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abdul rafeh Naqash



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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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      OA03.07 - Immune-Related Adverse Events and Clinical Outcome to Anti PD-1 Axis Inhibition in SCLC: A Multicenter Retrospective Analysis (Now Available) (ID 2880)

      13:30 - 15:00  |  Author(s): abdul rafeh Naqash

      • Abstract
      • Presentation
      • Slides

      Background

      Immune-checkpoint inhibitors (ICIs) have shown promising activity in only a fraction of patients with small cell lung cancer (SCLC), and factors associated with clinical benefit are not well characterized. The development of immune-related adverse events (irAEs) may correlate with benefit from immune checkpoint inhibitors (ICIs) among patients with cancer. Whether an association exists between irAE development and improved clinical outcomes to ICIs in small cell lung cancer (SCLC) is unknown.

      Method

      We retrospectively analyzed data from five participating academic centers: the Dana-Farber Cancer Institute, East Carolina University, Columbia University, Beth Israel Deaconess Medical Center, and Johns Hopkins University. Patients with SCLC who received at least one dose of a programmed death (ligand) PD-(L)1 inhibitor alone or in combination with a cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitor were included in this study. To account for the time-dependent nature of irAE onset and clinical benefit from immunotherapy, we identified patients with early irAEs (defined as those occurring within 6 weeks of ICI treatment initiation) and performed a landmark analysis at this time point.

      Result

      Among 157 patients treated with ICIs, 65 (41.4%) experienced at least one irAE. Median time to the first irAE onset was 28 days (IQR:15-56). Baseline clinicopathologic characteristics were well balanced between patients who developed irAEs and those who did not. Median tumor mutational burden (TMB) was significantly higher among patients with irAEs compared to those without (14.4 vs 8.4 mutations/megabase [mut/Mb], P <0.01). Patients who developed at least one irAE had a significantly higher objective response rate (26.3% versus 3.3%, P <0.001), and significantly longer median progression-free survival (mPFS, 4.1 vs 1.3 months, HR: 0.30 [0.20-0.43, P <0.001]) and median overall survival (mOS, 14.1 vs 2.9 months, HR: 0.32 [0.21-0.48], P <0.001). The proportion of patients who were progression-free at 6, 9, and 12 weeks was significantly higher in patients who developed early irAEs compared to those who did not develop early irAEs (6 weeks: 89.5% vs 69.5%, P =0.01; 9 weeks: 71.1% vs 40%, P =0.001; 12 weeks: 65.8% vs. 31.6%, P <0.001). The median TMB was also significantly higher in patients who developed early irAEs (14.5 vs 8.7 mut/Mb, P <0.01).

      Conclusion

      Patients with SCLC treated with ICIs who developed early irAEs had a higher TMB and enhanced antitumor responses compared to those who did not develop irAEs. Whether a higher TMB is associated with the development of irAEs remains to be determined mechanistically.

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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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      P1.04-60 - Impact of Metastatic Location on Survival in Stage-IV Non-Small Cell Lung Cancer (NSCLC) Treated with Immunotherapy (ID 1859)

      09:45 - 18:00  |  Author(s): abdul rafeh Naqash

      • Abstract

      Background

      Emerging preclinical data suggests that the heterogeneity in the metastatic site-specific tumor immune microenvironment, as well as organ specific mutational diversity, may impact antitumor response to immune checkpoint inhibition (ICI). However, there is a paucity of clinical data describing the efficacy of ICI across metastatic compartments. Therefore, we sought to elucidate the impact of the metastatic location on survival in ICI treated stage-IV NSCLC.

      Method

      We conducted a retrospective review of 140 stage-IV NSCLC patients treated with ICI between 4/2015 to 12/2018 at East Carolina University Cancer Center. Any non-skeletal lesion >0.5 cm on computerized tomography at an extrapulmonary site was considered as metastasis. Bone Iiesions were identified based on bone scan or positron emission tomography. ICI consisted of nivolumab, pembrolizumab, atezolizumab, Nivolumab+ ipilimumab and concurrent chemo+ ICI. Targeted next-generation sequencing (NGS) using Caris life sciences platform was used to determine tumor molecular profile. PD-L1pos was defined as ≥ 1% staining using 22c3 Dako assay. Tumor mutational burden (TMB) was measured by counting all somatic non-synonymous missense mutations using targeted NGS (592 genes). TMB-high (H) was defined as ≥ 10 mut/Mb. Chi-Square test compared categorical variables. Kaplan Meier method was used for progression-free survival (PFS) and overall survival (OS) analysis.

