Alterations in DNA Damage Response and Repair Genes and Response to PD-1/PD-L1 Inhibitors in Advanced Urothelial Cancer

Key Points

  • DDR gene alterations were associated with higher objective response rates.
  • DDR gene alterations were associated with improved progression-free and overall survival. 

In a study reported in the Journal of Clinical Oncology, Teo et al found that alterations in DNA damage response and repair (DDR) genes, particularly known or likely deleterious alterations, were associated with response to programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibition in patients with advanced urothelial cancer.

Study Details

The study involved data from 60 patients from trials of atezolizumab (Tecentriq) or nivolumab (Opdivo) who had targeted exon sequencing performed on preimmunotherapy tumor specimens. The presence of DDR alterations was correlated with best objective response on RECIST criteria.

Any DDR alterations and known or likely deleterious DDR mutations were identified in 28 (47%) and 15 (25%) patients. The presence of any DDR alteration was associated with a higher response rate (67.9% vs 18.8%, P < .001); the response rate among patients with known or likely deleterious mutations was 80%, compared with 54% in those with alterations of unknown significance and 19% among those with wild-type DDR genes (P < .001 overall).  

On multivariate analysis, both any DDR alteration vs wild-type (odds ratio [OR] = 5.79, P = .024) and known/likely deleterious DDR alteration vs wild-type (OR = 19.02, P < .001) were independently associated with objective response. The presence of visceral metastases was independently associated with a reduced likelihood of response.

Mutation load was a significant predictor of response on univariate analysis but was not included in the multivariate analysis including DDR status because of collinearity with DDR status. In an alternative multivariable model including mutation load in place of DDR status, mutation load, and visceral metastases were independent predictors of response, with an Akaike information criterion value of 70.25 vs 66.09 for the model including DDR status. The authors noted this finding suggests that models incorporating DDR alterations provide more information vs those including mutation load. DDR status also was an independent predictor of response when analysis controlled for mutation load.

Progression-Free and Overall Survival

Median progression-free survival was not reached among patients with deleterious DDR alterations (12-month rate = 56.6%), 15.7 months in those with DDR alterations of unknown significance, and 2.9 months in those without DDR gene alterations. Median overall survival was not reached (12-month rate = 71.5%), 23.0 months, and 9.3 months in the three groups, respectively.

The investigators concluded, “DDR alterations are independently associated with response to PD-1/PD-L1 blockade in patients with metastatic urothelial carcinoma. These observations warrant additional study, including prospective validation and exploration of the interaction between tumor DDR alteration and other tumor/host biomarkers of immunotherapy response.”

The study was supported by Roche, Genentech, Bristol-Myers Squibb, and a National Cancer Institute grant.

Jonathan E. Rosenberg, MD, of the Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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