DDR Alterations Associated With Increased Anti-PD-1/PD-L1 Activity in Bladder Cancer

Jonathan E. Rosenberg, MD

Alterations in DNA damage response and repair (DDR) genes were associated with an increased response to anti-PD-1/PD-L1 antibodies in patients with metastatic urothelial carcinoma, according to findings published in the Journal of Clinical Oncology.

In a retrospective analysis of 3 prospective trials, patients with any DDR and known or likely deleterious DDR mutations were more likely to respond to anti-PD-1/PD-L1 treatment (67.9% vs 18.8%; P <.001). Investigators also observed a higher response rate 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.

“Whether the association is predictive or prognostic should be investigated further in larger data sets from randomized studies that have led to the FDA approval of several anti-PD-1/PD-L1 agents. In addition, we plan to validate these findings prospectively in an upcoming randomized phase II study of atezolizumab or atezolizumab plus bevacizumab in metastatic urothelial carcinoma,” corresponding author Jonathan E. Rosenberg, MD, Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, and colleagues wrote.

“Additional investigation is warranted to evaluate the mechanisms that link DDR alterations beyond MMR, [mutation load] and neoantigen load, and immunotherapy response. If validated in other studies, DDR alterations may represent a useful predictive biomarker of response to anti-PD-1/PD-L1 in urothelial carcinoma,” added Rosenberg et al.

Rosenberg and his coinvestigators identified 60 patients with urothelial cancer who met inclusion criteria. They recorded 74 DDR gene alterations in 28 patients (46.7%), with a median of 1 DDR alteration per patient (range, 1-34). Overall, 15 patients (25%) were observed to have a total of 27 deleterious DDR gene alterations. The most commonly altered genes were ATM (n = 7) and POLE (n = 3).

The median age of the cohort was 67 years (range, 31.6-83.5), and 88.3% of patients were male. Fifteen patients (25.0%) had an ECOG performance status of 0, and the rest had an ECOG performance status of 1. Over three-fourths of patients (76.7%) had visceral metastases.

Five patients were treated with first-line anti-PD-1/PD-L1, and 17 were treated after progression within 12 months of neoadjuvant cisplatin-based chemotherapy. Median time from the end of platinum-based chemotherapy to anti-PD-1/PD-L1 was 9.2 months (range, 0.3-150.0). Most patients (71.7%) received nivolumab (Opdivo). The remaining patients were treated with atezolizumab (Tecentriq).

At a median follow-up of 19.6 months, the median progression-free survival (PFS) was not reached for patients with deleterious DDR alterations and the 12-month PFS rate was 56.6%. The median PFS for patients with DDR alterations of unknown significance was 15.7 months and 2.9 months for those without DDR gene alterations.

In a multivariable model, hemoglobin <10 g/dL was an independent poor prognostic indicator for PFS (HR, 4.3; 95% CI, 1.89-9.78; P <.001). Deleterious DDR alterations were significantly associated with improvement in PFS compared with patients without detectable alterations (HR, 0.20; 95% CI, 0.08-0.50; P <.001), whereas DDR alterations of unknown significance showed borderline improvement in PFS (HR, 0.44; 95% CI, 0.19-1.04; P = .062).

The median overall survival (OS) was not reached for patients with deleterious DDR alterations, with 71.5% of patients alive at 12 months. The median OS was 23.0 months for those with DDR alterations of unknown significance and 9.3 months for those with no detectable DDR alterations.

In multivariable analysis, hemoglobin <10 g/dL (HR, 7.41; 95% CI, 2.88-19.10; P <.001) and visceral metastases (HR, 3.53; 95% CI, 1.31-9.57; P <.013) were independent prognostic indicators for poorer OS. Deleterious DDR alterations were associated with superior OS compared with no detectable DDR gene alterations (HR, 0.27; 95% CI, 0.10-0.73; P = .001). Patients with DDR alterations of unknown significance showed borderline improvement in OS compared with unaltered DDR genes (HR, 0.46; 95% CI, 0.18-1.19; P = .109), which investigators suggested could mean that some of the alterations of unknown significance may be functional variants.

Additional multivariable analyses for PFS and OS with mutation load in place of DDR status, stratification by DDR status, and stratification by mutation load showed that DDR-containing models remained a superior predictor of outcomes compared with mutation load.

Teo MY, Seier K, Ostrovnaya I, et al. Alterations in DNA damage response and repair genes as potential marker of clinical benefit from PD-1/PD-L1 blockade in advanced urothelial cancers [published online February 28, 2018]. J Clin Oncol. doi: 10.1200/JCO.2017. 75.7740.