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Background: Breast cancer (BC) is the most frequent cancer and the second leading cause of cancer death for women. Although there is a need of new treatments to improve BC outcome, patients with BC are still under-represented in early phase trials, possibly because of the availability of numerous approved treatments and widely recruiting phase II and III trials. We aim to characterize the molecular profile, outcome and prognostic factors of patients with BC treated in a phase I trial at our institution. Methods: We retrospectively analyzed medical records of every BC patients treated consecutively in a phase I trial in the Early Drug Development Department (DITEP) at Gustave Roussy Cancer Center. Multivariate logistic regression models were used to determine the association between known prognostic factors such as ECOG, LDH or albumin levels, number of previous lines of treatment, metastatic sites and duration of treatment. When available, molecular profile was also reviewed. Results: Between April 1st 2008 and December 31th 2021, 4682 patients were enrolled and treated in a phase I trial in our department. Among them, 272 were treated for BC (5.8%): 271 women and 1 man, in 74 different trials. The median number of BC patients treated per year was 16.5 (min 1; max 33). Median time between consented date and C1D1 was 14 days (min 1; max 63). Median age at C1D1 was 50 years old (min 24; max 82). 5 patients (1.8%) were treated in an adjuvant setting (therapeutic vaccine) while all the others were metastatic. 12 patients (4.5%) had brain metastases and 127 patients (47.6%) had liver metastases. 186 patients (70%) had only 1 or 2 metastatic sites, and 81 (30%) had three or more sites. Triple negative was the most common subtype, representing 132 patients (48.5%), 125 (46%) were ER+ and 15 (5.5%) Her2+. Patients received a median number of 3 prior lines before enrollment (min 0; max 19). Overall, only 78 patients (28%) had a genetic testing: 30.7% had a germline BRCA1/2 mutation. 146 patients (54%) had a molecular profile (liquid biopsy or tissue sample) before their enrollment and among them 32,9% were oriented in a trial according to their specific profile. Regarding the type of treatments received: 21.7% were immunotherapy, 73.6% were targeted therapies (46.7% in monotherapy, 26.9% in different combinations with immunotherapy, chemotherapy, radiotherapy or endocrine treatments), 2.9% were chemotherapy and 1.8% endocrine therapy. The overall response rate was 11.1% (0.4% complete response, 10.7% partial response, 37.5% stable disease, 43.8% progressive disease and 7.6% not evaluable). Main reasons for discontinuation of treatment were: progressive disease (80.5%), toxicity (9.6%) and end of trial (6.6%). Median duration of treatment was 2 months (min 0; max 44), only 28.6% of patients were still treated after 3 months of trial and 10% at 6 months. At data cut off (June 21st 2022) median overall survival was 11 months. All patients had discontinued the trial by the time of the analysis: median number of lines of subsequent treatment was 2 (min 0; max 10) and 31 patients (11%) were enrolled in another phase I trial in our center. In a multivariate analysis, there was no prognostic factor associated with duration of treatment whether it was albumin (p=0.76) or LDH levels (p=0.68), ECOG (p=0.67), number of prior lines of treatment (p=0.79) or number of metastatic site (p=0.05). Conclusion: These results are consistent with prior published data as only few patients with BC are addressed for inclusion in a phase I trial, despite response rates and survival rates similar to other phase I patients. We did not find any specific factor associated with duration of treatment. It is likely that a thorough molecular profile could open more treatment options and access to phase I trials. Citation Format: Lauren Seknazi, Arthur Geraud, Vincent Goldschmidt, Capucine Baldini, Stéphane Champiat, Christophe Massard, Sophie Postel-Vinay, Aurelien Marabelle, Rastilav Bahleda, Antoine Hollebecque, Cristina Smolenschi, Anas Gazzah, Jean-Marie Michot, Patricia Martin-Romano, Aurore Vozy, Perrine Vuagnat, François-Xavier Danlos, Arnaud Bayle, Linda Mahjoubi, Barbara Pistilli, Yohann Loriot, Santiago Ponce-Aix, Kaissa Ouali. COBRA: Characteristics and Outcomes of patients with BReast cancer in phAse I trials at Gustave Roussy Cancer center [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-13-02.

Background: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. Methods: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. Findings: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7–30·4). Median overall survival was 12·7 months (95% CI 11·5–13·6) in the pembrolizumab group versus 10·9 months (9·9–11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72–0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. Interpretation: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

