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Background. Health-related quality of life (QoL) has been validated as a prognostic factor for cancer patients; however, to be used in routine practice, QoL scores must be dichotomized. Cutoff points are usually based on arbitrary percentile values. We aimed to identify optimal cutoff points for six QoL scales and to quantify their added utility in the performance of four prognostic classifications in patients with hepatocellular carcinoma (HCC). Methods.We reanalyzed data of 271 patients with advanced HCC recruited between July 2002 and October 2003 from 79 institutions in France in the CHOC trial, designed to assess the efficacy of long-acting octreotide. QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30). The scores ranged from 0 to 100. Identification of optimal cutoff points was based on the method of Faraggi and Simon [Stat Med 1996;15:2203-2213]. Improvement in the performance of prognostic classifications was studied with Harrell's C-index, the net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Results.Wefound that optimal cutoff points were50 for global health, 58.33 for physical functioning, 66.67 for role functioning, 66.67 for fatigue, 0 for dyspnea, and 33.33 for diarrhea.The addition of QoL and clinical factors improved the performance of all four prognostic classifications, with improvement in the range of 0.02-0.09 for the C-index, 0.24-0.78 for 3-month NRI, and 0.02-0.10 for IDI. Conclusion. These cutoff values for QoL scales can be useful to identify HCC patients with very poor prognosis and thus improve design of clinical trials and treatment adjustment for these patients. [ABSTRACT FROM AUTHOR]

Abstract: Background: The Fédération Francophone de Cancérologie Digestive phase III trial in patients with metastatic pancreatic adenocarcinoma comparing 5FU, folinic acid and cisplatin combination followed by gemcitabine (Arm A) versus the opposite sequence (Arm B) failed to demonstrate a benefit in overall survival. To longitudinally compare the quality of life (QoL) we explored different definitions of time until definitive deterioration (TUDD) of QoL scores according to minimal clinically important difference (MCID) cut-offs. Methods: QoL was evaluated using the EORTC QLQ-C30 every 8 weeks until death. The following scores were analysed: global health, emotional functioning, physical functioning, fatigue and pain. TUDD was defined as the time interval between randomisation and the first occurrence of a decrease in QLQ-C30 score ⩾5 points without any further improvement in QoL score ⩾5 points or any further available QoL data. Analyses were repeated using a 10 point MCID and/or including death as event. Results: From 08/2003 to 05/2006, 102 patients in Arm A and 100 in Arm B were included. Using a 5 and a 10 point MCID, TUDD curves of the 5 scores did not differ according to treatment arm., The median TUDD of global health was 5.2 months (4.3–6.2) in Arm A and 6.1 months (5.1–8.5) in Arm B (log-rank p =0.50) including death as an event for a 5 point MCID. Multivariate Cox model showed that tumour localisation and progression were independently associated with TUDD (p <0.05). Conclusions: The strategy of chemotherapy did not influence the deterioration of QoL. The TUDD approach seems to provide meaningful clinical results that are adapted to metastatic pancreatic adenocarcinoma trials. [Copyright &y& Elsevier]

In controlled phase II trials, major prognostic factors need to be well balanced between arms. The main procedures used are SPBR (Stratified Permuted Block Randomization) and minimization. First, we provide a systematic review of the treatment allocation procedure used in gastrointestinal oncology controlled phase II trials published in 2019. Second, we performed simulations using data from six phase II studies to measure the impacts of imbalances and bias on the efficacy estimations. From the 40 articles analyzed, all mentioned randomization in both the title and abstract, the median number of patients included was 109, and 77.5% were multicenter. Of the 27 studies that reported at least one stratification variable, 10 included the center as a stratification variable, 10 used minimization, 9 used SBR, and 8 were unspecified. In real data studies, the imbalance increased with the number of centers. The total and marginal imbalances were higher with SBR than with minimization, and the difference increased with the number of centers. The efficiency estimates per arm were close to the original trial estimate in both procedures. Minimization is often used in cases of numerous centers and guarantees better similarity between arms for stratification variables for total and marginal imbalances in phase II trials. [ABSTRACT FROM AUTHOR]

