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Biagio Ricciuti



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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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      MA09.11 - Mechanisms of Resistance to MET Tyrosine Kinase Inhibitors in Patients with MET Exon 14 Mutant Non-Small Cell Lung Cancer (Now Available) (ID 1421)

      15:15 - 16:45  |  Author(s): Biagio Ricciuti

      • Abstract
      • Presentation
      • Slides

      Background

      Type I and II MET tyrosine kinase inhibitors (TKIs) are under development for patients with MET exon 14 mutant non-small cell lung cancer (NSCLC). Understanding the mechanisms driving resistance to MET TKIs is critical to design novel treatment strategies for this molecular subtype of NSCLC.

      Method

      Among patients with MET exon 14 mutant NSCLC treated with MET TKIs, pre- and post-TKI tumor tissue specimens and plasma samples were analyzed using next-generation sequencing (NGS) to explore genomic mechanisms of resistance upon disease progression.

      Result

      Between April 2014 to March 2019, 38 patients were treated with MET TKIs. Among these, paired samples from 15 individuals were evaluable for this study. Patients were treated with MET TKIs in the first-line (N=7; 46.7%), second-line (N=5; 33.3%), third-line (N=1; 6.7%) and fourth-line (N=2: 13.3%) setting. Eight patients were treated with one type I MET TKI and 7 patients received ≥2 MET TKIs. On target mechanisms of resistance were identified in 5 patients (33.3%), through secondary mutations in the MET tyrosine kinase domain (N=4) and MET amplification (N=1). Single MET kinase domain mutations D1228H/N were detected in 2 patients progressing on treatment with a type I MET TKI. In two cases, tumor tissue revealed only one resistance mutation (case #1 with Y1230H; case #2 with H1094Y), whereas paired plasma analysis demonstrated ≥3 resistance mutations in ctDNA (case #1 with G1163R, D1228N, Y1230H/S; case #2 with H1094Y, L1195F/V), reflecting the emergence of polyclonal on-target resistance. Off-target mechanisms of acquired resistance were identified in 7 patients treated with Type I MET TKI (46.7%) and involved amplification of EGFR (N=2), EGFR/HER2 (N=1), EGFR/HER3 (N=1), KRAS (N=1), EGFR/KRAS/BRAF (N=1), CCND1 (N=1). In 2 cases with bypass activation, sequential treatment with type II MET TKIs did not confer benefit. A concurrent NF1 mutation was present at baseline in a patient with primary resistance to MET TKI (6.7%). In 2 patients (13.3%), no genomic mechanisms of resistance were identified.

      Conclusion

      The landscape of resistance mechanisms to MET TKIs in NSCLC includes single and polyclonal secondary kinase domain mutations and bypass track activation by amplification of key oncogenes involving the ErbB/HER family of tyrosine kinase receptors and the MAPK signaling pathway. Given the complexity of resistance, therapeutic efforts to prevent acquired resistance in MET exon 14 mutant NSCLC should be developed.

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

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

      14:00 - 15:30  |  Author(s): Biagio Ricciuti

      • 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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    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  |  Presenting Author(s): Biagio Ricciuti

      • 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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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-65 - Immune Gene Expression, Bayesian Network and Genetic Mutation Analysis in Advanced NSCLC Patients Treated with Immunotherapy (Now Available) (ID 1361)

      09:45 - 18:00  |  Author(s): Biagio Ricciuti

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitors (ICIs) have dramatically revoluzionized the therapeutic paradigm for NSCLC, but only a small subset of patients achieves durable benefit. The only adopted predictive biomarker, PD-L1 IHC testing, suffers from some limitations. A better understanding of biomarkers associated with response to ICIs is needed. Here, we studied immune gene-expression and genetic mutation profiles and association with clinical response to immunotherapy in advanced NSCLC patients treated with ICI.

      Method

      A total of 37 Formalin-fixed, paraffin-embedded (FFPE) samples from advanced NSCLCs were analyzed by RNA-Seq using the Oncomine Immuno Response Assay (OIRRA) (ThermoFisher Scientific) on Ion Torrent PGM and Transcriptome Analysis Console (TAC) 4.0 Software. This panel measures the expression level of 395 genes associated with 36 functional groups including checkpoint pathways, lymphocyte regulation and cytokine interactions. Gene network analysis based on Bayesian algorithm was performed by GeneMANIA database querying with the genes selected through mRNA expression analysis. Cancer somatic mutation analysis were performed using Ion NGS Panel on PGM Instrument.

