Abstract 107P
Background
Inactivating genomic alterations (GA) in the tumor suppressor genes STK11 (STK11mut) and KEAP1 (KEAP1mut) have been linked to ICPI resistance in NSCLC. The following pan-genomic study compares the CGP in both STK11mut and KEAP1mut solid tumors and hematologic malignancies.
Methods
CGP was performed on FFPE samples from 297,209 clinically advanced solid tumors and hematologic malignancies. Tumor mutational burden (TMB) was determined on 0.8 to 1.2 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression in tumor cells (Dako 22C3) was measured by IHC.
Results
11,670 (3.9%) and 5,027 (1.7%) featured STK11 and KEAP1 inactivating mutations respectively. Ages were similar; KEAP1mut patients slightly more often male. Inactivation of STK11 was by base substitution in 80% and genomic loss in 20% and for KEAP1 it was 92% base substitutions and 8% genomic loss. NSCLC was the predominant disease type with both SK11mut (65%) and KEAP1mut (55%) cases. 14% of NSCLC featured STK11mut which was most frequent in adenocarcinomas. CUP was the second most frequent tumor type with either STK11mut and KEAP1mut. No other tumor types featured greater than 5% mutation frequencies. Concurrent alteration of the two genes was seen in a greater portion of KEAP1mut than STK11mut (38% vs. 16%, p<0.001). STK11mut had 6.4 GA/tumor; median TMB of 7.4 mut/Mb and 37% PD-L1>1% staining. KEAP1mut had 7.4 GA/tumor, median TMB of 8.8 mut/Mb and 44% PD-L1>1% staining. GA in KRAS, TP53, CDKN2A/B and SMARCA4 were similar in both groups with the SMARCA4 possibly indicating a significant number of CUP cases were actually TTF-1 IHC negative NSCLC.
Conclusions
STK11mut and KEAP1mut occur predominantly in NSCLC with SK11mut more frequent in KEAP1mut cases than vice versa. STK11mut and KEAP1mut tumors are similar in disease type, age, gender, alteration types, frequencies of co-alterations with KRAS, TP53, CDKN2A/B, SMARCA4 and numerous other genes. In addition, STK11mut and KEAP1mut tumors feature biomarkers predictive of ICPI benefit despite the likelihood of resistance and a paucity of targeted therapy opportunities.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Foundation Medicine Inc.
Funding
Foundation Medicine Inc.
Disclosure
B. Alexander: Leadership role, Full/Part-time employment: Foundation Medicine Inc.; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Puma; Research grant/Funding (institution): Eli Lilly. E.S. Sokol: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. N.A. Danziger: Full/Part-time employment: Foundation Medicine Inc. D.C. Pavlick: Full/Part-time employment: Foundation Medicine Inc. J. Elvin: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. J.K. Killian: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. D.I. Lin: Full/Part-time employment: Foundation Medicine Inc. E. Williams: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. S. Ramkissoon: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. E. Severson: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc.; Full/Part-time employment: Partners Healthcare. A. Hemmerich: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. D. Duncan: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. C. Edgerly: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. R. Huang: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc.; Licensing/Royalties, IHC patent: Roche/Ventana. M. Hiemenz: Full/Part-time employment: Foundation Medicine Inc. P. Reddy: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. K. McGregor: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. J. Venstrom: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc.; Full/Part-time employment: Genentech. A.B. Schrock: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. J.S. Ross: Leadership role, Research grant/Funding (self), Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc.; Advisory/Consultancy: Celsius Therapeutics.