Gustave Roussy Research Articles

Implementing the European Society for Medical Oncology Scale for Clinical Actionability of Molecular Targets in a Comprehensive Profiling Program: Impact on Precision Medicine Oncology.

To facilitate implementation of precision medicine in clinical management of cancer, the European Society of Medical Oncology proposed in 2018 a new scale to harmonize and standardize the reporting and interpretation of clinically relevant genomics data (ESMO Scale of Actionability of molecular Targets [ESCAT]). This study aims to characterize the clinical impact of matching targetable genomic alterations (GAs) in patients with advanced cancer according to ESCAT. Analysis of next-generation sequencing results from 552 patients is included in two prospective precision medicine studies at Gustave Roussy. End points included objective response rates, progression-free survival, and overall survival according to ESCAT. Molecular data from 516 patients were available and discussed within a Molecular Tumor Board. The most common tumor types were GI (n = 164; 30%), lung (n = 137; 25%), and urologic tumors (n = 68; 13%). Overall, 379 GAs were considered as actionable targets according to ESCAT in 348 (67%) patients. In 31 (6%) patients, two concomitant actionable targets were identified. On the basis of ESCAT, GAs were considered to be classified as tier I in 120 patients (29%), II in 25 patients (5%), III in 80 patients (16%), and IV in 153 patients (30%). A total of 136 patients (27%) received a matched therapy. ESCAT was significantly associated with objective response rates and clinical benefit rates. The median progression-free survival was 6.5 months (95% CI, 4.2 to 8.9), 3 months (95% CI, 1 to not available), 3 months (95% CI, 2.2 to 3.8), and 4 months (95% CI, 2.8 to 6.3) for ESCAT I, II, III, and IV, respectively (<i>P</i> = .0125). Implementation of ESCAT classification for clinical decision making by Molecular Tumor Board is feasible and useful to better tailor therapies in patients with cancer.

CT-282 Case Report: Successful Management of Severe Veno-Occlusive Disease after Allogeneic Stem Cell Transplantation Using a Transjugular Intrahepatic Portosystemic Shunt

Veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (VOD/SOS), of the liver is a complication of allogeneic bone marrow or peripheral stem cell transplantation and is known to be an unpredictable, life-threatening complication with high mortality. We report here a case of a 24-year-old male patient who was diagnosed in 2019 at Gustave Roussy institute with AML. The patient was treated with the AML protocol 3+7 in December 2019 with a complete cytologic response and a positive MRD. Leukemia relapse was observed in September 2020, treated by gemtuzumab ozogomycin and cytarabine with a negative MRD. A successful allogeneic bone marrow transplantation from an HLA-matched pheno-identical related donor was conducted on December 22, 2020, using a myeloablative conditioning regimen. The patient was always controlled by a daily blood test and controlled blood transfusions, and a weekly repeated Doppler ultrasound examination did not indicate a high-risk profile of VOD. However, 12 days post transplant, the patient's condition deteriorated with the appearance of abdominal ascites, weight gain of 6 kg (per base 76 kg), and liver cytolysis with ASAT 72 UI/L, ALAT 86 UI/L, and normal bilirubin. Worsening cytolysis was observed, with ASAT 659 UI/L, ALAT 557 UI/L, and normal bilirubin. A Doppler ultrasound found 5 positive criteria of VOD (hepatomegaly, portal dilation, enlargement of the gall bladder wall, splenomegaly, ascites, decrease in the diameter of the subhepatic veins). Defibrotide was initiated. The patient's condition worsened and was refractory to medical therapy. Transjugular intrahepatic portosystemic shunting (TIPS) was performed 13 days after transplantation without technical complications in any case. The median hepatic venous pressure gradient prior to the procedure was 20 mmHg with a drop to 12 mmHg. An abdominal CT scan showed an under hepatic hematoma with hemorrhagic syndrome. Ascites puncture with abdominal drain installation was done. In summary, following TIPS, the patient showed clinical improvement, and VOD resolved subsequently with a complete remission post allogeneic transplant.