PURPOSE High-risk clonal hematopoiesis (CH) is frequently incidentally found in patients with solid tumors undergoing plasma cell–free DNA sequencing. Here, we aimed to determine if the incidental detection of high-risk CH by liquid biopsy may reveal occult hematologic malignancies in patients with solid tumors. MATERIALS AND METHODS Adult patients with advanced solid cancers enrolled in the Gustave Roussy Cancer Profiling study (ClinicalTrials.gov identifier: NCT04932525 ) underwent at least one liquid biopsy (FoundationOne Liquid CDx). Molecular reports were discussed within the Gustave Roussy Molecular Tumor Board (MTB). Potential CH alterations were observed, and patients referred to hematology consultation in the case of pathogenic mutations in JAK2, MPL, or MYD88, irrespective of the variant allele frequency (VAF), or in DNMT3A, TET2, ASXL1, IDH1, IDH2, SF3B1, or U2AF1 with VAF ≥ 10%, while also considering patient cancer-related prognosis. TP53 mutations were discussed case-by-case. RESULTS Between March and October 2021, 1,416 patients were included. One hundred ten patients (7.7%) carried at least one high-risk CH mutation: DNMT3A (n = 32), JAK2 (n = 28), TET2 (n = 19), ASXL1 (n = 18), SF3B1 (n = 5), IDH1 (n = 4), IDH2 (n = 3), MPL (n = 3), and U2AF1 (n = 2). The MTB advised for hematologic consultation in 45 patients. Overall, 9 patients of 18 actually addressed had confirmed hematologic malignancies that were occult in six patients: two patients had myelodysplastic syndrome, two essential thrombocythemia, one a marginal lymphoma, and one a Waldenström macroglobulinemia. The other three patients were already followed up in hematology. CONCLUSION The incidental findings of high-risk CH through liquid biopsy may trigger diagnostic hematologic tests and reveal an occult hematologic malignancy. Patients should have a multidisciplinary case-by-case evaluation.

Bevacizumab (bev) significantly improves outcomes of patients with metastatic colorectal cancer (mCRC). However, the addition of bev to concurrent chemotherapy significantly increased the risk of haemorrhage. We describe the case of a patient with mCRC who presented with acute diffuse abdominal pain following four cycles of bev-containing systemic chemotherapy. A CT revealed the appearance of bilateral adrenal enlargement suggestive of acute adrenal haematoma. Blood test results showed a dramatic decrease in cortisol level and highly elevated Adrenocorticotropic Hormone (ACTH) level suggesting an adrenal insufficiency. After differential diagnosis, we hypothesised that bev may have contributed to the development of a bilateral adrenal haematoma complicated by adrenal insufficiency. Bev was immediately withdrawn and the patient was subsequently treated with hydrocortisone substitution with favourable outcome. This case highlights for the first time the possibility of adrenal bleeding with bev-containing chemotherapy.

Background Standard therapy in gastric or gastro-esophageal junction (GOJ) adenocarcinoma is perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT regimen). FLOT offers significant histological response rates. The objective of our study was to evaluate the benefit of postoperative chemotherapy on recurrence free survival (RFS) in operated gastric or gastro-esophageal junction adenocarcinoma ypT0-3N0. Materials and Methods. This retrospective mulicenter study included patients with gastric or GOJ adenocarcinoma ypT0-3N0 treated with preoperative FLOT-type chemotherapy and operated between January 2017 and January 2022. Patients were divided into two groups: a group without postoperative chemotherapy (monitoring group) and a group with postoperative chemotherapy (chemotherapy group). Primary criterion was RFS. Secondary criterion was overall survival (OS). Results A total of 123 patients were included, 107 in the post chemotherapy group and 16 in the monitoring group. Patients in the chemotherapy group were younger (59 vs. 67 years) and had had less preoperative chemotherapy dose reduction (29 vs. 43,7%). There was no significant difference between the 2 groups concerning RFS (p = 0,87) and OS (p = 0,93). Conclusion Our study suggests that postoperative chemotherapy does not improve survival in gastric or GOJ adenocarcinoma following surgery and 4 cycles of preoperative FLOT. Our study paves the way for a prospective randomized trial focusing on the usefulness of 4 cycles of post operative FLOT. Publication type : MeSH : Academic Dissertation

Immunotherapy has demonstrated its effectiveness in many cancers. In hepatocellular carcinoma (HCC), promising results shown in the first phase II studies evaluating anti-PD-1 or anti-PD-L1 monotherapies resulted in their approval in the United States. Approval was not obtained in Europe; subsequent randomized studies in first- or second-line treatment did not confirm these initial results. However, first data with immunotherapy plus antiangiogenic treatments or dual immunotherapy combinations were positive. In this context, the combination of bevacizumab and atezolizumab took the lead. The IMbrave150 trial revealed an improved objective response rate (ORR), progression-free survival, and overall survival with this combination versus the previous standard, sorafenib. Subsequent results of dual immunotherapy with the anti-CTLA-4 and anti-PD-1 monotherapies tremelimumab and durvalumab (also superior to sorafenib monotherapy) confirmed the value of using a combination in first-line treatment. These significant therapeutic advances, and the increase in ORR, raise two main questions. Whereas response was very limited with previous treatments, the ORR reported with these new combinations are between 20% and 30%. This raises the question of whether immunotherapy (ICI single agent, combination of ICI with antiangiogenic agent or other antitumoral treatment) can be used in patients beyond those in BCLC group C, the traditional candidate group for systemic therapy. We have thus seen an increasing number of patients previously treated with trans-arterial chemoembolization (BCLC group B) receiving these new treatments, and we develop the results of several studies combining loco-regional therapies and immunotherapy-based systemic treatments. The other major question is that of how and when to use these medical treatments as “adjuvants” to interventional radiology or surgery; the results of several works are discussed for this purpose. In this review, we cover all of these points in a fairly comprehensive manner.

