentation
      • Slides

      Background

      STK11/LKB1 alterations are found in 20-30% of NSCLC and used to co-occur with KRAS mutations. Because LKB1 activates AMPK, many of the best known functions of LKB1 are attributed to its ability to control metabolic alterations in cells. Our laboratory have previously reported that loss of LKB1 promotes enhanced glycolysis and elevated lactate production and more recently we demonstrated that STK11/LKB1 mutations are the strongest predictors of de novo resistance to immunotherapy in NSCLC. Prior studies have revealed an association between alterations in the LKB1/AMPK pathway and worse clinical outcomes in NSCLC and in patients treated with chemotherapy and bevacizumab. Given the roles of LKB1 in the regulation of cell metabolism and resistance to immunotherapy, it is feasible that LKB1 also impacts on the response to anti-angiogenic therapies.

      Method

      Xenograft mouse models were established by subcutaneous injection of H460 cells (LKB1-deficient) and H460 LKB1-expressing in nude mice and LKR10 (KRASG12D) LKB1 wild-type (K) or LKB1- knockout (KL) into 129Svmice. Mice were randomized to vehicle or B20-4.1.1 anti-VEGF antibody. Glycolytic activity of LKB1-intact and -deficient NSCLC cells was measured by Seahorse assay. We analyzed gene expression of SLC16A3 (MCT4) by qPCR and Western blot. Genetic disruption of MCT4 in the K and KL cell lines was done using CRISPR-Cas9 and mouse models were established by subcutaneous injection into mice.

      Result

      Mice bearing LKB1-expressing H460 xenografts treated with anti-VEGF antibody showed a significant decrease in tumor volume (p<0.05) compared with their vehicle-treated counterparts. However, mice bearing LKB1-deficient H460 xenografts showed markedly reduced efficacy of anti-VEGF therapy compared with that in LKB1-expressing xenografts. Anti-VEGF therapy significantly reduced growth of LKR10 K tumors (p<0.001) but not in LKR10 KL tumors. Microvascular density was not increased in KL tumors following anti-VEGF treatment compared to K. Human isogenic LKB1-deficient cells showed a significantly increased rate of glycolysis and lactate secretion compared with cells expressing LKB1. Human and murine LKB1-deficient cells also had increased MCT4 expression compared to K cells. Immunofluorescence and RPPA analysis of tumor samples from the K and KL mouse models showed that KL tumors upregulated MCT4 protein expression compared with K tumors (p<0.0001). The genetic disruption of MCT4 KL tumors significantly improved tumor volume reduction to anti-VEGF therapies in vivo (p<0.001).

      Conclusion

      LKB1 loss is associated with increased lactate secretion and resistance to VEGF inhibition in NSCLC. The targeting of the lactate transporter MCT4 enhance the sensitivity of LKB1-deficient NSCLC to anti-VEGF therapy.

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    MA19 - Looking at PROs in Greater Detail - What Patients Actually Want and Expect (ID 147)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Now Available
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      MA19.03 - Differences in Symptom Burden Between Responsive and Progressive Disease in Advanced Non-Small Cell Lung Cancer (aNSCLC) (Now Available) (ID 845)

      11:30 - 13:00  |  Author(s): John Victor Heymach

      • Abstract
      • Presentation
      • Slides

      Background

      We have established a real-world Advanced Non-Small Cell Lung Holistic Registry (ANCHoR) to assess how immunotherapy impacts treatment choice, clinical outcomes, and patient-reported outcomes (PROs) of aNSCLC. Our aim in this analysis was to assess the ability of the MDASI-LC to differentiate between patients who are responding or who are progressing during treatment.

      Method

      Between May 2017 and December 2018, patients with aNSCLC at a single institution were enrolled in ANCHoR and completed the MDASI-LC prior to therapy (PTT) and at routine clinic visits. The MDASI-LC consists of 16 symptom severity and 6 interference items rated on 0-10 scales (0 = no symptom or interference, 10 = worst imaginable symptom or complete interference). MDASI-LC scores from PTT to first recorded response determination (FRD) were compared by response group using linear mixed modeling (LMM).

      Result

      One hundred one patients completed the MDASI-LC PTT and at FRD. Mean patient age was 63.8 years (standard deviation = 10.29) and 55% were males. Fifty percent of patients received chemotherapy (CTX), 22% immunotherapy (IM), 19% CTX+IM or angiogenesis inhibitor, and 9% targeted therapy. Median time from PTT to FRD was 105 days (lower quartile = 63, upper quartile = 224). Forty-six percent of patients had a complete or partial response (RECIST criteria CR, PR), 14% had stable disease (RECIST SD), and 41% progressed (RECIST PD). LMM showed progressing patients had significantly more fatigue (estimated effect [est] =1.39; p = 0.031), sleep disturbance (est=1.37; p = 0.046), and drowsiness (est=1.33; p = 0.037) and reported significantly more interference with work (est=1.67; p = 0.016) over time than responding patients.

      Conclusion

      The MDASI-LC differentiated the symptom burden of patients with responding disease from that of patients with progressive disease. Patients with progressive disease had more fatigue, disturbed sleep, drowsiness, and greater interference with work than those with responsive disease. Further research is needed to determine if the MDASI-LC can predict response to therapy in patients and may be useful in delineating treatment benefit.