The modified docetaxel, cisplatin, and fluorouracil (mDCF) regimen has shown efficacy and safety as first-line treatment for advanced squamous cell carcinoma of the anus, making it a standard regimen. Inhibitors of programmed cell death protein 1 and its ligand, such as pembrolizumab, nivolumab, retifanlimab, avelumab, and atezolizumab, have shown some antitumour activity as monotherapy in advanced squamous cell carcinoma of the anus that is refractory to chemotherapy. This phase 2 study evaluated the combination of mDCF and atezolizumab as first-line treatment in advanced squamous cell carcinoma of the anus. In this randomised, open-label, non-comparative, phase 2 study, participants from 21 centres (academic, private, and community hospitals and cancer research centres) across France with chemo-naive, metastatic, or unresectable locally advanced recurrent squamous cell carcinoma of the anus, aged 18 years or older, and with an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly allocated (2:1) to receive either atezolizumab (800 mg intravenously every 2 weeks up to 1 year) plus mDCF (eight cycles of 40 mg per m2 docetaxel and 40 mg per m2 cisplatin on day 1 and 1200 mg per m2 per day of fluorouracil for 2 days, every 2 weeks intravenously; group A) or mDCF alone (group B). Randomisation was done centrally using a minimisation technique and was stratified by age (<65 years vs ≥65 years) and disease status. The primary endpoint was investigator-assessed 12-month progression-free survival in the modified intention-to-treat population in group A (35% for the null hypothesis and 50% for the alternative hypothesis). This trial is registered with ClinicalTrials.gov , NCT03519295 , and is closed to new participants. 97 evaluable participants (64 in group A and 33 in group B) were enrolled between July 3, 2018, and Aug 19, 2020. The median follow-up was 26·5 months (95% CI 24·8–28·4). The median age of participants was 64·1 years (IQR 56·2–71·6), and 71 (73%) were female. 12-month progression-free survival was 45% (90% CI 35–55) in group A and 43% (29–58) in group B. In participants with a PD-L1 combined positive score of 5 or greater, 12-month progression-free survival was 70% (95% CI 47–100) in group A and 40% (19–85) in group B (interaction p=0·051) Both groups showed high compliance. Adverse events of grade 3 or higher were observed in 39 (61%) participants in group A and 14 (42%) in group B. The most common grade 3–4 adverse events were neutropenia (nine [14%] participants in group A vs five [15%] in group B), anaemia (nine [14%] vs one [3%]), fatigue (three [5%] vs four [12%]), and diarrhoea (seven [11%] vs one [3%]). Serious adverse events occurred in 16 (25%) participants in group A and four (12%) in group B, and these were mDCF-related in seven (11%) participants in group A and four (12%) in group B. Atezolizumab-related serious adverse events occurred in nine (14%) participants in group A, including grade 2 infusion-related reaction in three (5%), grade 3 infection in two (3%), and grade 2 colitis, grade 3 acute kidney injury, grade 3 sarcoidosis, and a grade 4 platelet count decrease each in one participant (2%). There were no treatment-related deaths. Despite a higher incidence of adverse events, combining atezolizumab with mDCF is feasible, with similar dose intensity in both groups, although the primary efficacy endpoint was not met. The predictive value of a PD-L1 combined positive score of 5 or greater now needs to be confirmed in future studies. GERCOR, Roche. [ABSTRACT FROM AUTHOR]