The TG6002.03 trial is a dose-escalation phase 1 clinical trial of TG6002 infusion via the hepatic artery in patients with liver-dominant colorectal cancer metastases. TG6002 is an engineered Copenhagen strain oncolytic Vaccinia virus, deleted of thymidine kinase and ribonucleotide reductase to enhance tumor selective viral replication and expressing FCU1, an enzyme converting the non-cytotoxic prodrug 5-fluorocytosine (5-FC) into the chemotherapeutic compound 5-fluorouracil (5-FU). In this trial, patients with advanced unresectable liver-dominant metastatic colorectal cancer who had failed previous oxaliplatin and irinotecan-based chemotherapy were treated with up to 2 cycles of TG6002 infusion 6 weeks apart via the hepatic artery on day 1 combined with oral 5-FC on days 5 to 14 (where day 1 = TG6002 infusion). TG6002 infusion was performed over 30 minutes via selective catheterization of the hepatic artery proper. 5-FC oral dosing was 50mg/kg x4 daily. Blood was sampled for TG6002 pharmacokinetics and 5-FC and 5-FU measurements. Sampling of liver metastases was performed at screening and on day 4 or day 8 for virus detection and 5-FC and 5-FU quantification. In total, 15 patients (median age 61 years, range 37-78) were treated in 1 UK centre and 2 centres in France and received a dose of TG6002 of 1 × 106 (n=3), 1 × 107 (n=3), 1 × 108 (n=3), or 1 × 109 pfu (n=6). Fourteen of the 15 patients received a single cycle of treatment, including one patient who did not received 5-FC, and one patient received two cycles. TG6002 was transiently detected in plasma following administration, suggesting a strong tissue selectivity for viral replication. In the highest dose cohort, a virus rebound was observed on day 8, concordant with replication time of the virus. In serum samples, 5-FU was present on day 8 in all patients with a high variability ranging from 0.8 to 1072 ng/mL and was measurable over several days after initiation of therapy. Seven of the 9 patients evaluable showed the biodistribution of the virus in liver lesions by PCR testing on day 4 or day 8. Translational blood samples showed evidence for T-cell activation and immune checkpoint receptor-ligand expression. At 1 × 109 pfu, there was evidence for T-cell proliferation and activation against tumour-associated antigens by ELISpot and for immunogenic cell death. In terms of safety, a total of 34 TG6002-related adverse events were reported, of which 32 were grade 1-2 and 2 were grade 3. The maximum tolerated dose was not reached, and a single dose-limiting toxicity was observed consisting of a myocardial infarction in a context of recent Covid-19 infection in a 78-year-old patient. These results indicate that TG6002 infused via the hepatic artery in combination with oral 5-FC was well tolerated, effectively localized and replicated in the tumor tissues, expressed its therapeutic payload and showed anti-tumoral immunological activity. Citation Format: Adel Samson, Cristina Smolenschi, Philippe Cassier, Jai V. Patel, Chris Hammond, Marta Kurzawa, Sophie Sainte-Croix, Emma West, Alain Sadoun, Kaidre Bendjama. Oncolytic virus TG6002 safety and activity after intrahepatic artery administration in patients with liver-dominant metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT190.

This cohort study assesses the outcome of oxaliplatin desensitization for patients with gastrointestinal cancers who experienced hypersensitivity reactions after oxaliplatin infusion.

Despite a significant improvement in overall survival over the last 15 years, colorectal cancer remains a major public health problem worldwide. Much effort has been made to develop an optimal choice of first-line treatments, but after progression the therapeutic possibilities and the criteria for choice are different.The purpose of this literature review is to discuss the different possibilities of second-line treatment and to specify the criteria for choice. Biological subgroups requiring specific therapeutic decisions will be described. We conducted a systematic review for randomized controlled trials published since 1995. A non-exhaustive review of published phase II studies, cohort studies, and international guidelines was also given and future leads were discussed.Some choices of second-line treatments are a direct result of the option chosen in the first line. Others are necessary because of the biological specificity of the tumor: immunotherapy for tumors with microsatellite instability, or the combination encorafenib cetuximab for mutated BRAF-V600E tumors. In many other circumstances, there are several options that require extensive involvement of multidisciplinary boards and the patient in the final therapeutic decision.

750 Background: KRAS mutation is the most common molecular alteration (MA) in pancreatic adenocarcinoma (PDAC), and only 8-10% of patients (pts) harbor KRAS wild-type tumors (WT). This study describes clinical and molecular features of KRAS WT PDAC and compares it to mutant KRAS (m KRAS) PDAC. Methods: A retrospective chart review of clinical/molecular data was performed on all pts with PDAC who had contributive molecular profile at Gustave Roussy. KRAS status was determined on tumor molecular profiling as part of routine care using an in-house panel or Foundation Medicine NGS either on tissue (63%) or liquid biopsy (37%). Results: Overall, 41 pts with KRAS WT PDAC were compared to 197 pts with mKRAS PDAC. Median OS (mOS) from initial diagnosis was significantly higher in the KRAS WT group compared to mKRAS group (32.8 months (mts), CI95% [25.9-NR] vs 21.5 mts, CI95% [18.8-24.9] respectively), as mOS from metastatic diagnosis, 26 mts, CI95% [15.7-NR] for KRAS WT pts vs 17.7 mts CI95% [15.5-19.3] for mKRAS (all p