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    OA03 - Systemic Therapies for SCLC: Novel Targets and Patients' Selection (ID 121)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
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      OA03.06 - ASCL1, NEUROD1, and POU2F3 Drive Distinct Subtypes of Small Cell Lung Cancer with Unique Therapeutic Vulnerabilities (Now Available) (ID 1433)

      13:30 - 15:00  |  Author(s): John Victor Heymach

      • Abstract
      • Presentation
      • Slides

      Background

      Background: Accounting for 15% of all lung cancer diagnoses, small cell lung cancer (SCLC) is an aggressive malignancy with dismal clinical outcomes, due in part to failure to define clinical biomarkers predictive of unique, targetable vulnerabilities. Recent data has begun to delineate molecular subsets of SCLC by uncovering inter-tumoral heterogeneity in features such as DNA damage response, EMT, and neuroendocrine (NE) status. However, it remains unclear whether the subsets defined by these features are predictive of response to cancer therapies and could be employed as patient selection criteria.

      Method

      Methods: Using RNAseq data from 81 resected SCLC tumor samples and 62 SCLC cell lines, we applied non-negative matrix factorization (NMF) to optimize delineation of transcriptionally defined clusters. Reverse phase protein array (RPPA) and drug response data for cell lines were analyzed post-clustering to compare features between clusters. Clustering analyses were validated in vivo using CTC-derived patient xenograft (CDX) models, while single-cell RNAseq (scRNAseq) from these same models was used to assess intratumoral heterogeneity among clusters.

      Result

      Results: NMF identifies four biologically distinct clusters among SCLC tumor samples and cell lines, each defined almost solely by differential expression of the transcription factors ASCL1 (SCLC-A, 36%), NEUROD1 (SCLC-N, 31%), and POU2F3 (SCLC-P, 16%), including a cluster defined by the absence of all three (SCLC-Inflamed/Mesenchymal, or SCLC-IM, 17%). SCLC-A are neuroendocrine, epithelial tumors with susceptibility to drug classes including BCL-2 inhibitors. SCLC-N are neuroendocrine, cMYC-high tumors with susceptibilities including Aurora kinase inhibitors that are neither epithelial nor mesenchymal. SCLC-P are non-neuroendocrine, epithelial tumors vulnerable to PARP inhibitors and nucleoside analogs. Lastly, SCLC-IM consists of mesenchymal, non-neuroendocrine tumors with high-expression of immune checkpoints, STING-related genes, and inflammatory markers that may represent those SCLC which are sensitive to immune checkpoint blockade. scRNAseq reveals intratumoral heterogeneity among cluster assignment within tumors that fluctuates coincident with the onset of therapeutic resistance.

      Conclusion

      Conclusions: SCLC tumors can be assigned to one of four molecular subtypes on the basis of differential expression of three transcription factors. These subtype assignments reflect profound distinctions in underlying biology and susceptibility to a range of candidate drug classes. While subtype assignment on a single-cell basis within a tumor is largely homogeneous, rare cells from distinct subtypes (or representing multiple subtypes), as well as shifting assignments following treatment indicate the possibility of subtype-switching, or subtype-selection, as mechanisms of therapeutic resistance.

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

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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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): John Victor Heymach

      • 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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    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): John Victor Heymach

      • 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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    OA15 - Targeted Agents and Immunotherapy for Small Cell Lung Cancer (ID 152)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
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      OA15.04 - Genomic and TCR Intratumor Heterogeneity of Small-Cell Lung Cancer by Multiregion Sequencing: An Association with Survival (Now Available) (ID 1458)

      14:30 - 16:00  |  Author(s): John Victor Heymach

      • Abstract
      • Presentation
      • Slides

      Background

      Small cell lung cancer (SCLC) is an aggressive cancer. Although sensitive to initial therapy, recurrence is almost inevitable. The molecular mechanisms underlying recurrence are unknown. We have previously demonstrated that complex genomic and T cell receptor (TCR) intratumor heterogeneity (ITH) was associated with increased risks of relapse in non-small cell lung cancers (NSCLC). Genomic ITH and TCR architecture of SCLC and its clinical impact have not been well studied, largely due to lack of tumor specimens as surgery is rarely used to treat SCLC.

      Method

      We performed multiregion whole-exome sequencing and TCR sequencing of 49 tumor samples from 18 resected limited-stage SCLCs to delineate the immunogenomic ITH of SCLC. We compared the results to those in NSCLC and assessed the association of genomic and TCR attributes with patient’s survival.