OBJECTIVES The 7th edition of American Joint Committee on Cancer (AJCC) staging system of oesophageal cancer and gastro-oesophageal junction has re-staged positive nodes into N1–3 according to the number of invaded lymph nodes (LNs). However, this new classification does not consider the potential negative impact of the extracapsular breakthrough on survival. This study aims at assessing prognosis according to whether LN involvement is intracapsular (ICLNI) or extracapsular (ECLNI) on disease-free survival (DFS) among the three sub-groups of LN-positive patients. METHODS Four hundred and sixteen consecutive R0 patients who underwent transthoracic oesophagectomy for cancer between 1996 and 2011 were retrospectively re-classified using the latest AJCC TNM classification. Among them, 230 (55%) patients have received a neoadjuvant chemoradiotherapy. Prognostic impact of ICLNI and ECLNI on DFS was assessed according to their new LN status. Multivariate analysis was drawn to determine factors affecting DFS. RESULTS Among the 416 patients, there were 138 (33%) patients with positive LN: 79 (57%) with ICLNI and 59 (43%) with ECLNI. The proportion of ECLNI was 21 of 73 (28%), 21 of 41 (51%) and 17 of 24 (70%) in N1, N2 and N3 patients, respectively. In N1 patients, median DFS was 48 months in ICLNI and 13 months in ECLNI (P = 0.068). In N2 patients, median DFS was 19 months in ICLNI and 9 months in ECLNI (P = 0.07). In N3 patients, median DFS was not reached in ICLNI and was 6 months in ECLNI (P = 0.002). On multivariate analysis, the ECLNI (P < 0.001, hazard ratio, HR: 2.51) and the post-T stage (P = 0.03, HR: 1.62) were the two independent factors affecting DFS. CONCLUSIONS Based on our limited study population, the existence of an ECLNI seems to have an additive negative impact on DFS, regardless of the pN stage. This suggests that extracapsular breakthrough status should be added to the new TNM staging system. This information has to be validated by further investigations. [ABSTRACT FROM AUTHOR]

There is no standard second-line treatment after platinum–etoposide chemotherapy for gastroenteropancreatic neuroendocrine carcinoma. We aimed to evaluate the efficacy of FOLFIRI plus bevacizumab, and FOLFIRI alone, in this setting. We did a randomised, non-comparative, open-label, phase 2 trial (PRODIGE 41-BEVANEC) at 26 hospitals in France. We included patients aged 18 years or older with locally advanced or metastatic gastroenteropancreatic neuroendocrine carcinoma or neuroendocrine carcinoma of unknown primary origin, documented progressive disease during or after first-line platinum–etoposide chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned (1:1; block size of three), without stratification, to receive FOLFIRI (irinotecan 180 mg/m2, calcium folinate 400 mg/m2 or levofolinate 200 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h) plus bevacizumab 5 mg/kg or FOLFIRI alone, intravenously, every 2 weeks until disease progression or unacceptable toxicity. Neither patients nor investigators were masked to group assignment. The primary outcome was overall survival at 6 months after randomisation, evaluated in the modified intention-to-treat population (all enrolled and randomly assigned patients who received at least one cycle of FOLFIRI). This study is now complete and is registered with ClinicalTrials.gov , NCT02820857. Between Sept 5, 2017, and Feb 8, 2022, 150 patients were assessed for eligibility and 133 were enrolled and randomly assigned: 65 to the FOLFIRI plus bevacizumab group and 68 to the FOLFIRI group. 126 patients (59 in the FOLFIRI plus bevacizumab group and 67 in the FOLFIRI group) received at least one cycle of FOLFIRI and were included in the modified intention-to-treat population, 83 (66%) of whom were male and 43 (34%) were female, and the median age of the patients was 67 years (IQR 58–73). The primary tumour location was colorectal in 38 (30%) of 126 patients, pancreatic in 34 (27%), gastro-oesophageal in 22 (17%), and unknown in 23 (18%). After a median follow-up of 25·7 months (95% CI 22·0–38·2), 6-month overall survival was 53% (80% CI 43–61) in the FOLFIRI plus bevacizumab group and 60% (51–68) in the FOLFIRI group. Grade 3–4 adverse events that occurred in at least 5% of patients were neutropenia (eight [14%] patients), diarrhoea (six [10%]), and asthenia (five [8%]) in the FOLFIRI plus bevacizumab group, and neutropenia (seven [10%]) in the FOLFIRI group. One treatment-related death (ischaemic stroke) occurred in the FOLFIRI plus bevacizumab group. The addition of bevacizumab did not seem to increase the benefit of FOLFIRI with regard to overall survival. FOLFIRI could be considered as a standard second-line treatment in patients with gastroenteropancreatic neuroendocrine carcinoma. French Ministry of Health and Roche SAS. [ABSTRACT FROM AUTHOR]