809 Background: Peritoneal carcinomatosis (PC) is a common manifestation in gastro-intestinal (GI) cancers.10-20 % of patients (pts) will present isolated, unresectable peritoneal disease with poor prognosis. In the past years, circulating tumor DNA (ctDNA) has emerged as a novel and less invasive biomarker for molecular diagnosis and disease monitoring. We aimed to evaluate the ability of PC to shed ctDNA into circulation in a cohort of pts with GI cancers and isolated PC treated in our institution. Methods: We reviewed retrospectively the results of liquid biopsies obtained at progression or at diagnosis. Genomic analysis was done using Foundation One liquid CDx panel. Data on demographics, tumor type, clinical outcomes and molecular alterations (MA) have been collected. Results: Out of 400 GI pts tested, 85 with exclusively PC were included in the analysis. The main characteristics were as follows: 45(53%) female, median age of 57 years (IQR: 24-79), majority have received systemic chemotherapy (all were progressive) (n=63, 74%) with median number of previous lines 1 (range: 0-3). Most common tumor types were as follows: gastric (n=24, 28%), colorectal (n=22, 26%) and primary peritoneal (n=20, 24%) cancers. The median index of peritoneal carcinomatosis was 23(IQR: 6-39). The tumor fraction was very low or undetectable in a proportion of 81% (n=69), median Tumor Mutational Burden was 1 mutation per megabase and was not correlated to tumor volume. Gene alterations were found in a proportion of 56% of pts (n=48) but most common alteration were TP 53 (n=22 pts, 26%) and KRAS mutation (n=14 pts, 16%). Targetable MA were identified only in 11 pts (13%) as follows: ATM, ARID1A, BRAFV600E, ERBB2, krasG12C. Three of them were included in a clinical trial. Germline mutations were found in 5 pts: ATM, CDH1, BRCA2, MSH6, BAP1. For colorectal pts known KRAS and BRAF V600E mutations were confirmed in plasma in a proportion of 32% (7 pts out of 22), for pancreatic cancer the KRAS in 17% (3 out of 18) and for gastric cancer, ERBB2 amplification in 5% (1 out of 22 pts). In pts with primary peritoneal disease: pseudomyxoma and mesothelioma, one patient harbored a known germline BAP 1 and kras G12C mutation without other targetable MA. The median survival in MA group was higher compared to non-MA. Conclusions: Isolated Pc and primary peritoneal cancers have distinct clinical and biological characteristics. The clinical utility of ctDNA seems to be limited in isolated PC or primary peritoneal cancers. However, it is not very clear if this to tumor location or to the ability of peritoneum to seed ctDNA.

Background: MSI-H/dMMR is considered the first predictive marker of efficacy for immune checkpoint inhibitors (ICIs). However, around 39% of cases are refractory and additional biomarkers are needed. We explored the prognostic value of pretreatment LIPI in MSI-H/dMMR patients treated with ICIs, including identification of fast-progressors. Methods: A multicenter retrospective study of patients with metastatic MSI-H/dMMR tumors treated with ICIs between April 2014 and May 2019 was performed. LIPI was calculated based on dNLR &gt, 3 and LDH &gt, upper limit of normal. LIPI groups were good (zero factors), intermediate (one factor) and poor (two factors). The primary endpoint was overall survival (OS), including the fast-progressor rate (OS &lt, 3 months). Results: A total of 151 patients were analyzed, mainly female (59%), with median age 64 years, performance status (PS) 0 (42%), and sporadic dMMR status (68%). ICIs were administered as first or second-line for 59%. The most frequent tumor types were gastrointestinal (66%) and gynecologic (22%). LIPI groups were good (47%), intermediate (43%), and poor (10%). The median follow-up was 32 months. One-year OS rates were 81.0%, 67.1%, and 21.4% for good, intermediate, and poor-risk groups (p &lt, 0.0001). After adjustment for tumor site, metastatic sites and PS, LIPI remained independently associated with OS (HR, poor-LIPI: 3.50, 95%CI: 1.46–8.40, p = 0.02. Overall, the fast-progressor rate was 16.0%, and 35.7% with poor-LIPI vs. 7.5% in the good-LIPI group (p = 0.02). Conclusions: LIPI identifies dMMR patients who do not benefit from ICI treatment, particularly fast-progressors. LIPI should be included as a stratification factor for future trials.

