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Tumour deposits (TD) and extramural venous invasion (EMVI) are key anatomopathology prognostic criteria in rectal cancer. According to the 2018 ESGAR recommendations, they should be included in every MRI report. The present study aimed at identifying pelvic MRI survival prognostic factors in locally advanced rectal cancers before neo-adjuvant treatment, with a focus on EMVI and TD (mrEMVI and mrTD).Between 2010 and 2014, we conducted a retrospective study about 69 patients who underwent a pre-operative radiotherapy for a non-metastatic rectal cancer. All MR images were acquired on machines with a 1.5 or 3.0 Tesla field strength and were interpreted in compliance with the 2018 ESGAR recommendations.Out of the 27 patients who were mrEMVI+ (39.1%), MRF was involved in 77.7% of the cases vs. 33.3% for the mrEMVI- tumours. Fifteen (55.5%) out of the 27 mrEMVI+ tumours were mrTD+. This represents 21.7% of our population. mrEMVI/mrTD+ tumours were more RCT resistant, their downstaging happened in 6.7% of cases. In case of tumour downstaging, DFS increased significantly (P=0.02) unlike OS (P=0.2).The present study supports the fact that both mrEMVI and mrTD status are important pelvic MRI prognostic factors. Future studies could focus on relating mrTD tumours status to pathological results to define if post-RCT downstaging of TD has an impact on OS.

Microsatellite unstable (MSI) colorectal cancers (CRCs) are due to DNA mismatch repair (MMR) deficiency and occurs in15% of non-metastatic diseases and 5% in the metastatic setting. Nearly 30% of MSI CRCs occur in a context of constitutional mutation of the MMR system (Lynch syndrome). Others are sporadic cancers linked to a hypermethylation of the MLH-1 promoter. The pathogenic alterations of MMR genes lead to the accumulation of frequent somatic mutational events and these tumours arbour a high antigen burden and are highly infiltrated with cytotoxic T-cell lymphocytes. Microsatellite instability/DNA mismatch repair deficiency (MSI/dMMR) status has prognostic and predictive implications in non-metastatic and metastatic CRCs. The prognostic value of MSI status in non-metastatic CRCs has been studied extensively, yet the data are more limited for its predictive value in terms of adjuvant chemotherapy efficacy. In both cases (metastatic and non-metastatic settings) treatment with immune check-point inhibitors (ICIs) have shown a remarkable effectiveness in the context of MSI/dMMR status. Indeed, recent data from prospective cohorts and randomised trials have shown a dramatical improvement of survival with immunotherapy (programmed death-ligand 1 [PD-(L)1] cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] blockage) in metastatic or non-metastatic MSI/dMMR CRC. In this review we report and discuss how and for whom to test for the MSI/dMMR phenotype, as well as the prognostic value of this phenotype and the new treatment recommendations options for this unique CRC population. Despite their efficacy, primary and secondary resistance to immune checkpoint inhibitors (ICIs) are observed in more than 50% MSI-H/dMMR CRC patients and in the future how to identify these patients and to overcome resistance will be an important challenge.

International audience; Background: Following European guidelines, patients with aggressive metastatic or locally advanced, non-resectable, duodeno-pancreatic (DP) neuroendocrine tumours (NETs) should receive systemic combination chemotherapy until progression. Aggressive disease is defined as progressive and/or symptomatic metastases with or without significant hepatic invasion (>30–50%), and/or bone metastases. Methods: This academic randomised, double-blind, placebo-controlled phase II study aims to evaluate lanreotide autogel 120 mg (LAN) as maintenance treatment after at least 2 months of first-line treatment (L1) in aggressive G1-G2 DP-NET. Patients were randomly assigned in a 1:1 ratio to receive LAN or placebo (PBO), every 28 days, until progression or toxicity. The primary end-point was progression-free survival (PFS) at 6 months. Results: Among the 118 planned patients, 53 were included. Of these, 81.1% had a G2 tumour, and 90.6% had metastatic disease. L1 therapy consisted of chemotherapy (96.8%). Median duration of L1 was 4.6 months (range: 2.0–7.7). At the time of randomisation, 81.1% of patients had stable disease. Median follow-up was 27.0 months (95% CI: 19.5; 31.2). PFS at 6 months was 73.1% (90% CI: 55.3; 86.6) in LAN versus 54.2% (90% CI: 35.8; 71.8) in PBO. Median PFS was 19.4 months (95% CI: 7.6; 32.6) and 7.6 months (95% CI: 3.0; 9.0), respectively. Median overall survival was 41.9 months in PBO and was not reached in LAN. The toxicity profile was mainly grade 1–2 expected toxicities. Conclusions: The encouraging results of lanreotide autogel 120 mg as a maintenance treatment after L1 in aggressive G1/2 DP-NET should be confirmed. Trial registration: NCT02288377 (clinicaltrials.gov). © 2022 The Authors

Many patients with inflammatory bowel disease [IBD] are treated with anti-tumour necrosis factor [TNF] therapies, of which infliximab [IFX] is most commonly used. Loss of response [LOR] to anti-TNF therapy due to immunogenic failure accounts for 20% of subsequent medical intervention and is defined, using a drug-sensitive assay, as low or undetectable concentration of drug with high titres of anti-drug antibodies [ADAb]. We performed a systematic review to investigate the use of a drug-tolerant assay during both induction and maintenance, to monitor patients treated with anti-TNFs. After the search on PubMed, 90 publications were reviewed. Most ADAb detection methods are drug-sensitive, cannot detect ADAb in the presence of drug, and therefore cannot be used close to drug administration when the drug concentration is too high. To overcome this major limitation, several drug-tolerant techniques have been developed and will be discussed in this review. Using drug-tolerant assays, ADAb against IFX or adalimumab [ADM] can be detected during induction and predict primary non-response or LOR. Drug-sensitive assays do not allow detection of ADAb during the induction phase when IFX or ADM concentration is typically high.

Although gemcitabine-based chemotherapy is the standard of care for advanced biliary tract cancers (BTCs), adjuvant phase III studies (BCAT in Japan, PRODIGE 12 in France) failed to show benefit, possibly owing to fewer patients (n = 225 and n = 194) compared with the adjuvant capecitabine BILCAP trial (n = 447). We performed a combined analysis of both gemcitabine-based chemotherapy adjuvant studies.We performed individual patient data meta-analysis of all patients included in BCAT and PRODIGE 12. BCAT study randomised patients with extrahepatic cholangiocarcinoma to single-agent gemcitabine or observation. PRODIGE 12 randomised patients with all BTC subtypes to gemcitabine-oxaliplatin combination or observation. Combined analysis was performed using Kaplan-Meier curves and a Cox regression model stratified on the trial.Two hundred and twelve versus 207 patients were randomised in the gemcitabine-based chemotherapy versus observation arms. Baseline characteristics were balanced between arms. The median follow-up was 5.5 years. After 258 relapse-free survival (RFS) events, there was no difference in RFS (log-rank p = 0.45; hazard ratio [HR] = 0.91 [95% confidence interval [CI] 0.71-1.16]; p = 0.46). RFS rates at five years were 40.8% (95%CI: 33.9%-47.5%) for gemcitabine-based chemotherapy versus 36.6% (95%CI: 29.8%-43.4%) for observation. After 201 deaths, there was no difference in overall survival (OS) (log-rank p = 0.83; HR = 1.03 [95%CI: 0.78-1.35]; p = 0.85). OS rates at five years were 50.5% (95%CI: 43.1%-57.4%) for gemcitabine-based chemotherapy versus 49.3% (95%CI: 41.6%-56.5%) for observation.With 419 patients included, this analysis did not show significant improvement in RFS and no trend in improvement in OS. Gemcitabine-based chemotherapy should not be used as an adjuvant treatment for BTC.