NADPH oxidase 1 (Nox1) is expressed mainly in colon epithelial cells and produces superoxide ions as a primary function. We showed that Nox1 knockdown inhibits directional persistence of migration on collagen I. This paper dissects the mechanism by which Nox1 affects the direction of colonic epithelial cell migration in a two-dimensional model. Transient activation of Nox1 during cell spreading on collagen 1 temporarily inactivated RhoA and led to efficient exportation of α 2β1 integrin to the cell surface, which supported persistent directed migration. Nox1 knockdown led to a loss of directional migration which takes place through a RhoA-dependent α 2/α integrin switch. Transient RhoA overactivation upon Nox1 inhibition led to transient cytoskeletal reorganization and increased cell-matrix contact associated with a stable increase in α 3 integrin cell surface expression. Blocking of α 3 integrin completely reversed the loss of directional persistence of migration. In this model, Nox1 would represent a switch between random and directional migration through RhoA-dependent integrin cell surface expression modulation. [ABSTRACT FROM AUTHOR]

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. 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. 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. The encouraging results of lanreotide autogel 120 mg as a maintenance treatment after L1 in aggressive G1/2 DP-NET should be confirmed. NCT02288377 (clinicaltrials.gov). • Duodeno-pancreatic NETs first-line treatment includes chemotherapy or targeted therapy. • First induction anti-tumour treatment often leads to long periods of non-progression. • This is the first study designed to evaluate a maintenance strategy in this situation. • A maintenance therapy using lanreotide 120 mg LP is feasible. • It appears to increase PFS without inducing excess toxicity or impairing quality of life. [ABSTRACT FROM AUTHOR]

Background: Cancer therapies targeting actionable molecular alterations (AMA) have developed, but the clinical routine impact of high-throughput molecular profiling remains unclear. We present a monocentric experience of molecular profiling based on liquid biopsy in patients with cancer. Methods: Patients included had solid cancer and underwent cfDNA genomic profiling with FoudationOne Liquid CDx (F1LCDx) test, analyzing 324 genes. Primary endpoint was to describe patients with an AMA for whom clinical decisions were impacted by F1LCDx test results. Results: 191 patients were included, mostly with lung cancer (46%). An AMA was found in 52%. The most common molecular alterations were: TP53 (52%), KRAS (14%) and DNMT3 (11%). The most common AMA were: CHEK2 (10%), PIK3CA (9%), ATM (7%). There was no difference in progression-free survival (2.66 months vs. 3.81 months, p = 0.17), overall survival (5.3 months vs. 7.1 months, p = 0.64), or PFS2/PFS1 ratio ≥ 1.3 (20% vs. 24%, p = 0.72) between patients receiving a molecularly matched therapy (MMT) or a non-MMT, respectively. Patients with a MMT had an overall response rate of 19% and a disease control of 32%. Conclusions: Routine cfDNA molecular profiling is feasible and can lead to the access of targeted therapies. However, no notable benefit in patient's outcomes was shown in this unselected pan-cancer study. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

