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Darragh Halpenny



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    MA19 - Genomic Markers of IO Response (ID 922)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 201 BD
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      MA19.09 - Concurrent Mutations in STK11 and KEAP1 is Associated with Resistance to PD-(L)1 Blockade in Patients with NSCLC Despite High TMB (ID 11983)

      16:10 - 16:15  |  Author(s): Darragh Halpenny

      • Abstract
      • Presentation
      • Slides

      Background

      Targeted next generation sequencing (NGS) testing for lung cancer patients identifies recurrent patterns of co-mutations. STK11 is known to be associated with poor outcomes with immunotherapy. We have identified that STK11 is commonly co-mutated with KEAP1, but the impact of this pattern of co-mutation on response to immunotherapy is not known.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We identified 308 patients with advanced lung cancer treated at Memorial Sloan Kettering Cancer Center who underwent NGS testing with MSK-IMPACT and received at least one dose of PD-(L)1 inhibitor. Progression free survival (PFS) and overall survival (OS) from treatment initiation of PD-(L)1 blockade were calculated using Kaplan-Meier methodology and compared using logrank method and t-test for continuous variables.

      4c3880bb027f159e801041b1021e88e8 Result

      In a cohort of 308 patients with NSCLC treated with PD-(L)1 blockade, STK11 or KEAP1 mutations occurred frequently (23% and 22% respectively) and concurrent STK11 and KEAP1 mutations (STK11mut/KEAP1mut) were common (56% of all STK11 mutant patients and 13% of all lung cancers, Fisher’s test of association p<0.0001). Other common co-mutations with STK11 included KRAS (50%) and TP53 (48%). STK11mut/KEAP1mut patients had higher TMB than STK11wt/KEAP1wt patients (median 9.4 vs 6.1, Mann-Whitney p= 0.0002).

      STK11mut/KEAP1mut (n=39) patients had diminished PFS and OS compared to patients with STK11wt/KEAP1wt (n=210) (PFS HR 1.5, p=0.02; OS HR 2.3, p=0.001). As context, outcomes in STK11mut/KEAP1mut patients were similarly poor to EGFR mutant patients (n=28) treated with PD-(L)1 blockade (PFS p=0.7) despite substantially different tumor mutation burden (9.4 vs 4.9 mut/Mb, p<0.0001). Among STK11mut/KEAP1mut patients, poor outcomes were unchanged irrespective of KRAS status (PFS p=0.8, OS p=0.5). Patients with mutations in STK11 alone (n=31) or KEAP1 alone (n=28) had outcomes that more closely mirrored STK11wt/KEAP1wt patients (PFS p=0.9 and 0.1 respectively, OS p=0.1 and 0.2 respectively).

      8eea62084ca7e541d918e823422bd82e Conclusion

      KEAP1 plus STK11 co-mutation is a common event in NSCLC that is distinctly associated with poor outcomes with PD-(L)1 blockade despite otherwise favor molecular features.

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