      Result

      On average, 544 mutations/sample were detected. The median proportion of trunk mutations (mutations identified in all regions within the same tumors) was 80.4% versus 70% in NSCLC (TRACERx, Jamal-Hanjani, NEJM, 2017, p=0.08) and all TP53 and RB1 mutations were trunk mutations, suggesting these mutations were early events during carcinogenesis of this cohort of SCLCs. A higher non-synonymous tumor mutational burden (TMB) was associated with a higher T cell density (infiltration) in the tumor (r=0.46, p=0.005). Compared to the TCR repertoire of NSCLC (Reuben, WCLC, 2017), these SCLC tumors demonstrated significantly lower T-cell density (0.05 versus 0.24, p<0.0001), richness (diversity, 1,043 versus 3,666, p<0.0001) and clonality (reactivity, average 0.02 versus 0.15, p<0.0001) despite similar non-synonymous TMB (average 187 in SCLC versus 176 mutations/sample in NSCLC). Only 0.2% to 14.6% of T cells were detectable across all regions from the same tumors, suggesting substantial TCR ITH. Jaccard index (JI), a parameter quantifying TCR ITH was significantly lower in SCLC than in NSCLC (0.06 versus 0.1, p<0.0001) implying higher level of TCR ITH in SCLC than NSCLC. Interestingly, higher T-cell density, richness or clonality appeared to be associated with lower risk of recurrence numerically. Furthermore, higher TCR JI (less degree of ITH) was associated with significantly longer overall survival (HR=0.15, p=0.04).

      Conclusion

      Limited-stage SCLC tumors have distinct TCR repertoire and genomic ITH architecture. Overall, SCLC may have a more pronounced immunosuppressive microenvironment and higher level of TCR repertoire ITH than NSCLC. Nevertheless, higher degree of T cell infiltration and clonal expansion as well as more homogeneous T cell response may be associated with more favorable clinical outcome in patients with limited-stage SCLC.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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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): John Victor Heymach

      • 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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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-11 - Depicting the Intra-Tumoral Viral and Microbial Landscape of Localized NSCLC Using Standard Next Generation Sequencing Data (ID 1126)

      09:45 - 18:00  |  Author(s): John Victor Heymach

      • Abstract
      • Slides

      Background

      Studies from our group and others have shown that bacteria and viruses present in the tumor may impact therapeutic responses. In the specific context of non-small cell lung cancer (NSCLC), intra-tumoral viral DNA and bacteria have been reported previously to be linked to therapeutic outcomes. However, the interplay between intra-tumoral microorganisms and the host immune response in NSCLC remains unknown. Moreover, the prognostic and predictive therapeutic value of localized NSCLC-specific microbial composition has yet to be defined.

      Method

      RNA-sequencing (RNA-seq) (n=82) and whole exome sequencing (WES) (n=80) was performed on surgically resected (pTNM I-III) tumors from lung cancer patients enrolled in the ImmunogenomiC prOfiling of NSCLC (ICON) project. Intra-tumoral bacteria, viruses and fungi were queried with MetaPhlAn2, a bioinformatical analysis pipeline which employs unique clade-specific marker genes, using reads from RNA-seq and WES that did not map to the human genome/transcriptome. Generated data were correlated to patients’ clinicopathologic parameters as well as immune profiling using previously validated multiplex IHC panels based on Vectra 3.0™ multispectral microscopy IHC panels and image analysis (InForm™ 2.2.1 software).

      Result

      Our analyses revealed that 18.29% (n=15/82) of tumors contained bacterial signatures. The most frequent bacterial signature was related to Escherichia (n=9/15). Moreover, 6.49% (n= 5/77) of tumors had evidence of human viral signatures, including the Epstein-Barr virus (n=1/5). No tumors contained fungal signatures. Preliminary clinicopathologic analyses suggested that patients whose tumors harbor bacterial signatures had a trend towards decreased overall survival (p=0.12). Tumors from former smokers were also more likely to contain bacterial signatures (p=0.11). Preliminary multiplex immune cell IHC analyses did not highlight statistically significant associations with the presence of intra-tumoral bacteria.

      Conclusion

      Our results suggest that a significant proportion of localized NSCLC tumors may harbor components of the human microbiome. Further studies using larger cohorts and dedicated intra-tumoral microbiome and virome methodologies will be needed to better define these findings and to delineate associations with the local immune infiltrate.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-08 - Activity of Poziotinib and Other 2nd-Gen Quinazoline EGFR TKIs in Atypical Exon18 and Acquired Osimertinib Resistance Mutants (ID 2694)

      09:45 - 18:00  |  Author(s): John Victor Heymach

      • Abstract

      Background

      In EGFR, exon 18 encodes for the P-loop (L718-V726), and mutations in this region (G719S/A, L718Q/V, G724S) are known to reduce sensitivity to osimertinib and first-generation EGFR TKIs. Osimertinib resistance is associated with a number of acquired mutations in exons 19 and 20 (S784F, L747S, C797S and L792H). We investigated the frequency and drug sensitivity of these and other osimertinib-resistant EGFR mutations

      Method

      We generated ~50 different Ba/F3 cell line models expressing classical and/or atypical EGFR mutations (exons 18-21) and evaluated the transforming ability and sensitivity to 14 EGFR TKIs including non-covalent (first-generation), afatinib, dacomitinib, and poziotinib (quinazoline and covalent, second-generation), and covalent T790M-specific (third-generation) inhibitors. Impact of atypical mutations was analyzed by in silico modeling.

