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ObjectivesIn patients with IBD experiencing an immune-mediated loss of response (LOR) to antitumour necrosis factor (anti-TNF), algorithms recommend a switch of anti-TNF without immunosuppressive drug. The aim of our study was to compare in these patients two strategies: either switch to a second anti-TNF alone or with addition of azathioprine (AZA). After randomisation outcomes (time to clinical and pharmacokinetic failure) were compared between the two groups during a 2-year follow-up period.DesignConsecutive IBD patients in immune-mediated LOR to a first optimised anti-TNF given in monotherapy were randomised to receive either AZA or nothing with induction by a second anti-TNF in both arms. Clinical failure was defined for Crohn’s disease (CD) as a Harvey-Bradshaw index ≥5 associated with a faecal calprotectin level >250 µg/g stool and for UC as a Mayo score >5 with endoscopic subscore >1 or as the occurrence of adverse events requiring to stop treatment. Unfavourable pharmacokinetics of the second anti-TNF were defined by the appearance of undetectable trough levels of anti-TNF with high antibodies (drug-sensitive assay) or by that of antibodies (drug-tolerant assay).ResultsNinety patients (48 CDs) were included, and 45 of them received AZA after randomisation. The second anti-TNF was adalimumab or infliximab in 40 and 50 patients, respectively. Rates of clinical failure and occurrence of unfavourable pharmacokinetics were higher in monotherapy compared with combination therapy (p<0.001; median time of clinical failure since randomisation 18 vs >24 months). At 24 months, survival rates without clinical failure and without appearance of unfavourable pharmacokinetics were respectively 22 versus 77% and 22% versus 78% (p<0.001 for both) in monotherapy versus combination therapy. Only the use of combination therapy was associated with favourable outcomes after anti-TNF switch.ConclusionIn case of immune-mediated LOR to a first anti-TNF, AZA should be associated with the second anti-TNF.Trial registration number03580876.

Data on the value of therapeutic drug monitoring of infliximab (IFX) to predict mucosal healing (MH) in inflammatory bowel diseases (IBD) are scarce. All consecutive patients with IBD receiving ongoing IFX (5 mg/kg) treatment and developing secondary failure to IFX were enrolled in a prospective study between June 2010 and May 2011. IFX trough levels, antibodies to IFX concentrations, C-reactive protein levels, and fecal calprotectin were measured before IFX optimization and at week 8. A proctosigmoidoscopy was performed on the day of first IFX optimization and at week 8 in all patients with ulcerative colitis (UC). MH was defined by fecal calprotectin <250 μg/g stools in Crohn's disease (CD) and by an endoscopic Mayo score of 0 or 1 in UC. This study included 52 patients with IBD: 34 patients with CD (mean Crohn's Disease Activity Index, 300; mean C-reactive protein, 28 ± 10 mg/L; mean fecal calprotectin, 705 ± 300 μg/g) and 18 patients with UC (mean Simple Clinical Colitis Activity Index, 7; mean Mayo endoscopic score, 3). After IFX dose intensification, half of CD and UC patients achieved MH. Increase in IFX trough levels (called \"delta IFX\" in micrograms per milliliter) was associated with MH in both CD and UC (P = 0.001). A delta IFX >0.5 μg/mL was associated with MH (sensitivity [se], 0.88; specificity [sp], 0.77; P = 0.0001, area under the receiver operating characteristic curve, 0.89). On multivariate analysis, the only factor associated with MH after IFX optimization was a delta IFX >0.5 µg/mL (likelihood ratio = 2.02; 95% confidence interval, 1.01-4.08; P = 0.048) in patients with IBD. Therapeutic drug monitoring of IFX strongly predicts the likelihood of achieving MH following IFX dose intensification in both CD and UC.

