Alterations in DNA damage response and repair genes may be useful biomarkers for response to immune checkpoint inhibitors in patients with urothelial carcinoma, investigators contend.

Among 60 patients with urothelial carcinoma in prospective trials of antibodies directed against the immune checkpoint inhibitor programmed cell death protein-1 and its ligand (PD-1/PD-L1), 28 (47%) had a damage response and repair (DDR) gene of any kind, and 15 (25%) had DDR mutations that are thought to be deleterious. Patients with any DDR mutations were more likely to have a clinical response to anti–PD-1/PD-L1 therapy, especially patients with likely deleterious mutations, reported Jonathan E. Rosenberg, MD and colleagues from Memorial Sloan Kettering Cancer Center, New York.

In addition to higher objective response rates, patients with DDR gene alterations had longer progression-free survival (PFS) and better overall survival (OS) than did patients with wild-type DDR genes, they noted in a study published in the Journal of Clinical Oncology .

“This study shows that patients with DDR gene alterations are more likely to experience objective responses, longer PFS, and improved OS than patients with wild-type DDR genes. Whether the association is predictive or prognostic should be investigated further in larger data sets from randomized studies that have led to the FDA [Food and Drug Administration] approval of several anti–PD-1/PD-L1 agents,” they wrote.

Previous studies have shown that in patients with metastatic urothelial carcinoma treated with platinum-based chemotherapy, alterations in DDR genes are associated with elevations in mutational load, increases in tumor-infiltrating lymphocytes, and improved survival, the investigators noted.

To see whether DDR gene alterations were also associated with better outcomes with PD-1/PD-L1 inhibitors, the investigators examined tumor genomes and survival data from patients with metastatic urothelial carcinoma who were enrolled in prospective clinical trials of anti–PD-1/PD-L1 monotherapy. The agents used in the trials were atezolizumab(Tecentriq) and nivolumab(Opdivo).

The investigators correlated the presence of DDR gene alterations with best objective responses according to RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1.

They found that the presence of any DDR gene alteration was associated with higher response rates, compared with wild-type DDR (67.9% vs. 18.8%; P less than .001).

Additionally, patients whose tumors contained known or likely deleterious DDR mutations were significantly more likely to respond than were patients with either mutations of uncertain significance or wild-type DDR (overall response rate 80%, 54%, and 19%, respectively; P less than .001).

Patients with deleterious DDR alterations had significantly better PFS than patients without detectable alterations (hazard ratio, 0.20; P less than .001); DDR mutations of unknown significance trended toward better PFS (HR, 0.44), but was not statistically significant.

Median OS was not reached for patients with deleterious DDR gene mutations, with 71.5% alive at 12 months, compared with a median of 23 months for patients with alterations of unknown significance, and 9.3 months for patients with wild-type DDR.

In multivariable analysis, independent predictors for worse OS included hemoglobin levels below 10 g/dL and visceral metastases. In contrast, any versus no detectable DDR gene alterations was associated with better OS (HR, 0.27; P = .001).

The investigators are planning a prospective evaluation of the potential association between DDR alterations and outcomes in a phase 2 study of atezolizumab with or without bevacizumab(Avastin) in patients with metastatic urothelial carcinoma.

“Additional investigation is warranted to evaluate the mechanisms that link DDR alterations beyond MMR [DNA mismatch repair], [mutational] 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,” they concluded.

The study was funded by Roche, Genentech, Bristol-Myers Squibb, and a National Cancer Institute Cancer Center support grant. Dr. Rosenberg disclosed stock or other ownership with Merck and Illumina, and consulting/advisory roles and travel support from Roche, Genentech, Bayer, and others. Multiple coauthors reported similar relationships.

SOURCE: Rosenberg JE et al. J Clin Oncol. 2018 Feb 28. doi: 10.1200/JCO.2017.75.7740 .


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