ABCL-209 Comprehensive Geriatric Assessment as an Important Tool in Elderly Patients diagnosed With Diffuse Large B-Cell Lymphoma

Diffuse large-B cell lymphoma (DLBCL) is the most common type of lymphoma and the most common aggressive B-cell lymphoma. It commonly presents in elderly patients often with comorbidities, not always evaluated with a Comprehensive Geriatric Assessment (CGA). We retrospectively revised the registers of 24 patients above 70 years old diagnosed with DLBCL and treated with R-mini-CHOP protocol between 2018 and 2022 at Gustave Roussy Cancer Campus in France. Data collection was done after reviewing their medical records. Statistical analysis was done using IBM SPSS Statistics. One-third of the patients were women. The median age of all patients was 83 years. Two-thirds of patients had a limited-stage disease. According to IPI score, ten patients had a low risk, whereas five, six, and three patients had a low intermediate, high intermediate, and high risk, respectively. The 1-year progression-free survival rate was 73.7%. Before treatment, 14 patients were assessed with a CGA, of which 71.4% were classified as frail, 28.6% as vulnerable, and 0% as robust. 90% and 80% of unassessed patients had all-grade and grade III-IV toxicities, compared to 50% and 21.4% of assessed patients, respectively. CGA remains an important tool for the management of elderly patients diagnosed with DLBCL.

AML-078 Pain and Anxiety Associated With Bone Marrow Aspiration in Hematologic Patients

Bone marrow aspiration is an essential procedure used to diagnose hematologic malignancies, monitor treatment, and evaluate the response. It is painful and feared by patients but has to be done frequently during the course of the disease. The objective of this study was to assess the degree of pain and anxiety in patients undergoing bone marrow aspiration in order to make it easier and more tolerable. We observed 54 patients admitted for bone marrow aspiration in the outpatient hospital unit of the Department of Hematology in Gustave Roussy Institute in Paris during the month of February 2022. The patients were adults already diagnosed with hematologic malignancies who were undergoing treatment or under surveillance. Each patient filled out a questionnaire before and after the procedure, and another was filled out by the doctor performing the procedure. The Hospital Anxiety and Depression Scale (HADS) was used to evaluate anxiety in patients during this period of their lives. Pain was assessed using the Wong-Baker FACES® pain scale with numbers ranging from zero to 10 and was compared to the patient's expectations. On the other hand, the doctor noted the analgesics used and graded the anxiety and the pain he observed in the patient on a scale of one to 10. The average HADS score was 7.85/21, suggesting a basal anxious state in patients, and anxiety assessed by doctors was 4.7/10. Pain during the procedure averaged 3.25/10 and exceeded expectations in only 2 patients. We can see that anxiety is the main problem in patients undergoing bone marrow aspiration, whereas objective pain is well controlled by analgesics. These results encourage the use of anxiolytics before the procedure to make it more comfortable for patients and doctors.

ABCL-126 Comprehensive Geriatric Assessment in Older Adult Patients Treated With R-Mini-CHOP for Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma (NHL) is more common in older adult patients, and R-mini-CHOP chemotherapy is often the standard treatment protocol. The Comprehensive Geriatric Assessment (CGA) is a key element for better management of these patients. We retrospectively reviewed the records of 35 patients over the age of 70 who received R-mini-CHOP protocol for their NHL between 2018 and 2022 at Gustave Roussy Cancer Campus in France. Patient demographics and disease characteristics were collected. Other data, such as the CGA, were also recorded. The median age of the patients was 83 years [70-102], and 60.0% were men. Diffuse large B-cell lymphoma (68.6%) was the most common type, followed by follicular lymphoma (8.6%), marginal zone lymphoma (8.6%), and others. Twenty-one patients had a CGA before starting chemotherapy. CGA was done in 20% of the patients with a performance status (PS) equal to 0, compared with two-thirds of patients with a PS of 1. One-third of the unassessed patients and half of the assessed patients had a PS of 2. Of the assessed patients, 61.9% had at least one grade III or IV comorbidity; 61.9% were classified as frail, 28.6% as vulnerable, and 9.5% as robust. A total of 82.9% received anthracyclines, of which 90.5% had a CGA and 71.4% did not. Of all patients, 82.9% and two-thirds received the first 3 cycles and completed all protocol cycles, respectively, similarly in both assessed and unassessed patients. One-third of patients had a dose reduction in both groups. All-grade and grade III-IV toxicities occurred in 71.4% and 57.2% of unassessed patients, respectively, versus 47.6% and 28.6% of patients assessed with a CGA. Cardiac toxicities were most frequent (14.3%), along with fatigue. CGA in treatment decisions of older adult patients diagnosed with NHL can reduce toxicities despite patient frailty and without compromising the chemotherapy protocol.