      Result

      Among 37 FFPE samples only 18 showed more than 300 OIRRA detectable target genes. In this subgroup, gene expression analysis revealed 7 genes (CCR2, CRTAM, FASLG, SELL, TIGIT, TNFRSF4, and TP63) up-regulated and one gene (CXCL8) down-regulated (p-value < 0.05) in ICI-responders compare to ICI-no responders. Bayesian enrichment computational analysis of eight gene expression signature showed a more complex network which involves other 10 genes (SIRPG, GZMK, XCL2, CD8A, CD2, IFNG, SIT1, TAGAP, PTPRC and GZMH), correlated with different functional groups. Three main immune-pathways were identified (p < 0.01) (T cell activation, leucocyte activation and migration) involving TIGIT, TNFRSF4, CCR2 and CXCL8 genes among the gene expression signature identified. Gene mutational analysis was feasible for 28 samples. KRAS mutation was detected in 41% of ICI-responders respect to 12.5% of ICI-no responders. Conversely, no STK11 mutation was found in ICI-responders, consistent with previous reports.

      Conclusion

      Our results revealed an immune response gene expression signature of 8 genes differentially expressed between ICI and ICI-no responders. Cancer systems biology analysis approach strengthen our findings identifying an immune molecular network and confirm the correlation of the gene expression signature with relevant immune regulatory functions. If validated, our results may have an important role for the development of a robust test to select patients properly and predict immune response to enable precision immunotherapy. Furthermore, TMB assessment in such subset of patients is under investigation and more data will be available for the meeting.

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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
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-04 - DNA Damage Response Gene Alterations Are Associated with High Tumor Mutational Burden and Clinical Benefit from PD-1 Axis Inhibition in NSCLC (Now Available) (ID 2620)

      09:45 - 18:00  |  Presenting Author(s): Biagio Ricciuti

      • Abstract
      • Slides

      Background

      DNA damage response (DDR) gene alterations are associated with increased tumor infiltrating lymphocytes, higher genomic instability, and higher tumor mutational burden (TMB) in cancer. Whether DDR alterations are associated with benefit from immune-checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) is unknown.

      Method

      Clinicopathologic and genomic data were collected from patients (pts) with advanced NSCLC at the Dana-Farber Cancer Institute treated with PD-(L)1 inhibitors. Targeted next-generation sequencing (NGS) by OncoPanel was used to determine DDR gene mutation status and TMB. All loss-of-function alterations in DDR genes (including nonsense, frameshift, or splice site) were classified as pathogenic. Missense mutations were manually evaluated and classified as pathogenic if considered to be deleterious in the Catalogue of Somatic Mutations in Cancer (COSMIC) and ClinVar databases, as well as the PolyPhen-2 (Polymorphism Phenotyping v2) functional prediction tool.

      Result

      Of 223 pts with successful NGS who received ICIs, 116 (52.0%) were identified as having pathogenic DDR mutations (DDRpos) with alterations in the following genes: FANC genes (20%) ATM (13.9%), POL genes (11%), ERCC genes (8%), BRCA1/2 (8%), MLH1/MSH2/MSH6 (7%), CHEK1/2 (7%), RAD genes (6%), ATR (5%), BRIP1 (3%), XRCC genes (3%), BARD1 (2%), PMS (2%), NEIL (2%), BAP1 (1%), PALB2 (1%). DDRpos and DDR negative (DDRneg) groups were well balanced in terms of age, gender, histology, performance status (PS), smoking status, baseline presence of brain metastasis. The median TMB was significantly higher in the DDRpos group compared to the DDRneg group (12.9 vs 8.3 mutations/megabase [mut/Mb], P < 0.001), including among never smokers (11.0 vs 6.8 mut/Mb, P = 0.02). No difference in median PD-L1 expression was observed between groups (50% vs 50%, P = 0.52). Compared to DDRneg pts (N=107), DDRpos pts had a significantly higher objective response rate (30.4% vs 16.8%, P = 0.001), longer median progression-free survival (4.3 vs 2.3 months, HR: 0.64 [95%CI: 0.48-0.86], P = 0.003) and median overall survival (16.5 vs 11.2 months, HR: 0.62 [95%CI: 0.44-0.88], P = 0.008) with PD-(L)1 therapy. After adjusting for ECOG PS, smoking status, baseline brain metastasis, and line of therapy, DDRpos status was associated with significantly longer PFS (HR: 0.64 [0.48-0.86], P < 0.01) and OS (HR: 0.58 [95%CI: 0.41-0.83], P < 0.01) in multivariate analysis.