Perioperative FLOT (fluorouracil, oxaliplatin, and docetaxel) triplet chemotherapy is the standard of care for localised and resectable gastric and gastro-oesophageal junction adenocarcinoma. We aimed to compare a modified FLOT regimen (also known as TFOX) with FOLFOX as first-line treatment for patients with HER2-negative advanced gastric and gastro-oesophageal junction adenocarcinoma. PRODIGE 51-FFCD-GASTFOX is an open-label, multicentre, randomised, phase 3 trial conducted at 96 medical centres in France. Eligible individuals were aged 18 years or older, had histologically confirmed, HER2-negative adenocarcinoma of the stomach or gastro-oesophageal junction that was locally advanced unresectable or metastatic and previously untreated, measurable disease per Response Evaluation Criteria in Solid Tumours, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Patients were randomly assigned (1:1), using the minimisation method, to receive FOLFOX (folinic acid 400 mg/m2, oxaliplatin 85 mg/m2, and 5-fluorouracil bolus 400 mg/m2 then 5-fluorouracil 2400 mg/m2 as a continuous 46 h infusion every 2 weeks) or TFOX (docetaxel 50 mg/m2, folinic acid 400 mg/m2, and oxaliplatin 85 mg/m2 then 5-fluorouracil 2400 mg/m2 as a continuous 46 h infusion every 2 weeks). Randomisation was stratified by centre, ECOG performance status, (neo)adjuvant chemotherapy or chemoradiotherapy, tumour stage, tumour location, and pathological histological subtype. The primary endpoint was progression-free survival (assessed in the intention-to-treat population), defined as time from randomisation to the first radiological or clinical progression (or both), or death due to any cause, whichever occurred first. Secondary endpoints included overall survival (defined as time from randomisation to death due to any cause) and objective response rate (defined as the proportion of patients with a best overall complete or partial response). Hazard ratio and 95% CIs were estimated using an unstratified Cox proportional hazards model. When the proportional hazards assumption was violated, the restricted mean survival time was used to estimate the treatment effect size. This study is registered with ClinicalTrials.gov, NCT03006432, and EudraCT, 2016–002331–16. Between Dec 19, 2016, and Dec 26, 2022, 507 patients were randomly assigned (254 to the TFOX group and 253 to the FOLFOX group [intention-to-treat population]). The median age was 64·2 years (IQR 56·7–70·8), and 399 (79%) participants were male and 108 (21%) were female. At median follow-up of 42·8 months (25·8–49·9), the median progression-free survival was 7·59 months (95% CI 7·06–7·95) in the TFOX group versus 5·98 months (5·65–6·97) in the FOLFOX group. The assumption of proportional hazards was violated (p=0·013); therefore, the 12-month restricted mean progression-free survival was calculated: 7·52 months (7·06–7·97) in the TFOX group versus 6·62 months (6·16–7·09) in the FOLFOX group (p=0·0072). The median overall survival was 15·08 months (13·70–16·72) in the TFOX group versus 12·65 months (10·94–14·00) in the FOLFOX group (proportional hazards assumption was confirmed; HR 0·82 [0·68–0·99]; p=0·048) and the objective response rate was 62·3% (56·0–68·3) versus 53·4% (47·0–59·8; p=0·045). The most common grade 3 and 4 treatment-emergent adverse events were diarrhoea (37 [15%] in the TFOX group vs 18 [7%] in the FOLFOX group), peripheral neuropathy (80 [32%] vs 49 [20%]), neutropenia (67 [27%] vs 44 [18%]), and fatigue (40 [16%] vs 20 [8%]). Serious treatment-related adverse events occurred in 66 (27%) participants in the TFOX group and 33 (13%) in the FOLFOX group. There were two (<1%) treatment-related deaths in the TFOX group (one due to septic shock and one due to gastrointestinal perforation) and one (<1%) in the FOLFOX group (due to septic shock). The modified FLOT/TFOX regimen significantly improved progression-free survival, overall survival, and objective response rate compared with FOLFOX in previously untreated patients with advanced HER2-negative gastric and gastro-oesophageal junction adenocarcinoma. The modified FLOT/TFOX regimen might represent a new first-line treatment option for patients eligible for this docetaxel triplet chemotherapy. Fédération Francophone de Cancérologie Digestive.

