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MA19 - Genomic Markers of IO Response (ID 922)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Immunooncology
- Presentations: 1
- Coordinates: 9/25/2018, 15:15 - 16:45, Room 201 BD
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): Niamh Long
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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