PURPOSE Whether triplet chemotherapy is superior to doublet chemotherapy in advanced biliary tract cancer (BTC) is unknown. METHODS In this open-label, randomized phase II-III study, patients with locally advanced or metastatic BTC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) to receive oxaliplatin, irinotecan, and infusional fluorouracil (mFOLFIRINOX), or cisplatin and gemcitabine (CISGEM) for a maximum of 6 months. We report the results of the phase II part, where the primary end point was the 6-month progression-free survival (PFS) rate among the patients who received at least one dose of treatment (modified intention-to-treat population) according to Response Evaluation Criteria in Solid Tumors version 1.1 (statistical assumptions: 6-month PFS rate ≥ 59%, 73% expected). RESULTS A total of 191 patients (modified intention-to-treat population, 185: mFOLFIRINOX, 92; CISGEM, 93) were randomly assigned in 43 French centers. After a median follow-up of 21 months, the 6-month PFS rate was 44.6% (90% CI, 35.7 to 53.7) in the mFOLFIRINOX arm and 47.3% (90% CI, 38.4 to 56.3) in the CISGEM arm. Median PFS was 6.2 months (95% CI, 5.5 to 7.8) in the mFOLFIRINOX arm and 7.4 months (95% CI, 5.6 to 8.7) in the CISGEM arm. Median overall survival was 11.7 months (95% CI, 9.5 to 14.2) in the mFOLFIRINOX arm and 13.8 months (95% CI, 10.9 to 16.1) in the CISGEM arm. Adverse events ≥ grade 3 occurred in 72.8% of patients in the mFOLFIRINOX arm and 72.0% of patients in the CISGEM arm (toxic deaths: mFOLFIRINOX arm, two; CISGEM arm, one). CONCLUSION mFOLFIRINOX triplet chemotherapy did not meet the primary study end point. CISGEM doublet chemotherapy remains the first-line standard in advanced BTC.

PURPOSE Metastatic pancreatic cancer (mPC) still harbors a dismal prognosis. Our previous trial (PRODIGE 4—ACCORD 11) demonstrated the superiority of 6-month chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) over gemcitabine for overall survival. The high limiting oxaliplatin-related neurotoxicity supports the evaluation of an oxaliplatin stop-and-go strategy and a sequential strategy in mPC. METHODS In this phase II study, patients were randomly assigned to receive either 6 months of FOLFIRINOX (arm A), 4 months of FOLFIRINOX followed by leucovorin plus fluorouracil maintenance treatment for controlled patients (arm B), or a sequential treatment alternating gemcitabine and fluorouracil, leucovorin, and irinotecan every 2 months (arm C). The primary end point was progression-free survival at 6 months. RESULTS Between January 2015 and November 2016, 276 patients (mean age: 63 years; range: 40-76 years) were enrolled (A: 91, B: 92, and C: 90). Grade 3 or 4 neurotoxicity occurred in 10.2% of patients in arm A and 19.8% in arm B. The median ratio of received dose/targeted dose of oxaliplatin was 83% in arm A and 92% in arm B. The 6-month progression-free survival was 47.1% in A, 42.9% in B, and 34.1% in C. The median overall survival was 10.1 months in arm A, 11.2 in arm B, and 7.3 in arm C. Median survival without deterioration in quality-of-life scores was higher in the maintenance arm (11.4 months) than in arms A and C (7.2 and 7.5 months, respectively). CONCLUSION Maintenance with leucovorin plus fluorouracil appears to be feasible and effective in patients with mPC controlled after 4 months of induction chemotherapy with FOLFIRINOX. Severe neurotoxicity was higher in the maintenance therapy arm, probably because of the higher cumulative dose of oxaliplatin.

Background In cases of loss of response due to mechanistic failure under antitumor necrosis factor agents, it is recommended to switch to another class of biologics. Two different strategies were compared in patients with inflammatory bowel disease (IBD) who were treated with nonoptimized adalimumab (ADA) and experienced a loss of response despite therapeutic trough levels of adalimuma—either ADA dose optimization or switching to vedolizumab or ustekinumab. Methods Patients under maintenance therapy with ADA monotherapy (40 mg every 14 days) and who experienced a secondary loss of response with trough levels > 4.9 μg/mL were included prospectively in this nonrandomized study. The primary end point was the survival rate without therapeutic discontinuation after ADA dose optimization or switching to another class of biologics. Results Adalimumab was optimized (n = 61 patients, 42 Crohn’s disease, 19 ulcerative colitis) or swapped for vedolizumab (n = 40, 20 ulcerative colitis) or ustekinumab (n = 30, 30 Crohn’s disease). At 24 months, 11 out of 70 patients (14.8%) in the swap group discontinued treatment compared with 36 out of 61 (59.6%) patients in the optimization group (P 24 months) than in the optimization group (13.3 months, P 500 μg/g (HR, 3.53; 95% CI, 1.16–10.72; P = 0.026) and inversely associated with variation of trough levels of adalimumab (>2 µg/mL from baseline to week 8 after optimization; HR, 0.51; 95% CI, 0.13–0.82; P = 0.03). In the swap group, no factor was associated with treatment discontinuation. Conclusion In IBD patients under ADA maintenance therapy who experience a secondary loss of response and in whom trough levels are >4.9µg/mL, swapping to another class is better than optimizing ADA, which is, however, appropriate in a subgroup of patients.

Stratification of colon cancer (CC) of patients with stage II and III for risk of relapse is still needed especially to drive adjuvant therapy administration. Our study evaluates the prognostic performance of two known biomarkers, CDX2 and CD3, standalone or their combined information in stage II and III CC.CDX2 and CD3 expression was evaluated in Prodige-13 study gathering 443 stage II and 398 stage III primary CC on whole slide colectomy. We developed for this study an H-score to quantify CDX2 expression and used our artificial intelligence (AI)-guided tissue analysis ColoClass to detect CD3 in tumour core and invasive margin. Association between biomarkers and relapse-free survival was investigated.Univariate analysis showed that the combined variable CD3-TC and CD3-IM was associated with prognosis in both stage II and stage III. CDX2, on the contrary, was associated with prognosis only in stage III. We subsequently associated CDX2 and combined immune parameters only in stage III. This multivariate analysis allowed us to distinguish a proportion of stage III CC harbouring a high CDX2 expression and a high immune infiltration with a particularly good prognosis compared to their counterpart.This study validated the prognostic role of CDX2 and CD3 evaluated with immunohistochemistry procedures in stage III but not in stage II. This association would be conceivable in a routine pathology laboratory and could help oncologist to consider chemotherapy de-escalation for a part of stage III patients.