      Result

      We found 3.6% (N=32/895) of EGFR-mutant patients had atypical, exon 18, P-loop mutations in the MD Anderson GEMINI database. Modeling of classical EGFR mutations revealed osimertinib has distinct interactions between the solvent front of osimertinib and residues within the P-loop of EGFR, whereas second-generation quinazoline TKIs, such as poziotinib, extend into the pocket, near T790, lacking these interactions. Mutations in the P-loop were predicted to shift osimertinib out of alignment with V726 and F723, causing resistance to osimertinib but not quinazoline-based TKIs. Atypical exon 18 mutations (G719S/A, L718Q/V, G724S) had IC50 values of 113.6nM, 1.6nM, and 137.5nM for first-, second-, and third-generation TKIs, respectively. Second-generation TKIs inhibited G719S/A-T790M mutations at concentrations 2-fold lower than third-generation TKIs (IC50 = 23.4nM and 46nM). Osimertinib-resistance mutations (L747S, S784F, C797S, L792H) co-occurring with classical sensitizing mutations (L858R or ex19del) had IC50 values of 56.8nM, 1.4nM, and 996nM to first, second and third-generation inhibitors. Of the second-generation TKIs tested, poziotinib was the most potent for atypical exon 18 P-loop mutations; G719S/A-T790M mutations; and classical mutants with acquired osimertinib-resistance mutations (IC50= 0.4nM, 3.2nM, 0.8nM).

      Conclusion

      Exon 18 atypical P-loop mutations and osimertinib-resistance mutations demonstrated high sensitivity to second-generation quinazoline TKIs, compared to first- and third-generation inhibitors. Mutations in the P-loop of EGFR confer resistance to third-generation TKIs by destabilizing solvent front interactions of the molecule, and osimertinib-resistance mutations interfere with covalent binding at C797. Second-generation TKIs, especially poziotinib, are potent inhibitors of these mutations because they have increased hydrophobic interactions at the back of the drug binding cleft that are retained without covalent binding. Together, these data indicate that poziotinib and other second-generation TKIs may be useful for the treatment of NSCLC patients with atypical P-loop and selected osimertinib-resistant EGFR mutations.

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      P1.14-17 - Genomic Evolution During TKI Treatment in Non-Small Cell Lung Cancer Patients With or Without Acquired T790M Mutation (ID 2988)

      09:45 - 18:00  |  Author(s): John Victor Heymach

      • Abstract

      Background

      EGFR-mutant non-small-cell lung cancer (NSCLC) patients inevitably develop drug resistance when treated with EGFR tyrosine kinase inhibitors (TKIs). Clonal and clinical analyses of genetic alterations at baseline and progressive disease (PD), as well as differences between acquired T790M and T790M-negative patients in drug-resistant mechanisms, have not been systematically studied.

      Method

      We performed targeted sequencing of pre-treatment and PD tumor samples from 54 EGFR-mutant NSCLC patients. Ten additional patients were sequenced using whole exome sequencing to infer the clonal evolution patterns.

      Result

      We observed new co-occurring alterations and pathways limiting EGFR-inhibitor response, including 9p34.3/19p13.3 (NOTCH1/STK11) co-deletion and TGF-beta pathway alterations. Besides acquired T790M mutation, chromosomal instability (CIN) related genes including AURKA and TP53 alterations were the most frequently acquired events. CIN significantly increased with TKI treatment in T790M-negative patients. Transcriptional regulators including HNF1A, ATRX and NKX2-1 acquired alterations were enriched in T790M-positive patients, and diverse oncogenic pathway alterations were more common in T790M-negative patients. T790M-positive patients had improved PFS compared to T790M-negative patients. We further identified subgroups within T790M-positive or T790M-negative patients with distinct PFS. Clonal evolution analysis indicated progression of T790M-positive patients depends on competition between T790M and non-T790M resistant subclones.

      Conclusion

      Our study is the first attempt to identify co-occurring copy number events to stratify patients resistant to TKI treatment. Besides acquired T790M mutation, chromosomal instability (CIN) related genes were identified as the most frequently acquired events. Clonal evolution analysis indicated indicate that higher competitive advantage of T790M was associated with improved PFS.

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    P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.16-31 - Body Mass Index Relating to Patient-Reported Symptoms in First-Line Treatment of Metastatic Non-Small Cell Lung Cancer (ID 2619)

      09:45 - 18:00  |  Author(s): John Victor Heymach

      • Abstract

      Background

      Patient-reported outcomes (PROs) provide information on patient treatment experience. Our aim in this analysis was to assess the longitudinal relationship between body mass index (BMI) with patient-reported symptom severity and interference during treatment.

      Method

      Between May 1, 2017 and December 7, 2018, patients with mNSCLC at a single institution were enrolled in a real-world Advanced Non-Small Cell Lung Holistic Registry (ANCHoR) and completed the MDASI-LC prior to start of therapy and at routine clinic visits. MDASI-LC consists of 16 symptom severity and 6 symptom interference items rated on 0-10 scales (0 = no symptom or interference, 10 = worst imaginable symptom or complete interference). BMI was measured at the same schedule as MDASI-LC. Mixed-effects models were used to examine the longitudinal association between BMI and symptom levels during treatment.