BackgroundClinical studies have highlighted the efficacy of anti-programmed death 1 (αPD-1) monoclonal antibodies in patients with DNA mismatch repair-deficient (MMRD) tumors. However, the responsiveness of MMRD cancers to αPD-1 therapy is highly heterogeneous, and the origins of this variability remain not fully understood.Methods4T1 and CT26 mouse tumor cell lines were inactivated for the MMRD geneMsh2,leading to a massive accumulation of mutations after serial passages of cells. Insertions/deletion events and mutation load were evaluated by whole exome sequencing. Mice bearing highly mutated MMRD tumor or parental tumors were treated with αPD-1 and tumor volume was monitored. Immune cell type abundance was dynamically assessed in the tumor microenvironment and the blood by flow cytometry. Neutrophils were depleted in mice using αLY6G antibody, and regulatory T (Treg) cell population was reduced with αCD25 or anti-cytotoxic T-lymphocytes-associated protein 4 (αCTLA-4) antibodies. Patients with MMRD tumors treated with immune checkpoint blockade-based therapy were retrospectively identified and neutrophil-to-lymphocyte ratio (NLR) was evaluated and examined for correlation with clinical benefit.ResultsBy recapitulating mismatch repair deficiency in different mouse tumor models, we revealed that elevated circulating tumor-induced neutrophils (TIN) in hypermutated MMRD tumors hampered response to αPD-1 monotherapy. Importantly, depletion of TIN using αLy-6G antibody reduced Treg cells and restored αPD-1 response. Conversely, targeting Treg cells by αCD25 or αCTLA-4 antibodies limited peripheral TIN accumulation and elicited response in αPD-1-resistant MMRD tumors, highlighting a crosstalk between TIN and Treg cells. Thus, αPD-1+αCTLA-4 combination overcomes TIN-induced resistance to αPD-1 in mice bearing MMRD tumors. Finally, in a cohort of human (high microsatellite instability)/MMRD tumors we revealed that early on-treatment change in the NLR ratio may predict resistance to αPD-1 therapy.ConclusionsTIN countered αPD-1 efficacy in MMRD tumors. Since αCTLA-4 could restrict TIN accumulation, αPD-1+αCTLA-4 combination overcomes αPD-1 resistance in hosts with hypermutated MMRD tumors displaying abnormal neutrophil accumulation.

Simple Summary A new era has emerged in oncology in the last ten years with the development of immune therapies. However, single-agent immune therapy such as immune checkpoint inhibitors seems to have a limited clinical activity in biliary tract cancers and are still largely investigational, except for the few patients with microsatellite-instable tumors. Here, we review: (i) the molecular and immune landscape of biliary tract cancers, (ii) the existing results of immune therapies in biliary tract cancers, and (iii) the future of immune therapies in biliary tract cancers, with the identification of predictive biomarkers for response to these therapies, and the ongoing therapeutic trials. Abstract Biliary tract cancers are rare tumors with a poor prognosis. Two-thirds of these primary liver malignancies are diagnosed at advanced stages where therapeutic options are limited. Whereas several molecular targeted therapies emerge in biliary tract cancers, immunotherapy is still investigational, the only approved immunotherapy to date being the immune checkpoint inhibitor pembrolizumab for the small fraction of patients with microsatellite-instable tumors. In microsatellite-stable, pre-treated biliary tract cancers, single-agent immune checkpoint blockade has a limited albeit often long-lasting clinical activity in a still ill-defined subgroup of patients. The identification of predictive biomarkers will allow a better selection of patients that may benefit from immunotherapy. Combinations of immunotherapies with each other, with chemotherapy or targeted molecular therapies are being investigated in early lines of therapy, including first-line.

International audience; Anti-angiogenic therapy with bevacizumab is a widely used therapeutic option for recurrent glioblastoma (GBM). Nevertheless, the therapeutic response remains highly heterogeneous among GBM patients with discordant outcomes. Recent data have shown that radiomics, an advanced recent imaging analysis method, can help to predict both prognosis and therapy in a multitude of solid tumours. The objective of this study was to identify novel biomarkers, extracted from MRI and clinical data, which could predict overall survival (OS) and progression-free survival (PFS) in GBM patients treated with bevacizumab using machine-learning algorithms. In a cohort of 194 recurrent GBM patients (age range 18–80), radiomics data from pre-treatment T2 FLAIR and gadolinium-injected MRI images along with clinical features were analysed. Binary classification models for OS at 9, 12, and 15 months were evaluated. Our classification models successfully stratified the OS. The AUCs were equal to 0.78, 0.85, and 0.76 on the test sets (0.79, 0.82, and 0.87 on the training sets) for the 9-, 12-, and 15-month endpoints, respectively. Regressions yielded a C-index of 0.64 (0.74) for OS and 0.57 (0.69) for PFS. These results suggest that radiomics could assist in the elaboration of a predictive model for treatment selection in recurrent GBM patients.