Role of locoregional disease in the definition of radioiodine refractory thyroid cancer

Definition of RAI refractory cancer does not include the cervical lymph nodes (LN) radioiodine (RAI) uptake status. The aim of this study is to assess the outcome and the frequency of distant metastases (DM) and RAI uptake status in patients with non-RAI-avid metastatic LN compared with patients having RAI-avid metastatic LN. A retrospective study of consecutive patients followed in Gustave Roussy institute between 1990 and 2015 who underwent at least one RAI therapy and one cervical LN relapse surgery with Proven pathology. Finding Study cohort consisted of 145 patients [58.6 % females, median age at diagnosis of 38 years, papillary 135 (93 %), median follow-up of 14 years (2–42)]. All patients underwent total thyroidectomy and at least one RAI administration. Seventy-seven (53 %) patients disclosed uptake in neck LN (LN-RAI-pos) and 68 did not have any RAI uptake or disclosed a heterogeneous uptake (overall considered LN-RAI-neg). The risk of structural incomplete response at the last assessment was greater in LN-RAI-neg patients (38 %) compared with LN-RAI-pos patients (13 %) (p 0.0005). LN-RAI-neg was associated with an increased risk of DM compared with patients with LN-RAI-pos (35 % vs 18 % OR 2.4 95 %CI : 1.0747–5.715 ; p 0.024). The risk of occurrence of DM not disclosing RAI uptake was higher in the LN-RAI-neg group compared with the LN-RAI-pos group (58 % vs. 21 %, OR 89.4 95 %CI 6.1202–6154.8943 ; p < 0.0002). LN-RAI-neg status is significantly associated to a worse patient outcome and to the occurrence of DM and RAI-refractory DM.

147P Blind validation of an AI-based tool for predicting distant relapse from breast cancer HES stained slides

147P Blind validation of an AI-based tool for predicting distant relapse from breast cancer HES stained slides

461P Overview of patients inclusions and outcomes into modern phase I trials at Gustave Roussy over the last 5 years, OVATION study

Phase I trials historically involve heavily pretreated patients (pts) with no more effective therapeutic options available and generally with poor expected outcomes (objective response rate (ORR): 9% and mOS: 9.9 mo, Arkenau et. al, BJH 2008). Phase I trials evolved over the past years and are now widely considered. However, there is scare data regarding phase I cancer centers activity and outcomes of pts enrolled into modern phase I trials. Here, we sought to provide an overview of pts inclusions and outcomes into early phase trials at Gustave Roussy (GR) over the last 5 years.

91P Liquid biopsy, a tool to detect genetic alterations with therapeutic impact in international patients: Prospective data on 47 patients from Gustave Roussy

Liquid biopsy (LB), or cell-free DNA analysis (cfDNA), is a novel non-invasive approach to detect molecular alterations (MAs) in cancer patients (pts) allowing personalized therapy. It has been validated in clinical trials, however, the real-world evidence is still in its initial steps. The aim is to evaluate the outcomes of LB in ICP (International cancer pts) with the intention of offering novel treatment options.

767P Refining patients’ selection for immunotherapeutic early-phase clinical trials (ieCTs): A single phase I unit experience

Identifying patients mostly benefitting from ieCTs is of crucial importance in the era of precision medicine. The Gustave Roussy Immune Score (GRImS) identifies two prognostic categories (low risk, 0-1; high risk, 2-3) based on three objective variables: LDH > ULN, albumin < 35 g/dl, NLR>6 and has been proved to work as a good prognostic index. However, no predictive score has been validated to be used in clinical practice so far.

PALLIA 10 score in phase I cancer studies

ObjectivePhase I clinical trials usually include patients with advanced disease who have failed standard therapies and should benefit from early palliative care. We try to assess whether PALLIA 10, a...

Isothermal Rolling Circle Amplification and Lanthanide‐Based FRET for Femtomolar Quantification of MicroRNA

AbstractInvited for this month′s cover are the collaborating groups of Prof. Niko Hildebrandt at Université de Rouen Normandie, France, and Dr. Pierre Busson at Gustave Roussy, France. The cover picture shows a Rolling Circle Amplification (RCA) product formed from a single microRNA and its detection via lanthanide (Tb and Eu) based multicolor FRET. More information can be found in the Research Article by N. Hildebrandt and co‐workers.

ASO Visual Abstract: Changes in the Gustave Roussy Immune Score as a Powerful Prognostic Marker of the Therapeutic Sensitivity of Nivolumab in Advanced Gastric Cancer: A Multicenter, Retrospective Study.

ASO Visual Abstract: Changes in the Gustave Roussy Immune Score as a Powerful Prognostic Marker of the Therapeutic Sensitivity of Nivolumab in Advanced Gastric Cancer: A Multicenter, Retrospective Study.

Changes in the Gustave Roussy Immune Score as a Powerful Prognostic Marker of the Therapeutic Sensitivity of Nivolumab in Advanced Gastric Cancer: A Multicenter, Retrospective Study.