      Result

      103 patients completed the MDASI-LC prior to start of therapy and at least 2 follow-up assessments. Mean patient age was 64.3 years (standard deviation = 11.5) and 50% were males. 22% of patients received chemotherapy (CTX), 34% immunotherapy (IM), 23% CTX+IM or angiogenesis inhibitor, and 20% targeted therapy. The median pre-treatment BMI was 25.2 (inter quartile range, 5.2). BMI did not change during treatment and no significant difference was found among treatment groups. Compared with the obese group (BMI≥30), the overweight group (25≤BMI<30) experienced lowest levels of fatigue (estimation(est)=-1.23, standard error (SE)=0.49, p=0.016), disturbed sleep (est=-1.66, SE=0.49, p=0.002), distress (est=-0.90, SE=0.40, p=0.030) and less interference on mood (est=-1.03, SE=0.46, p=0.030) and interference with walking (est=-1.50, SE=0.51, p=0.005). The normal group (BMI<25) demonstrated lower levels of fatigue (est=-1.05, standard error (SE)=0.47, p=0.032) and disturbed sleep (est=-1.15, SE=0.47, p=0.018), compared with the obese group.

      Conclusion

      For patients with mNSCLC, obesity was related with higher symptom burden during active treatment. This analysis provides pilot data for future studies on balanced weight control and patients’ wellbeing during cancer treatment.

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    P1.18 - Treatment of Locoregional Disease - NSCLC (ID 190)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.18-02 - The AEGEAN Phase 3 Trial of Neoadjuvant/Adjuvant Durvalumab in Patients with Resectable Stage II/III NSCLC (ID 1375)

      09:45 - 18:00  |  Presenting Author(s): John Victor Heymach

      • Abstract

      Background

      For patients (pts) with early stage non-small cell lung cancer (NSCLC) (Stages I–IIIA) surgery is the primary treatment. Adjuvant and neo-adjuvant chemotherapy (CTx) are both accepted approaches for resectable NSCLC, and result in modest but clinically meaningful improvements in overall survival (OS) compared with surgery alone; nevertheless, recurrence rates remain high and improved therapies are needed. Checkpoint inhibitors that block programmed death 1 (PD-1)/PD ligand 1 (PD-L1) have shown benefit as monotherapy and in combination with CTx in NSCLC. Durvalumab (durva), a selective, high-affinity, human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80, significantly improved progression-free survival and OS in pts with unresectable Stage III NSCLC who did not progress following chemoradiotherapy (Antonia et al, NEJM 2017; 2018). The AEGEAN study (NCT03800134) will assess the activity and long-term clinical outcomes of durva plus CTx prior to surgery, as well as further administration of durva post-surgery, in pts with resectable Stages II and III NSCLC.

      Method

      The AEGEAN trial is a Phase 3, double-blind, placebo-controlled, multi-center study. Approximately 300 pts with resectable Stage II and III NSCLC will be randomized 1:1 to receive either durva (1500 mg intravenously) or placebo every 3 weeks (wks) alongside platinum-based CTx (4 cycles) prior to surgery, followed by either durva or placebo alone every 4 wks for an additional 12 cycles post-surgery. Pts will be stratified by disease stage and PD-L1 expression levels (<1% vs ≥1%); the number of pts with EGFR/ALK mutations will be capped at 20%. Tumor size (according to RECIST v1.1 criteria) will be evaluated at completion of neo-adjuvant CTx prior to surgery, every 12 wks for the first year; every 24 wks for 2–4 years; then yearly thereafter. The primary endpoint is major pathological response (≤10% residual viable tumor in the resected primary lung tumor after neoadjuvant treatment) in the full analysis set (FAS). Secondary endpoints include safety assessments, a range of efficacy measures including complete pathological response (FAS and PD-L1-TC ≥1%) and OS, pt-reported outcomes, durva pharmacokinetics and immunogenicity. This trial is currently recruiting.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-07 - Open-Label, Biomarker-Directed Platform Study in NSCLC Patients Who Progressed on an Anti-PD-(L)1-Containing Therapy (HUDSON) (ID 643)

      10:15 - 18:15  |  Author(s): John Victor Heymach

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitor (ICI)-containing regimens have significantly improved survival outcomes in first- and second-line non-small cell lung cancer (NSCLC). However, few patients have-durable responses to anti-programmed cell death‑1/programmed cell death-ligand 1 (anti-PD-[L]1)-containing therapy (primary resistance) or other patients progress during anti-PD-(L)1-containing therapy (acquired resistance). HUDSON addresses the urgent need to identify new treatments and understand ICI resistance for patients who progressed after receiving anti-PD-(L)1-containing therapy.

      Method

      HUDSON is a multi-centre, international, multi-arm, platform study (NCT03334617), which will 1) evaluate therapies to reverse ICI resistance and 2) define mechanisms of ICI resistance in patients with NSCLC who have progressed following standard-of-care platinum- and ICI-based therapies. HUDSON consists of biomarker matched and non-matched groups (Figure). Allocation is guided by tumour molecular profile, using a pre-specified algorithm. Pre-existing local next generation sequence (NGS) data enables rapid patient allocation to biomarker-matched groups. Central molecular profiling comprises NGS and immunohistochemistry data. New groups will be added as new translational hypotheses emerge. Translational research will employ serial peripheral blood samples (including ctDNA) and tumour biopsies.

      Figure. Study design and biomarker prevalence

      wclc 2019 abstract figure.jpg

      Result

      Enrolment is ongoing; as of 01 April 2019, patients have been dosed in each of the drug combinations currently open for recruitment. Analyses of tissue and blood samples collected for exploratory research are ongoing, including genomic, transcriptomic and chemistry biomarkers such as tumour mutation burden, human leukocyte antigen status, T-cell receptor repertoire, and peripheral immune activation signatures.