To report the current clinical practice of French physicians for metachronous resectable liver metastasis (LM) occurring after a FOLFOX adjuvant chemotherapy for primary cancer. Twenty four clinical situations were proposed to a panel of experts via 4 learned societies. Clinical situations varied according time of recurrence (early between 6 and 12 month or > 12 month), extension of LM (limited ≤ 2 or extended > 2 lesions), presence of a neuropathy or not, and of a RAS or BRAF mutation. A total of 157 physicians participated in this study. A consensus was reached in 17 (71%) clinical situations. For an early limited recurrence, whatever presence of neuropathy, the preferred therapeutic approach (45%) was upfront surgery. For an early extended recurrence, whatever presence of neuropathy, there was a consensus (64%) for a preoperative chemotherapy by FOLFIRI + biologic agent. For a late recurrence without neuropathy, there was a consensus (50%) for a preoperative FOLFOX chemotherapy, whatever the extension of LM. For a late recurrence with neuropathy, upfront surgery was chosen (52%) for limited LM, and preoperative chemotherapy by FOLFIRI + biologic agent (73%) for extended LM. No response was influenced by the RAS mutation status. There was a strong consensus for intensified preoperative chemotherapy in all clinical situations for BRAF-mutated LM. This national survey provides an overview of the practice patterns in the treatment of LM occurring after adjuvant FOLFOX for primary. It could be a basis to establish expert’s recommendations for the clinical practice.

Background Maintenance treatments with fluoropyrimidine alone or combined with bevacizumab after induction chemotherapy are two standard options in first-line metastatic colorectal cancer (mCRC). However, no trial has compared these two maintenance regimens. Methods BEVAMAINT is a multicenter, open-label, randomized phase III trial comparing fluoropyrimidine alone or plus bevacizumab as maintenance treatment after induction polychemotherapy in mCRC. The primary endpoint is the time-to-treatment failure (TTF), calculated from date of randomization to first radiological progression, death, start of a new chemotherapy regimen (different from induction or maintenance chemotherapy) or end of maintenance treatment without introduction of further chemotherapy. We expect a 2-month TTF improvement from 6 months in the monotherapy arm to 8 months in the combination arm (hazard ratio [HR], 0.75). Based on a two-sided α risk of 5% and a power of 80%, using Schoenfeld method, 379 events are required (planned enrolment, 400 patients). Patients with mCRC, whose disease is measurable according to RECIST 1.1 criteria and controlled (objective response or stable disease) – but remains unresectable – after 4 to 6 months of induction polychemotherapy (doublet or triplet chemotherapy with or without anti-EGFR or bevacizumab), and who have recovered from limiting adverse events of induction polychemotherapy are eligible for randomization. Randomization is stratified according to center, response to induction chemotherapy (objective response vs stable disease), ECOG performance status (0-1 vs 2), maintenance fluoropyrimidine (5-fluorouracil vs capecitabine) and primary tumor status (resected vs not). Capecitabine or bolus and infusional 5-fluorouracil plus folinic acid (simplified LV5FU2 regimen) are both accepted for maintenance chemotherapy, at investigator's discretion. Clinical evaluation, tumor imaging, carcinoembryonic antigen and circulating tumor DNA dosages are planned at enrolment and every 9 weeks. The maintenance treatment will be discontinued in the event of unbearable toxicity, progression or patient refusal. After maintenance discontinuation, reintroduction of induction polychemotherapy is recommended; otherwise a second-line treatment is started. The enrolment has begun in January 2020.

The 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. To compare the trough levels of ADA (TLA) and the occurrence of anti-ADA antibodies (AAA) between these two treatment regimens. This 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. Sixty-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

National audience; La mutation BRAFV600E, observée chez 8 % des cancers colorectaux (CCR), confère un phénotype particulier et un mauvais pronostic aux CCR, que ce soit au stade localisé ou métastatique. Les CCR BRAF mutés sont préférentiellement des cancers du côlon droit, peu différenciés, à composante mucineuse, touchant une population plus âgée et plus souvent féminine et sont associés à une évolution métastatique ganglionnaire et péritonéale plus fréquente. La mutation de BRAFV600E est associée à une instabilité des microsatellites (MSI) d’origine sporadique dans 20 à 40 % des cas. En situation localisée, elle n’implique aucune modification du traitement adjuvant. En situation métastatique, il faut systématiquement faire la recherche d’un phénotype MSI, compte tenu de sa fréquente association avec la présence d’une mutation de BRAF, afin de proposer une immunothérapie démontrée très efficace dans ce cas. Pour les CCRm non-MSI, une trichimiothérapie associée au bevacizumab est à privilégier chez les patients en bon état général mais l’association à un anti-EGFR peut se discuter, notamment, quand l’objectif est la réponse tumorale. Parallèlement, la chirurgie doit être systématiquement discutée en cas de métastase(s) hépatique(s) résécable(s) car la présence d’une mutation de BRAFV600E n’est pas un facteur de risque de récidive et qu’une survie prolongée peut être observée. En deuxième ou troisième ligne, le triplet encorafenib, binimetinib et cetuximab, ainsi que le doublet encorafenib et cetuximab sont supérieurs à l’association irinotécan plus cetuximab en termes de réponse et de survie (étude BEACON) et représentent un nouveau standard thérapeutique. Leur utilisation en première ligne est à l’étude.

International audience; Introduction - Patients treated for malignancy are considered at risk of severe COVID-19. This exceptional pandemic has affected countries on every level, particularly health systems which are experiencing saturation. Like many countries, France is currently greatly exposed, and a complete reorganization of hospitals is ongoing. We propose here adaptations of diagnostic procedures, therapies and care strategies for patients treated for digestive cancer during the COVID-19 epidemic. Methods - French societies of gastroenterology and gastrointestinal (GI) oncology carried out this study to answer two main questions that have arisen (i) how can we limit high-risk situations for GI-cancer patients and (ii) how can we limit contact between patients and care centers to decrease patients' risk of contamination while continuing to treat their cancer. All recommendations are graded as experts' agreement according to the level of evidence found in the literature until March 2020. Results - A proposal to adapt treatment strategies was made for the main GI oncology situations. Considering the level of evidence and the heterogeneous progression of the COVID-19 epidemic, all proposals need to be considered by a multidisciplinary team and implemented with patient consent. Conclusion - COVID-19 epidemic may significantly affect patients treated for digestive malignancies. Healthcare teams need to consider adapting treatment sequences when feasible and according to the epidemic situation.

Background Identifying patients with metastatic colorectal cancer who will have an early disease progression during induction chemotherapy (IC) and identifying patients who may have a chemotherapy-free interval (CFI) after IC are two major challenges. Methods A logistic model was used to identify factors associated with early progression during IC and with short duration of the first CFI in 488 patients enrolled in the PRODIGE 9 trial. Independent factors were defined with a threshold 0.10. Results In multivariate analysis, baseline leukocytes >10 × 109/L (OR = 1.98 [1.02–3.8], p = 0.04), and stable or increasing CEA at 2 months (OR = 3.61 [1.68–7.75], p = 0.01) were independent factors associated with progression during IC. Male gender (OR = 1.725 [0.92–3.325], p = 0.09) and no tumour response at first evaluation (OR = 1.90 [0.96–3.76], p = 0.07) were significantly associated with a short CFI. The presence of BRAF V600E mutation was also associated with short CFI (OR = 4.59 [0.95; 22.3], p = 0.058). Conclusion High baseline leukocyte count and the lack of CEA decrease level at first evaluation were associated with early progression, and could be in favour of early chemotherapy intensification. Male gender, no tumour response at first evaluation and BRAF mutation are associated with a short CFI, and may be considered for maintenance chemotherapy after IC. Clinical trial number NCT00952029.

International audience; Objective: The 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.Design: Translational 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.Results: Of 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).Conclusions: In 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.

International audience; Background: Immune checkpoint inhibitors (ICI) targeting Programmed death-1 (PD-1) have shown their efficacy in advanced MSI/dMMR (microsatellite instability/deficient mismatch repair) tumors. The MSI/dMMR status predicts clinical response to ICI. The promising results evaluating ICI in localized MSI/dMMR tumors in neoadjuvant setting need to be confirmed in MSI/dMMR solid tumors. The aim of the IMHOTEP trial is to assess the efficacy of neoadjuvant anti-PD-1 treatment in MSI/dMMR tumors regarding the pathological complete response rate. Methods: This study is a prospective, multicenter, phase II study including 120 patients with localized MSI/dMMR carcinomas suitable for curative surgery. A single dose of pembrolizumab will be administered before the surgery planned 6 weeks later. Primary objective is to evaluate the efficacy of neoadjuvant pembrolizumab according to pathological complete tumor response. Secondary objectives are to assess safety, recurrence-free survival and overall survival. Ancillary studies will assess molecular and immunological biomarkers predicting response/resistance to ICI. First patient was enrolled in December 2021. Discussion: The IMHOTEP trial will be one of the first clinical trial investigating perioperative ICI in localized MSI/dMMR in a tumor agnostic setting. Assessing neoadjuvant anti-PD-1 is mandatory to improve MSI/dMMR patient's outcomes. The translational program will explore potential biomarker to improve our understanding of immune escape and response in this ICI neoadjuvant setting.

573 Background: CABO is approved in second (2L) or third line (3L) systemic therapy for pts with advanced HCC after SOR failure, based on results of the CELESTIAL phase 3. CLERANCE was designed to evaluate safety and efficacy of CABO in pts with HCC in real-world practice in a French population. Methods: This prospective, French multicentre (n=17), interventional study aims to recruit 110 pts with unresectable HCC when a decision of CABO treatment was made in 2L or 3L after prior sorafenib (SOR) failure, according to the French health authority approved label. The primary endpoint is the incidence of treatment-related adverse events (TRAE) of grade > 2 (NCI-CTCAE v5) by a central review committee. Secondary endpoints include overall survival (OS), objective response rate (ORR) (RECIST v1.1 per investigator assessed), progression-free survival (PFS), time to progression (TTP) and profiles of CABO administration. Results: Of 110 pts enrolled, the final analysis focused on the 99 pts who starting CABO (11 pts withdrawn due to screen failure) and followed up to 12 mo (data cut-off: November 8, 2021). Pts were mainly males (89%), 69 years median age (range 24-85), Child-Pugh A (94.9%) / B7 (5.1%), and ALBI score-1 (33%), 2 (60%), 3 (5%), not evaluated (NE) (2%). About 59% pts received CABO in 2L after SOR, whereas 41% were in 3L after SOR and another line (TKI or IO). SOR was discontinued due to tumor progression (68%) or intolerance (32%) with a median duration of 4.2 mo (95% CI 3.5-4.8) and a median dose of 800 mg (95% CI 631-800). In the 99 pts starting CABO, 128 treatment-emergent adverse events (TEAE) of grade > 2 were reported, 40 of them classified as TRAE: hand foot skin reaction (14%), diarrhea (11%), asthenia and/or anorexia and/or weight loss (12%), arterial hypertension (4%). The ORR was 7% with 58% of disease control rate (DCR). Median PFS was 6.2 mo (95% CI, 5.3-8.7), TTP 8.2 mo (95% CI 6.1-12.8), without any difference when CABO used in 2L or 3L line (with prior IO [11%] or not). OS was 11.5 mo (95% CI 9.2-14.6) since start of CABO and 23 mo (95% CI 17.3-29.4) since the first systemic line. ALBI score at 1 was an independent marker of better OS in multivariate analysis (Exp[b] 3.26, 95% CI 1.86-5.69, p

BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is a common complication of chronic liver disease with diverse underlying aetiologies. REACH/REACH-2 were global phase III studies investigating ramucirumab in advanced HCC (aHCC) following sorafenib treatment. We performed an exploratory analysis of outcomes by liver disease aetiology and baseline serum viral load. METHODS Meta-analysis was conducted in patients with aHCC and alpha-fetoprotein (AFP) ≥400 ng/mL (N = 542) from REACH/REACH-2 trials. Individual patient-level data were pooled with results reported by aetiology subgroup (hepatitis B [HBV] or C [HCV] and Other). Pre-treatment serum HBV DNA and HCV RNA were quantified using Roche COBAS AmpliPrep/COBAS TaqMan. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method and Cox proportional hazard model (stratified by study). RESULTS Baseline characteristics were generally balanced between arms in each subgroup (HBV: N = 225, HCV: N = 127, Other: N = 190). No significant difference in treatment effect by aetiology subgroup was detected (OS interaction P-value = .23). Median OS (ramucirumab vs placebo) in months was 7.7 versus 4.5 (HR 0.74, 95% CI 0.55-0.99) for HBV, 8.2 versus 5.5 (HR 0.82, 95% CI 0.55-1.23) for HCV and 8.5 versus 5.4 (HR 0.56, 95% CI 0.40-0.79) for Other. Ramucirumab showed similar overall safety profiles across subgroups. Worst outcomes were noted in patients with a detectable HBV load. Use of HBV antiviral therapy, irrespective of viral load, was beneficial for survival, liver function and liver-specific adverse events. CONCLUSIONS Ramucirumab improved survival across aetiology subgroups with a tolerable safety profile, supporting its use in patients with aHCC and elevated AFP.

International audience; Pembrolizumab, a PD1 immune checkpoint inhibitor (ICI), was recently reported to be very effective in patients with microsatellite instable/deficient mismatch repair metastatic colorectal cancer (MSI/dMMR mCRC), unlike patients with microsatellite stable/proficient MMR (MSS/pMMR) mCRC, in whom ICIs are generally ineffective. However, about 15% of MSS/pMMR CRCs are highly infiltrated by tumour infiltrating lymphocytes. In addition, both oxaliplatin and bevacizumab have been shown to have immunomodulatory properties that may increase the efficacy of an ICI. We formulated the hypothesis that patients with MSS/pMMR mCRC with a high immune infiltrate can be sensitive to ICI plus oxalipatin and bevacizumab-based chemotherapy. POCHI is a multicenter, open-label, single-arm phase II trial to evaluate efficacy of Pembrolizumab with Capox Bevacizumab as first-line treatment of MSS/pMMR mCRC with a high immune infiltrate for which we plan to enrol 55 patients. Primary endpoint is progression-free survival (PFS) at 10 months, which is expected greater than 50%, but a 70% rate is hoped for. Main secondary objectives are overall survival, secondary resection rate and depth of response. Patients must have been resected of their primary tumour so as to evaluate two different immune scores (Immunoscore® and TuLIS) and are eligible if one score is "high";. The first patient was included on April 20, 2021.