OBJECTIVE Malnutrition is common after oesophageal cancer surgery. This study aims to investigate body mass index (BMI) kinetics and the risk factors of malnutrition among 1-year disease-free survivors after radical transthoracic oesophagectomy for cancer. METHODS From a prospective single-institution database, 118 1-year disease-free survivors having undergone a R0 transthoracic oesophagectomy with gastric tubulization between 2000 and 2008 were identified retrospectively. BMI values were collected at the onset of the disease (pre-treatment BMI), at the time of surgery (preoperative BMI), at postoperative 6 months and 1 year after oesophagectomy (1-year BMI). Logistic regression was performed with adjustment for confounders to estimate odds ratios of the factors associated with a 1-year weight loss (WL) of at least 15% of the pre-treatment body weight (BW). RESULTS At the onset of the disease, 5 patients (4%) were underweighted (BMI < 8.5 kg/m²), 65 (55%) were normal (BMI = 18.5–24.9 kg/m²), 36 (31%) were overweighted (BMI > 25 kg/m²) and 12 (10%) were obese (BMI > 30 kg/m²). Mean pre-treatment, preoperative, postoperative 6-month and 1-year BMI values were 24.64 ± 4 kg/m², 23.55 ± 3.8 kg/m², 21.7 ± 3 kg/m² and 21.97 ± 4 kg/m², respectively. One-year WL ≥ 15% of the pre-treatment BW was present in 29 patients (25%): 18 among the 48 patients (37%) with a pre-treatment BMI ≥ 25 and 11 among the 70 patients (15%) with pre-treatment BMI < 25 (P = 0.006). On logistic regression, initial overweighting was the sole independent prognosticator of 1-year postoperative WL of at least 15% of the pre-treatment BW (P = 0.039; OR: 2.96, [1.06–8.32]). CONCLUSIONS Postoperative malnutrition remains a severe problem after oesophageal cancer resection, even in long-term disease-free survivors. Overweight and obese patients are the segment population most exposed to this postoperative malnutrition, suggesting that such surgery could have substantial bariatric effect. A special vigilance programme on the nutritional status of this sub-group of patients should be the rule. [ABSTRACT FROM AUTHOR]

OBJECTIVES Recent studies have suggested that postoperative complications could have a potential negative effect on long-term outcome after oesophagectomy for cancer. Because respiratory failures represent the most frequent postoperative complication, we have investigated the prognostic impact of these complications on disease-free survival (DFS). METHODS From a prospective single-institution database of 405 consecutive patients who underwent transthoracic oesophagectomy for cancer, we retrospectively analysed medical charts of all patients with microscopically complete resection (R0, n = 384 patients). Complications were graded according to the modified Clavien classification. Respiratory complications were defined as atelectasis, pneumonia or acute respiratory distress syndrome in the absence of early surgical complications. Patients with grade 5 (postoperative mortality, n = 43, 11%) were excluded from the analysis. The remaining 341 patients were analysed for estimation of DFS according to the Kaplan–Meier method. Logistic regression analysis was conducted to discriminate predictive factors affecting DFS. RESULTS According to the modified Clavien classification, postoperative complications rates were grade 0: 147 (44%), grade 1: 7 (2%), grade 2: 56 (16%), grade 3: 69 (20%) and grade 4: 62 (18%). Five-year DFS rates were not significantly different between grade 0 (no complication, 38%, n = 147) and other grades (grade 1, 2, 3 and 4 (64, 45, 56 and 48%, respectively)). Respiratory complications occurred in 107 patients (31%) and the 5-year DFS in this subgroup was 47% compared with 38% observed in grade 0 patients (P = 0.75). Clavien classification and respiratory complications did not come out in the univariate analysis of factors affecting DFS. On logistic regression, only two variables affected DFS: c-N stage and extracapular lymph node involvement. CONCLUSIONS When postoperative mortality is excluded, postoperative complications do not affect DFS in patients with complete resection. This deserves substantial information regarding the prognosis of subgroup of patients in critical situations where incrementing intensive care is debated. [ABSTRACT FROM AUTHOR]

