ASCO 2017: DNA damage repair and response gene alterations and response to PD1/PDL1 blockade in platinum-treated metastatic urothelial carcinoma

Chicago, IL ( Recent introduction of PD/PDL1 immune checkpoint inhibitors (ICI) has redefined the treatment landscape of metastatic urothelial carcinoma. Different potential biomarkers of treatment responses have been proposed. It is known that mutational load (ML) is associated with clinical response to ICI in urothelial carcinoma (UC) and other cancers. ML is a continuous variable without a validated cut-off point for clinical benefit and lower values do not preclude benefit.

DNA damage response (DDR) genes maintain genomic fidelity. DDR defects therefore, can lead to genomic instability, tumorigenesis and cancer progression. It has been shown that genomic alterations in DDR genes are frequent UC. Additionally, DDR alterations (DDRALTs) are associated with clinical benefits in platinum treated UC. Additionally, DDRALT is associated with higher mutational load. (Teo et al, CCR 2017).

Dr. Teo presented a study examining the relationship between DDRALT and response to PD1/PDL1 blockade in metastatic UC. The study included metastatic UC patients enrolled to phase 2 trials of atezolizumab or nivolumab who had targeted exon sequencing of 410 genes (MSK-IMPACT). Patients were divided into 2 groups based on presence of DDRALTs in a panel of 34 DDR genes.

Two analyses were performed:
(1) Any DDRALTs
(2) Deleterious DDRALTs (frameshift, splice site, nonsense or Hotspot point mutations). Mutation load was defined as total number of nonsynonymous mutations by MSK-IMPACT. The MSK- IMPACT is the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets. This is an approved hybridization capture based next generation sequencing clinical assay of >=341 cancer related genes. The primary endpoint of the study was best objective response (OR) and secondary endpoints were progression free survival and overall survival (OS).

Overall, after exclusion of 18 patients, 51 pts were identified and analyzed. Median age was 66 years (range: 32 – 84) and majority (44) were male. Median platinum-free interval was 9.9 months (range: 0.3 – 150). DDR and deleterious DDR were seen in 25 (48.1%) and 14 (26.9%) patients. OR rate was 46.2%. Responses were associated with DDRALTs but not with age, gender, treatment, platinum-free interval or mutational load. In univariate logistic regression model, DDR status was associated with OR (p<.001) while a trend was observed with a mutational load as a continuous variable (p=.051). While DDRALTs were associated with higher mutational load, the effect of DDRALTs on OR remained significant regardless of the mutational load, indicating that the effect of DDR was completely independent of the mutational load.

Study limitations included its small sample size from only one institution, a clear selection bias of patients with better prognostic features (possibly accounting for the higher response rates), and the assumption that each DDR gene or mechanism confers similar clinical and genetic impact.

Dr. Teo concluded his presentation by stating that DDRALTs are seen in almost 50% of these patients, and that they appear to be associated with OR to PD1/PDL1 and improved progression free and overall survival. Naturally, these preliminary findings warrant further validation in future prospective studies.

Presented By: MinYuen Teo, Memorial Sloan Kettering Cancer Center, New York, NY; Memorial Sloan-Kettering Cancer Center, New York, NY

Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre
Twitter: @GoldbergHanan

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA