Citations

4003 Background: Pembro has shown promising antitumor activity and manageable safety in a phase 1 study of pts with previously treated advanced gastric cancer. We conducted a global, multicohort, phase 2 study of pembro in pts with advanced gastric or gastroesophageal junction (G/GEJ) cancer (KEYNOTE-059;NCT02335411). Methods: Cohort 1 enrolled 259 pts, aged ≥18 y with measurable recurrent or metastatic G/GEJ adenocarcinoma who had progressed on ≥2 prior chemotherapy regimens and had ECOG PS 0-1. Pts received pembro 200 mg Q3W up to 2 y or up to disease progression, investigator/pt decision to withdrawal, or unacceptable toxicity. PD-L1+pts had expression in ≥1% tumor or stromal cells using IHC (22C3 antibody). Primary end points: ORR (RECIST 1.1, by central review), safety, and tolerability. Results: Of 259 pts in cohort 1, 76.4% were men; median age was 62.0 y. 51.7% and 48.3% received pembro as 3rd-line (3L) and 4L+ therapy, respectively. 57.1% had PD-L1+ tumors. At data cutoff (Oct 19, 2016), median duration of follow-up was 5.4 mo (range, 0.5 to 18.7). Overall ORR (CR + PR) was 11.2% (95% CI, 7.6-15.7); 1.9% of pts (95% CI, 0.6-4.4) had CR, 9.3% had PR (95% CI, 6.0-13.5), 17% (95% CI, 12.6-22.1) had SD, and 55.6% (95% CI, 49.3-61.7) had PD. Median DOR was 8.1 mo (range, 1.4+ to 15.1+). ORR was 14.9% (95% CI, 9.4-22.1) in 3L pts and 7.2% (95% CI, 3.3-13.2) in 4L+. In PD-L1+ pts, ORR was 15.5% (95% CI, 10.1-22.4) with 2.0% (95% CI, 0.4-5.8) CR and 13.5% (95% CI, 8.5-20.1) PR; in PD-L1– pts, ORR was 5.5% (95% CI, 2.0-11.6), with 1.8% (95% CI, 0.2-6.5) CR and 3.7% (95% CI, 1.0-9.1) PR. In 3L pts with PD-L1+ tumors, ORR was 21.3% (95% CI, 12.7-32.3), with 4.0% (95% CI, 0.8-11.2) CR; in 3L pts with PD-L1– tumors, ORR was 6.9% (95% CI, 1.9-16.7), with 3.4% (95% CI, 0.4-11.9) CR. Grade 3-5 treatment-related AEs (TRAEs) occurred in 43 pts (16.6%). TRAEs led to discontinuation in 2 pts (abnormal LFT, bile duct stenosis) and were fatal in 2 pts (acute kidney injury, pleural effusion). Conclusions: Pembro showed encouraging efficacy and manageable safety after ≥2 prior lines of therapy in pts with advanced G/GEJ cancer in this large phase 2 trial. Survival and additional biomarker data, including MSI status, will be presented. Clinical trial information: NCT02335411.

Abstract Background IV ciclosporin therapy is effective in steroid-refractory ulcerative colitis. The optimal drug level to achieve response and minimize complications during induction therapy is not known. Aim The primary aim was to evaluate if serum ciclosporin drug levels are associated with increased risk of colectomy within 90 days of hospitalization. Secondary aims were to determine if ciclosporin levels are associated with avoidance of colectomy at 7 and 30 days, if ciclosporin levels are associated with drug-related and postoperative complications, and if patient-specific factors are associated with response to ciclosporin. Methods We conducted a retrospective analysis of 81 hospitalized patients with steroid-refractory ulcerative colitis treated with ciclosporin. Risk factors for colectomy within 7, 30, and 90 days, medication-specific and postoperative complications were compared by first, mean, and peak ciclosporin level during IV induction therapy. Results There were 47 patients (58%) who underwent surgery. There were no differences between initial, mean, and peak ciclosporin levels among responders and nonresponders and treatment-related or postoperative complications. Responders within 90 days had lower C-reactive-protein levels (20mg/L vs. 38mg/L, P = 0.01), lower serum albumin concentrations (3.4g/dL vs. 3.7g/dL, P = 0.03), and higher rates of kidney injury (50% vs 17%, P = 0.002). Conclusion Initial, mean, and peak serum levels of ciclosporin did not correlate with response or toxicity. However, C-reactive-protein levels levels and kidney injury may be helpful in predicting clinical response to ciclosporin.

514 Background: Randomized trials and OCSs have demonstrated that BV treatment in 1st-line (1L), in 2L, and across multiple lines is associated with longer survival in patients (pts) with mCRC. This analysis was aimed at comparing the effectiveness of BV after 1st disease progression (PD) between male and female mCRC pts who received 1L BV-containing therapy in a real-world setting. Methods: ARIES is a large, prospective OCS that enrolled pts who received BV and chemotherapy (CT) for 1L mCRC. Post-PD effectiveness was assessed for men and women characterizing BV use by cumulative and dichotomous approaches. The primary analysis treated BV exposure as cumulative BV doses after 1st PD and post-progression overall survival (ppOS) as the time from 1st PD to death. A time-dependent Cox regression model was fitted to assess the effect of cumulative BV exposure on ppOS, while controlling for potential confounders. A dichotomous secondary analysis characterized BV exposure as receipt of CT + BV (BBP) or CT alone (No BBP) within 2 months after PD and ppOS as time from 1st PD + 2 months to death. Results: Among the 1,550 1L mCRC pts enrolled, 1,199 (532 women) had PD. In the primary analysis, hazard ratios (HRs) for ppOS decreased, on average, by 1.2% with each additional BV dose. When stratified by sex, the average risk reduction per BV dose over 15 doses was 1.8% in women and 0.7% in men. In the secondary analysis that included 331 women (BBP, 180; No BBP, 151) and 417 men (BBP, 245, No BBP, 172) who received BV ± CT within 2 months post-PD, the HRs for ppOS with BBP treatment were 0.46 (95% CI, 0.35–0.59) in women and 0.52 (95% CI, 0.41–0.67) in men. Statistical interaction tests for differences in the effectiveness of BV between men and women were negative for primary and secondary analyses (P of 0.58 and 0.77). Protocol-specified adverse events occurred in 17.8% of women and 10.2% of men in the BBP population; this difference was largely related to rates of hypertension (8.3% vs 2.4%, respectively). Conclusions: In ARIES, the effectiveness of BV after first PD was not statistically different between women and men with mCRC. Clinical trial information: NCT00388206.

535 Background: Prior ARIES analyses showed that BV-treated mCRC patients (pts) receiving chemotherapy (CT)/biologics + BV within 2 months (mo) after 1st progressive disease (PD) had longer post-progression survival (PPS) than pts receiving only CT/biologics. The present analysis evaluated whether this effect of BV was consistent when used with common 2L CT regimens— irinotecan- (iri-) and oxaliplatin- (ox-) based—in mCRC pts exposed to 1L BV in ARIES. Methods: ARIES enrolled mCRC pts receiving 1L CT + BV. No tx regimens or assessments were protocol specified. This analysis evaluated 1L BV-treated mCRC pts who had PD, survived ≥2 mo after PD, and received 2L iri- or ox-based tx. PPS was estimated by Kaplan-Meier methods. Cox regression was used to estimate hazard ratios (HRs), while adjusting for covariates (eg, 1L time to progression). Results: Of 1550 1L pts in ARIES, 1074 had 1st PD and survived ≥2 mo after PD. Of these 1074, 390 and 114 received 2L iri- and ox-based tx, respectively, ± BV ( table ). Baseline characteristics were generally similar between groups. The incidence of targeted adverse events (TAEs) was as expected and similar between the BV and No BV groups over time. In pts receiving 2L iri- or ox-based CT tx, PPS in BV-treated pts was longer compared to those not on BV. Analyses may be limited by small pt numbers in some groups. Conclusions: Consistent with prior ARIES analyses, the continued use of BV after 1st PD was associated with prolonged PPS regardless of the 2L CT backbone used. [Table: see text]