The SCOPE project aimed to better understand practice patterns, identify drivers for treatment goals, and determine third- and fourth-line treatment choices for patients with metastatic colorectal cancer (mCRC). The survey was developed by an expert panel of gastrointestinal oncologists. Questions concerned general practice patterns, and treatment decisions for three hypothetical patient case scenarios. Participants had to routinely manage patients with mCRC. We present results from 629 participants who provided input on patient treatment scenarios (data cutoff: 17/01/2020). Prolonging overall survival (OS, 51%) was the main aim in first line. In third line, quality of life (QOL) was the primary goal (34%). Forty-three percent also cited efficacy-focused goals, 18% and 13% noted prolonging OS and improving progression-free survival as main aims, respectively. For fit and active patients, 89% of respondents considered trifluridine-tipiracil an appropriate third-line treatment, regorafenib (31%) or clinical trial enrollment (29%) were the fourth-line options. For patients with comorbidities and limited caregiver support, trifluridine-tipiracil was the preferred third-line treatment (70%). For KRAS-mutated patients with comorbidities and adverse events who received prior oxaliplatin, 90% considered oxaliplatin rechallenge an unsuitable third-line treatment, mainly due to the risk of cumulative toxicity (75%). In the third/fourth-line settings, trifluridine-tipiracil followed by regorafenib was the most common option (54%), 17% chose regorafenib followed by trifluridine-tipiracil. Efficacy coupled with QOL are important goals in third-line treatment. Daily practice patterns reflect the guideline recommendations in third- and fourth-line settings, with a trend toward using trifluridine-tipiracil versus regorafenib in KRAS-wildtype and KRAS-mutant tumors.

Background Patients with RAS wild‐type (WT) nonresectable metastatic colorectal cancer (mCRC) may receive either bevacizumab or an anti‐epidermal growth factor receptor (EGFR) combined with first‐line, 5‐fluorouracil‐based chemotherapy. Without the RAS status information, the oncologist can either start chemotherapy with bevacizumab or wait for the introduction of the anti‐EGFR. Our objective was to compare both strategies in a routine practice setting. Materials and Methods This multicenter, retrospective, propensity score–weighted study included patients with a RAS WT nonresectable mCRC, treated between 2013 and 2016 by a 5‐FU‐based chemotherapy, with either delayed anti‐EGFR or immediate anti‐vascular endothelial growth factor (VEGF). Primary criterion was overall survival (OS). Secondary criteria were progression‐free survival (PFS) and objective response rate (ORR). Results A total of 262 patients (129 in the anti‐VEGF group and 133 in the anti‐EGFR group) were included. Patients receiving an anti‐VEGF were more often men (68% vs. 56%), with more metastatic sites (>2 sites: 15% vs. 9%). The median delay to obtain the RAS status was 19 days (interquartile range: 13–26). Median OS was not significantly different in the two groups (29 vs. 30.5 months, p = .299), even after weighting on the propensity score (hazard ratio [HR] = 0.86, 95% confidence interval [CI], 0.69–1.08, p = .2024). The delayed introduction of anti‐EGFR was associated with better median PFS (13.8 vs. 11.0 months, p = .0244), even after weighting on the propensity score (HR = 0.74, 95% CI, 0.61–0.90, p = .0024). ORR was significantly higher in the anti‐EGFR group (66.7% vs. 45.6%, p = .0007). Conclusion Delayed introduction of anti‐EGFR had no deleterious effect on OS, PFS, and ORR, compared with doublet chemotherapy with anti‐VEGF. Implications for Practice For RAS/RAF wild‐type metastatic colorectal cancer, patients may receive 5‐fluorouracil‐based chemotherapy plus either bevacizumab or an anti‐epidermal growth factor receptor (EGFR). In daily practice, the time to obtain the RAS status might be long enough to consider two options: to start the chemotherapy with bevacizumab, or to start without a targeted therapy and to add the anti‐EGFR at reception of the RAS status. This study found no deleterious effect of the delayed introduction of an anti‐EGFR on survival, compared with the introduction of an anti‐vascular endothelial growth factor from cycle 1. It is possible to wait one or two cycles to introduce the anti‐EGFR while waiting for RAS status., More than half of the cases of metastatic colorectal cancer harbor a RAS mutation; however, the time to obtain RAS status might be long enough to consider delayed anti‐EGFR treatment. This article reports on the two main treatment strategies for these cases.

PurposeThe objective of this study was to build and validate a radiomic signature to predict early a poor outcome using baseline and 2-month evaluation CT and to compare it to the RECIST1·1 and morphological criteria defined by changes in homogeneity and borders.MethodsThis study is an ancillary study from the PRODIGE-9 multicentre prospective study for which 491 patients with metastatic colorectal cancer (mCRC) treated by 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) and bevacizumab had been analysed. In 230 patients, computed texture analysis was performed on the dominant liver lesion (DLL) at baseline and 2 months after chemotherapy. RECIST1·1 evaluation was performed at 6 months. A radiomic signature (Survival PrEdiction in patients treated by FOLFIRI and bevacizumab for mCRC using contrast-enhanced CT TextuRe Analysis (SPECTRA) Score) combining the significant predictive features was built using multivariable Cox analysis in 120 patients, then locked, and validated in 110 patients. Overall survival (OS) was estimated with the Kaplan-Meier method and compared between groups with the logrank test. An external validation was performed in another cohort of 40 patients from the PRODIGE 20 Trial.ResultsIn the training cohort, the significant predictive features for OS were: decrease in sum of the target liver lesions (STL), (adjusted hasard-ratio(aHR)=13·7, p=1·93×10–7), decrease in kurtosis (ssf=4) (aHR=1·08, p=0·001) and high baseline density of DLL, (aHR=0·98, p0·02 had a lower OS in the training cohort (pConclusionA radiomic signature (combining decrease in STL, density and computed texture analysis of the DLL) at baseline and 2-month CT was able to predict OS, and identify good responders better than RECIST1.1 criteria in patients with mCRC treated by FOLFIRI and bevacizumab as a first-line treatment. This tool should now be validated by further prospective studies.Trial registrationClinicaltrial.gov identifier of the PRODIGE 9 study: NCT00952029.Clinicaltrial.gov identifier of the PRODIGE 20 study: NCT01900717.

Summary Background VEGF and VEGF receptor 2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether the addition of ramucirumab, a VEGFR-2 antagonist monoclonal antibody, to first-line chemotherapy improves outcomes in patients with metastatic gastric or gastro-oesophageal junction adenocarcinoma. Methods For this double-blind, randomised, placebo-controlled, phase 3 trial done at 126 centres in 20 countries, we recruited patients aged 18 years or older with metastatic, HER2-negative gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. Eligible patients were randomly assigned (1:1) with an interactive web response system to receive cisplatin (80 mg/m2, on the first day) plus capecitabine (1000 mg/m2, twice daily for 14 days), every 21 days, and either ramucirumab (8 mg/kg) or placebo on days 1 and 8, every 21 days. 5-Fluorouracil (800 mg/m2 intravenous infusion on days 1–5) was permitted in patients unable to take capecitabine. The primary endpoint was investigator-assessed progression-free survival, analysed by intention to treat in the first 508 patients. We did a sensitivity analysis of the primary endpoint, including a central review of CT scans. Overall survival was a key secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT02314117. Findings Between Jan 28, 2015, and Sept 16, 2016, 645 patients were randomly assigned to receive ramucirumab plus fluoropyrimidine and cisplatin (n=326) or placebo plus fluoropyrimidine and cisplatin (n=319). Investigator-assessed progression-free survival was significantly longer in the ramucirumab group than the placebo group (hazard ratio [HR] 0·753, 95% CI 0·607–0·935, p=0·0106; median progression-free survival 5·7 months [5·5–6·5] vs 5·4 months [4·5–5·7]). A sensitivity analysis based on central independent review of the radiological images did not corroborate the investigator-assessed difference in progression-free survival (HR 0·961, 95% CI 0·768–1·203, p=0·74). There was no difference in overall survival between groups (0·962, 0·801–1·156, p=0·6757; median overall survival 11·2 months [9·9–11·9] in the ramucirumab group vs 10·7 months [9·5–11·9] in the placebo group). The most common grade 3–4 adverse events were neutropenia (85 [26%] of 323 patients in the ramucirumab group vs 85 [27%] of 315 in the placebo group), anaemia (39 [12%] vs 44 [14%]), and hypertension (32 [10%] vs 5 [2%]). The incidence of any-grade serious adverse events was 160 (50%) of 323 patients in the ramucirumab group and 149 (47%) of 315 patients in the placebo group. The most common serious adverse events were vomiting (14 [4%] in the ramucirumab group vs 21 [7%] in the placebo group) and diarrhoea (11 [3%] vs 19 [6%]). There were seven deaths in each group, either during study treatment or within 30 days of discontinuing study treatment, which were the result of treatment-related adverse events. In the ramucirumab group, these adverse events were acute kidney injury, cardiac arrest, gastric haemorrhage, peritonitis, pneumothorax, septic shock, and sudden death (n=1 of each). In the placebo group, these adverse events were cerebrovascular accident (n=1), multiple organ dysfunction syndrome (n=2), pulmonary embolism (n=2), sepsis (n=1), and small intestine perforation (n=1). Interpretation Although the primary analysis for progression-free survival was statistically significant, this outcome was not confirmed in a sensitivity analysis of progression-free survival by central independent review, and did not improve overall survival. Therefore, the addition of ramucirumab to cisplatin plus fluoropyrimidine chemotherapy is not recommended as first-line treatment for this patient population. Funding Eli Lilly and Company.

4036 Background: Efficacy of 2nd line chemotherapy in advanced gastric/gastro-oesphageal junction (GEJ) adenocarcinoma remains limited. No study up until now has evaluated the efficacy of immune checkpoint inhibitors combined with chemotherapy as 2ndline treatment of advanced gastric/GEJ adenocarcinoma. Methods: DURIGAST PRODIGE 59 is a randomized, multicenter, phase II study designed to assess the efficacy and safety of the combination of FOLFIRI plus durvalumab (anti-PD-L1 until progression) (FD) versus FOLFIRI plus durvalumab and tremelimumab (anti-CTLA-4 for 4 cycles) (FDT). Key eligibility criteria included advanced gastric/GEJ adenocarcinoma, platinum-based first-line chemotherapy and ECOG performance status (PS) 0 or 1. Patients were randomized in a 1:1 ratio to FD versus FDT. The primary endpoint is progression-free survival (PFS) at 4 months, which was expected to be 70% (H0:50%). With an α risk of 5%, a power of 85% and 5% of non-evaluable patients, 47 evaluable patients are needed by arm. Secondary endpoints included safety, overall survival (OS) and quality of life. Results: Between August 2020 and June 2021, 96 patients were randomized, 48 in each arm. The median age was 59.7 years, 30.4% were women and 66.3% ECOG PS 1. All in all, 22.8% had HER2+ tumors and 4.3% dMMR/MSI tumors. The 4-month PFS were 44.7% [90%CI: 32.3–57.7] and 57.8% [90%CI: 44.5–70.3] in the FD and FDT arms, respectively. Primary endpoint was not met. Median PFS were 3.8 and 5.9 months, disease control rates 68.9% and 73.8% and median OS not reached and 10.1 months in FD and FDT arms, respectively. Eight patients in FDT arm had tremelimumab re-introduction at progression. Twenty-one patients, 8 in FD arm and 13 in FDT arm, are still being treated with a median duration of treatment of 7.8 and 10.9 months. All in all, 50.0% and 47.8% of patients experienced at least one grade 3-4 adverse events related to the treatment (neutropenia: 13.0 vs 21.7%, anemia: 10.9 vs 6.5%, diarrhea: 2.2 vs 8.7% and vomiting: 6.5 vs 10.9%), in FD and FDT arms, respectively. In both arms there was no clinically significant deterioration of quality of life superior to 10 points according to EORTC QLQ-C30 global health status. Conclusions: The DURIGAST PRODIGE 59 trial demonstrates an acceptable safety profile of immune checkpoint inhibitors plus FOLFIRI in 2nd line treatment for advanced gastric/GEJ adenocarcinoma. FDT combination demonstrates a clinically relevant efficacy never before achieved with a median PFS of 6 months and should be evaluated in a phase III trial. Updated results including PFS according to centralized review and PD-L1 status will be presented during ASCO meeting. Clinical trial information: NCT03959293.

Aim: We report real-world evidence with regorafenib in previously treated metastatic colorectal cancer from the French cohort of the international, prospective, observational CORRELATE study. Patients & methods: Patients receiving regorafenib according to French health authority approval were included. The primary end point was treatment-emergent adverse events. Overall survival and progression-free survival were secondary end points. Results: Two hundred and forty-two patients (61% male, median age: 66 years) were enrolled. The most common grade ≥3 drug-related treatment-emergent adverse events were hand–foot skin reaction (10.3%), asthenia/fatigue (9.9/1.2%) and hypertension (6.2%). Median overall survival and progression-free survival were 6.8 (95% CI: 6.3–7.6) and 2.8 months (95% CI: 2.6–3.0), respectively. Conclusion: The real-world safety and effectiveness data of regorafenib in metastatic colorectal cancer in France align with findings from Phase III clinical trials and the global CORRELATE population.

OBJECTIVES The total psoas area index (TPI) is an emerging alternative to the total skeletal muscle area index as a prognostic factor but has never been evaluated in metastatic pancreatic cancer (mPC). METHODS Areas were manually recorded, as previously described. Sex-specific cutoffs were identified by optimum stratification of TPI using log-rank χ2 statistic associated with mortality to define sarcopenic psoas. Progression-free survival (PFS) and overall survival (OS) were the primary objectives. Two period groups were used as internal validation. RESULTS During the period study, 79 patients were treated for mPC. The TPI was correlated with PFS (hazards ratio, 0.81; P = 0.02) and OS (hazards ratio, 0.7; P < 0.001). Optimum thresholds defining sarcopenic psoas were less than 5.73 cm2/m2 in men and less than 4.37 cm2/m2 in women. Patients with sarcopenic psoas (62.0%) had shorter median PFS (2.9 months) compared with the others (6.6 months, adjusted P log-rank = 0.01), independently to the intensity of chemotherapy, weight loss, and performance status greater than 1. Similarly, OS was independently shorter in patients with sarcopenic psoas (7.6 months) versus the others (22.2 months, adjusted P < 0.001). These results were confirmed in the 2 period groups. CONCLUSIONS A low TPI is a stronger independent prognostic factor in mPC.

