Outcomes of patients with or without DNA repair pathway alterations: the MD Anderson IMPACT2 study.

DNA repair deficiencies result in genomic instability. Data suggest that genomic instability is associated with response to immuno-oncology (IO) therapies. We analyzed outcomes of patients in the IMPACT2 study by the presence of DNA damage response (DDR) alterations and treatment type. Of 662 patients with ≥1 alterations: 109 (16.5%) had DDR alterations (treated, N = 85) and 553 (83.5%) were DDR wild-type (treated, N = 426). In patients with DDR alterations, absence of liver metastases (p = 0.029) and IO therapy (vs. chemotherapy, p = 0.020; vs. anti-DDR agents, p = 0.048) were independent factors predicting longer overall survival (OS). In the DDR-wild-type cohort, independent factors predicting longer OS were IO therapy (compared with each other treatment group: vs. IO+non-IO combinations, p = 0.003; vs. chemotherapy, p < 0.001; vs. anti-DDR agents, p < 0.001; vs. other targeted therapies, p = 0.006), absence of liver metastases (p < 0.001), and normal albumin (p < 0.001) and lactate dehydrogenase (p = 0.001) levels. Prospective studies are warranted to refine the role of DDR alterations as biomarkers of IO response.