BACKGROUNDTo evaluate the impact of depression before autologous and allogeneic hematopoietic cell transplantation (HCT) on clinical outcomes post‐transplantation.METHODSWe analyzed data from the Center for International Blood and Marrow Transplant Research to compare outcomes after autologous (n = 3786) or allogeneic (n = 7433) HCT for adult patients with hematologic malignancies with an existing diagnosis of pre‐HCT depression requiring treatment versus those without pre‐HCT depression. Using Cox regression models, we compared overall survival (OS) between patients with or without depression. We compared the number of days alive and out of the hospital in the first 100 days post‐HCT using Poisson models. We also compared the incidence of grade 2‐4 acute and chronic graft‐versus‐host disease (GVHD) in allogeneic HCT.RESULTSThe study included 1116 (15%) patients with pre‐transplant depression and 6317 (85%) without depression who underwent allogeneic HCT between 2008 and 2012. Pre‐transplant depression was associated with lower OS (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.04‐1.23; P = 0.004) and a higher incidence of grade 2‐4 acute GVHD (HR, 1.25; 95% CI, 1.14‐1.37; P < 0.0001), but similar incidence of chronic GVHD. Pre‐transplant depression was associated with fewer days‐alive‐and‐out‐of‐the hospital (means ratio [MR] = 0.97; 95% CI, 0.95‐0.99; P = 0.004). There were 512 (13.5%) patients with Pre‐transplant depression and 3274 (86.5%) without depression who underwent autologous HCT. Pre‐transplant depression in autologous HCT was not associated with OS (HR, 1.15; 95% CI, 0.98‐1.34; P = 0.096) but was associated with fewer days alive and out of the hospital (MR, 0.98; 95% CI, 0.97‐0.99; P = 0.002).CONCLUSIONPre‐transplant depression was associated with lower OS and higher risk of acute GVHD among allogeneic HCT recipients and fewer days alive and out of the hospital during the first 100 days after autologous and allogeneic HCT. Patients with pre‐transplant depression represent a population that is at risk for post‐transplant complications. Cancer 2017;123:1828–1838. © 2017 American Cancer Society.

ABSTRACT A 2-year longitudinal microbiome study of 22 patients who underwent colectomy with an ileal pouch anal anastomosis detected significant increases in distinct populations of Bacteroides during 9 of 11 patient visits that coincided with inflammation (pouchitis). Oligotyping and metagenomic short-read annotation identified Bacteroides populations that occurred in early samples, bloomed during inflammation, and reappeared after antibiotic treatment. Targeted cultivation of Bacteroides isolates from the same individual at multiple time points and from several patients detected subtle genomic changes, including the identification of rapidly evolving genomic elements that differentiate isogenic strains of Bacteroides fragilis from the mucosa versus lumen. Each patient harbored Bacteroides spp. that are closely related to commonly occurring clinical isolates, including Bacteroides ovatus , B. thetaiotaomicron , B. vulgatus , and B. fragilis , which contained unique loci in different patients for synthesis of capsular polysaccharides. The presence of unique Bacteroides capsular polysaccharide loci within different hosts and between the lumen and mucosa may represent adaptations to stimulate, suppress, and evade host-specific immune responses at different microsites of the ileal pouch. IMPORTANCE This longitudinal study provides an opportunity to describe shifts in the microbiomes of individual patients who suffer from ulcerative colitis (UC) prior to and following inflammation. Pouchitis serves as a model for UC with a predictable incidence of disease onset and enables prospective longitudinal investigations of UC etiology prior to inflammation. Because of insufficient criteria for predicting which patients will develop UC or pouchitis, the interpretation of cross-sectional study designs suffers from lack of information about the microbiome structure and host gene expression patterns that directly correlate with the onset of disease. Our unique longitudinal study design allows each patient to serve as their own control, providing information about the state of the microbiome and host prior to and during the course of disease. Of significance to the broader community, this study identifies microbial strains that may have genetic elements that trigger the onset of disease in susceptible hosts.

