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Evolution of the maximal variant allelic fraction during the first three cycles in the 40 patients with all three available points.

Description of patients' characteristics according to tertiles of ctDNA VAF frequency at baseline

Description of the studied population

Multivariate analysis of prognostic factors at baseline

Figure S2a: Overall survival of patients with or without at least one available plasma sample. Figure S2b: Overall survival curves according to treatment arms for the 122 patients with at least one available plasma sample. Figure S2c: Progression free survival curves according to treatment arms for the 122 patients with at least one available plasma sample.

Patients characteristics at baseline according the presence or not of ctDNA

Interaction between the presence of ctDNA at baseline and eryaspase efficacy on PFS and OS

Regorafenib has shown substantial clinical activity in patients with advanced biliary tract cancers (BTCs). Preclinical data suggested that this drug modulates antitumour immunity and is synergistic with immune checkpoint inhibition.This is a single-arm, multicentric phase II trial. Regorafenib was given 3 weeks/4, 160 mg quaque die (once a day) (QD); avelumab 10 mg/kg IV was given every two weeks, beginning at C1D15 until progression or unacceptable toxicity. The primary end-point was the confirmed objective response rate under treatment, as per Response Evaluation Criteria in Solid Tumours 1.1. The secondary end-points included the following: 1-year non-progression rate; progression-free survival (PFS) and overall survival; safety and biomarkers studies performed on sequential tumour samples obtained at baseline and at cycle 2 day 1.Thirty-four patients were enrolled in four centres. Twenty-nine patients were assessable for efficacy after central radiological review. The best response was partial response for four patients (13.8%), stable disease for 11 patients (37.9%) and progressive disease for 14 patients (48.3%). The median PFS and overall survival were 2.5 months (95% confidence interval [CI] [1.9-5.5]) and 11.9 months (95%CI [6.2-NA]) respectively. The most common grade 3 or 4 clinical adverse events related to treatment were hypertension (17.6%), fatigue (14.7%) and maculopapular rash (11.8%). High baseline levels of programmed cell death ligand 1 and of indoleamine 2, 3-dioxygénase expression were associated with improved outcomes.Regorafenib combined with avelumab has antitumour activity in a subset of heavily pretreated biliary tract cancer population. Further investigations are needed in patients selected based on tumour microenvironment features.NCT03475953.

PURPOSE In the phase III KEYNOTE-181 study ( NCT02564263 ) of patients with advanced esophageal cancer (EC), pembrolizumab monotherapy prolonged overall survival versus chemotherapy as second-line therapy in patients with programmed death ligand 1 combined positive score (CPS) ≥ 10. We present the results of the prespecified health-related quality-of-life (HRQoL) analyses of the squamous cell carcinoma (SCC), CPS ≥ 10, and CPS ≥ 10 SCC populations. PATIENTS AND METHODS HRQoL was measured using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30), EORTC QLQ EC questionnaire (OES18), and EuroQol 5-dimension questionnaire (EQ-5D). Data were analyzed in patients who received ≥ 1 dose of study treatment and completed ≥ 1 HRQoL assessment. Key analyses included baseline to week 9 least squares mean change in global health status/quality of life, functional or symptom subscales, and time to deterioration (≥ 10-point deterioration) for specific subscales. RESULTS The HRQoL population included 387 patients with SCC. Compliance and completion rates for all three questionnaires were similar in both treatment groups at baseline and week 9. No clinically meaningful differences in global health status/quality of life scores were observed between treatment groups from baseline to week 9 (least squares mean difference, 2.80; 95% CI, –1.48 to 7.08); patients in both treatment groups generally exhibited stable functioning and symptom scores of the QLQ-C30 and QLQ-OES18 from baseline to week 9. Time to deterioration for pain (hazard ratio [HR], 1.22; 95% CI, 0.79 to 1.89), reflux (HR, 2.38; 95% CI, 1.33 to 4.25), and dysphagia (HR, 1.53; 95% CI, 1.02 to 2.31) subscales were similar between treatment groups. These findings were generally similar in the CPS ≥ 10 (n = 218) and CPS ≥ 10 SCC (n = 166) subgroups. CONCLUSION In patients with advanced EC, pembrolizumab monotherapy and chemotherapy maintained HRQoL in patients with SCC, CPS ≥ 10, and CPS ≥ 10 SCC.

Esophageal cancer is the sixth most common cause of cancer death worldwide. In France, Brittany is one of the regions most seriously affected. This increased incidence is usually linked to high rates of alcohol overconsumption and smoking, established risk factors for esophageal cancer, but the region has special occupational exposures. We aim to describe the occupational exposures of patients with esophageal cancer. Between June and October 2020, we conducted a monocentric descriptive study in a French Teaching Hospital and identified 37 eligible patients. We gathered data through a systematic individual interview for each participant and by an analysis of their medical file. We were able to include 36 patients; most were men (n = 27, 75.0%) and smokers (n = 25, 69.4%), 21 (58.3%) presented an adenocarcinoma esophageal cancer, 13 (36.1%) a squamous cell cancer, and 2 other types. On occupational exposure, patients declared respectively high exposure by manipulating asbestos materials for 11 (30.6%) patients, regularly in contact with benzene by handling fuel in 7 cases (19.4%), chlorinated solvents in 4 cases (11.1%), pesticides in 4 cases, and ionizing radiation exposure in 3 patients (8.3%). Our findings support the creation of a large-scale study to explore the impact of occupational exposures, particularly exposure to asbestos and hydrocarbons.

To evaluate the cancer research effort of some major countries over two 5-year periods (2010-2014 and 2015-2019) on the basis of scientific publications and interventional clinical trial metrics and to analyze the relationship between research effort and cancer burden (incidence and mortality).Clinical trials were extracted from ClinicalTrials.gov using a specific query. Publications were identified in Web of Science (WoS) using a query based on keywords and were then analyzed using InCites, a bibliometric tool. Bibliometric indicators were computed per country and per period.During 2010-2019, 1 120 821 cancer-related publications were identified in WoS, with 447 900 and 672 921 (+50%) articles respectively published in 2010-2014 and 2015-2019. Meanwhile, 38% and 7% of the articles were published in oncology and cell biology journals, respectively. Exactly 30% of the published articles were contributed by the USA. In the study period, China strongly increased its production and overspecialization. Apart from China, which had a low normalized citation impact (NCI), almost all countries increased their NCIs; in particular, France's NCI increased from 1.69 to 2.44. As for clinical trials, over 36 856 were opened worldwide during that period. Over 17 000 (46.5%) opened in the USA, which remained the leader during the study period. China ranked second worldwide in terms of the number of open trials in 2015-2019. Results revealed that the 17 cancer localizations versus cancer burden and research effort showed no evident relationship.The results may provide a scientific basis for decision making for continued research. Based on bibliometric data, this type of study will aid public health policymaking and lead to a more transparent public fund allocation.