ObjectiveThe prognostication of metastatic pancreatic adenocarcinoma (mPDAC) patients remains uncertain, mainly based on carbohydrate antigen 19-9 (CA19-9), with limited utility. Circulating tumour DNA (ctDNA) has been suggested as a prognostic factor, but its added value has been poorly explored. The objective was to determine whether ctDNA is an independent factor for the prognostication of mPDAC.DesignTranslational study based on two prospective collections of plasma samples of mPDAC patients naïve for chemotherapy. One used as a test series and the other as validation series coming from two randomised trials (Prodige 35 and Prodige 37). CtDNA was assessed by digital droplet PCR targeting two methylated markers (HOXD8 and POU4F1) according to a newly developed and validated method. Univariate and multivariate analyses were performed according to ctDNA status.ResultsOf 372 plasma samples available, 354 patients were analyzed for survival. In the validation series, 145 of 255 patients were found ctDNA positive (56.8%), Median PFS and OS were 5.3 and 8.2 months in ctDNA-positive and 6.2 and 12.6 months in ctDNA-negative patients, respectively. ctDNA positivity was more often associated with young age, high CA19-9 level and neutrophils lymphocytes ratio. In multivariate analysis including these previous markers, ctDNA was confirmed as an independent prognostic marker for PFS (adjusted hazard ratio (HR) 1.5, CI 95% [1.03–2.18], p = 0.034) and OS (HR 1.62, CI 95% [1.05–2.5], p = 0.029).ConclusionsIn this first ctDNA assessment in a large series of mPDAC derived from clinical trials, ctDNA was detectable in 56.8% of patients and confirmed as an independent prognostic marker.

Background Randomized trials have shown a survival benefit for regorafenib over placebo in patients with metastatic colorectal cancer (mCRC) that progressed after standard therapies. We evaluated survival and safety outcomes in patients treated with regorafenib in a real-life setting. Methods REBECCA is a cohort study nested within a compassionate use program designed to evaluate survival, safety, and potential prognostic factors for outcome associated with regorafenib in patients with mCRC refractory to standard therapies. Treatment effects according to various patient and tumour characteristics were evaluated using univariate and multivariate Cox proportional hazards regression models. Results Of 1178 patients in the compassionate use program, 654 were in the full analysis set. Median follow-up was 16.5 months. Median survival was 5.6 months. The 12-month survival rate was 22 %. Survival was independently and unfavourably affected by the following variables: poor performance status, short time from initial diagnosis of metastases to the start of regorafenib, low initial regorafenib dose, >3 metastatic sites, presence of liver metastases, and KRAS mutations. We identified prognostic groups of patients with low, intermediate, and high risk of death, with a median survival of 9.2, 5.2, and 2.5 months, respectively. Five-hundred-twenty-four patients (80 %) experienced at least one regorafenib-related adverse event, most commonly, fatigue, hand-foot skin reaction, diarrhea, anorexia, arterial hypertension, and mucositis. Conclusion The safety and efficacy profile of regorafenib in REBECCA are similar to those in randomized trials. Our prognostic model identified subgroups of mCRC patients who derived a minimal and maximum benefit from regorafenib. Trial registration Clinicaltrials.gov NCT02310477 .

