Abstract 97P
Background
Response to immune checkpoint inhibitors (ICI) relies on T-cell recognition of neoantigens on the surface of tumor cells. It is hypothesized that the clonality of a neoantigen determines the probability of its presentation to the immune system, with more clonal neoantigens having a higher likelihood of recognition. Using a TMB (tumor mutational burden) metric that is comprised of only clonal variants (cTMB) could refine TMB as a biomarker of ICI response. We sought to describe the pan-cancer landscape of cTMB as compared to TMB.
Methods
Tumor samples were assayed during routine clinical care, by hybrid capture-based comprehensive genomic profiling (Foundation Medicine, MA, USA). TMB was defined as the number of non-driver somatic mutations identified on up to 1.1 megabases (Mb) of sequenced DNA. For every sample, TMB variants with a cancer cell fraction < 0.5 were filtered out to calculate the cTMB. Mutational signatures (sig) were assigned based on the COSMIC (Catalogue of somatic mutations in cancer) signatures.
Results
The median TMB and median cTMB of the evaluable cohort (N=233,981) across 46 solid tumor types was 3.7 [1.3-6.7] and 2.7 [1.3-5.3] mutations per Mb (mut/Mb) respectively, with 59.1% of the samples having an identical TMB and cTMB (ITC). Distribution across major tumor types shown below (Table). Smoking sig in NSCLC (Non-small cell lung cancer; 34.7% vs 50.8%, P=8.9x10-105), ultra-violet sig in melanoma (55.1% vs 75.4%, P=1.7x10-67), mismatch repair sig in colorectal (26.0% vs 62.7%, P=1.5x10-229) and alkylating sig in glioma (7.1% vs 73.4%, P=1.4x10-55) had significantly lower ITC compared to their respective wildtypes. Local tumors had a comparable ITC to that of metastatic tumors (59.1% vs 58.9%). Table: 97P
| Sig | N | Median TMB | Median cTMB | ITC (%) | |
| NSCLC | Smoking | 5220 | 14.7[10.1-21.4] | 12.9[8.3-18.7] | 34.7 |
| Smoking wt | 33127 | 5.5[2.7-10.1] | 4.6[2.7-8.3] | 50.8 | |
| Colorectal | dMMR | 2021 | 10.7[6.4-41.4] | 8.3[5.3-36.1] | 26.0 |
| dMMR wt | 28648 | 2.8[1.8-5.3] | 2.7[1.3-4.0] | 62.7 | |
| Glioma | Alkylation | 127 | 65.5[39.8-106.9] | 40.1[17.4-62.6] | 7.1 |
| Alkylation wt | 7595 | 1.8[0.9-2.8] | 1.3[0.9-2.8] | 73.4 | |
| Melanoma | UV | 3394 | 21.2[12.0-38.8] | 20.1[12.0-36.8] | 55.1 |
| UV wt | 3184 | 2.7[1.3-5.3] | 2.7[0.9-4.0] | 75.4 | |
| Breast | 29190 | 2.7[1.3-5.3] | 1.8[1.3-4.0] | 57.8 | |
| Ovary | 16314 | 2.7[1.3-4.0] | 1.8[0.9-2.8] | 58.7 | |
| Pancreas | 11995 | 1.8[1.3-2.8] | 1.3[0.9-2.7] | 75.8 | |
| Prostate | 11829 | 1.8[1.3-3.7] | 1.3[0.9-2.7] | 70.5 | |
| Esophagus | 7777 | 4.0[2.7-6.7] | 2.8[1.3-5.3] | 47.9 |
Conclusions
cTMB is diverse across tumor types and it needs to be evaluated as a predictor of ICI response pan-cancer, using tumor-type specific cTMB thresholds.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Foundation Medicine, Inc.
Funding
Has not received any funding.
Disclosure
A.R. Parikh: Financial Interests, Personal, Stocks/Shares: C2i Genomics; Financial Interests, Personal, Advisory Role: Eli Lilly, Natera, Checkmate Pharmaceuticals, Pfizer, Inivata, Biofidelity, Guardant Health; Financial Interests, Personal, Research Grant: Plexxicon (Inst), Takeda (Inst), Bristol Myers Squibb (Inst), Genentech (Inst), Guardant Health (Inst), Novartis Pharmaceuticals UK Ltd (Inst), PureTech (Inst), PMV Pharma, Mirati Therapeutics (Inst), Daiichi Sankyo (Inst); Financial Interests, Personal, Other, DSMC: Roche. K. Murugesan: Financial Interests, Institutional, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Institutional, Stocks/Shares: Roche Holding AG. J.F. Hopkins: Financial Interests, Institutional, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Institutional, Stocks/Shares: Roche Holding AG. Z. Arshad: Financial Interests, Institutional, Full or part-time Employment: Georgia Institute of Technology. D.X. Jin: Financial Interests, Institutional, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Institutional, Stocks/Shares: Roche Holding AG. S.J. Klempner: Financial Interests, Personal, Stocks/Shares: Turning Point Therapeutics, Nuvalent Inc.; Financial Interests, Personal, Other, Honoraria: Natera; Financial Interests, Personal, Advisory Role: Lilly, Astellas Pharma, Bristol Myers Squibb, Pieris Pharmaceuticals, Merck, Daiichi Sankyo/UCB Japan, Sanofi/Aventis, Mersana; Financial Interests, Personal, Research Grant: Leap Therapeutics (Inst), BeiGene (Inst), Silverback Therapeutics (Inst); Financial Interests, Personal, Other: NCCN. D.A. Fabrizio: Financial Interests, Institutional, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Institutional, Stocks/Shares: Roche Holding AG. G.M. Frampton: Financial Interests, Institutional, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Institutional, Stocks/Shares: Roche Holding AG. J. He: Financial Interests, Institutional, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Institutional, Stocks/Shares: Roche Holding AG. M. Montesion: Financial Interests, Institutional, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Institutional, Stocks/Shares: Roche Holding AG.