Purpose: Regorafenib is synergistic with immune checkpoint inhibition in colorectal cancer preclinical models. Patients and Methods: This was a single-arm, multicentric phase II trial. Regorafenib was given 3 weeks on/1 week off, 160 mg every day; avelumab 10 mg/kg i.v. was given every 2 weeks, beginning at cycle 1, day 15 until progression or unacceptable toxicity. The primary endpoint was the confirmed objective response rate under treatment, as per RECIST 1.1. The secondary endpoints included a 1-year nonprogression rate, progression-free survival (PFS), and overall survival (OS), safety and biomarkers studies performed on sequential tumor samples obtained at baseline and at cycle 2 day 1. Results: Forty-eight patients were enrolled in four centers. Forty-three were assessable for efficacy after central radiological review. Best response was stable disease for 23 patients (53.5%) and progressive disease for 17 patients (39.5%). The median PFS and OS were 3.6 months [95% confidence interval (CI), 1.8–5.4] and 10.8 months (95% CI, 5.9–NA), respectively. The most common grade 3 or 4 adverse events were palmar-plantar erythrodysesthesia syndrome (n = 14, 30%), hypertension (n = 11, 23%), and diarrhea (n = 6, 13%). High baseline infiltration by tumor-associated macrophages was significantly associated with adverse PFS (1.8 vs. 3.7 months; P = 0.002) and OS (3.7 months vs. not reached; P = 0.002). Increased tumor infiltration by CD8+ T cells at cycle 2, day 1 as compared with baseline was significantly associated with better outcome. Conclusions: The combination of regorafenib + avelumab mobilizes antitumor immunity in a subset of patients with microsatellite stable colorectal cancer. Computational pathology through quantification of immune cell infiltration may improve patient selection for further studies investigating this approach.

Introduction: For several centuries, scientists such as Avicenna have been trying to understand the processes involved in the spread of epidemics. Isolation instructions appeared during the black plague. Magistrates and crisis managers manage the protection of all populations. Nowadays, regional health agencies regulate the provision of health care even in times of health crisis. Methods: The creation of the COVID and Cancer regional committee organized and run by the ARS and the Oncobretagne regional cancer network enables exchanges between oncology health professionals. This committee relays information to national representatives: Ministry, INCa (National Cancer Institute) who adjust their recommendations to cancer patients. In addition, the players are alerted to the dysfunctions caused by the COVID pandemic and can improve their actions. Moreover, the action of the Brittany regional health agency immediately follows the instructions of the ministry and adapts them to the regional context. Results. The impact of the COVID pandemic in Brittany had little effect on chemotherapy, radiotherapy and oncological surgery activities in 2020 compared to 2019. Only oncological digestive surgery on all these organs shows a clear decrease in activity, it will require follow-up in the future. Surgical activity in otorhinolaryngology is also experiencing a decline to monitor. Maintaining the organization of RCPs (Multidisciplinary consultation meetings), regional RCPs and RCPs of recourse managed by the regional oncology pole does not present any major difficulty apart from logistical adjustments. The inclusions in therapeutic trials have decreased due to the promoters' decisions but with no clear interruption. The decisions collaboratively taken by ARS Brittany and the regional cancer center allow the maintenance of therapeutic trials in Brittany and in the inter-region. The feedback from the experience carried out in Brittany continues to support the decisions taken by ARS (Regional Health Agency) Brittany to facilitate the care of cancer patients during the COVID pandemic period. Conclusion: The Brittany Regional Health Agency in collaboration with the Oncobretagne regional cancer network and the regional cancer center are succeeding in limiting the impact of the COVID pandemic for cancer patients. The creation of the COVID and Cancer committee is one of the organizations initiated by the Brittany Regional Health Agency and oncobretagne, which enables the day-to-day management of regional actions on the cancer theme. Few references exist to allow us a precise comparison with other international healthcare systems in the context of the COVID and Cancer action. © 2021 Lavoisier. All rights reserved.

Background The IMMUNOBIL PRODIGE 57 trial is a non-comparative randomized phase II study assessing the efficacy and safety of the durvalumab (an anti-PD-L1) and tremelimumab (an anti-CTLA4) combination with or without weekly paclitaxel in patients with advanced biliary tract carcinoma (BTC) after failure of platinum-based chemotherapy. Taxanes have already been safely combined with immune checkpoint inhibitors in other tumors. We report results of the 20-patient safety run-in. Methods Patients received durvalumab (1500 mg at day 1 [D1] of each cycle)/tremelimumab (75 mg at D1 for 4 cycles; Arm A) or durvalumab/tremelimumab with paclitaxel (80 mg/m2 at D1, D8, D15; Arm B) every 28 days. Results Twenty patients were enrolled (Arm A/B: 10/10). There were no dose-limiting toxicities (DLTs) in Arm A. Six DLTs were observed in five patients (50%) in Arm B, meeting a stopping rule for the trial inclusions. DLTs included three serious anaphylactic reactions (with one cardiac arrest), two enterocolitis, and one infectious pneumopathy with septic shock. There were no patients with history of personal or familial auto-immune disease. Conclusion The safety run-in part of IMMUNOBIL PRODIGE 57 raised concerns regarding co-administration of paclitaxel with durvalumab and tremelimumab in BTC, with an unexpected increase in anaphylactic adverse events. Phase II of the study will only evaluate the durvalumab and tremelimumab combination arm. ClinicalTrials registration NCT03704480 .

PATIENTS AND METHODS Patients with WD-GEP-NET who benefited from a pretherapeutic 68Ga-DOTATOC PET/CT and a 177Lu-DOTATATE SPECT/CT after the cycle 1 of peptide receptor radionuclide therapy were prospectively included. SPECT/CT acquisitions were performed on a system calibrated with a conversion factor of 9.48 counts/MBq per second and were reconstructed with an iterative algorithm allowing quantification using the SPECTRA Quant software (MIM Software, Cleveland, OH). For each patient, different SUV parameters were recorded on both PET/CT (Ga parameters) and SPECT/CT (Lu parameters) for comparison: physiological uptakes (liver/spleen), tumor uptake (1-10/patient; SUVmax, SUVmean, SUVpeak, MTV), tumor-to-liver and tumor-to-spleen ratios according to liver/spleen SUVmax and SUVmean (TLRmax, TLRmean, TSRmax, and TSRmean, respectively). RESULTS Ten patients (8 female; 2 male) aged from 50 to 83 years presenting with a metastatic progressive WD-GEP-NET (7 small intestine, 2 pancreas, 1 rectum) were included. Median values of lesional Lu-SUV were significantly lower than the corresponding Ga-SUV (P < 0.001), whereas median values of lesional Lu-MTV, Lu-TLR, and Lu-TSR were significantly higher than the corresponding Ga-MTV, Ga-TLR, and Ga-TSR (P < 0.02). Pearson correlation coefficients were strong for both SUV and MTV parameters (0.779-0.845), weak for TLR parameters (0.365-0.394), and moderate-to-strong for TSR parameters (0.676-0.750). CONCLUSIONS Our results suggest the feasibility of 177Lu-DOTATATE SPECT/CT quantification in clinical practice and show a strong correlation of several SUV-based parameters with the corresponding in 68Ga-DOTATOC PET/CT.

