DNA repair pathway alterations and correlation with immunotherapy response.

Abstract

e14150 Background: Over the past decade, a better understanding of cancer biology has led to a revolution in immunotherapy. Checkpoint inhibitors (ICI), bispecific antibodies and agonistic agents have shown benefit in cancer treatment. Unfortunately, not all patients benefit and, despite the advances achieved in discovering markers of response, the selection of patients can still be challenging in everyday practice. Methods: We conducted a retrospective analysis of potential prognostic and predictive factors of survival in a cohort of 186 patients enrolled into Phase I Trials testing immunotherapeutic agents at our institution. We computed univariate and multivariate analysis (MVA) of demographics, clinical and molecular characteristics to assess their prognostic and predictive potential of clinical benefit (defined as achieving Complete or Partial Response (CR/PR) as best response or disease stabilization lasting > 120 days) and survival. Molecular testing included Next Generation Sequencing (NGS - Oncomine Comprehensive Assay) grouped in DNA repair, Transcription regulation, Signal Transduction and Cell-Cell interaction pathways. Results: A total of 186 patients (Male/Female: 81/105; median age 61yo) received treatment with either immune checkpoint inhibitors (122 (65,6%)), checkpoint agonists (37 (19.9%)); bispecific antibodies (19 (10.21%) or other immunotherapies (8 (4.29%)) between November 2015 and July 2018. Royal Marsden Score (RMH) was assessed and correlated with progression free survival and overall survival in the total cohort. Median Overall Survival (mOS) was 422 days (CI95%: 345-500 days), 387 (CI95%: 297-478 days), 235 (CI95%: 131-338 days), and 167 (CI95% 64-270 days) for RMH 0, 1, 2 and 3, respectively (p = 0.007). Among 57 patients with NGS results, those with pathogenic mutations in DNA repair pathways (n = 26) showed a trend towards a higher response rate (69% vs 30% p = 0.064) and clinical benefit (65% vs 35%; p = 0.034). Conclusions: Alterations in DNA repair pathways are a potential predictor of benefit of immunotherapy and warrants further studies. A larger cohort of patients is currently being explored in our center to further validate these findings.