Background: Radiotherapy combined with fluorouracil (5FU) and cisplatin for locally advanced esophageal cancer is associated with a 20-25% pathologic complete response (pCR) rate. Cetuximab increases the efficacy of radiotherapy in patients with head and neck carcinomas. The aim of this phase I/II trial was to determine the optimal doses and the pCR rate with chemoradiotherapy (C-RT) plus cetuximab., Methods: A 45-Gy radiotherapy regimen was delivered over 5 weeks. The phase I study determined the dose-limiting toxicity and the maximum tolerated dose of 5FU-cisplatin plus cetuximab. The phase II trial aimed to exhibit a pCR rate > 20 % (25 % expected), requiring 33 patients (6 from phase I part plus 27 in phase II part). pCR was defined as ypT0Nx., Results: The phase I study established the following recommended doses: weekly cetuximab (400 mg/m 2 one week before, and 250 mg/m 2 during radiotherapy); 5FU (500 mg/m 2 /day, d1-d4) plus cisplatin (40 mg/m 2 , d1) during week 1 and 5. In the phase II part, 32 patients received C-RT before surgery, 31 patients underwent surgery, and resection was achieved in 27 patients. A pCR was achieved in five patients (18.5 %) out of 27. After a median follow-up of 19 months, the median progression-free survival was 13.7 months, and the median overall survival was not reached., Conclusions: Adding cetuximab to preoperative C-RT was toxic and did not achieve a pCR > 20 % as required. The recommended doses, determined during the phase I part, could explain these disappointing results due to a reduction in chemotherapy dose-intensity., Trial Registration: This trial was registered with EudraCT number 2006-004770-27., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TA declares Conference for Pfizer, Roche, Sanofi, Léo Pharma, Amgen, BMS, Servier, Shire, Ipsen ; Board for Pierre Fabre Ipsen, HalioDX, BMS ; Travels and congress for Ipsen, Novartis, Roche, Hospira : Research grant from Novartis. RG declares travels grants and congress registration from Merck., (© 2024 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Importance: Efficacy of second-line chemotherapy in advanced gastric or gastrooesphageal junction (GEJ) adenocarcinoma remains limited., Ojectives: To determine the efficacy of 1 or 2 immune checkpoint inhibitors combined with FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) in the treatment of advanced gastric/GEJ adenocarcinoma., Design, Setting, and Participants: The PRODIGE 59-FFCD 1707-DURIGAST trial is a randomized, multicenter, noncomparative, phase 2 trial, conducted from August 27, 2020, and June 4, 2021, at 37 centers in France that included patients with advanced gastric/GEJ adenocarcinoma who had disease progression after platinum-based first-line chemotherapy., Intervention: Patients were randomized to receive FOLFIRI plus durvalumab (anti-programmed cell death 1 [PD-L1]) (FD arm) or FOLFIRI plus durvalumab and tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4 [CTLA-4]) (FDT arm). The efficacy analyses used a clinical cutoff date of January 9, 2023., Main Outcome and Measures: The primary end point was progression-free survival (PFS) at 4 months according to RECIST 1.1 criteria evaluated by investigators., Results: Overall, between August 27, 2020, and June 4, 2021, 96 patients were randomized (48 in each arm). The median age was 59.7 years, 28 patients (30.4%) were women and 49 (53.3%) had GEJ tumors. Four month PFS was 44.7% (90% CI, 32.3-57.7) and 55.6% (90% CI, 42.3-68.3) in the FD and FDT arms, respectively. The primary end point was not met. Median PFS was 3.8 and 5.4 months, objective response rates were 34.7% and 37.7%, and median overall survival was 13.2 and 9.5 months in the FD and FDT arms, respectively. Disease control beyond 1 year was 14.9% in the FD arm and 24.4% in the FDT arm. Grade 3 to 4 treatment-related adverse events were observed in 22 (47.8%) patients in each arm. A combined positive score (CPS) PD-L1 of 5 or higher was observed in 18 tumors (34.0%) and a tumor proportion score (TPS) PD-L1 of 1% or higher in 13 tumors (24.5%). Median PFS according to CPS PD-L1 was similar (3.6 months for PD-L1 CPS ≥5 vs 5.4 months for PD-L1 CPS <5) by contrast for TPS PD-L1 (6.0 months for PD-L1 TPS ≥1% vs 3.8 months for PD-L1 TPS <1%)., Conclusions and Relevance: Combination of immune checkpoint inhibitors with FOLFIRI in second-line treatment for advanced gastric/GEJ adenocarcinoma showed an acceptable safety profile but antitumor activity only in a subgroup of patients., Trial Registration: ClinicalTrials.gov Identifier: NCT03959293.