Background/aims The Bretagne-Pays de la Loire cancer observatory, an oncology network created by the French Ministry of Health, is specifically dedicated to assess the use of new targeted anticancer therapies in routine practice. In line with the French National Cancer III program, our cancer network set up a real-life cohort, which is independent of the pharmaceutical industry, for patients with colorectal cancer to monitor patient safety and quality of care and promote pharmacovigilance. Materials and methods Panitumumab monotherapy was assessed in 243 patients with wild-type Kirsten rat sarcoma who were treated for metastatic colorectal cancer (mCRC) between July 2008 and December 2010 after prior chemotherapy using oxaliplatine and irinotecan. This was a post-European medicine agency marketing (EMA-M) study Results: This study shed light on the best practices, strategic adaptations, clinical results (treatment objective responses, 13%; progression free survival, 2.99 months [2.73-3.15]; and overall survival, 6.8 months [5.49-8.38]) as well as expected or unexpected (grade 3 or 4: 11.5%) secondary effects in the phase IV panitumumab treatment of mCRC. Conclusion Our results are similar to those by Amado whose phase III study led to obtaining EMA-M for panitumumab and tend to confirm the antitumor activity of this antiepidermal growth factor receptor antibody in the treatment of mCRC. In addition, our results opened avenues to further assessment of panitumumab use as monotherapy as well as its benefit-risk ratio while taking into account the patients' general and clinical characteristics. In 2012, the French National Authority for Health appended these data to the panitumumab transparency committee report.

Purpose: Eryaspase is composed of l-asparaginase encapsulated in erythrocytes and has demonstrated significant efficacy in a randomized phase II trial. We assessed the prognostic and predictive value of circulating tumor DNA (ctDNA) in patients, plasma included in this trial. Experimental Design: Samples prospectively collected pretreatment were centrally analyzed by next-generation sequencing. Prognostic values of baseline ctDNA and ctDNA early changes between day 0 and 28 were assessed in both arms combined on objective response rate (ORR), progression-free survival (PFS), and overall survival (OS); three groups were defined: negative ctDNA (Neg), ctDNA responders (Resp), and ctDNA nonresponders (NResp). Predictive value of ctDNA for eryaspase efficacy was investigated. Results: ctDNA was positive at baseline in 77 patients of the 113 tested patients (68%). Detectable ctDNA was an independent negative prognostic factor for OS (4.6 vs. 8.8 months; P = 0.0025) and PFS (1.6 vs. 3.3 months; P = 0.00043). Early change in ctDNA levels was correlated with ORR (20%, 26%, 0%; P < 0.04), PFS (3.7, 3.4, 1.6 months; P < 0.0001), and OS (11.7, 6.5, 4.3 months; P < 0.0001) according to the three defined groups (Neg, Res, NResp, respectively). In patients with ctDNA detectable at baseline, eryaspase was associated with better PFS [HR = 0.53; 95% confidence interval (CI): 0.3–0.94)] and OS (HR = 0.52; 95% CI: 0.29–0.91). Conclusions: We confirm from a prospective randomized trial that: (i) the presence of ctDNA at baseline is a major prognostic factor, (ii) the early change of ctDNA correlates with treatment outcome, and (iii) the ctDNA could be a predictive biomarker of eryaspase efficacy.

International audience; Background With the development of precision oncology, Molecular Tumor Boards (MTB) are developing in many institutions. However, the implementation of MTB in routine clinical practice has still not been thoroughly studied. Material and methods Since the first drugs approved for targeted therapies, patient tumor samples were centralized to genomic testing platforms. In our institution, all tumor samples have been analyzed since 2014 by Next Generation Sequencing (NGS). In 2015, we established a regional MTB to discuss patient cases with 1 or more alterations identified by NGS, in genes different from those related to drug approval. We conducted a retrospective comparative analysis to study whether our MTB increased the prescriptions of Molecular Targeted Therapies (MTT) and the inclusions of patients in clinical trials with MTT, in comparison with patients with available NGS data but no MTB discussion. Results In 2014, 86 patients had UGA, but the results were not available to clinicians and not discussed in MTB. During the years 2015 and 2016, 113 patients with an UGA (unreferenced genomic alteration) were discussed in MTB. No patients with an UGA were included in 2014 in a clinical trial, versus 2 (2%) in 2015-2016. 13 patients with an UGA (12%) were treated in 2015-2016 with a MTT whereas in 2014, no patient (p = 0.001). Conclusions In this retrospective analysis, we showed that the association of large-scale genomic testing and MTB was feasible, and could increase the prescription of MTT. However, in routine clinical practice, the majority of patients with UGA still do not have access to MTT.

Half of patients newly diagnosed with esophageal squamous cell cancer (ESCC) have metastatic disease (mESCC) and therefore a poor prognosis. Furthermore, half of patients with initial loco-regional disease present disease recurrence after surgery and/or chemoradiation. In mESCC, the recommended first-line treatment combines 5-fluorouracil and cisplatin, although this has not been validated by a phase III trial. Patients with disease progression or recurrence after platinum-based chemotherapy and good performance status probably benefit from second-line chemotherapy. Several molecules have been evaluated in phase I/II trials or retrospective studies (docetaxel, paclitaxel and irinotecan) but no randomised studies are available. OESIRI is a multicentre, randomised, open-label phase II trial designed to evaluate efficacy and safety of liposomal irinotecan (nal-IRI) plus 5-FU versus paclitaxel as second-line therapy in patients with mESCC. The main inclusion criteria are histologically proven mESCC in progression after first-line platinum-based chemotherapy. Patients with initial resectable disease can be included if recurrence occurred within 6 months. The primary objective is to evaluate the percentage of patients alive 9 months after randomisation. Secondary endpoints are progression-free survival, overall survival, response rate, safety and quality of life. In addition, circulating tumour DNA will be monitored to assess its prognostic value.

In recent years, neoadjuvant therapy of locally advanced rectal cancer has seen tremendous modifications. Adding neoadjuvant chemotherapy before or after chemoradiotherapy significantly increases loco-regional disease-free survival, negative surgical margin rates, and complete response rates. The higher complete rate is particularly clinically meaningful given the possibility of organ preservation in this specific sub-population, without compromising overall survival. However, all locally advanced rectal cancer most likely does not benefit from total neoadjuvant therapy (TNT), but experiences higher toxicity rates. Diagnosis of complete response after neoadjuvant therapy is a real challenge, with a risk of false negatives and possible under-treatment. These new therapeutic approaches thus raise the need for better selection tools, enabling a personalized therapeutic approach for each patient. These tools mostly focus on the prediction of the pathological complete response given the clinical impact. In this article, we review the place of different biomarkers (clinical, biological, genomics, transcriptomics, proteomics, and radiomics) as well as their clinical implementation and discuss the most recent trends for future steps in prediction modeling in patients with locally advanced rectal cancer.