Gut dysbiosis, host genetics, and environmental triggers are implicated as causative factors in inflammatory bowel disease (IBD), yet mechanistic insights are lacking. Longitudinal analysis of ulcerative colitis (UC) patients following total colectomy with ileal anal anastomosis (IPAA) where >50% develop pouchitis offers a unique setting to examine cause vs. effect. To recapitulate human IPAA, we employed a mouse model of surgically created blind self-filling (SFL) and self-emptying (SEL) ileal loops using wild-type (WT), IL-10 knockout (KO) (IL-10), TLR4 KO (T4), and IL-10/T4 double KO mice. After 5 wk, loop histology, host gene/protein expression, and bacterial 16s rRNA profiles were examined. SFL exhibit fecal stasis due to directional motility oriented toward the loop end, whereas SEL remain empty. In WT mice, SFL, but not SEL, develop pouchlike microbial communities without accompanying active inflammation. However, in genetically susceptible IL-10-deficient mice, SFL, but not SEL, exhibit severe inflammation and mucosal transcriptomes resembling human pouchitis. The inflammation associated with IL-10 required TLR4, as animals lacking both pathways displayed little disease. Furthermore, germ-free IL-10 mice conventionalized with SFL, but not SEL, microbiota populations develop severe colitis. These data support essential roles of stasis-induced, colon-like microbiota, TLR4-mediated colonic metaplasia, and genetic susceptibility in the development of pouchitis and possibly UC. However, these factors by themselves are not sufficient. Similarities between this model and human UC/pouchitis provide opportunities for gaining insights into the mechanistic basis of IBD and for identification of targets for novel preventative and therapeutic interventions.

Abstract Background. The Avastin® Registry: Investigation of Effectiveness and Safety (ARIES) study is a prospective, community-based observational cohort study that evaluated the effectiveness and safety of first-line treatment patterns, assessing the impact of chemotherapy choice and treatment duration. Methods. The ARIES study enrolled patients with metastatic colorectal cancer (mCRC) receiving first-line chemotherapy with bevacizumab and followed them longitudinally. The protocol did not specify treatment regimens or assessments. Analyses included all patients who initiated bevacizumab in combination with either first-line oxaliplatin with infusional 5-fluorouracil and leucovorin (FOLFOX) or irinotecan with infusional 5-fluorouracil and leucovorin (FOLFIRI). Progression-free survival (PFS) and overall survival (OS) times were estimated using Kaplan–Meier methods. Hazard ratios (HRs) were estimated with multivariate Cox regression analysis, adjusting for potential confounding factors. Results. In total, 1,550 patients with first-line mCRC were enrolled (median follow-up, 21 months) and most received FOLFOX–bevacizumab (n = 968) or FOLFIRI–bevacizumab (n = 243) as first-line therapy. The baseline characteristics and median treatment duration were generally similar between subgroups. There were no significant differences in the median PFS (10.3 months vs. 10.2 months) or OS (23.7 months vs. 25.5 months) time between the FOLFOX–bevacizumab and FOLFIRI–bevacizumab subgroups, respectively, by unadjusted analyses. Multivariate analyses showed FOLFIRI–bevacizumab resulted in a similar PFS (HR, 1.03; 95% confidence interval [CI], 0.88–1.21) and OS (HR, 0.95; 95% CI, 0.78–1.16) outcome as with FOLFOX–bevacizumab. The incidence proportions of bevacizumab-associated adverse events were similar for FOLFOX- and FOLFIRI-based therapies. Conclusions. In first-line mCRC patients, the FOLFOX–bevacizumab and FOLFIRI–bevacizumab regimens were associated with similar treatment patterns and clinical outcomes.