Author of

• 25910

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  MA19 - Genomic Markers of IO Response (ID 922)

  • Event: WCLC 2018
  • Type: Mini Oral Abstract Session
  • Track: Immunooncology
  • Presentations: 2
  • Moderators:
  • Coordinates: 9/25/2018, 15:15 - 16:45, Room 201 BD

  • 26112

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    MA19.01 - Efficacy and Genomic Correlates of Response to Anti-PD1/PD-L1 Blockade in Non-Small Cell Lung Cancers Harboring Targetable Oncogenes (ID 12921)

    15:15 - 15:20  |  Author(s): Hira Rizvi
    • Abstract
    • Presentation
    • Slides

    Background
    

    Immune-checkpoint inhibitors (ICIs) are associated with improved outcomes in a subset of patients with advanced non-small cell lung cancer (NSCLC). NSCLCs with targetable oncogenes are thought to be less responsive to ICI therapy, possibly due to association with never smoking status and reduced tumor mutational burden (TMB), but this has not been comprehensively characterized. We evaluated the responsiveness of NSCLCs with targetable oncogenes to ICIs, and if mutation type or TMB influence response.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    Clinicopathologic, radiographic response, and sequencing data for patients with advanced NSCLC treated with ICI therapy was acquired from two separate cohorts (DFCI Oncopanel, n=296; MSKCC MSK-IMPACT, n=202). Durable clinical benefit (DCB) was defined as responsive/stable disease > 6 months. Samples with activating mutations in EGFR, ALK, ROS, BRAF, MET, and RET were identified. TMB was calculated as the sum of nonsynonymous mutations divided by the coding region captured in each panel. Objective response rates (ORR), DCB, and TMB were compared in targetable oncogene positive (TOP) vs oncogene negative (TON) patients. TMB was considered within each cohort to avoid confounding for differences in NGS panel technique.

    4c3880bb027f159e801041b1021e88e8 Result
    

    Targetable oncogenes were identified in 16% (82/498) of patients; 44(9%) EGFR, 15(3%) MET exon 14 splice site mutated, 8(2%) BRAF V600E, 6(1%) ROS1 rearranged, 5(1%) ALK rearranged, and 4(1%) RET re-arranged. Response to ICIs was similar in TOP vs TON patients, with ORR of 18% and 20%, and median PFS of 2.7 vs 2.8 months in TOP vs TON patients respectively. Among TOP patients, response rates differed by mutation type; ORR rate was 11%(5/44) in EGFR mutated, 40%(6/15) in MET mutated, 25%(2/8) in BRAF mutated, 33%(2/6) in ROS1 rearranged, and 0% in RET and ALK rearranged cancers (0/4, 0/5 respectively). Compared to WT, TMB was lower in TOP tumors (OncoPanel median 9vs11, p=0.0064; IMPACT median 4vs8, p=2.25e-06). TMB did not correlate with objective response or DCB in TOP tumors when considered collectively or by mutation type (OncoPanel median TMB 10vs8 in DCB vs NDB, p=0.52; IMPACT median TMB 3vs5 in DCB vs NDB, p=0.31)(Mann-Whitney U for all).

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    Despite lower TMB in oncogene positive NSCLC, these patients still derive clinical benefit from ICIs. ICI responsiveness is likely mutation specific, and is most pronounced in MET and BRAF mutated cancers. Among targetable oncogene positive NSCLC, TMB did not distinguish benefit. Taken together, low TMB in the presence of oncogenic driver mutations should not preclude ICI therapy.

    6f8b794f3246b0c1e1780bb4d4d5dc53

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  • 26119

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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): Hira Rizvi
    • 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.

    6f8b794f3246b0c1e1780bb4d4d5dc53

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