Alterations in DNA Damage Response and Repair Genes as Potential Marker of Clinical Benefit from PD-1/PD-L1 Blockade in Advanced Urothelial Cancers

Alterations in DNA damage response and repair (DDR) genes are associated with increased mutation load and improved clinical outcomes in platinum-treated metastatic urothelial carcinoma. We examined the relationship between DDR alterations and response to PD-1/PD-L1 blockade.

Methods: Detailed demographic, treatment response and long-term outcome data were collected on patients with metastatic urothelial carcinoma treated with atezolizumab or nivolumab who had targeted exon sequencing performed on pre-immunotherapy tumor specimens. Presence of DDR alterations was correlated with best objective response per Response Evaluation Criteria in Solid Tumors (RECIST) and progression-free and overall survival.

Results: Sixty patients with urothelial cancer enrolled in prospective trials of anti-PD-1/PD-L1 antibodies met inclusion criteria. Any DDR and known or likely deleterious DDR mutations were identified in 28 (47%) and 15 (25%) patients, respectively. The presence of any DDR alteration was associated with a higher response rate (67.9% v 18.8%; P < .001).  A higher response rate was observed in patients whose tumors harbored known or likely deleterious DDR alterations (80%) compared with DDR alterations of unknown significance (54%) and in those whose tumors were wild-type for DDR genes (19%; P < .001). The correlation remained significant in multivariable analysis that included presence of visceral metastases.

DDR alterations also were associated with longer progression-free and overall survival.

Conclusion:  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.

Author Information:
Teo MY1, Seier K1, Ostrovnaya I1, Regazzi AM1, Kania BE1, Moran MM1, Cipolla CK1, Bluth MJ1, Chaim J1, Al-Ahmadie H1, Snyder A1, Carlo MI1, Solit DB1, Berger MF1, Funt S1, Wolchok JD1, Iyer G1, Bajorin DF1, Callahan MK1, Rosenberg JE1.

Min Yuen Teo, Kenneth Seier, Irina Ostrovnaya, Ashley M. Regazzi, Brooke E. Kania, Meredith M. Moran, Catharine K. Cipolla, Mark J. Bluth, Joshua Chaim, Alexandra Snyder, Maria I. Carlo, Michael F. Berger, Samuel Funt, Jedd D. Wolchok, Margaret K. Callahan, and Jonathan E. Rosenberg, Memorial Sloan Kettering Cancer Center; and Hikmat Al-Ahmadie, David B. Solit, Gopa Iyer, and Dean F. Bajorin, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY.

J Clin Oncol. 2018 Jun 10;36(17):1685-1694. doi: 10.1200/JCO.2017.75.7740. Epub 2018 Feb 28