BackgroundMatrix metalloproteinase-9 (MMP9) selectively cleaves extracellular matrix proteins contributing to tumor growth and an immunosuppressive microenvironment. This study evaluated andecaliximab (ADX), an inhibitor of MMP9, in combination with nivolumab (NIVO), for the treatment of advanced gastric cancer.MethodsPhase 2, open-label, randomized multicenter study evaluating the efficacy, safety, and pharmacodynamics of ADX+NIVO versus NIVO in patients with pretreated metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events (AEs). We explored the correlation of efficacy outcomes with biomarkers.Results144 patients were randomized; 141 were treated: 81% white, 69% male, median age was 61 years in the ADX+NIVO group and 62 years in the NIVO-alone group. The ORR was 10% (95% CI 4 to 19) in the ADX+NIVO group and 7% (95% CI 2 to 16) in the NIVO-alone group (OR: 1.5 (95% CI 0.4 to 6.1; p=0.8)). There was no response or survival benefit associated with adding ADX. AE rates were comparable in both treatment groups; the most common AEs were fatigue, decreased appetite, nausea, and vomiting. Programmed cell death ligand 1, interferon-γ (IFN), and intratumoral CD8+ cell density were not associated with treatment response or survival. The gene signature most correlated with shorter survival was the epithelial-to-mesenchymal gene signature; high transforming growth factor (TGF)-β fibrosis score was negatively associated with OS (p=0.036). Gene expression analysis of baseline tumors comparing long-(1+ years) and short-term (ConclusionCombination of ADX+NIVO had a favorable safety profile but did not improve efficacy compared with NIVO alone in patients with pretreated metastatic gastric or GEJ adenocarcinoma. HER2 positivity, higher TMB or GRB7, and lower TGF-β were associated with improved outcomes.Trial registration numberNCT02864381or GS-US-296–-2013.

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.

Resume Introduction L’Observatoire dedie au Cancer des OMEDITs Bretagne et Pays de la Loire a mene une enquete visant a connaitre et cartographier les pratiques actuelles de prise en charge des patients par Voie Orale antiCancereuse (VOC) en inter-region. Methode Quarante-huit etablissements de cancerologie ont recu en juillet et octobre 2016 un questionnaire concernant la prise en charge des VOC : de la prescription par le specialiste en cancerologie, a l’intervention du pharmacien (analyse et entretien pharmaceutique), au suivi par l’infirmier (IDE), ainsi que le financement de cette activite et le ressenti des acteurs sur cette organisation en place. Resultats Cinquante-sept professionnels de 31 etablissements dont les plus representatifs, ont repondu a l’enquete. La moitie des etablissements realise une analyse pharmaceutique pour une partie ou l’ensemble des prescriptions de VOC et seul 30 % realise un entretien pharmaceutique. La consultation IDE est par contre plus largement implantee (74 % des etablissements) ainsi que le suivi telephonique (67 %). Plus de 90 % des professionnels pensent que l’organisation en place pourrait etre amelioree et davantage securisee par, notamment, l’implication plus forte des pharmaciens, le developpement d’outils pour les IDE (pour le suivi, l’education therapeutique…) et par l’amelioration du lien ville–hopital. Conclusion Cette enquete montre la variabilite de la prise en charge des patients sous VOC en raison de l’insuffisance de moyens octroyes pour garantir l’equite et la perennite de l’organisation en place. Le lien ville–hopital pourrait encore etre optimise pour securiser la prise en charge des patients.

4007 Background: The benefit of adapted physical activity (APA) on health-related quality of life (HRQoL) in Pts with advanced pancreatic ductal adenocarcinoma (aPDAC) treated by chemotherapy (CTx) has never been prospectively assessed. Methods: Pts with aPDAC and ECOG performance status (PS) 0–2 were randomized 1:1 to receive usual care (UC) including first-line CTx at the investigator’s choice (standard arm), or UC plus a home-based 16-week APA program (APA arm). The APA program consisted of personalized aerobic and resistance exercises, with a weekly remote supervision by an APA professional trainer, and unsupervised sessions with a family member or friend (APA partner). The primary objective was the effect on HRQoL at week 16 (W16) measured by 3 dimensions of the EORTC QLQ-C30, global health status (GHS), physical functioning (PF), and fatigue (FA), with a one-sided type I error of 0.016 for each dimension. The primary HRQoL analysis was performed in Pts with available baseline and W16 scores for the 3 targeted dimensions (mITT1). Secondary analyses of HRQoL changes by the mixed model for repeated measures (MMRM) and time until definitive deterioration (TUDD) methods included Pts with baseline and ≥1 follow-up score (mITT2). Differences > 5 points in scores were considered clinically significant. Results: A total of 313 Pts (median age: 64 years; men: 55%, ECOG PS 0-1: 93%; metastatic: 77%; FOLFIRINOX: 78%, gemcitabine-based: 13%) were included from 11/2014 to 10/2020 (standard arm: n = 157, APA arm: n = 156). In the mITT1 population (n = 172), mean differences in HRQoL at W16 adjusted from baseline were -0.98 (SD 23.87; p = 0.39), -2.08 (SD 21.34; p = 0.26), and 4.16 (SD 29.18; p = 0.18) for GHS, PF, and FA, respectively. In the mITT2 population (n = 259), APA was associated with significant improvements in 5 (GHS, PF, cognitive functioning [CF], social functioning [SF], appetite loss) and 8 (GHS, CF, emotional functioning [EF], SF, insomnia, constipation, pain, financial difficulties) dimensions of HRQoL by MMRM and TUDD, respectively (Table). Secondary endpoints, including overall survival, progression-free survival, and chemotherapy toxicity will be presented. Conclusions: APA in combination with usual care improved several dimensions of HRQoL in Pts with aPDAC receiving first-line CTx. Clinical trial information: NCT02184663. [Table: see text]