Background: To examine the relationship between carcinoembryonic antigen (CEA) kinetics and prognosis in metastatic colorectal cancer (mCRC) patients receiving first-line chemotherapy in the PRODIGE9 trial., Methods: Associations between monthly CEA measurements within 6 months since baseline and progression-free survival (PFS) were evaluated using a joint-latent class-mixed model. A validation set was used to test our prognosis model. Correlations between CEA trajectories (classes) and baseline characteristics were also investigated., Results: Three classes were identified. Class 1 had low baseline CEA with small variations. Class 2 had high baseline CEA with a rapid decrease reaching the same CEA level at 6 months as in class 1. Class 3 had high baseline CEA with a transient decrease followed by an increase to reach, at 6 months, the same CEA level as at baseline. Six-month PFS was significantly lower in class 3 than in classes 1 and 2 (57% vs. 91% and 93% respectively; p<0.01). Class 3 was significantly associated with ECOG 2 status, a high LDH level and non-resected primary tumor., Discussion: Variations in CEA kinetics correlate with prognosis in patients receiving first-line chemotherapy for mCRC. We propose here a user-friendly application to classify CEA trajectory., Competing Interests: Conflict of interest DS, MH, KLM and OB have no conflict of interest to declare TA declared Honoraria from Sanofi, Roche, Amgen, Servier, Pierre Fabre and Astra Zeneca ; Consultancy / Advisory role for Bioven, Pierre Fabre, MSD and Sirtec ; Travel accommodations from Roche. CL has received personnal fees of Amgen, Bayer, Ipsen and Pierre Fabre; Consultancy /Advisory role for Advanced Accelerator Applications, Novartis; Travel, Accommodations, Expenses: Novartis, Bayer, Sanofi/Aventis, Merck Serono and Ipsen JT has received personal fees from Amgen, Roche, Merck Serono, Pierre Fabre, MSD, Sanofi, Servier, Shire, and non-financial support from Amgen, Merck Serono, and Roche OB has received personal fees from Amgen, Apmonia Therapeutics, Bayer, Merck, Pierre Fabre, Roche, Sanofi and Servier VB reports grants, personal fees, and non-financial support from Merck Serono, personal fees and non-financial support from Bayer, personal fees and non-financial support from Roche, non-financial support from Sanofi, personal fees and non-financial support from Ipsen, personal fees and non-financial support from Merck MSD, personal fees from BMS, personal fees from Eisai, personal fees from Novartis, and personal fees and non-financial support from Amgen outside the submitted work. JMP has received personnal fees of Merck Serono, Roche, Sanofi, Amgen, Lilly, Servier, Bayer; Consultancy / Advisory role for Roche, Merck Serono, Amgen, Servier, Bayer and Sanofi; Research Funding: Roche, Merck Serono; Travel Accommodations/Expenses: Roche, Merck Serono, Bayer, Servier, Sanofi and Amgen JB has received personal fees from Amgen, AstraZeneca, Bayer, Merck Serono, Pierre Fabre, Roche, Sanofi, Servier, Shire, and non-financial support from Amgen, Merck Serono, and Roche LD has received personal fees of Amgen, BMS, Servier, Oseus and Mylan JMG has received personal fees from Abbvie, Janssen Cilag, MSD, Sanofi and Takeda, and non-financial support from Fresinius Kabi and Pfizer, (Copyright © 2022. Published by Elsevier Ltd.)