The aim of this meta-analysis was to explore the magnitude of the association between pharmacokinetics of adalimumab and clinical response in patients with inflammatory bowel disease.MethodsA literature search was performed up to December 2013. MEDLINE, EMBASE, Cochrane, and meeting abstracts were reviewed. Studies were included if they analyzed the association of trough levels of adalimumab (TRA) or antibodies against adalimumab (AAA) with clinical response in adult or pediatric inflammatory bowel disease. A Mantel–Haenszel pooled risk estimate provided a measure of the association.ResultsFourteen studies enrolling 1941 patients with inflammatory bowel disease were included in the systematic review. Thirteen studies analyzed clinical outcomes according to TRA. In only 1 study, there was no correlation between high TRA and clinical response. Six of the 7 studies reported a negative correlation between AAA and clinical outcomes. Six studies enrolling 536 patients (Crohn's disease [CD] only) met the meta-analysis inclusion criteria. The pooled odds ratio (OR) for loss of clinical response to adalimumab in patients with CD (N = 4) with positive AAAs was 10.15 (95% confidence interval [CI]: 3.90–26.40, P < 0.0001). Patients with CD with TRA over a predefined cutoff were more likely to be in clinical remission with an OR of 2.6 (95% CI: 1.79–3.77, P < 0.0001). The association was stronger if the analysis was limited to the adult population (N = 3, OR: 7.05, 95% CI: 3.58–13.9, P < 0.0001).ConclusionsThe presence of AAA is associated with a higher risk of loss of clinical response to adalimumab, whereas high TRA is associated with greater clinical response rates in CD. More data are needed in ulcerative colitis.

Previous studies have suggested an association between cytomegalovirus (CMV) infection and steroid-refractory inflammatory bowel disease. In this study, the use of CMV DNA load during acute flare-ups of ulcerative colitis (UC) to predict resistance to immunosuppressive therapy was evaluated in intestinal tissue. Forty-two consecutive patients (sex ratio M/F: 0.9, mean age: 43.6 years) hospitalized for moderate to severe UC and treated with IV steroids were included prospectively. A colonoscopy was performed for each patient at inclusion; colonic biopsy samples of the pathological tissue, and if possible, of the healthy mucosa, were tested for histological analysis and determination of CMV DNA load by real-time polymerase chain reaction assay. Patients were treated as recommended by the current guidelines. Sixteen patients were found positive for CMV DNA in inflamed intestinal tissue but negative in endoscopically healthy tissue; all of these patients were positive for anti-CMV IgG, three exhibited CMV DNA in blood, and none was positive for intestinal CMV antigen by immunohistochemistry detection. In the 26 remaining patients, no stigmata of recent CMV infection were recorded by any technique. By multivariate analysis, the only factor associated with CMV DNA in inflammatory tissue was the resistance to steroids or to three lines of treatment (risk ratio: 4.7; 95% confidence interval: 1.2-22.5). A CMV DNA load above 250 copies/mg in tissue was predictive of resistance to three successive regimens (likelihood ratio+=4.33; area under the receiver-operating characteristic curve=0.85). Eight UC patients with CMV DNA in inflamed tissue and therapeutic failure received ganciclovir; a clinical remission was observed in seven cases, with a sustained response in five of them. The CMV DNA load determined in inflamed intestinal tissue predicts resistance to steroid treatment and to three drug regimens in UC. Initiation of an early antiviral treatment in these patients might delay the occurrence of resistance to current treatments.

