DNA damage response and repair gene defects linked to PD-1 pathway blockade response
medwireNews: In patients with metastatic urothelial carcinoma treated with agents targeting programmed cell death protein 1 (PD-1) or its ligand (PD-L1), the presence of alterations in tumoral DNA damage response and repair (DDR) genes is associated with better outcomes, findings indicate.
Among 60 participants of three phase II trials evaluating the PD-1 blocker nivolumab or the anti-PD-L1 agent atezolizumab, the objective response rate (ORR) was significantly higher for the 28 patients with tumors harboring any aberrations in a panel of DDR genes than for the 32 with tumors that were wild-type for these genes, at 67.9% and 18.8%, respectively.
Of note, participants with known or likely deleterious DDR alterations had a significantly better response than those with mutations of unknown significance, with ORR rates of 80.0% versus 53.9%.
And in multivariate analysis accounting for a host of factors including the presence of visceral metastases, deleterious DDR alterations were associated with a significant 19.02-fold improved likelihood of achieving a response relative to wild-type DDR genes, while for DDRs of unknown significance the odds were improved 5.79-fold.
DDR defects were also associated with improvements in progression-free survival (PFS), such that in patients with deleterious mutations the median PFS was not reached, compared with 15.8 months for those with DDR alterations of unknown significance and 2.9 months for those with wild-type DDR genes.
The corresponding median overall survival (OS) times were unreached, 23.0, and 9.3 months, according to the report published in the Journal of Clinical Oncology.
And again, the presence of deleterious DDR alterations remained a significant predictor of PFS and OS in multivariate analysis, with hazard ratios (HRs) of 0.20 and 0.27 relative to wild-type, while the HRs for DDR variants of unknown significance were only borderline significant.
Researcher Jonathan Rosenberg (Memorial Sloan Kettering Cancer Center, New York, USA) and team explain that “[a]lterations in DDR genes are associated with an elevated [mutational load], increased tumor-infiltrating lymphocytes, and enhanced platinum responsiveness, which lead to a higher likelihood of pathologic downstaging in neoadjuvantly treated bladder cancers and improved survival outcomes in the metastatic setting.”
They continue: “[T]his 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.”
And the researchers conclude: “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.”
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