DNA damage repair and response (DDR) gene alterations (alt) and response to PD1/PDL1 blockade in platinum-treated metastatic urothelial carcinoma (mUC).

Abstract

4509 Background: Somatic DDR alts are associated with increased mutation load (ML) and improved clinical outcomes for platinum-treated mUC (Teo et al, CCR 2017). We examined the relationship between DDR alts and response to PD1/PDL1 blockade. Methods: mUC pts enrolled to phase 2 trials of atezolizumab or nivolumab who had targeted exon sequencing of 410 genes (MSK-IMPACT) were identified. Pts were dichotomized based on presence of alts in a panel of 34 DDR genes. Analyses were performed based on: (1) any DDR alts and (2) deleterious DDR alts (frameshift, splice site, nonsense or Hotspot point mutations). Study endpoint was overall response (OR) per RECIST. ML was defined as total number of nonsynonymous mutations by MSK-IMPACT. Fisher exact, Wilcoxon rank sum, and stratified logistic regression were used. Results: Fifty two pts were identified (atezo: n=18, nivo: n=34). Median age was 67 years (range: 32 – 84) and majority (44) was male. Median platinum-free interval was 10.2 months (range: 0.3 – 150.4). DDR and deleterious DDR were seen in 25 (48.1%) and 14 (26.9%) pts (including 2 MSI and 1 POLE). OR rate was 46.2%. Responses were associated with DDR alts but not with age, gender, treatment, platinum-free interval or ML (table). In univariate logistic regression model, DDR status was associated with OR (p<.001) while a trend was observed with ML as a continuous variable (p=.051). While DDR alts were associated with higher ML (all: p=.001, deleterious: p=.004), the effect of DDR alts on OR remained significant regardless of ML (>median: p=.027; ≤median: p=.023), indicating that the effect of DDR was independent of ML. Conclusions: DDR alts appeared to be associated with OR to PD1/PDL1 blockade and should be integrated into future validation efforts along with other potential predictors of response. [Table: see text]

ATM/RB1 mutations predict shorter overall survival in urothelial cancer

“…Recently, there is an increased interest in cancer somatic mutation load because it is being considered a potential predictive biomarker of response to immune checkpoint inhibitors across tumor types, including UC [ 14 ]. Tumor cells with high mutation load may have more neoantigens, and therefore are more likely to respond to immunotherapy.…”

Immune checkpoint inhibitors in urothelial cancer: recent updates and future outlook

“… 88 Teo et al recently reported, based on an analysis of 52 patients with advanced UC, that the presence of alterations in DNA damage response genes correlated positively with response to PD-1/PD-L1 blockade, and this effect was independent of mutational load. 89 Similarly, Iyer et al in a study of UC patients found that dMMR tumors, though rare (3%), were characterized by high mutational load, MSI-high status, strong association with Lynch syndrome and durable response to ICI. 90 …”

Novel therapies in urothelial carcinoma: a biomarker-driven approach

“…Defects in other DDR genes, including RB1, ATM, and FANCC, were detected in patients who responded to NAC [69]. Emerging evidence also suggests an association between overall response to PD1/PD-L1 blockade and the presence of somatic DDR alterations [70]. A high frequency of patients with germline DDR mutations has also been reported.…”