BackgroundThere is still controversial data regarding prognostic value of Venous ThromboEmbolism (VTE) in advanced Pancreatic Ductal AdenoCarcinoma (PDAC) and thromboprophylaxis is poorly prescribed despite international recommendations.MethodsMedical charts of patients consecutively treated for advanced PDAC from 2010 to 2019 were retrospectively reviewed. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier method. Prognostic Factors were identified using a multivariate Cox’s proportional hazard model. Early VTE was defined as VTE occurring within the third months from PDAC diagnosis.ResultsA total of 174 patients were included (median age: 67 years; males: 55.2%; performance status (PS) 0-1: 88.5%) with metastatic disease in 74.7%. At baseline, Khorana score was high (≥3) in the vast majority of cases (93.7%). The cumulative incidences of VTE were 12.4% (95% CI: 7.3-17.2) at 3 months, 20.4% (95% CI: 13.9-26.4) at 6 months and 28.1% (95% CI: 20.0-35.3) at 12 months. Early VTE was associated with shorter PFS (3.8 months vs. 7.1 months; HR=2.02; 95%CI: 1.21-3.37; p=0.006) and shorter OS (8.0 months vs. 14.1 months; HR=2.42; 95%CI: 1.37-4.30; p=0.002) compared to the remnant patients, independently of the other prognostic factors including PS, liver metastases, carcinomatosis, and chemotherapy regimen.ConclusionEarly VTE is a strong prognostic factor in advanced PDAC and occurs in about 1 in 10 patients.

Background: Gemcitabine/nab-paclitaxel (GN) and FOLFIRINOX (FFX) are two standard first-line therapies for metastatic pancreatic cancer (PC) but have rarely been compared, especially in patients with locally advanced PC (LAPC). Methods: This is a retrospective European multicenter study including patients with LAPC treated with either GN or FFX as the first-line therapy between 2010 and 2019. Coprimary objectives were progression-free survival (PFS) and overall survival (OS), both estimated using the Kaplan–Meier method. Results: A total of 147 patients (GN: n = 60, FFX: n = 87) were included. Tumor resection rates were similar between the two groups (16.7% vs. 16.1%, p = 1), with similar R0 resection rates (88.9%). Median PFS rates were not statistically different: 9 months (95% CI: 8–13.5) vs. 12.1 months (95% CI: 10.1–14.6, p = 0.8), respectively. Median OS rates were 15.7 months (95% CI: 12.6–20.2) and 16.7 months (95% CI: 14.8–20.4, p = 0.7), respectively. Abdominal pain at the baseline (HR = 2.03, p = 0.03), tumors located in the tail of the pancreas (HR = 4.35, p = 0.01), CA19-9 &gt, 200 UI/L (HR = 2.03, p = 0.004) and tumor resection (HR = 0.37, p = 0.007) were independent prognostic factors for PFS, similarly to OS. CA19-9 ≤ 200 UI/L (OR = 2.6, p = 0.047) was predictive of the tumor response. Consolidation chemoradiotherapy, more often used in the FFX group (11.7% vs. 50.6%, p &lt, 0.001), was not predictive. Conclusion: This retrospective study did not show any difference between GN and FFX as the first-line treatment in patients with LAPC.

Anti-drug antibodies develop mostly during the induction therapy with anti-tumour necrosis factor (TNF) drugs and can be revealed by means of a drug-tolerant assay.To investigate whether the early detection of anti-drug antibodies during the induction therapy was predictive of treatment discontinuation.In a prospective study, consecutive patients with inflammatory bowel disease (IBD), who should start an anti-TNF, were enrolled and followed regularly during 24 months or less in case of non- or loss of response (LOR) or adverse events requiring treatment discontinuation. Anti-TNF levels and anti-drug antibodies were measured at week 2 for adalimumab (ADA) and weeks 2 and 6 for infliximab (IFX) using a drug-tolerant assay.One hundred and eight patients were enrolled (54 under ADA). At week 2, antibodies to ADA and to IFX were detected in 76% and 67% of patients. Time to treatment discontinuation was significantly shorter (P 0.001) in patients with antibodies to ADA ≥2.0 µg/mL-eq (6.0 vs 24 months, HR = 18.51, 95% CI [4.35-78.71]) or with antibodies to IFX ≥4.0 µg/mL-eq (5.5 vs24 months, HR = 13.89, 95% CI [4.08-47.31]) at week 2 compared to patients without positive antibodies. Antibodies to ADA and to IFX were predictive of treatment failure within 24 months with a sensitivity of 79% and 62%, and specificities and positive predictive values of 100%. In multivariate analysis, antibodies to ADA or to IFX at week 2 were the only factors associated with treatment discontinuation.The prevalence of antibodies to anti-TNF is high when detected early using a drug-tolerant assay, and their appearance predicts further treatment discontinuation.

Background Cancer patients are thought to have an increased risk of developing severe Coronavirus Disease 2019 (COVID-19) infection and of dying from the disease. In this work, predictive factors for COVID-19 severity and mortality in cancer patients were investigated. Patients and Methods In this large nationwide retro-prospective cohort study, we collected data on patients with solid tumours and COVID-19 diagnosed between March 1 and June 11, 2020. The primary endpoint was all-cause mortality and COVID-19 severity, defined as admission to an intensive care unit (ICU) and/or mechanical ventilation and/or death, was one of the secondary endpoints. Results From April 4 to June 11, 2020, 1289 patients were analysed. The most frequent cancers were digestive and thoracic. Altogether, 424 (33%) patients had a severe form of COVID-19 and 370 (29%) patients died. In multivariate analysis, independent factors associated with death were male sex (odds ratio 1.73, 95%CI: 1.18-2.52), ECOG PS ≥ 2 (OR 3.23, 95%CI: 2.27-4.61), updated Charlson comorbidity index (OR 1.08, 95%CI: 1.01-1.16) and admission to ICU (OR 3.62, 95%CI 2.14-6.11). The same factors, age along with corticosteroids before COVID-19 diagnosis, and thoracic primary tumour site were independently associated with COVID-19 severity. None of the anticancer treatments administered within the previous 3 months had any effect on mortality or COVID-19 severity, except cytotoxic chemotherapy in the subgroup of patients with detectable SARS-CoV-2 by RT-PCR, which was associated with a slight increase of the risk of death (OR 1.53; 95%CI: 1.00-2.34; p = 0.05). A total of 431 (39%) patients had their systemic anticancer treatment interrupted or stopped following diagnosis of COVID-19. Conclusions Mortality and COVID-19 severity in cancer patients are high and are associated with general characteristics of patients. We found no deleterious effects of recent anticancer treatments, except for cytotoxic chemotherapy in the RT-PCR-confirmed subgroup of patients. In almost 40% of patients, the systemic anticancer therapy was interrupted or stopped after COVID-19 diagnosis., Highlights • A total of 1289 patients with solid tumours and COVID-19 were analysed. • Mortality and COVID-19 severity were mainly driven by patient general characteristics. • Overall, we found no deleterious effects of recent anticancer treatments on mortality. . • Systemic anticancer treatment was interrupted or stopped in 39% of patients.