      Result

      Median age at treatment was 64 years. Bone (Bo-44.3%) was the most common metastatic site followed by brain (Br-37.9%) and liver (L-17.1%). Majority of patients had an oligometastatic disease (58.6% ) with Br only metastasis present in 30.0% and Bo only metastasis in 26.4%. L only metastasis was rare (4.3%) but more commonly associated with bone involvement (L+Bo) in 17.7%.TMB was assessed in 34.3% and PD-L1 in 46.4%. NGS identified TMB-high to be more prevalent in patients with Br metastasis compared to no-Br disease (84.6 vs 52.1%; p=0.02). Across metastatic sites, Br only metastasis had a greater proportion of TMB-high compared to Bo only (85.0 vs 33.3 %; p=0.01). L+Bo had lower median PFS vs. Br alone (3.2 vs 8.3 months; p<0.01) and a trend towards inferior PFS vs. Bo alone (3.2 vs 4.1 months; p=0.08). L+Bo also had shorter OS compared to Br alone (3.2 vs 10.2, p<0.01) and Bo alone (3.2 vs.8.8; p=0.047). Patients with >1 metastatic site had inferior PFS (9.4 vs 11.8 months ;p=0.04) and inferior OS (3.70 vs 11.0 months; p=0.01). 30.7% of the patients were treated with concurrent chemo+ICI. In the entire cohort, compared to ICI alone, concurrent chemo+ICI had significantly better median PFS (9.2 vs 4.3 months; p<0.01) and OS (Not reached vs 5.2 months; p <0.001). In patients with an oligometastatic disease, chemo+ICI also demonstrated improved OS for both Br only (Not reached vs 6.7 months; p=0.01) and Bo only disease (Not reached vs 4.8 months;p=0.06).

      Conclusion

      Our data demonstrate non-uniform responses to ICI based on the site of metastasis and the number of metastatic sites. We observed Br to have a higher proportion of TMB-high with improved survival when treated with concurrent chemo+ICI. Further studies to identify metastatic site-specific biomarkers to optimally guide ICI related treatment decisions are required.

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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
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-100 - Spectrum of EGFR Exon 20 Insertion Mutations and Co-Occurring Genetic Alterations in Patients with Non-Small-Cell Lung Cancer (ID 2538)

      10:15 - 18:15  |  Author(s): abdul rafeh Naqash

      • Abstract

      Background

      Epidermal growth factor receptor (EGFR) exon 20 insertion mutations are associated with a low response rate to approved EGFR tyrosine kinase inhibitors (EGFR-TKIs) and short progression-free survival. Pre-clinical studies have shown differences in the affinity of EGFR exon 20 insertion mutations for EGFR-TKIs, suggesting that the location of the insertion within the C-helix may play an important role in determining EGFR-TKI sensitivity. Several EGFR-TKIs designed to target EGFR exon 20 insertion mutations are in clinical development. Comprehensive genomic profiling has allowed for identification of co-occurring genomic alterations, which may help us identify additional pathways that may drive disease progression and drug resistance.

      Method

      Formalin-fixed paraffin-embedded (FFPE) samples from patients with non-small cell lung cancer (NSCLC) were profiled by targeted next-generation sequencing (NGS) using Caris Molecular Intelligence (Caris Life Sciences, Phoenix, AZ). Mutations and copy number variations (CNV) were assessed for each gene included in the NGS panel. Gene amplification (including low amplifications) was defined as gene copy number ≥ 4 and copy number loss as gene copy number < -1.4.