4125 Background: There is no standard treatment for patients (pts) with advanced extra-pulmonary neuroendocrine tumors (NET) and carcinomas (NEC) after failure of chemotherapy in the metastatic setting. PD-1/PD-L1 expression is frequent in these tumors. Combining anti-PD1/PDL1 agents with anti-angiogenics has been shown to be synergistic in several tumor models. Methods: This is a single-arm open-label multicentric phase II trial assessing the efficacy and safety of regorafenib (R) (160 mg QD 3weeks/4) + Avelumab (A) (10 mg/kg every 2 weeks) combination in pts with advanced or metastatic grade 2 or 3 (G2/3) gastroenteropancreatic (GEP)-NET or GEP-NEC. The primary endpoint was the confirmed objective response rate, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and Safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline. Results: Between May 2019 and Apr. 2021, 46 pts were enrolled in 6 centers. Median age was 63 (range 31 – 80). 10 pts presented with a NEC and 36 pts with a G2/3 NET. Median follow-up was 6.5 months (95% CI: 5.3 - 9.6). Median number of previous treatment lines was: 2 (range 0 – 8). 39 (84.8%) pts experienced at least 1 dose modification or treatment interruption. The most common grade 3/4 adverse events were : Hypertension (13% of pts), fatigue (13%), and diarrhea (11%). One death was related to the treatment. Among the 42 assessable pts, 7 (16.7%) achieved a partial response: 6 pts with a G2/3 NET and 1 patient with a NEC. 22 (52.4%) pts demonstrated stable disease, 22 (52.4%) pts had tumor shrinkage and 10 (23.8%) pts had progressive disease. 3 (7.1%) pts were inevaluable as per RECIST. The median duration of response was 15.5 months (95%CI: 3.7 - not reached (NR)). The median PFS and OS were 5.5 months (95% CI: 3.6 – 9.2) and NR respectively. One year OS rate was 69.4 % (95% CI: 45.1 % – 84.5 %). Conclusions: REGOMUNE is the largest prospective study ever conducted in pts with grade 2/3 GEP-NET or GEP-NEC refractory to cytotoxic chemotherapy. The R+A combination has significant clinical activity in pts with refractory disease. Full Biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03475953.

4148 Background: OSE2101 is a multiple neoepitope vaccine restricted to HLA-A2 positive Pts. This study aimed to assess the efficacy and safety of OSE2101 ± anti-PD1 nivo as maintenance therapy in Pts with aPDAC after FOLFIRINOX induction chemotherapy. Methods: TEDOPaM-PRODIGE 63 was initially a 3-arm, open-label, randomized, non-comparative phase II study. Pts with aPDAC, HLA-A2 positive (blood) and no progression after 8 cycles of (modified) FOLFIRINOX were randomized 1:1:1 to receive FOLFIRI (standard Arm A), OSE2101 (subcutaneous injection on D1 Q3W x 6 doses then Q8W until M12 then Q12W up to M24, experimental Arm B) or OSE2101 + nivo (360 mg IV on D1 Q3W x 6 then 480 mg Q4W up to M24, experimental Arm C). FOLFIRI was reintroduced at disease progression in Arms B and C. Primary endpoint was overall survival (OS) rate at 12 months (M12) (Fleming two-stage design, H0: 25%; H1: 50%, one-sided alpha: 2.5%, power: 90%). 156 Pts were planned. Results: Following the occurrence of 2 tumor flares in Arm C, an Independent Data Monitoring Committee (IDMC) recommended to continue FOLFIRI as backbone in experimental Arm B and stop Arm C. Interim analysis results refer to 29 randomized Pts: 9/10/10 in Arm A/B/C, respectively. Median age was 63 years, 52% were men, 55% had ECOG PS 0, and 83% were metastatic. Best response to induction FOLFIRINOX was partial response in 48% and stable disease in 52%. With a median follow-up of 23 months, M12-OS rate was 44%, 40%, and 30% in Arm A, B and C. Other efficacy results are summarized in Table below. No OSE2101-related toxicity of grade ≥ 3 (G≥3) were observed in Arm B; 1 G3 cytokine-release syndrome (OSE2101-related) and 2 tumor flares (nivo-related) leading to death were observed in Arm C. Conclusions: Maintenance OSE2101 monotherapy showed a favorable safety profile and encouraging time to strategy failure warranting further evaluation. OSE2101 + nivo was associated with poorer outcomes leading to close Arm C. Following IDMC recommendation, the study is ongoing with the new design (maintenance FOLFIRI vs. FOLFIRI + OSE2101). Clinical trial information: NCT03806309. [Table: see text]

4108 Background: D (anti-PDL1) plus T (anti-CTLA-4) combination immunotherapy showed encouraging results in hepato-biliary cancers. Its efficacy in non-Asian Pts with pretreated BTC is unknown. Methods: IMMUNOBIL GERCOR-D18-1 PRODIGE-57 was initially a 2-arm, open-label, randomized non-comparative phase II study. Pts with recurrent/advanced pathologically proven BTC (intrahepatic cholangiocarcinoma [iCCA]/extrahepatic CCA [eCCA]/gallbladder cancer [GC]), ECOG PS 0-1, pre-treated with platinum-based CTx were randomized (1:1) to D (1500 mg Q4W) plus T (75 mg Q4W x 4 cycles [T75]) (Arm A) or D plus T in combination with weekly paclitaxel (Arm B). Arm B was closed prematurely for toxicity after inclusion of 10 Pts. The study continued with Arm A only. It was further amended to modify the T schedule (300 mg at cycle 1 [T300], amended Arm A) due to higher efficacy reported in other tumors as compared to T75 mg x 4. The new primary endpoint was the overall survival (OS) rate at 6 months (M6) in amended Arm A (D + T300) with a Fleming two-stage design (H0: 50%, H1: 65%, one-sided alpha: 5%, power: 90%). A total of 100 evaluable Pts were required (efficacy threshold: 59%). We present here the efficacy data of Arm A (D + T75). Results: From 12/2018 to 12/2020, 106 Pts were included in Arm A; 103 were evaluable for OS at M6. Median age was 66 years, 47% were male, 46% had ECOG PS 0, 69%/18%/13% had iCCA/eCCA/GC, 76% had metastatic disease, and 28% had prior tumor resection. First-line CTx was GEMCIS/GEMOX/5-FU-based/other in 63%/22%/4%/11%. The M6-OS rate was 59.2%. With a median follow-up of 12 months (95% Cl 11.4-14.9), the median OS was 8.0 months (95% Cl 5.7-11.7) and median PFS was 2.5 months (95% Cl 2.0-3.2). Complete response (CR) was observed in 2 (1.9%) Pts, partial response (PR) in 8 (7.8%), and stable disease (SD) in 32 (31.1%), resulting in an objective response rate of 9.7% and a disease control rate of 40.8%. Absence of progression (PD, iRECIST) after 2 cycles (M6-OS rate: 84% vs 41%, median OS: 17.9 months vs 4.4 months) and CR/PR as a best overall response (M6-OS rate: 100% vs 84% and 39% for SD and PD, respectively) were associated with markedly prolonged OS. 65 (63.1%) Pts had ≥1 grade 3-4 (G3-4) adverse event (AE) and 22 (21.4%) had ≥1 G3-4 treatment-related AE (TRAE). The most commonly reported G3-4 AEs were fatigue (12.6%), abdominal pain (5.8%), and aspartate aminotransferase increase (5.8%) and G3-4 TRAEs were fatigue (4.9%) and diarrhea (2.9%). One death was possibly related to treatment. Conclusions: Although no statistical conclusions can be drawn from this exploratory analysis of Arm A, D+T75 reached the pre-defined threshold for efficacy, with no unexpected toxicity. Results from amended Arm A (D+T300, N = 106 additional Pts), quality of life, and ancillary studies are pending. Clinical trial information: NCT03704480.