Background Hepatic arterial infusion (HAI) combined with systemic chemotherapy has shown promising results in patients with unresectable colorectal liver metastases (CRLM), even after failure to systemic therapy. Addition of systemic targeted therapies has been investigated with controversial results regarding tolerance, especially with HAI-floruxidine when combined with systemic bevacizumab. Our study aimed to analyse feasibility, safety and efficacy of HAI-oxaliplatin plus systemic chemotherapy and targeted therapies. Methods Between 2005 and 2016, single-centre consecutive patients with unresectable CRLM who received at least one cycle of HAI-oxaliplatin plus systemic chemotherapy and targeted therapies (cetuximab/panitumumab or bevacizumab) were analysed. Results A total of 89 patients (median age 55 years (range, 26–76 years) who previously received a median number of one systemic chemotherapy regimen (range, 0–5) including oxaliplatin in 78% of cases were included. Median number of HAI-oxaliplatin cycles was 9 (range, 1–28) combined with systemic chemotherapy and targeted therapies (LV5FU2 [63%], FOLFIRI [36%]) plus anti-EGFR (30%), or bevacizumab (70%). Grade 3/4 toxicities included neutropenia (40%), HAI-related abdominal pain (43%) and neurotoxicity (12%). The intent-to-treat objective response rate was 42%, and 45% had stable disease, allowing complete CRLM resection/ablation in 27% of patients. After a median follow-up of 72 months, median overall and progression-free survival was 20 and 9 months, respectively. Conclusion Addition of targeted therapy to systemic chemotherapy combined with HAI-oxaliplatin is feasible, safe and shows promising activity, even after systemic chemotherapy failure.

Liver metastases are mainly supplied by the hepatic artery, allowing the administration of intra-arterial hepatic chemotherapy (IAHC) while preserving normal parenchyma. The progression-free survival and response rate are prolonged by IAHC which can improve the rate of secondary resectability. Severe abdominal pain requiring high-dose opioids can appear during HIAC administration. This pain is related to extrahepatic infusion and gastroduodenal ulceration. However, intense abdominal pain was observed under oxaliplatin IAHC specifically without any extrahepatic infusion. We retrospectively reviewed the charts of 68 patients who received IAHC in our center between 2011 and 2015. Patient’s demographics and disease characteristics were collected. Other variables such as the type, duration, and dosage of the chemotherapy administered, as well as the usage of painkillers before, during, or after intra-arterial administration, were also registered. The mean age of the patients was 59 years. 61.7% were male (n = 42). The mean dose of oxaliplatin administered was 162 mg per cure over 6.7-h course. Fifty percent were diagnosed with a left colon cancer, and 85.2% had synchronous liver metastasis. While 47% of patients received IAHC as a third-line therapy, the main chemotherapeutic drug was oxaliplatin (85.2% of cases; n = 58), then OPTILIV protocol (5FU, irinotecan, oxaliplatin) (13.3%; n = 9), and mitomycin C (1.5%; n = 1). A dose reduction of 23.6% had been noted in 58.8% (n = 40) cases due to adverse effects. Among patients who received opioids during IAHC (n = 40), 20% required opioids in intercure. Before, during, and after IAHC administration, patients complained of abdominal pain in 8.8%, 58.8%, and 19.1%, and opioids were used in 10.2%, 57.3%, and 19.1%, respectively. The main onset of pain occurs during the third cycle of chemotherapy. Among our patients, 11.7% and 22% had ulcer and extrahepatic perfusion, respectively, while 7.3% of them were asymptomatic. The mean occurrence of these signs was during the fourth cycle of IAHC. 33.8% and 52.9% of patients had abdominal pain while an extended and short infusion time, respectively. Lengthening of the infusion time did not prevent the occurrence of abdominal pain significantly but was nonetheless decreased compared with patients undergoing short infusion durations. Pain was more common in patients who did not have a dose reduction and who presented with ulcer and extrahepatic perfusion. Abdominal pain occurred on average one cycle before ulcer or extrahepatic perfusion diagnosis. In current practice, pain should be an alarming indicator in patients receiving IAHC, as it may be associated with ulcer or extrahepatic perfusion and thus requiring opioids.

605 Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of death by cancer worldwide. Mostly diagnosed with locally advanced or metastatic disease, patients lack for treatment options. Gene alterations (GAs) are frequently observed in PDAC, some of them considered as actionable with molecular targeted therapies (MTTs), with potential clinical benefits and improved outcomes. Methods: We conducted a retrospective analysis of all patients, aged ≥18 years, with histologically confirmed PDAC, who underwent tumor molecular profiling between 2010 and 2020 in our institution as part of personalized medicine trials. Overall survival was the primary study endpoint (minimal follow-up after molecular profiling, 6 months). Results: Of 115 eligible patients, molecular profiling was successful in 102 patients (89%). KRAS mutations were the most frequent GAs, mostly G12D. Actionable GAs were found in 29 patients (28%), involving mainly BRCA1/2 (5 [18%]), HER2 (5 [18%]), MTAP (5 [18%]), and FGFR (3 [11%]). Only 12 of these 29 patients (41%, or 10% of the whole population) could receive MTTs accordingly, with a median progression-free survival of 1.6 months. Median OS was 17 months in patients with actionable GAs treated with MTTs (n = 12 [11.8%]), 14 months in patients with actionable GAs not treated with MTTs (n = 17 [16.7%]), and 19 months in patients without actionable GAs treated with standard therapies (n = 73 [71.5%]; p = 0.26). The absence of liver metastases was associated with better OS (HR = 0.471, p = 0.01). The longest duration of response with MTTs was observed in patients with BRCA mutations treated with olaparib. Conclusions: Actionable GAs are found in more than the quarter of patients with advanced PDAC. Overall, targeting actionable GAs with MTTs was not associated with improved OS in this retrospective study. However, selected GA/MTT duets (e.g., BRCA mutations/olaparib) were associated with better outcome.