      Conclusion

      Pathogenic DDR alterations are frequent in NSCLC and are associated with higher TMB and improved clinical outcomes among NSCLC pts treated with PD-1 axis inhibition.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-32 - Comparison of Clinicopathological and Genomic Characteristics Between NSCLCs with a PD-L1 Tumor Proportion Score of ≥90% vs &lt;1% (Now Available) (ID 2618)

      10:15 - 18:15  |  Author(s): Biagio Ricciuti

      • Abstract
      • Slides

      Background

      Determinants of PD-L1 expression in non-small cell lung cancer (NSCLC) are poorly defined. To identify characteristics associated with high vs. absent PD-L1 expression, we compared clinicopathologic and genomic features of NSCLCs at the two ends of PD-L1 expression spectrum: a PD-L1 tumor proportion score (TPS) of ≥90% or a PD-L1 TPS of <1%.

      Method

      We retrospectively collected clinicopathologic and genomic data (via targeted NGS) from consecutive NSCLC patients who had consented to an IRB-approved correlative research study and whose tumor PD-L1 TPS was either ≥90% or <1%. Single nucleotide variations, insertions/deletions, and copy number alterations were compared using Fisher’s exact test. Tumor mutational burden (TMB) was compared using Mann-Whitney test.

      Result

      421 NSCLCs with PD-L1 TPS ≥90% (N=133) or <1% (N=288) and successfully performed NGS were identified. There was no difference in age, sex, histology, or stage at diagnosis between the two groups. Patients with a PD-L1 TPS of ≥90% were more likely to be smokers (86.5% vs 76.4%; P=0.02) compared to patients with a PD-L1 TPS of <1%, and tumors in the PD-L1 TPS ≥90% group had higher TMB (10.89 vs 8.47 mutations/megabase; P=0.004) than those in the PD-L1 TPS <1% group. Tumors in the PD-L1 TPS ≥90% group were more likely to have KRAS (47.3% vs 31.3%; P=0.002), MET exon 14 (9.6% vs 2.1%; P=0.003), and TP53 mutations (71.0% vs 49.7%; P<0.001) than those in the PD-L1 TPS <1% group. Compared to the PD-L1 TPS ≥90% group, the PD-L1 TPS <1% group was more likely to have EGFR (23.6% vs 8.2%; P<0.001) and STK11 (23.4% vs 5.0%; P<0.001) mutations, as well as the absence of known oncogenic driver mutations (35.2% vs 24.8%; P=0.04). Chromosomal gain alterations (amplification or copy number gain) of the 9p24.1 locus, where the PD-L1, PD-L2, and JAK2 genes are located, were more common in the PD-L1 TPS ≥90% group than in the PD-L1 TPS <1% group (11.4% vs 2.8%, respectively; P<0.001). Chromosomal loss alterations (copy loss or deletion) of the 9p24.1 locus were more common in the PD-L1 TPS <1% than in the PD-L1 TPS ≥90% group (27.5% vs 3.8%, respectively; P<0.001). A repeated biopsy case showed acquired loss PD-L1 expression (PD-L1 TPS changed from 90% to 0%) with concomitant acquired loss of the 9p24.1 locus.

      Conclusion

      High PD-L1 expression in NSCLC is associated with tobacco use, high TMB, gain of the 9p24.1 locus and mutations in KRAS, MET exon 14, and TP53. PD-L1 negativity is associated with never smoking status, low TMB, loss of the 9p24.1 locus, mutations in EGFR and STK11, and the absence of oncogenic driver mutations.

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