      Result

      Among the 1,556 patients with EGFR mutations, 104 (6.7%) patients were found to harbor an EGFR exon 20 insertion mutation. There were 70 (67.3%) females and 34 (32.7%) males with a mean age 62 (± 11.5 years). 61 (58.7%) samples came from primary lung sites and 43 samples (41.3%) came from metastatic sites. The main histological types were: adenocarcinoma 89 (85.5%), acinar adenocarcinoma 6 (5.7%), papillary adenocarcinoma 5 (4.8%), adenocarcinoma with bronchoalveolar features 1 (1%), squamous cell carcinoma 1 (1%) and carcinoma not otherwise specified 2 (2%). The most common exon 20 insertion mutation was A767_V769dup (25%), followed by S768_D770dup (13%), H773_V774insAH (5%) and H773dup (5%). The most common pathogenic mutations (including presumed pathogenic) included TP53 (51%), followed by CTNNB1 (6%), PIK3CA (4%), PTEN (3%), SMAD4 (3%), and CHEK2 (2%). Of the 104 cases, CNVs were available from 54 patients. Among these patients, commonly amplified genes included CDK4 (11%), EGFR (9%), MDM2 (9%), FOXA1 (7%), and HMGA2 (6%). Copy number loss was observed with CDKN2A (7%), CTNNB1 (2%), ATR (2%), BRCA2 (2%), and FANCL (2%).

      Conclusion

      The diverse spectrum of EGFR exon 20 insertion mutations shows molecular heterogeneity of this rare type of EGFR mutations. The presence of co-occurring genomic alterations that may promote tumor progression and drug resistance suggests that combination approaches may be necessary to overcome resistance to EGFR-TKI therapy in some patients with an EGFR exon 20 insertion mutation.

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      P2.01-29 - The Correlation Between K-Ras Mutant Subsets with TP53 Mutation and PD-L1 in Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 2756)

      10:15 - 18:15  |  Author(s): abdul rafeh Naqash

      • Abstract
      • Slides

      Background

      Despite its role in non-small cell lung cancer (NSCLC), K-ras gene mutations are considered is a non-targetable with no established predictive value. And so far, programmed death ligand-1 (PD-L1) is the only approved predictive marker for immunotherapy in NSCLC patients and has been associated with smoking, while TP53 mutations has been linked to neoplasms with aggressive nature. Meanwhile, K-ras mutation has been identified with smoking and linked to aggressive NSCLC. Accordingly, we hypothesized that k-ras mutant NSCLC has higher PD-L1 expression which suggests an improved response to immunotherapy in these patients.

      Method

      The CARIS database from 2016 - 2018 was queried and patients with NSCLC were identified. PD-L1 antibody 22c3 ≥1% was considered positive. PD-L1 expression as well as k-ras and TP53 mutation status were analyzed and correlation between different variables were identified using ANOVA.

      Result
      Table 1: showing the percentage expression of PD-L1 in each K-ras mutation subtype
      K-ras mutation sub-type PD-L1 negative (n,%) PD-L1 positive (n,%) Total (n,%)
      G12V

      205 (20.8%)

      239 (18%) 444 (19.2%)
      G12D 142 (14.4%) 194 (14.6%) 336 (14.5%)
      G12A 56 (5.7%) 72 (5.4%) 128 (5.5%)
      G12C 337 (34.2%) 566 (42.7%) 903(39.1%)
      G13C 51 (5.2%) 46 (3.5%) 97 (4.2%)
      Q6H 54 (5.5%) 67 (5.1%) 121 (5.2%)
      G12R 18 (1.8%) 18 (1.4%) 36 (1.6%)
      G12S 18 (1.8%) 16 (1.2%) 34 (1.5%)
      Non-Specified 104 (10.6%) 108 (8.1%) 212 (9.2%)
      Total 985 (100%) 1326 (100%) 2311 (100%)

      We identified 8,471 patients with NSCLC. TP53 mutation was detected in 66% where k-ras mutation in 26.9%. Combined K-ras and TP53 mutations was detected in 12% where 71.48% were PD-L1 positive in this combined category. There was female predominance with a female to male ratio of 1.4:1. We looked for the eight main K-ras mutation subsets and G12C was the most common identified mutation. G12C was associated with a higher occurrence of PD-L1 positivity (42.7%), followed by G12V (18.0%) with a significant difference in PD-L1 expression among K-ras mutations subtypes with P value of 0.004. (table 1). PD-L1 expression in wild type K-ras tumors was 69.4% and although high, wild type K-ras cases showed higher percentage of PD-L1 expression negativity (76.2%).

      Conclusion

      Patients with G12C, amongst other k-ras mutation subsets, have higher occurrence of PD-L1 expression which is suggestive of improved response to immunotherapy. The subset of combined K-ras and p-53 mutations showed 71.48% positive PD-L1 expression.

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