95 Background: Oxaliplatin, a major drug in metastatic colorectal cancer (MCRC), is responsible for a cumulative and limiting peripheral neuropathy (PN). Hepatic arterial infusion (HAI) chemotherapy, which makes sense in cases of exclusive or predominant liver metastases, increases the intratumor concentration of the administered drug(s) to improve efficacy and limit systemic toxicity. Methods: We compared the frequency and severity of NP in oxaliplatin-naive patients with MCRC included in trials that evaluated treatment with oxaliplatin administered either by HAI (CHOICE, OSCAR, and PACHA-01 trials) or by intravenous (IV) route (FFCD 2000-05 trial). The primary endpoint was the occurrence of clinically significant NP (grade 2-4) according to the cumulative dose of oxaliplatin received. The secondary endpoints were the occurence of severe NP (grade 3-4) and time to onset of NP. Results: 342 patients were included (IV oxaliplatin: 300; HAI: 42). 180 patients in the IV group (60%) and 24 patients in the HAI group (57%) developed clinically significant NP, with no significant difference between the 2 groups (p = 0.85). 95 patients in the IV group (32%) and 8 patients in the HAI group (19%) developed severe NP, with no significant difference between the 2 groups (p = 0.082). NP appeared earlier in the HAI group, with more treatment discontinuations for neurotoxicity. Conclusions: The administration of oxaliplatin HAI rather than IV in the treatment of MCRC does not seem to reduce the incidence, precocity and severity of NP.

Background Studies over the past 10 years strongly support an association between skeletal muscle mass (SMM) depletion and outcome in metastatic colorectal cancer (mCRC). Factors influencing SMM changes over time are, however, poorly studied. We analyzed the impact of SMM on overall survival and chemotherapy toxicities in mCRC patients treated with first-line chemotherapy. Changes in weight and body composition were evaluated during follow-up. Methods Patients enrolled in the randomized phase II ACCORD trial comparing two chemotherapy regimens were screened. Body composition parameters (SMM, adipose tissue) were assessed prospectively with computed tomography (CT) imaging, and toxicities were recorded. Mixed models were used to assess weight and BC changes during 4 months of treatment follow-up. Results Among 145 patients included in ACCORD, 76 had available baseline CT scans and were included in the current study. Mean age was 60.6 ± 10.0 years, 50% were women, 82% had colon cancer, and 62% had two or more metastatic sites. At baseline, 49% had lost at least 5% of their initial weight, including 26% who had lost more than 10%; 53% had SMM depletion. In this homogenous cohort, there were no statistically significant associations between SMM depletion and overall survival, progression-free survival or chemotherapy toxicity. There were no decreases in weight or SMM during follow-up. Weight and SMM changes were not influenced by diarrhea either grade 3–4 or any grade (reported in 74% of patients). For patients with weight loss ≥10% at baseline, SMM increased significantly after 4 months of follow-up and after disease stabilization following chemotherapy (P = 0.008). Conclusions In a homogenous mCRC cohort, SMM depletion was not associated with survival or chemotherapy toxicity. Despite most patient experiencing diarrhea, no changes in weight or SMM were found during 4 months of follow-up. However, hypotheses deriving from our exploratory study have to be tested in further larger sample size studies. Trial registration Clinicaltrials.gov NCT00423696 (2011). Electronic supplementary material The online version of this article (10.1186/s12885-019-6086-2) contains supplementary material, which is available to authorized users.

Over the past two decades, the molecular characterization of metastatic colorectal cancer (mCRC) has been revolutionized by the routine implementation of RAS and BRAF tests. As a result, it is now known that patients with mCRC harboring BRAF mutations experience a poor prognosis. Although it accounts for only 10% of mCRC, this group is heterogeneous; only the BRAF-V600E mutation, also observed in melanoma, is associated with a very poor prognosis. In terms of treatment, these patients do not benefit from therapeutics targeting the epidermal growth factor receptor (EGFR). In first-line chemotherapy, there are two main options; the first one is to use a triple chemotherapy combination of 5-fluorouracil, irinotecan, and oxaliplatin, with the addition of bevacizumab, because post hoc analysis of randomized trials have reported interesting results. The other option is to use double chemotherapy plus bevacizumab, since anti-EGFR seems to have modest activity in these patients. Only a small percentage of patients who experience failure of this first-line treatment receive second-line treatment. Monotherapy with BRAF inhibitors has failed in this setting, and different combinations have also been tested. Using the rationale that BRAF inhibitor monotherapy fails due to feedback activation of the EGFR pathway, BRAF inhibitors have been combined with anti-EGFR agents plus or minus MEK inhibitors; however, the results did not live up to the hopes raised by the concept. To date, the best results in second-line treatment have been obtained with a combination of vemurafenib, cetuximab, and irinotecan. Despite these advances, further improvements are needed.