TPS2703 Background: Recent studies have shown shown that genetic depletion of EZH2 in Tregs (using FoxP3creEZH2fl/fl mice) and pharmacological inhibition of EZH2 elicits phenotypic and functional alterations of Tregs, leading to an effector-like T cell profile. Further, EZH2 inhibition enhances the cytotoxicity of human Teffs in vitro and the proportion of tumor-infiltrating cytotoxic T cells in vivo in murine models. It has been shown that immune checkpoint inhibition (ICI) increases EZH2 expression in human T cells across various tumor types and that increased EZH2 expression in T cells inversely correlate with clinical outcome. Upregulation of EZH2 mediated by immune checkpoint inhibition in T cells modulates T cell responses and diminishes the effectiveness of immunotherapy. Consistent with this mechanism, pharmacologic inhibition of EZH2 has been shown to increase effector-like T cell responses and enhances effectiveness of immune checkpoint therapy in tumor-bearing mice [16-17]. Our group also reported first clinical data from a participant with sarcoma showing strong T cell infiltration after treatment with tazemetostat (Italiano et al Lancet Oncol 2018). Altogether, these findings pave the way for clinical trials combining ICI with the specific EZH2 inhibitor, tazemetostat in solid tumors. Methods: CAIRE (NCT04705818) is a multi-cohort, four single-arm phase 2, multicenter, open-label study investigating tazemetostat combined with durvalumab in patients with advanced cancers: pancreatic adenocarcinoma (cohort A), microsatellite stable colorectal cancer (cohort B), solid tumors with presence of tertiary lymphoid structures (assessed centrally) (cohort C), soft-tissue sarcomas (cohort D). Cohort A will enroll ̃32 patients and cohorts B, C and D ̃47 patients respectively. Eligible patients must have no standard treatment options available or a contraindication to standard treatment options, and ECOG PS 0–1. Patients with prior exposure to EZH2 inhibitor and/or PD1/PDL1 monoclonal antibodies are excluded. Tazemetostat will be administered per-os, twice daily (800 mg x 2), continuously. Treatment by Tazemetostat will start on Day 1 (of cycle 1). Durvalumab will be administered by intravenous infusion (1120 mg) on day 1, every 3 weeks. Treatment by Durvalumab will start on Day 1 of cycle 2. The primary endpoints are disease control rate within 24 weeks of treatment as per RECIST 1.1 in cohort A and B; objective response rate within 24 weeks of treatment as per RECIST 1.1 in cohort C, and 6-months non progression rate for cohort D. Secondary endpoints include adverse events (AEs)/serious AEs, duration of response, and progression-free survival. Pharmacodynamic and other biomarkers will be explored. The first patient received study drug on July, 30, 2022 and 1 site across France are currently enrolling patients. Clinical trial information: NCT04705818.

4060 Background: Combination VEGF and PD-1/PD-L1 axis blockade has shown benefit in various tumors and is emerging as a promising combination strategy. Methods: This is a single-arm open-label multicentric phase II trial assessing the efficacy and safety of regorafenib (R) (160 mg QD 3weeks/4) + avelumab (A) (10 mg/kg every 2 weeks) combination in advanced or metastatic oesophageal or gastric carcinoma (OGC) patients (pts). The primary endpoint was the confirmed objective response rate, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline. Results: Between Dec. 2018 and Mar. 2021, 49 pts were enrolled in 6 centers: 33 adenocarcinoma (ADK), 16 squamous cell carcinoma (SCC). Median age was 63.9 (range 33 – 80). Median follow-up was 14.5 months. Median number of previous treatment lines was: 2 (range 1 – 6). 29 (59.2%) pts experienced at least 1 dose modification or treatment interruption due to an adverse event related to treatment. The most common grade 3/4 adverse events were : Hypertension (12.2% of pts), palmar-plantar erythrodysesthesia syndrome (10.2%), and hypophosphatemia (8.2%). No death was related to the treatment. Among the 42 (29 ADK and 13 SCC) pts who had at least one imaging tumor assessment, 8 (19.1%) achieved a partial response, 5 (17.2%) and 3 (23.1%) in the ADK and SCC group respectively. 12 pts (28.6%) demonstrated stable disease and 22 pts (52.3%) had progressive disease. The median PFS and OS were 1.9 months (95%CI 1.8 – 3.5) and 7.5 months (95%CI 4.5 – 15.7) respectively. Conclusions: The R+A combination is associated with encouraging antitumor activity in patients with OGC. Full Biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03475953.

4023 Background: Metastatic pancreatic cancer (mPC) remains a deadly disease with very limited treatment options. FFX is a standard first-line therapy for mPC with a median overall survival (mOS) of 11.1 months. CPI-613 is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase enzymes of the tricarboxylic cycle preferentially within the mitochondria of cancer cells. In a phase I study, CPI-613+mFFX was safe and exhibited promising signal of efficacy. Methods: A global, randomized phase 3 trial was conducted across 73 sites to investigate the efficacy and safety of CPI-613 in combination with mFFX compared to standard dose FFX in treatment-naïve patients with mPC. Treatment was administered in 2-weekly cycles until progression or intolerable toxicity. In the experimental arm, CPI-613 at 500 mg/m2 was given intravenously on days 1 and 3. The doses of irinotecan, oxaliplatin, and 5-fluorouracil in the experimental arm were 65 mg/m2, 140 mg/m2, and 2,400 mg/2, respectively. Primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), overall response rate (ORR), duration of response, pharmacokinetics, patient reported outcomes and safety. Results: 528 patients were randomly assigned (266 in test and 262 in control arm). There were 362 deaths, with a mOS of 11.1 months for CPI-613+mFFX vs. 11.7 months for FFX [hazard ratio (HR), 0.95; 95% CI, 0.77 to 1.18; P = 0.655]; mPFS was 7.8 months vs. 8.0 months respectively [HR, 0.99; 95% CI, 0.76 to 1.29; P = 0.94]; ORR was 39% in the test arm vs. 34% in the control arm [ORR ratio, 1.23 (95% CI, 0.86 to 1.75)]. Grade ≥ 3 treatment-emergent adverse events with ≥ 10% frequency in CPI-613 plus mFFX vs. FFX arm were diarrhea (11.2% vs. 19.6%), hypokalemia (13.1% vs. 14.9%), anemia (13.9% vs. 13.6%), neutropenia (11.2% vs. 14.0%), thrombocytopenia (11.6% vs. 13.6%) and fatigue (10.8% vs. 11.5%). Conclusions: The addition of CPI-613 to mFFX failed to show significant improvements of ORR, PFS or OS. The mFFX in the test arm that had the lowest prospectively tested doses of FFX was without compromise on PFS or OS and may be considered as a reference for future FFX administration. Clinical trial information: NCT03504423.