IntroductionThe pharmacokinetic equivalence of dose intensification with adalimumab (ADA) 80 mg every other week (EOW) compared to weekly 40 mg has only been supported by modeling systems.Aim of the StudyTo compare the trough levels of ADA (TLA) and the occurrence of anti-ADA antibodies (AAA) between these two treatment regimens.Patients and MethodsThis was a prospective study including all consecutive patients with inflammatory bowel disease (IBD) who had reached a longstanding and deep remission under treatment with ADA 40 mg once a week. In these patients, the ADA regimen was changed from 40 mg/week to 80 mg EOW. TLA and AAA levels using a drug-tolerant assay were monitored before and ten weeks after from the change in the ADA regimen and the results compared by a Wilcoxon paired test. ResultsSixty-two patients (60% CD, mean age 35 years) were included. Before and ten weeks after the changes of ADA regimen, the median TLA were (6.9 µg/mL versus 7.0 µg/mL, respectively; P = 0.34) and the AAA levels (3.4 µg/ml-eq versus 3.0 µg/ml-eq, respectively; P = 0.25.) were quite similar. Likewise, quartiles of TLA (Kendall test r = 0.91; P < 0.001) and AAA (r = 0.78; P < 0.001) did not differ before and after ADA regimen. When stratifying all the patients into 4 groups based on drug/antibody levels (immunogenic, subtherapeutic, therapeutic, or supratherapeutic), no patient needed for returning to the previous weekly regimen. In terms of acceptability, more than 60% of patients preferred an injection EOW compared once a week. ConclusionsIn IBD patients who achieved a deep clinical remission under ADA 40 mg once a week, the pharmacokinetic of ADA was similar when ADA regimen was changed to 80 mg EOW. Given the patient’s preference for the latter regimen, a modification of injection regimen should be systematically proposed.

Immunosuppressive therapies used for treating ulcerative colitis are known to favor chronic and latent viral diseases. This study aimed at evaluating prospectively the association between colonic cytomegalovirus (CMV) reactivation and anti–tumor necrosis factor (TNF) monoclonal antibodies (mabs) by comparison to azathioprine (AZA) in a series of flare-ups occurring in consecutive ulcerative colitis patients.MethodsA total of 109 flare-ups were recorded in 73 patients receiving a maintenance therapy by anti-TNF mabs (n = 69) or AZA (n = 40). The CMV DNA load in colonic tissue was determined by reverse transcription polymerase chain reaction on a pair of biopsies.ResultsThe number of CMV reactivation was of 35% and 38% in patients receiving anti-TNF mabs and AZA, respectively. The median of CMV DNA load was 378 [10–29,800] and 8300 [10–3,25,000] copies/mg of tissue in patients treated by anti-TNF mabs and AZA, respectively (P = 0.11 by Mann–Whitney U test). In a subgroup of 45 patients under anti-TNF mabs requiring an optimized treatment by infliximab, clinical remission (partial Mayo score <3) was not significantly impacted by the presence of CMV reactivation at the time of flare-up (P = 0.52). Twenty of these patients underwent a second colonic biopsy 8 weeks after the initiation of flare-up therapy; except for 3 patients, the colonic CMV DNA load was stable or decreased.ConclusionsPatients under anti-TNF maintenance therapy are not at higher risk of CMV reactivation in case of flare-up. No reciprocal adverse influence was observed between anti-TNF mabs and CMV infection, suggesting that these drugs must be considered for treating flare-ups associated to CMV reactivation.

BackgroundPost-hoc analyses of AFP response and progression and their relationship with objective measures of response and survival were performed in patients from REACH.MethodsSerum AFP was measured at baseline and every 3 cycles (2 weeks/cycle). Associations between AFP and radiographic progression and efficacy end points were analysed.ResultsMedian percent AFP increase from baseline was smaller in the ramucirumab than in the placebo arm throughout treatment. Time to AFP progression (HR 0.621; P < 0.0001) and to radiographic progression (HR 0.613; P < 0.0001) favoured ramucirumab. Association between AFP and radiographic progression was shown at 6 (OR 6.44, 95% CI 4.03, 10.29; P < 0.0001) and 12 weeks (OR 2.28, 95% CI 1.47, 3.53; P = 0.0002). AFP response was higher with ramucirumab compared with placebo (P < 0.0001). More patients in the ramucirumab arm experienced tumour shrinkage and AFP response compared with placebo. Survival was longer in patients with AFP response (13.6 months) than in patients without (6.2 months), irrespective of treatment (HR 0.457, P < 0.0001).ConclusionsTreatment with ramucirumab prolonged time to AFP progression, slowed AFP increase and was more likely to induce AFP response. Similar benefits in radiographic progression and response correlated with AFP changes.