Prevalence and Prognostic Effect of High Tumor Mutation Burden (TMB-H) Across Multiple Less Common Solid Cancers Using a Real-World Dataset

Abstract Background Little is known about the prognostic effect of TMB-H among patients with less common cancers who did not receive an immunotherapy (IO). Methods The de-identified Flatiron Health-Foundation Medicine (FMI) Clinico-Genomic Database was used to select patients (pts) with any of 10 solid cancers (Table). 109 Pts with confirmed microsatellite instability-high (MSIH) cancers were excluded, of which 101 pts were endometrial cancer. TMB-H was defined as ≥ 10 mutations per megabase (Mut/Mb) with an additional analysis using a cutoff of 13 Mut/Mb. For overall survival (OS) analysis, Pts with IO were excluded if start of IO earlier than or equal to FMI report date (69 pts), or censored if start of IO later than FMI report date (243 pts). OS was analyzed using Kaplan-Meier method and Cox proportional hazard model, adjusting for age, gender, cancer types, practice type and albumin. A non-inferiority test of TMB-H having longer OS than TMB-low (-L) was carried out with a prespecified hazard ratio (HR) of 0.75. Results Of the 2,589 pts (table), average age at diagnosis was 64 years and 65% were female. Median TMB was 2.6 Mut/Mb overall, ranged from 1.7 (Meso, salivary, thyroid) to 8.7 (SCLC) Mut/Mb. Overall 12.8% were TMB-H with the highest in SCLC (40.0%) and lowest in meso (1.2%). The adjusted HR (AHR) of TMB-H vs. -L was 0.94 (95% CI: 0.77-1.13) for OS from FMI report date, which met the prespecified threshold for non-inferiority by rejecting the null hypothesis. The AHR was 0.84 (0.67-1.05) using alternative cutoff of 13 Mut/Mb. Comparable results were observed when including MSI-H pts and calculating OS from 1st observed antineoplastic treatment date. Table: 1877PD . N TMB-H OS (month, 95%CI) HRadjust Padjust n % TMB-H TMB-L Total 2,589 332 12.8 8.4 (7.4; 11.4) 10.5 (9.5; 11.5) 0.94 (0.77; 1.13) 0.491 SCLC 305 122 40.0 6.4 (5.4; 7.5) 7.4 (5.5; 10.5) 1.03 (0.74; 1.44) 0.863 Neuroendocrine 164 48 29.3 10.4 (6.4; NA) 6.4 (4.5; 10.5) 0.83 (0.48; 1.44) 0.506 Cervical 114 17 14.9 NA (6.4; NA) 7.4 (4.4; 11.5) 0.32 (0.08; 1.31) 0.113 Anal 125 17 13.6 7.4 (2.5; NA) 7.5 (5.5; 15.4) 0.84 (0.40; 1.79) 0.659 Vulvar 30 4 13.3 8.5 (0.5; NA) 6.5 (2.5; NA) 1.18 (0.22; 6.29) 0.848 Salivary 169 22 13.0 4.5 (3.5; NA) 15.5 (10.5; 21.5) 1.20 (0.48; 2.99) 0.691 Endometrial 590 66 11.2 11.4 (8.5; 26.5) 13.5 (11.5; 15.4) 1.15 (0.75; 1.75) 0.522 Biliary 706 28 4.0 11.5 (7.4; NA) 8.4 (7.4; 10.4) 0.65 (0.35; 1.19) 0.162 Thyroid 223 6 2.7 10.2 (1.5; NA) 27.5 (21.5; NA) 1.64 (0.39; 6.96) 0.502 Meso 163 2 1.2 NA 12.5 (8.5; 15.5) - 0.997 Conclusions There is a wide range of TMB among these cancers. Non-inferiority testing and HR estimates comparing OS for TMB-H (≥10 Mut/Mb) vs. -L did not support an effect of TMB on OS in the absence of IO for these cancers. Further research is needed to explore whether the prognostic effect of TMB varies by tumor type or threshold. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure D. Backenroth: Shareholder / Stockholder / Stock options, Full / Part-time employment: Flatiron Health Inc. C. Shao: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co. G. Li: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. L. Huang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co.. S.K. Pruitt: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. E. Castellanos: Full / Part-time employment: Flatiron Health Inc.. G.M. Frampton: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. K.R. Carson: Full / Part-time employment: Flatiron Health Inc.. T. Snow: Full / Part-time employment: Flatiron Health Inc.. G. Singal: Full / Part-time employment: Foundation Medicine. D. Fabrizio: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. B.M. Alexander: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. F.J. Jin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. W. Zhou: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc..