Clinical outcomes of patients with or without DNA repair pathway alterations by treatment type: The MD Anderson Cancer Center IMPACT 2 study.

Abstract

2660 Background: DNA repair deficiency is common among tumors, and emerging data suggest that genomic instability is associated with response to immuno-oncology (IO) therapies (PMID 28630051). We evaluated patients with advanced metastatic cancer across tumor types, who were treated on the IMPACT2 study (NCT02152254) and analyzed their clinical outcomes by treatment type (anti-DNA damage repair [DDR] agents, IO, or other [non-IO, non-anti-DDR]). Methods: Patients had tumor biopsies followed by molecular profiling in a CLIA-certified lab. All cases were discussed at Molecular Tumor Board meetings. Patients were treated on early-phase clinical trials. Progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) were compared by therapy type in patients with or without DDR/MMR mutations (DDR+). Results: Of 829 enrolled patients, 510 had molecular profiling and received anticancer therapy: 85 were DDR+ (PS 1, 75%; med. age, 59 yrs; males 56.5%; med prior therapies 4; PDL1+ 44.9%; TMB-H 18%,) and 425 DDR- (PS 1, 88%; med. age, 60 yrs; men 47%, med. No. prior therapies 3; PDL1+ 46%; TMB-H 6.5%). Results are shown in the Table. In patients with DDR mutations, IO was associated with a higher ORR compared with “other” treatments (p=0.044); and with longer PFS compared with anti-DDR therapies (p = 0.044); no difference was noted in OS by treatment type. In the DDR-neg group, IO was associated with longer PFS (p = 0.017), and longer OS (p = 0.0004) compared with anti-DDR therapy; OS was longer in the IO group compared with “other” treatments (p = 0.029) and in the “other” treatments group compared with anti-DDR agents (p=0.006). Conclusions: Our data indicate the complexity of assessing outcomes in patients with various tumor types and without DDR mutations. Further work is needed to develop predictive biomarkers for IO and anti-DDR agents. Clinical trial information: NCT02152254 . Rx type DDR-pos N Outcome Anti-DDR vs IO IO vs Other Anti-DDR vs Other DDR-neg N Outcome Anti-DDR vs IO IO vs Other Anti-DDR vs Other Overall response (%) IO 34 6 (25%) OR* 0.78; p=0.81 OR* 20.73; p=0.044 OR* 16.09;p=0.1 116 9 (11%) OR* 0.34;p=0.46 OR* 2;p=0.13 OR* 0.67;p=0.79 Anti-DDR 18 1 (16.7%) 52 0 (0%) Other 33 0 (0%) 257 12 (5.9%) PFS, med. (95% CI) IO 34 4.26 (2.3, 7.4) HR 2.01 (1.02,3.96) (p=0.044) HR 0.91 (0.56,1.47)p=0.69 HR 1.82 (0.95,3.49)p=0.07 116 5.42(3.02,6.61) HR 2.02 (1.14,3.61) p= 0.017 HR 0.85 (0.68,1.06)p= 0.15 HR 1.71 (0.98,2.99)p=0.058 Anti-DDR 18 2.58 (1.68, NA) 52 1.64 (1.45, NA) Other 33 4.54 (3.06, 6.54) 257 3.98 (3.45, 4.57) OS, med. (95% CI) IO 34 14.37 (10.22, NA) HR 1.68 (0.82,3.42)p=0.16 HR 0.73 (0.43,1.23)p=0.24 HR 1.23 (0.62,2.42)p=0.56 116 12.46 (8.75, 20.78) HR 2.98 (1.62,5.48) p= 0.0004 HR 0.76 (0.6,0.97) p=0.029 HR 2.27 (1.27,4.07) p= 0.006 Anti-DDR 18 8.98 (3.48, NA) 52 4.31 (2.66, NA) Other 33 10.82 (7, 16.83) 257 9.4 (8.28, 11.21) *OR, Odds Ratio, p values, unadjusted for multiple comparisons.