      Conclusion

      Specific differences between patients on individual HUDSON arms that inform anti-PD(L)1 resistance mechanisms, plus learnings from the implementation of this innovative and complex platform study will be presented.

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      P2.01-93 - Detection of Giant Cancer-Associated Macrophage-Like Cells After Concurrent Chemoimmunoradiation Is Associated with Poor Survival in NSCLC (ID 2350)

      10:15 - 18:15  |  Author(s): John Victor Heymach

      • Abstract
      • Slides

      Background

      Circulating cancer-associated macrophage-like cells (CAMLs) are a recently described stromal cell found in the peripheral blood of cancer patients that have been shown to be associated with disease progression. The presence of giant CAMLs (≥50 µm) was previously reported to be predictive of disease progression in multiple tumor types. In this phase II DETERRED trial of patients with unresectable locally advanced non-small cell lung cancer (NSCLC) treated with atezolizumab (atezo) combined with concurrent chemoradiation, we explored the utility of CAMLs in predicting progression based on blood samples collected throughout treatment and follow up.

      Method

      Patients were enrolled between February 2016 and April 2018. Patients were treated with carboplatin/paclitaxel (CP) and conventionally fractionated radiation therapy (60 – 66 Gy) with atezo, followed by CP-atezo, followed by maintenance atezo. Median follow up after the completion of concurrent chemoimmunoradiation (cCIRT) was 13.5 months. CAMLs were collected by obtaining peripheral blood from patients at baseline at the beginning, during, at the end, at first follow up, and final follow up after cCIRT. Blood was filtered using CellSieveTM filtration and CAMLs quantified. CAML size ≤49 µm or ≥50 µm was quantified with the observer blinded to clinical information. Relapse free survival (RFS), distant metastasis free survival (DMFS), progression free survival (PFS), and overall survival (OS) were analyzed at each time point.

      Result

      We evaluated 40 patients with unresectable locally advanced NSCLC and obtained a total of 375 samples. CAMLs were identified in 80.5% of samples, averaging 2.5 CAMLs per 7.5 mL sample. Patients with giant CAMLs (≥50 µm) compared to those with smaller CAMLs (≤49 µm) exhibited no difference in RFS, PFS, DMFS, or OS at baseline, during, or immediately after completion of cCIRT. Patients with detectable giant CAMLs at the first follow up (median time 29 days from completion of cCIRT) demonstrated significantly worse RFS (HR=11.79, 95% CI 4.27-32.56, p=0.0021), DMFS (HR=6.48, 95% CI 2.15-19.54, p=0.0009), and PFS (HR=12.47, 95% CI 4.66-33.37, p=0.0014) while OS trended towards statistical significance (HR=5.39 95% CI 1.33-21.81, p=0.071). Long term evaluation of patients with CAML ≥50 µm at first follow up (N=16) revealed 3 patients who converted to CAML<49 µm at last follow up. Patients who converted did not experience any relapses, while all 13 patients who continued to have CAML ≥50 µm experienced progression or death.

      Conclusion

      Giant CAMLs at first follow up after completion of concurrent chemoimmunoradiation is predictive of disease progression and death. This may represent an immediate surrogate marker for poor response at the completion of definitive therapy. Long term follow up with maintenance immunotherapy indicates that a subset of patients convert from giant CAMLs to smaller CAMLs, with better outcomes than those that do not, suggesting that these patients may have derived benefit from maintenance immunotherapy. Continued prospective validation of CAMLs as a peripheral blood-based biomarker is needed to validate these findings.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 4
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-19 - Neoadjuvant Chemotherapy Is Associated with Immunogenic Cell Death and Increased T Cell Infiltration in Early-Stage NSCLC (ID 1122)

      10:15 - 18:15  |  Author(s): John Victor Heymach

      • Abstract
      • Slides

      Background

      Recent success using immune checkpoint blockade (ICB) in the metastatic setting has raised the need to understand the immune microenvironment (IME) in early-stage disease. Moreover, pre-clinical evidence suggests that cytotoxic agents can modulate this IME. A recent study conducted by our group showed that non-small cell lung cancer (NSCLC) patients who received neoadjuvant chemotherapy followed by surgery (NCT), as compared to patients who received upfront surgery (US), had higher densities of CD3+ lymphocytes and CD68+ tumor-associated macrophages (TAMs). CD3+CD4+ lymphocytes and TAMs also correlated with better clinical outcomes. In this study, we explored the relationships between NCT and the IME by harvesting tumor samples of multiple surgical NSCLC cohorts.

      Method

      The PROSPECT microarray database was queried in NCT (n=45) and US (n=200) patients to investigate differentially expressed genes related to immunogenic cell death (ICD), susceptibility to CD8+ T cell and NK cell cytotoxicity, priming of antigen presenting cells, immunosuppressive enzymes and intra-tumoral cytokines. Available data from the ImmunogenomiC prOfiling of NSCLC (ICON) and other surgical NSCLC cohorts was evaluated to determine: 1) differential immune profiling using FACS (NCT=17; US=39) and multiplex IHC imaging (NCT=10; US=72); 2) plasma circulating cytokines (NCT=18; US=73); 3) tumor mutational burden (TMB) (NCT=40; US=61). Participants who received NCT or US were excluded according to these criteria: 1) concurrent treatment in addition to NCT; 2) sarcomatoid and small cell histologies; 3) clinical or pathological TNM Stage 4 disease; 4) synchronous malignancies other than lung.

