Background: ICIs targeting PD-1/L1 and/or CTLA-4 have activity against many different cancers. We and others have previously shown that a higher TMB, a surrogate for an increased number of expressed tumor neoantigens, is an important biomarker for response to anti-PD-1/L1 monotherapy. Whether the relationship between the TMB and response to ICIs extends beyond anti-PD-1/L1 is unknown. Methods: We identified 30 major solid tumor types for which TMB has been described using a genomic profiling assay performed by Foundation Medicine. We conducted searches of MEDLINE (from Jan 1, 2010 to Jan 20, 2019), as well as abstracts presented at ASCO, ESMO, AACR Annual Meetings 2010-2018 to identify the objective response rate (ORR) for anti-PD-1/L1, anti-CTLA-4 and combination anti-PD-1/L1 plus anti-CTLA-4, in each of these cancer types. We pooled the response data from the largest published studies that evaluated the ORR. We excluded studies that; enrolled < 10 evaluable patients, investigated ICI therapies in combination with other agents, and studies that selected patients based on immune-related biomarkers. Across tumor types, median TMB was compared to ORR utilizing the coefficient of determination (r²) derived from simple linear regressions. Results: TMB is strongly associated with response to anti-PD-1/L1 monotherapy (n = 8798, r²= 0.4704, p < 0.001), and combination anti-PD-1/L1 plus anti-CTLA-4 (n = 2280,r²= 0.4082, p = 0.004). Available ORR data were more limited with CTLA-4 monotherapy and the relationship between ORR and TMB did not meet statistical significance (n = 1377, r²= 0.2606, p = 0.1086). The additional ORR benefit of adding a CTLA-4 inhibitor to anti-PD-1/PDL1 therapy increased with increasing TMB. In tumor types with a lower TMB ( < 10 mutations/MB), combined ICI therapy led to an average improvement of 5.5% in ORR over PD-1/L1 monotherapy, versus 21.8 % ORR improvement in high TMB tumors (≥10 mutations/MB). Conclusions: A strong relationship exists between TMB and clinical activity of both PD-1/L1 monotherapy and combination ICIs with PD-1/L1 plus CTLA-4. The clinical benefit of adding anti-CTLA-4 to anti-PD-1/L1 is greatest in high TMB tumors and limited in low TMB tumors.