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Stephanie S Yee



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    MA25 - Precision Medicine in Advanced NSCLC (ID 352)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA25.04 - Blood-Based Tumor Mutation Burden as a Predictive Biomarker for Outcomes After Pembrolizumab Based First Line Therapy in Metastatic NSCLC (Now Available) (ID 2717)

      14:30 - 16:00  |  Author(s): Stephanie S Yee

      • Abstract
      • Presentation
      • Slides

      Background

      PD-1 blockade with pembrolizumab (P) as monotherapy in patients with PD-L1 TPS > 50% or in combination with platinum based chemotherapy (PC) is the current standard front-line therapy for metastatic non-small cell lung cancer (mNSCLC). We explored the correlation of blood (b) based tumor mutational burden (TMB) using circulating tumor DNA (ctDNA) with outcomes after front line P and PC therapy.

      Method

      Patients with newly diagnosed metastatic NSCLC starting standard of care front line P-based therapy were enrolled. Plasma was prospectively collected at baseline prior to initiation of P or PC therapy for mNSCLC. A 2.145 megabase (Mb) next-generation sequencing panel was used to assess bTMB. A bTMB cutoff of ≥16 mut/Mb was selected based on previously published data (Gandara et al, Nature 2018). Response was assessed using RECIST 1.1. Durable clinical benefit (DCB) was defined as complete response/ partial response/ stable disease that lasted > 6 months. Correlations were made for patient demographics, tumor characteristics, DCB, progression free survival (PFS), and overall survival (OS) using logistic regression and Cox proportional hazards models. Significance was determined at the 0.05 level.

      Result

      66 pts with mNSCLC were enrolled, median age 67 years (range 47-89), current or ex-smokers (n=61, 92%). Thirty-one patients (47%) received P (all PD-L1>50%); 35 received platinum-pemetrexed based PC. At the time of data cut off, median OS for P was 14.8 months, and not reached for PC. bTMB was evaluable for 52 patients (n=26 P, 26 PC), median bTMB was 16.8 mutations per Mb (mut/Mb, range 1.9-52.5). There was no correlation between bTMB and tumor PD-L1 (p=0.28). Median bTMB for patients achieving DCB was higher than for those with no clinical benefit, 21.3 mut/Mb vs. 12.4 mut/Mb, p=0.004. For patients with bTMB ≥ 16 mut/Mb, median PFS was 13.8 vs. 4.7 months for patients with bTMB <16 mut/Mb (HR 0.27 [0.13-0.55]). Median OS was not reached for bTMB ≥ 16 mut/Mb (HR 0.47 [0.20-1.1]). Loss of function mutations in STK11, KEAP1, or PTEN, or ERBB2 exon 20 insertion were enriched in patients with no clinical benefit. Combined score using bTMB ≥ 16 mut/Mb and mutations in STK11, KEAP1, or PTEN, or ERBB2 exon 20 insertions resulted in improved prediction for DCB; PFS HR of 0.18 [0.08-0.41] and OS HR of 0.27 [0.10-0.73].

      Conclusion

      Our early results suggest that bTMB using plasma ctDNA may predict therapeutic outcomes after first line P-based therapy in mNSCLC. Loss of function mutations in STK11/KEAP/PTEN and ERBB2 exon 20 insertion mutations appear to be negative predictors of benefit. As the sample size is limited and findings are reported on a pooled group of P and PC patients, the role of bTMB and response to P and PC based therapy separately should be validated in a larger prospective study.

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