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.

To present the feasibility of a dynamic whole-body (DWB) 68Ga-DOTATOC-PET/CT acquisition in patients with well-differentiated neuroendocrine tumors (WD-NETs). Sixty-one patients who underwent a DWB 68Ga-DOTATOC-PET/CT for a histologically proven/highly suspected WD-NET were prospectively included. The acquisition consisted in single-bed dynamic acquisition centered on the heart, followed by the DWB and static acquisitions. For liver, spleen and tumor (1–5/patient), Ki values (in ml/min/100 ml) were calculated according to Patlak's analysis and tumor-to-liver (TLR-Ki) and tumor-to-spleen ratios (TSR-Ki) were recorded. Ki-based parameters were compared to static parameters (SUVmax/SUVmean, TLR/TSRmean, according to liver/spleen SUVmean), in the whole-cohort and according to the PET system (analog/digital). A correlation analysis between SUVmean/Ki was performed using linear and non-linear regressions. Ki-liver was not influenced by the PET system used, unlike SUVmax/SUVmean. The regression analysis showed a non-linear relation between Ki/SUVmean (R2 = 0.55,0.68 and 0.71 for liver, spleen and tumor uptake, respectively) and a linear relation between TLRmean/TLR-Ki (R2 = 0.75). These results were not affected by the PET system, on the contrary of the relation between TSRmean/TSR-Ki (R2 = 0.94 and 0.73 using linear and non-linear regressions in digital and analog systems, respectively). Our study is the first showing the feasibility of a DWB 68Ga-DOTATOC-PET/CT acquisition in WD-NETs.

PURPOSE Patients with advanced esophageal cancer have a poor prognosis and limited treatment options after first-line chemotherapy. PATIENTS AND METHODS In this open-label, phase III study, we randomly assigned (1:1) 628 patients with advanced/metastatic squamous cell carcinoma or adenocarcinoma of the esophagus, that progressed after one prior therapy, to pembrolizumab 200 mg every 3 weeks for up to 2 years or chemotherapy (investigator’s choice of paclitaxel, docetaxel, or irinotecan). Primary end points were overall survival (OS) in patients with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 10, in patients with squamous cell carcinoma, and in all patients (one-sided α 0.9%, 0.8%, and 0.8%, respectively). RESULTS At final analysis, conducted 16 months after the last patient was randomly assigned, OS was prolonged with pembrolizumab versus chemotherapy for patients with CPS ≥ 10 (median, 9.3 v 6.7 months; hazard ratio [HR], 0.69 [95% CI, 0.52 to 0.93]; P = .0074). Estimated 12-month OS rate was 43% (95% CI, 33.5% to 52.1%) with pembrolizumab versus 20% (95% CI, 13.5% to 28.3%) with chemotherapy. Median OS was 8.2 months versus 7.1 months (HR, 0.78 [95% CI, 0.63 to 0.96]; P = .0095) in patients with squamous cell carcinoma and 7.1 months versus 7.1 months (HR, 0.89 [95% CI, 0.75 to 1.05]; P = .0560) in all patients. Grade 3-5 treatment-related adverse events occurred in 18.2% of patients with pembrolizumab versus 40.9% in those who underwent chemotherapy. CONCLUSION Pembrolizumab prolonged OS versus chemotherapy as second-line therapy for advanced esophageal cancer in patients with PD-L1 CPS ≥ 10, with fewer treatment-related adverse events.

Simple Summary It is getting more and more clear that cancer cell culture models are switching from two-dimension to three-dimensional, in order to better reflect in vivo situations where tumor cells have to cope with a highly interactive three-dimensional microenvironment. Several such culture models have been reported, predominantly multicellular tumor spheroids (MCTS) and patient-derived tumor organoids (PDTO). These are used both to investigate fundamental aspects of cancer development and as test systems for innovative therapies against gastric cancer, the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. The authors review the actual state of research in this field to provide an overview of the contribution of MCTS and PDTO, especially in the areas of molecular profiling, drug discovery, pathogen infection, and personalized medicine. Abstract Gastric cancer (GC), which includes cancer of the esophagus, the oesophagogastric junction, and the stomach fundus, is highly deadly with strong regional influence, Asia being the most affected. GC is often detected at late stages, with 30% of metastatic cases at diagnosis. Many authors have devised models to both unravel the mechanisms of GC development and to evaluate candidate therapeutics. Among these models, 2D-cell cultures are progressively replaced by 3D-cell cultures that recapitulate, much more comprehensively, tumor cellular and genetic heterogeneity, as well as responsiveness to environmental changes, such as exposure to drugs or irradiation. With respect to the specifics of GC, there are high hopes from such model systems, especially with the aim of identifying prognostic markers and novel drug targets.

Background: There is a lack of knowledge regarding the experience of patients with neuroendocrine tumors (NET) in France. Materials & methods: A patient survey that captured information on diagnosis, disease impact/management and awareness was conducted. Data of respondents from France were analyzed and compared with US data as a reference. Results: Key topics included delays in diagnosis, negative impact on quality of life, patient access to NET medical experts and treatments, and information on NET and treatments. Significant differences were observed between France and the USA regarding NET diagnosis. Conclusion: This survey highlights the considerable burden experienced by patients in France with NET and differences in patient experience between France and the USA that may result from different healthcare and social systems.

International audience; PURPOSE: This Phase IIb (NCT02195180) open-label study evaluated erythrocyte-encapsulated asparaginase (eryaspase) in combination with chemotherapy in second-line advanced pancreatic adenocarcinoma.METHODS: Eligible patients were randomized 2:1 to either eryaspase in combination with gemcitabine or mFOLFOX6 (eryaspase arm), or to gemcitabine or mFOLFOX6 alone (control arm). Co-primary endpoints were overall survival (OS) and progression-free survival (PFS) in patients with low asparagine synthetase (ASNS) expression. Secondary endpoints included OS and PFS in the entire population.RESULTS: 141 patients were randomized (eryaspase arm, n = 95; control arm, n = 46). Median OS and PFS in patients with low ASNS expression were 6.2 months (95% CI, 5.1-8.8) in the eryaspase arm versus 4.9 months (3.1-7.1) in the control arm (HR, 0.63; 95% CI, 0.39-1.01; P = 0.056) and 2.0 months (95% CI, 1.8-3.4) in the eryaspase arm versus 1.8 months (1.4-3.8) in the control arm (HR, 0.67; 95% CI, 0.40-1.12; P = 0.127), respectively. In the entire population, median OS and PFS for the eryaspase arm versus control were 6.0 months versus 4.4 months (HR, 0.60; P = 0.008) and 2.0 months versus 1.6 months (HR, 0.56; 95% CI, 0.37-0.84; P = 0.005), respectively. The combination of eryaspase and chemotherapy was well tolerated. The most frequent Grade 3/4 adverse events in the eryaspase arm (n = 93) were gamma-glutamyltransferase increase (16 [17.2%]), neutropenia (12 [12.9%]), and physical health deterioration (12 [12.9%]).CONCLUSION: Eryaspase in combination with chemotherapy is associated with improvements in OS and PFS, irrespective of ASNS expression in second-line advanced pancreatic adenocarcinoma. A Phase III trial is underway.

