Grothey, Axel

60 Background: DDR mutations are associated with higher neoantigen load and tumor infiltrating lymphocytes, and are a potential biomarker for immunotherapy. We investigated the association of DDR mutations in gastric (GC), esophageal (EC), and gastroesophageal junction (GEJ) cancers with MSI, PD-L1, and TMB, known predictors for immune checkpoint inhibitors. Methods: 20 DDR mutations were tested by Next-Generation Sequencing (NGS) with a 592-gene panel on a total of 1935 (709 EC; 831 GC; 355 GEJ) cancers. TMB was assessed by NGS, MSI by NGS or fragment analysis, and PD-L1 by IHC (22c3 for CPS or SP142). Results: GC had the highest DDR mutation rate compared to EC and GEJ (27% vs. 20%, p = 0.0005 and 17%, p = 0.0002, respectively). MSI-High (MSI-H) was significantly more common in the DDR mutated cohort (DDR-M) compared to non-mutated cancers (18% vs. 1%; p < 0.0001). TMB-High (≥ 10 mutations/megabase [mt/MB]) was higher in DDR-M (35% vs. 21%; p < 0.0001); in DDR-M cohort, GC had the highest TMB compared to DDR-M EC and GEJ (mean: 13.8 vs. 9.4 vs. 10 mt/MB, respectively; p < 0.0001). DDR mutations were more frequent in the PD-L1 combined positive score (CPS) ≥ 50 group than CPS 0 (42.9% vs. 24%; p = 0.037) and CPS 1-9 (42.9% vs. 20.6%; p = 0.005). ARID1A, ATRX, BRCA2, and PTEN were the most prevalent DDR mutations in MSI-H (87%, 31%, 25%, 24%, respectively); ARID1A, ATRX, BRCA2, and PTEN in TMB-High (47%, 7.7%, 6.7%, 6.8%) and ARID1A, BRCA2, RAD50, and WRN in PD-L1 high (CPS ≥ 10) (48.5% vs. 5.2% vs. 2.5% vs. 3.4%). Conclusions: MSI-H, TMB-high and high PD-L1 expression were significantly more prevalent in the DDR-M cohort compared to non-DDR-mutated cancers, most pronounced in GC. Alterations in ARID1A, ATRX, BRCA2, and PTEN were correlated with MSI-H and TMB-high while ARID1A, BRCA2, RAD50, and WRN were correlated with increased PD-L1 expression. Our findings may help identify patients for tailored immunotherapy approaches in future clinical trials.

728 Background: Adjuvant FOLFOX therapy for stage II patients remains controversial, and selection criteria are imprecise. We examined the trend of disease-free survival (DFS: time to recurrence or death, whichever occurs first); time to recurrence (TTR: time to recurrence, censored at death without recurrence); survival after recurrence (SAR); and overall survival (OS) of pts treated with FOLFOX over a ten-year period. Methods: Outcomes of pts with stage II colon cancer enrolled in 6 adjuvant trials receiving FOLFOX alone were analyzed. Pt enrollment period was dichotomized as old (1998 – 2003) vs. new era (2004 – 2009) based on the FDA approval date of bevacizumab. 3/5yr event-free rates were estimated using adjusted Kaplan-Meier methods. Outcomes were compared between the two eras by multivariate Cox model. To control for potential confounding effects, all analyses were adjusted for age, gender, performance score, T stage, number of lymph nodes (LNs) examined, tumor side, and histologic grade. Results: In total, 1,122 pts with stage II were identified; 71% and 29% were treated in the old and new era, respectively. Pts enrolled in the new era were significantly younger and more likely to have higher tumor-grade and right-sided tumors compared to old era. More pts in the new era (71%) had ≥12 LNs examined compared to the old era (53%). After adjusting for potential confounding effects, no difference in DFS, TTR, SAR or OS between old and new eras was found (Table). Although median SAR increased from 13.6 to 26 months over time, this was not statistically significant, likely due to lack of power. An increased TTR over time (HRadj. 0.41, padj.= 0.002) was observed in pts with ≥12 LNs examined (3-yr TTR: 92% in old era vs. 96% in new era), but not pts with <12 LNs examined (pinteraction = 0.04). Conclusions: In stage II colon cancer pts who received adjuvant FOLFOX, no significant increase of DFS or OS was observed over time. However TTR was longer only in pts with ≥12 LNs examined. [Table: see text]

TPS3619 Background: Cancer stem cells are considered to be fundamentally important for resistance to therapy, recurrence and metastasis. Napabucasin is a first-in-class cancer stemness inhibitor in development identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al, PNAS 112(6):1839, 2015). Preclinically, napabucasin sensitizes cancer cells to chemotherapeutics, including 5-FU and irinotecan. Encouraging anticancer activity in advanced CRC was observed in a phase Ib/II (Bendell et al, GI ASCO 2017) study of 63 pts with disease control rate (DCR) of 93% (28/30) and overall response rate (ORR) of 33% (10/30) in FOLFIRI-naïve pts who have had an on-study RECIST evaluation. On the basis of these data, a phase III trial is being conducted in North America, Europe, Australia, and Asia. Methods: This study (ClinicalTrials.gov NCT02753127) will assess the efficacy of napabucasin+FOLFIRI vs FOLFIRI in pts with mCRC (n = 1250). Addition of bevacizumab (bev) is permissible per investigator choice. Pts must have failed 1 prior line of therapy with oxaliplatin and a fluoropyrimidine +/- bev for metastatic disease. Pts are randomized 1:1 to receive napabucasin 240 mg PO BID plus FOLFIRI bi-weekly, or FOLFIRI bi-weekly (bev may be added to FOLFIRI by investigator choice) and stratified by geography, time to progression on 1st-line therapy, RAS mutation status, bev as part of study treatment and primary tumor location. Treatment will continue until disease progression, or another discontinuation criterion. Primary endpoint is overall survival (OS) in the general study population (ITT) (HR 0.80 for OS improvement from 12.54 to 15.68 months); secondary endpoints include OS in the biomarker positive (biomarker+) population, progression free survival (PFS) in the ITT population, PFS in biomarker+ population, ORR and DCR in the ITT and in biomarker+ populations, safety and quality of life. Also, blood and tumor archival tissue will be assessed for PK and biomarker analyses. Global enrollment is underway. Clinical trial information: NCT02753127.