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Deepti Venkatraman



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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): Deepti Venkatraman

      • 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): Deepti Venkatraman

      • 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  |  Author(s): Deepti Venkatraman

      • 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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