Supplemental Material, Supplemental_material for Comparison of 4 Screening Methods for Detecting Fluoropyrimidine Toxicity Risk: Identification of the Most Effective, Cost-Efficient Method to Save Lives by Olivier Capitain, Valérie Seegers, Jean-Philippe Metges, Roger Faroux, Claire Stampfli, Marc Ferec, Tamara Matysiak Budnik, Hélène Senellart, Valérie Rossi, Nadège Blouin, Jonathan Dauvé and Mario Campone in Dose-Response

241 Background: At interim analysis of the phase 3, randomized, double-blind KEYNOTE-590 (NCT03189719) study, 1L pembrolizumab (pembro) + chemotherapy (chemo) vs chemo alone provided superior OS, PFS, and ORR with a manageable safety profile in patients (pts) with untreated, advanced/unresectable or metastatic adenocarcinoma or esophageal squamous cell carcinoma (ESCC) or Siewert type 1 esophagogastric junction adenocarcinoma (EGJ). We report efficacy, safety, and health-related quality of life (HRQoL) results with an additional 12 months (mo) of follow-up. Methods: 749 eligible pts were randomized 1:1 to pembro 200 mg or placebo Q3W for up to 2 yr + chemo. Randomization was stratified by geographic region, histology, and performance status. Treatment continued until progression, unacceptable toxicity, or withdrawal, or 2 yr. No crossover was permitted. Primary endpoints were OS in pts with ESCC PD-L1 combined positive score (CPS) ≥10 tumors, and OS and PFS (RECIST v1.1; by INV) in ESCC, PD-L1 CPS ≥10, and all pts. Secondary endpoints included ORR, DOR, safety, and HRQoL. HRQol was assessed in 711 treated pts with ≥1 HRQoL assessment (356 pembro + chemo; 355 chemo). Data cutoff was July 9, 2021. Results: At data cutoff, median follow-up (randomization to data cutoff) was 34.8 mo. Median OS was longer with pembro + chemo vs chemo in pts with ESCC CPS ≥10 (HR 0.59; 95% CI, 0.45-0.76), ESCC (HR 0.73; 95% CI, 0.61-0.88), CPS ≥10 (HR 0.64; 95% CI, 0.51-0.80), and all pts (HR 0.73, 95% CI, 0.63-0.86). In pts with adenocarcinoma OS HR was 0.73 (95% CI, 0.55-0.99). The 24-mo OS rate in all pts was 26.3% vs 16.1%. Median PFS was longer with pembro + chemo vs chemo in ESCC (HR 0.65; 95% CI, 0.54-0.78), CPS ≥10 (HR 0.51; 95% CI, 0.41-0.65), and all pts (HR 0.64; 95% CI, 0.55-0.75). The 24-mo PFS rate in all pts was 11.6% vs 3.3%. Confirmed ORR was 45.0% (25 CR [6.7%]) vs 29.3% (9 CR [2.4%]), with median DOR of 8.3 vs 6.0 mo. Approximately 20% vs 6% of pts had response duration ≥24 months. Grade 3-5 drug-related AE rates were 72% vs 68%. Discontinuation rates from drug-related AEs were 21% vs 12%. There was no significant difference in least square mean (LSM) change from baseline to wk 18 between arms in EORTC QLQ-C30 global health status/quality-of-life (LSM difference -0.10; 95% CI, -3.40-3.20). LSM change from baseline to wk 18 was better with pembro + chemo vs chemo for QLQ-OES 18 pain (-2.94; 95% CI, -5.86 to -0.02) and dysphagia (-5.54; 95% CI, -10.92 to -0.16). Conclusions: With an additional 12 months of follow-up, pembro + chemo continued to provide significant and clinically meaningful improvement in OS, PFS, and ORR vs chemo with a manageable safety profile, and stable quality-of-life for pts with untreated, advanced esophageal and EGJ cancer. These data continue to support 1L pembro + chemo as a new standard of care in these patients. Clinical trial information: NCT03189719.

518 Background: Eryaspase, asparaginase encapsulated in red blood cells is an investigational product under development. The encapsulated asparaginase induces the degradation of asparagine and glutamine, crucial for cancer cell growth and survival. An earlier Phase 2b study in patients with advanced pancreatic cancer showed an improvement in overall survival (OS) and progression free survival (PFS) with eryaspase plus chemotherapy. Methods: TRYbeCA-1 was a randomized, open-label Phase 3 trial of eryaspase combined with chemotherapy in patients with advanced adenocarcinoma of the pancreas who have progressed on only one prior line of systemic anti-cancer therapy. Patients were randomized in a 1:1 ratio to gemcitabine/nab-paclitaxel or irinotecan/fluorouracil (5FU) therapy (depending on first-line received) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria included progression on or following first-line systemic treatment, ECOG performance status 0 or 1, stage III-IV disease, documented evidence of disease progression, available tumor tissue and adequate organ function. The primary endpoint was OS. A total of 412 events were required for 90% power to detect a treatment effect hazard ratio (HR) of 0.725 at a two-sided significance level of 5%. Results: A total of 512 patients were included. Baseline characteristics were well balanced between the treatment arms. The study did not meet the OS primary endpoint [HR: 0.92 (95% confidence interval (CI), 0.76-1.11), p-value 0.375]. The median OS for patients treated with eryaspase plus chemotherapy was 7.5 mo (95% CI, 6.5-8.3), compared to 6.7 mo (95% CI, 5.4-7.5) for chemotherapy alone. There was a trend of nominal OS benefit in 107 patients treated with eryaspase and irinotecan-5FU compared to 109 patients in control subgroup, with a median OS of 8.0 mo versus 5.7 mo, respectively [HR: 0.81 (95% CI: 0.60- 1.09)]. Treatment effect was consistent across various prognosis factors. Median PFS was 3.7 mo vs. 3.5 mo in the eryaspase and control arms, respectively [HR: 0.89 (95% CI: 0.73-1.07), p-value 0.215]. Disease control rate was 57.6% and 49.0% (p-value 0.047) in the eryaspase and control arms, respectively. The most common adverse events were in the eryaspase arm were asthenia, diarrhea, and anemia (Grade 3-4: 16.9%, 7.66% and 17.3%, respectively). Eryaspase did not appear to enhance toxicity of chemotherapy. Conclusion: This large prospective study did not meet it primary endpoint of improving OS in patients treated with eryaspase. The addition of eryaspase demonstrated nevertheless a well-tolerated profile and an encouraging survival benefit in the irinotecan/5FU subgroup, warranting further investigation. Clinical trial information: NCT03665441.