Association between tumor mutational burden (TMB) and immune-related adverse events (irAEs) in patients (pts) with metastatic urothelial carcinoma (mUC) during checkpoint immunotherapy.

Abstract

489 Background: Immune checkpoint inhibition (ICI) has greatly improved clinical outcomes for pts with mUC and other cancers. ICI is associated with a class of AEs, deemed irAEs due to immune activation. Nonetheless, biomarkers associated with irAE are still lacking. We hypothesized that the immune response against neoantigens is partly responsible for irAEs and investigated the association between irAEs, TMB and response to ICI. Methods: We identified patients with mUC at Dana Farber Cancer Institute who were treated with ICI (monotherapy or combination) and had available tumor sequencing data through Oncopanel. TMB was calculated using the number of non-synonymous exonic mutations per megabase. The severity of irAEs was graded using CTCAE v.5.0. Mann-Whitney U test was performed to identify association between TMB, incidence and grade of irAEs. A cut-off of 10/mb was assigned for TMB. Fisher’s exact test was used to evaluate the radiologic response between pts with and without irAEs and low vs. high TMB. Multivariable linear regression was used to assess the relationship between TMB, irAEs and response. p-values were adjusted using Benjamini-Hochberg method. Results: Of 101 pts with mUC who met the inclusion criteria, 32 (32%) reported irAEs. 6 (6%) were grade (G)1, 20 (20%) were G2, and 6 (6%) were G3. Median(m) time on therapy was 84 days for pts without irAEs and 88 days for pts with irAEs. Pts with irAEs had higher mTMB (15.4/mb) compared to pts with no irAEs (9.8) ( p = 0.01). In pts on monotherapy (93), those with irAEs (n=27) had a higher mTMB (15.13/mb) compared to pts with no irAEs (n=66) (mTMB = 10.20/mb) ( p = 0.01). Out of 94 pts with radiological data, response was achieved in 16 (50%) pts with irAE vs 10 (16%) pts with no irAE ( p < 0.001). When both irAE and response were included in a multivariable regression, the association between irAE and TMB was not significant ( p = 0.4). Pts with both irAE and high TMB had a response rate of 56% which was significantly higher than those with either irAE but low TMB (28.6%) or high TMB but no irAE (21.2 %) or low TMB and no irAE (10.3%) (Chi-square test p = 0.002; FDR corrected p-values for individual comparisons in Table). There was no association between TMB and irAE grade. Conclusions: Higher TMB was associated with higher incidence of irAEs in pts with mUC on ICIs. Moreover, pts with both high TMB and irAEs exhibited better response rates than those with only high TMB or irAEs, suggesting that they may provide complementary tumor and host characteristics. Further evaluation in mUC is needed to confirm this relationship between TMB, irAEs and response in a larger cohort and explore specific mutational signatures that may be associated with irAEs. [Table: see text]