      Result

      PROSPECT NCT patients expressed increased damage-associated molecular pattern (DAMP) genes (HSPA2, HSPA4, HSPE1, and S100A2; p<0.05) and T cell-related chemotaxis and antigen presentation genes (CXCR7, CD1A; p<0.05). Concordantly, the ICON cohort FACS results showed that NCT patients display increases in: 1) infiltration of CD8+ T cells (p=0.004); 2) proliferating Ki67+CD8+ T cells (p=0.02); 3) tissue resident memory CD8+CD103+ (p=0.02) and CD4+CD103+ non-Treg cells (p=0.01). Trends from the ICON multiplex IHC also highlighted increases in CD8+ T cells (p=0.09), CD20+ cells (p=0.08), as well as PD-L1+ malignant cells (p=0.08) and PD-L1+ TAMs (p=0.08) in NCT patients, the latter finding being supported by increased circulating MCP-1 (p=0.03). TMB was similar between NCT and US groups (p=0.912).

      Conclusion

      Our data provides the first evidence of ICD (i.e., increased DAMP gene expression) following NCT in human early-stage NSCLC. Furthermore, our data highlights the association of NCT with a favorable IME (i.e., increased T cell infiltration), supporting the rationale of NCT and ICB combinations in localized NSCLC.

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      P2.04-31 - Immune Phenotypic Biomarkers in Locally Advanced Non-Small Cell Lung Cancer Treated with Definitive Chemoradiation and Atezolizumab (ID 2597)

      10:15 - 18:15  |  Author(s): John Victor Heymach

      • Abstract

      Background

      Consolidation durvalumab is the current standard of care for locally advanced non-small cell lung cancer (LA-NSCLC) after chemoradiation (CRT). However, predictive and prognostic biomarkers of response to immunotherapy are still poorly characterized. In particular, minimally-invasive blood-based biomarkers that can be sequentially assessed during therapy may prove useful in understanding the characteristics of response and optimal sequencing of therapy. We report serial blood immune-phenotyping of patients undergoing concurrent chemoradiation therapy (CRT) with PD-L1 blockade with atezolizumab.

      Method

      Between February 2016 and October 2018, 40 LA-NSCLC patients were evaluated in conjunction with the single-institution DETERRED trial. The first 10 patients were treated with carboplatin/paclitaxel chemotherapy and atezolizumab for two cycles followed by maintenance atezolizumab for 1 year after completing CRT, followed by 30 patients treated with atezolizumab concurrent with CRT followed by chemotherapy/atezolizumab and maintenance atezolizumab. In all, 38 patients were evaluable. Peripheral blood was drawn at the beginning (baseline), midway through CRT (2-4 weeks), and at the end of CRT, with periodic follow up samples for up to two and a half years. Immune phenotyping was performed by flow cytometry on fresh, whole blood within 24 hours of phlebotomy. Cox regression was preformed to assess biomarker correlations with survival.

      Result

      At the second blood sample midway through CRT, patients who eventually progressed had a larger increase from baseline in the percentage of peripheral blood CD4 T helper cells expressing PD-1 (p = 0.042) and this change was associated with both progression-free (PFS, p = 0.039) and overall survival (OS, p = 0.042). Progressors had a mean increase of 2.5 percentage points while non-progressors had a mean drop of 1.9. At the first post-CRT follow-up, an increase in the percentage of CD8 cytotoxic T lymphocytes expressing PD-1 was negatively associated with survival (PFS p = 0.0015, OS p = 0.023) as well as the percentage of granulocytic myeloid suppressor cells (PFS p = 0.0089, OS p = 0.034). These comparisons were not significant when corrected for multiple testing. However, the change in CD4 PD1 after 2-4 weeks of CRT was an independent prognostic indicator of PFS in multivariate cox regression analysis including age, stage, and histology (p = 0.02, hazard ratio 1.2, 95% CI 1.03 to 1.4).

      Conclusion

      Increases in peripheral blood lymphocytes expressing PD1 and myeloid suppressor cells may be prognostic for locally advanced patients treated with CRT and immune checkpoint blockade but additional studies are needed to verify these markers in immunotherapy resistance.

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      P2.04-37 - Phase I/II Trial of Durvalumab and Tremelimumab with Continuous or Intermittent MEK Inhibitor Selumetinib in Advanced NSCLC (ID 1130)

      10:15 - 18:15  |  Author(s): John Victor Heymach

      • Abstract
      • Slides

      Background

      Despite therapeutic progress in other molecular subsets of non-small cell lung cancer (NSCLC), little progress has been made for KRAS-mutant NSCLC. Because RAS remains an elusive pharmacological target, agents targeting downstream elements of the MAPK signaling pathway have been developed, including MEK inhibitors. However, substantial benefits have not been achieved due to the development of drug resistance. Current strategies to improve outcomes in this population include MEK inhibitors and PD-1 / PD-L1 immune checkpoint blockade (ICB) combinations (e.g., NCT03225664). On the other hand, combined anti-CTLA-4 and PD-1 / PD-L1 axis ICB improves response rates in melanoma, but similar benefits remain to be seen in NSCLC: MYSTIC trial updates failed to show a progression-free survival (PFS) advantage over standard of care, and CheckMate 227 reported significantly longer PFS with first-line double ICB in the high tumor mutational burden subgroup only. Thus, the objectives of this study are: 1) to determine the safety and efficacy of combined MEK inhibition, anti-PD-L1 and anti-CTLA-4 and; 2) to unveil mechanistic insights for response and resistance.