Pancreatic cancer is considered to be one of the most aggressive cancers. For unknown reasons, the incidence of pancreatic cancer is slowly rising and so too are mortality rates. Over 75% of patients are diagnosed with locally advanced disease or with metastases; and more than 95% of patients have metastases at diagnosis or will develop metastases during their follow-up. Despite recent improvements in the therapy of pancreatic cancer, initially with demonstration of the activity of the FOLFIRINOX regimen and subsequently the approval of nab-paclitaxel in combination with gemcitabine, prognosis remains poor and the 5-year survival rate is less than 5%. To date, neither personalized medicine nor immunotherapy, the 2 recent revolutions of cancer treatment, have delivered major positive results in the treatment of pancreatic cancer; and it is especially clear that immune checkpoint inhibitors will not become a major tool in the treatment of pancreatic cancer. There are many ongoing studies, including those exploring combinations of chemotherapy with immunotherapy. Vaccines or T cells modified with a chimeric antigen receptor (CAR-T cells) could also play a role in the treatment of cancer in the future. The aim of this review is to discuss recent improvements in standard of care, major obstacles to overcome, recent results of new treatment combinations, and the most interesting innovative approaches.

Angiogenesis represents a hallmark of glioblastoma but most trials disappointed and failed to change the poor outcome of this disease. However, Bevacizumab (Bev) is widely used in clinical practice by expert oncologists due to experience or efficacy in real life.We retrospectively reviewed the use of Bev and its benefit in terms of Time to treatment failure (TTF), Overall Survival(OS), Objective Response Rate (ORR) and clinical benefit. METHODS: We analyzed two hundred and two patients treated at Gustave Roussy Cancer Campus with Bev until definitive failure for recurrent glioblastoma between 2006 and 2016. Patients were treated with Bev alone or in association with radiotherapy, temozolomide, lomustine or irinotecan. RESULTS: The median duration of Bev treatment until definitive failure was 6 months. The median TTF was 7.27 months(95%CI 6.30-8.24) and the median OS from diagnosis was 22.43 months(95%CI 19.68-25.18). Two patients were still alive without active treatment at the end of study. A hundred and fourteen (56%) patients experienced symptom amelioration and seventy-five (37%) improved their Performance Status. Fifty percent of patients exhibited Partial and Complete Response on MRI, as best radiological response, within 1.6 months. No patient had anaphylactic reaction. Grade 1-2 hypertension(HT)(17%) and grade 1(10%) proteinuria were most common. Six patients presented lethal toxicity: 4 with GI perforation, 1 p with cerebral hemorrhage and 1 p with arterial bleeding. HT was correlated with treatment response in 67% of patients. A neutrophil count superior to 6000/mm³ was associated with longer TTF(mTTF 8.23m(95%CI 6.64-9.82). CONCLUSION: This retrospective study reports a substantial clinical benefit of Bev in patients with recurrent glioblastoma with an acceptable toxicity profile. As the panel of therapeutic option is still very limited in these tumors, this work supports the maintained use of Bev as a therapeutic option.

552 Background: Biliary tract cancers (BTC) are rare and heterogeneous cancers with poor prognosis. Several actionable genomic targets have been described in BTC but data on the efficacy of targeted therapies remain limited. The main objectives of this retrospective study was to evaluate the frequency of actionable genomic alterations among BTC and the impact of targeted therapy. Methods: We performed a retrospective analysis on BTC patients seen at Gustave Roussy (IGR) from Dec 2011 to Jul 2019. All clinical and genomic reports were reviewed. Results: The study population included 212 patients with the main following characteristics: median age 61 years, female 51%, intrahepatic cholangiocarcinoma 57%, median of 2 previous lines. Of 212 BTC patients, 170 patients had a genomic profile based on archival tissue or a new tumor biopsy (IGR panel n = 120; Foundation One panel n = 92 ). 124 patients (73%) had at least one genomic alteration and 68 (40%) patients had genomic alteration considered as actionable. The most common actionable targets were FGFR2 rearrangement/mutation (n = 24, 35.3%), HER2/3 mutations (n = 9, 13.2%) and IDH1/2 mutations (n = 7, 10.3%). Of those 68 patients, 58 received the matched targeted therapy: FGFR inhibitor n = 24, HER2/3 inhibitors n = 9, Akt/PIK3CA/mTOR inhibitors n = 7, IDH1 inhibitor n = 6. In the treated population, the objective response rate was 36.2% and the disease control rate 85.1%. Progression-free survival (PFS) was 6.2 months compared to 2.8 months (p = 0.02) for patients who did not received targeted treatment. Overall survival (OS) was 17.7 months compared to 11.0 months (p = 0.03) for patients who did not received targeted treatment. Conclusions: Actionable genomic targets are frequent among BTC. Profiling-directed therapies resulted in a 36% response rate, a 85% tumor control rate and a 6.2 months PFS which compare favorably to second-line chemotherapy. A randomized trial is required to confirm the benefit of precision medicine in BTC.

e16119Background: Benefit of CT beyond standard 1st-line (L1) gemcitabine plus cisplatin (GEMCIS) or oxaliplatin (GEMOX) in aBTC is unclear. Our aim was to identify and validate prognostic factors ...