Background Immune checkpoint inhibitors (ICI) are very effective in deficient DNA mismatch-repair system (dMMR)/microsatellite instable (MSI) metastatic colorectal cancer (mCRC). About 15% of MSS/pMMR CRCs are highly infiltrated by tumor infiltrating lymphocyte (TIL) with a good prognosis. Some immune scores based on CD3+ and/or CD8+ T-cells infiltration are validated and reproducible, especially TuLIS1 and Immunoscore®.2 No data are available concerning efficacy of ICI in this subpopulation of mCRC. Pembrolizumab, an anti-PD1 (programmed death-1) monoclonal antibody has been recently reported very effective in patients with MSI/dMMR mCRC. Immunogenic cell death induced by chemotherapy, such as oxaliplatin, could increase the efficacy of ICI. We formulated the hypothesis that patients with a pMMR mCRC with a high immune infiltrate can be sensitive to ICI plus oxalipatin-based chemotherapy. Methods POCHI is a multicenter, open-label, single-arm phase II trial to evaluate efficacy of pembrolizumab in combination with chemotherapy as first-line treatment of pMMR mCRC with a high immune infiltrate. Primary objective is PFS at 10 months, i.e. number of patients alive and without radiological and/or clinical progression at 10 months evaluated by the investigator. Main secondary objectives are overall survival, secondary resection rate, depth of response and early tumour shrinkage. Main inclusion criteria are pMMR mCRC untreated for metastatic disease and with at least one measurable metastatic target according to RECIST v1.1 criteria. Patients must have resected primary tumor to evaluate two different immune scores (Immunoscore® and TuLIS) and patients are eligible if one score is ‘high’. Patients will receive combination of pembrolizumab (200 mg), bevacizumab (7.5 mg/kg), oxaliplatin (130 mg/m²) and capecitabine (2000 mg/m²/day, on day 1 to 14). Treatment will be repeated every 3 weeks until disease progression or unacceptable toxicity. The clinical hypotheses are to increase PFS at 10 months from 50% to 70%. With a one-sided type error of 5%, power of 85%, 10% rate of patients lost to follow-up or not evaluable, 55 patients have to be included. If 32 patients or more are alive and without progression at 10 months, the treatment will be considered as effective. Thus, with 15% ‘high’ immune score, about 400 patients must be tested in order to include 55 patients in POCHI trial. The ancillary study will consist to identify predictive biomarkers of response and included expression of PD-L1, circulating lymphocytes circulating tumour DNA, mutational load and gut microbiota. Inclusions will start in September 2020 and theoretical end of recruitment is 2023. Results N/A Conclusions N/A Acknowledgements We thank all the cooperative groups (FFCD – UNICANCER GI– GERCOR) for their contribution and participation to the present trial. We thank MSD and HalioDX for their support. Trial Registration NCT04262687 Ethics Approval This study was approved by ‘Agence Nationale de Securite du Medicament et des produits de sante (ANSM)’ on 24/03/2020; approval number MEDAECNAT-2020-01-00038_2019-002407-18.’ Consent N/A References Emile JF, et al., Prospective validation of a lymphocyte infiltration prognostic test in stage III colon cancer patients treated with adjuvant FOLFOX. Eur J Cancer 2017 Sep;82:16–24 Pages, et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet 2018 May 26;391(10135):2128–2139.

BACKGROUND: In RECOURSE (, trifluridine/tipiracil significantly improved overall survival and progression-free survival (PFS) versus placebo in patients with pretreated metastatic colorectal cancer (mCRC). PRECONNECT was designed to further characterise safety and clinical use of trifluridine/tipiracil. METHODS: In this ongoing, international, multicentre, open-label trial, patients with pretreated mCRC received oral trifluridine/tipiracil 35 mg/m2 twice daily on days 1-5 and 8-12 of each 28-day cycle. The primary endpoint was safety; secondary endpoints included PFS and quality of life (QoL). RESULTS: 793 patients (median age 62 years) from 13 countries received trifluridine/tipiracil for a median of 2.84 months (IQR 2.64). Adverse events (AEs) were experienced by 96.7%; the most common (≥20% of patients) were neutropaenia, asthenia/fatigue, nausea, anaemia and diarrhoea. Grade ≥3 AEs occurred in 73.9% of patients, with the most common being neutropaenia (39.1% of patients), anaemia (9.8%) and asthenia/fatigue (5.0%). Median PFS was 2.8 months (95% CI 2.7 to 2.9). Median time to Eastern Cooperative Oncology Group performance status deterioration (≥2) was 8.9 months (range 0.03-14.72). There was no clinically relevant change from baseline in QoL. CONCLUSIONS: PRECONNECT showed consistent results with the previously demonstrated safety and efficacy profile of trifluridine/tipiracil, with no new safety concerns identified. QoL was maintained during treatment. TRIAL REGISTRATION NUMBER: NCT03306394. ispartof: ESMO OPEN vol:5 issue:3 ispartof: location:England status: published

The BRAF

International audience; Background: Several guidelines dedicated to metastatic colorectal cancer (mCRC) are available. Since 2013 no recent guidelines are specifically dedicated to older patients and based on a systematic review. Materials and methods: A multidisciplinary Task Force with digestive oncologists, geriatricians and methodologists from the SoFOG was formed in 2016 to update recommendations on medical treatment of mCRC based on a systematic review of publications from 2000 to 2018. Search strategy has followed a standardized protocol from the formulation of clinical questions and definition of a search algorithm to the selection of complete articles for recommendations. Results: The four selected key questions were: For which older patients with mCRC can we considered: (1) Any chemotherapy, (2) Mono or poly-chemotherapy, (3) Anti-angiogenic therapy, (4) Other targeted therapy. Main recommendations for older patients are: (1) Omission of chemotherapy should be discussed with a geriatrician for patients with severe comorbidities, advanced dementia, uncontrolled psychiatric disorder or severe loss of autonomy. (2) If tumor response is not the main aim, a mono-chemotherapy with 5-fluorouracil combined with bevacizumab is recommended as first-line. (3) For patients with symptoms related to metastases or with a planned metastasis ablation, a doublet chemotherapy combined with bevacizumab or anti-EGFR antibody in the context of a RAS wild type tumor is recommended as first-line. Preliminary data suggest that regorafenib may be used, in its registered indication, in patients under 80 with a performance status of 0 and no autonomy alterations and that trifluridine-tipiracil may be used with a tight supervising of hematological function.

We described for the first time the contrast enhancement of a giant fibrovascular esophageal polyp using ultrasound contrast agent, Sonovue® (Bracco, Milan, Italy) during echoendoscopy. Fine Doppler was unsuccessful in showing vascularization due to the mobile characteristic of the tumor. In contrast, via Sonovue® , tissue microcirculation was highlighted inside the entire head of the polyp, leading to better appreciate the risk of bleeding related to its resection. In a second part, we showed the feasibility of classic polypectomy for this giant polyp (5×5 cm) without complication and results of control endoscopy at 3 months. The present case is summarized in a video.

Aims To assess the interest of induction chemotherapy (ICT) intensification before chemoradiotherapy (CRT) in patients with locally advanced pancreatic cancer. Methods Charts of patients treated between February 2010 and November 2016 with consolidation capecitabin based-CRT were retrospectively reviewed in this bicentric study. Patients who underwent Gemcitabine as ICT (Group G) were compared to patients treated with intensive ICT (group I). Primary objectives were progression-free survival (PFS), defined as the time from the first day of ICT to progression or last follow-up, and Time without treatment (TWT), as the time from the last day of CRT to progression. Results Patients' characteristics were balanced between group I (Folforinox: n = 24; GemOx: n = 6) and group G (n = 16) including mean age (63.7 vs 68.1 years), and performance status (PS 0-1 :90% vs 93.7%). Median PFS (17.8 months vs 12 months; p = 0.02) and TWT (7.4 months vs 2.5 months p = 0.01) were statistically better in group I vs group G. These results remained statistically and clinically significant by comparing Folfirinox subgroup to Gemcitabine. A trend to a better median overall survival was observed in group I (20.4 months) vs group G (18.3 months; p = 0.07). After adjusting for ICT duration, PS, and CA19.9 level, ICT intensification remains independently prognostic. Toxicity profile was in accordance with Literature. Conclusion This study shows ICT intensification before CRT is an interesting approach in patients with locally advanced pancreatic cancer. Further studies are needed to confirm these results, and to assess the specific role of CRT in this setting.