      Method

      This is a single center, Phase I/II study comparing two combination schedules of selumetinib (AZD6244, ARRY-142886), tremelimumab and durvalumab with historical controls in patients with previously treated, unresectable NSCLC. Forty patients will be accrued at the University of Texas MD Anderson Cancer Center. In the first arm, participants receive selumetinib PO BID on days 1-7 and 15-21 and durvalumab IV on day 1. Participants also receive tremelimumab IV on day 1 for courses 1-4 (courses repeat every 28 days in the absence of disease progression or unacceptable toxicity). The second arm differs by the continuous selumetinib schedule: PO BID on days 1-28. Primary objectives include the maximum tolerated dose (MTD; dose-escalation phase) and PFS (dose expansion phase). Standard 3+3 design will be applied to determine the MTD among the three pre-defined dose levels. Estimated PFS will be provided with 95% confidence interval. Secondary objectives include: 1) response rate by RECIST 1.1; 2) disease control rate (complete response + partial response + stable disease); 3) overall survival; 4) safety and; 5) duration of response. Exploratory objectives will assess biomarkers of response and resistance in pre- and on-treatment biopsies as well as peripheral blood using immune profiling, transcriptome and protein readouts.

      Result

      Section not applicable (Clinical Trial in Progress)

      Conclusion

      The estimated start date for this trial (NCT03581487) is April 15th, 2019, and the estimated study completion is scheduled for April 2021.

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      P2.04-90 - Nodal Immune Flare (NIF) Following Neoadjuvant Anti-PD-1 and Anti-CTLA-4 Therapy in Non-Small Cell Lung Cancer   (Now Available) (ID 2065)

      10:15 - 18:15  |  Author(s): John Victor Heymach

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitors (ICIs) have induced durable responses in selected non-small cell lung cancer (NSCLC) patients. However, ICIs have also shown to induce tumor pseudo-progression in some cases. We report the incidence and consequences of a distinct phenomenon – the apparent radiographic progression of lymph nodes without pathological evidence of tumor – that we define “nodal immune flare” (NIF), following neoadjuvant ICIs in the NEOSTAR phase 2 trial of nivolumab or nivolumab plus ipilimumab for operable NSCLCs.

      Method

      NEOSTAR randomized 44 patients with stage I-IIIA (AJCC 7th edition) to nivolumab (3 mg/kg IV, days 1, 15, 29) or nivolumab/ipilimumab (1 mg/kg IV, day 1) with planned surgery between 3-6 weeks after last dose. Computed tomography (CT) and positron emission tomography (PET-CT) were obtained prior to ICIs and prior to resection. Response Evaluation Criteria in Solid Tumors v1.1 were used to evaluate responses.

      Result

      44 patients, median age 66 years (range 43-83), 28 (64%) males, 37 (84%) white were randomized to nivolumab (n=23) or nivolumab/ipilimumab (n=21). 26 (59%) had adenocarcinoma, 17 (39%) squamous cell, 1 (2%) adenosquamous carcinoma. 23 (52%) stage I, 12 (27%) stage II, 9 (20%) stage IIIA. 39 (89%) underwent complete resection, 2 off trial, and 5 (11%) were not resected.

      NIF occurred in 5/44 (11%) patients, 3 post nivolumab (3/23, 13%) and 2 (2/21, 10%) post nivolumab/ipilimumab. All patients had no evidence of malignancy in nodes of interest prior to ICIs. 2 (2/26, 8%) occurred in adenocarcinoma and 3 (3/17, 18%) in squamous cell. 2 (5%) required additional invasive restaging, 3 (7%) change in surgical plan, 1 (2%) declined surgery, 1 (2%) was thought to have disease progression and was treated with chemotherapy plus ICI prior to resection off study, and 1 (2%) underwent planned resection. Pathologic evaluation of the flared nodes revealed no evidence of cancer in all 5 patients, rather demonstrated noncaseating granulomata.

      In a previous neoadjuvant trial utilizing platinum-based chemotherapy with nintedanib, we did not observe NIF in 21 patients in absence of pathologic evidence of tumor progression (primary or nodal metastases).

      Conclusion

      NIF occurred in 11% of patients following neoadjuvant ICIs and changed treatment plan in 9% of patients. This is the first preliminary report of NIF in operable NSCLCs treated with neoadjuvant single and combined ICIs. Considering the number of ongoing neoadjuvant immunotherapy trials, we highlight the importance of judicious and invasive restaging of sites of suspected progression after neoadjuvant ICIs prior to definitive treatment decisions.

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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): John Victor Heymach

      • 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