Identification of positive biomarkers for the effects of nivolumab on patients with advanced gastric cancer (AGC) is significant. The Gustave Roussy Immune Score (GRIm-s) is associated with therapeutic resistance of immune checkpoint inhibitors (ICIs) in other cancers. This multicenter, retrospective study was designed to analyze the association of GRIm-s with therapeutic sensitivity of nivolumab in patients with AGC. We reviewed 58 patients with AGC treated with nivolumab from October 2017 to November 2018 at five participating institutions. We performed blood tests before the start of nivolumab and after administration of two courses. We evaluated the correlation between the best overall response and GRIm-s. Additionally, we focused on the changes in GRIm-s before the start of nivolumab and after administration of two courses. Of the 58 patients, 21 (36.2%) were classified into the disease control (DC) group and 37 (63.8%) into the progressive disease (PD) group. GRIm-s before nivolumab treatment did not correlate with the best therapeutic response (p = 0.086). However, GRIm-s after two courses of nivolumab showed that significantly more PD cases were in the high-risk group (p < 0.0001). After two courses of nivolumab, overall survival was significantly worse in the high-risk group (p < 0.0001). For progression-free survival, the high-risk group had a significantly worse prognosis both before (p = 0.04) and after two courses of nivolumab treatment (p < 0.0001). GRIm-s after two courses of nivolumab and its changes compared to pretreatment values proved beneficial in predicting nivolumab sensitivity.

ASO Author Reflections: Changes in the Gustave Roussy Immune Score is an Important Biomarker for Therapeutic Sensitivity of Nivolumab in Gastric Cancer

ASO Author Reflections: Changes in the Gustave Roussy Immune Score is an Important Biomarker for Therapeutic Sensitivity of Nivolumab in Gastric Cancer

First person – Charlotte Canet-Jourdan

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping early-career researchers promote themselves alongside their papers. Charlotte Canet-Jourdan is first author on ‘ Patient-derived organoids identify an apico-basolateral polarity switch associated with survival in colorectal cancer’, published in JCS. Charlotte conducted the research described in this article while a PhD student in Fanny Jaulin's lab at Institut Gustave Roussy, Villejuif, France, and is now a postdoc in the lab of Ana-Maria Lennon-Duménil at Institut Curie, Paris. She is passionate about cancer cell biology and is now investigating the intricate relationships between tumor and immune cells, especially macrophages.

Feasibility, safety and efficacy of human intra-tumoral immuno-therapy. Gustave Roussy's initial experience with its first 100 patients

PurposeMany intratumoural (IT) immunotherapies are currently developed in the clinic with the aim of overcoming primary and secondary resistance and/or to limit on-target/off-tumour toxicities of immune checkpoint targeted therapies. This study aimed to describe the feasibility, safety and efficacy of IT immunotherapy treatments. DesignThis retrospective single-centre study included the first 100 consecutive patients enrolled in Gustave Roussy's Human IntraTumoral-ImmunoTherapy (HIT-IT) program. Patient characteristics, target description, image guidance, safety and response according to iRECIST (Response Evaluation Criteria in Solid Tumours for immunotherapy trials) were recorded. Predictive factors of complications and responses were analysed. Survival was also reported. ResultsFrom 09/2015 to 05/2020, 100 patients had 115 tumours injected during 423 treatment cycles. Most frequent primary tumour arose from the skin (n = 49), digestive track (n = 4) or head and neck (n = 8). Injected tumours’ mean diameter was 37 ± 23 mm, and a median number of 4 IT injections per patient (interquartile range:3–5) were performed. Targeted tumours for IT injections were superficial lymph nodes (36.5%), subcutaneous lesions (25.2%), liver tumours (20.9%) and others (17.4% including tumour sites such as deep lymph nodes or lung). Most patients (72%) received systemic immunotherapy in combination with HIT-IT. Procedure- and drug-related adverse events (AEs) occurred in 11.3% and 33.3% of the treatment cycles, respectively. Only 3 procedure-related AEs were grade-3 (0.7%); and no grade-4 or 5 occurred. Among all cycles, 7 grade-3 and 1 grade-5 drug-related AEs were reported. Complete and partial responses were achieved for 5% and 18% of patients, respectively, while stable disease was the best response for 11%. Patients receiving HIT-IT as a 1st-line treatment (24%), or not previously pre-treated with immunotherapy (53%) responded better, p = 0.001 and p = 0.004, respectively. From 1st cycle of IT, 12-month overall progression-free survival and overall survival were 21% (14–31%) and 57% (47–68%), respectively. ConclusionsThis retrospective study, conducted on patients with cancer and treated within clinical trials at Gustave Roussy, demonstrates the feasibility and safety of the IT immunotherapy strategy.

Abstract 5714: Characterization of SWI/SNF complex gene mutations, protein expression and tumor immune microenvironment in cholangiocarcinoma

Abstract Introduction: Cholangiocarcinoma (CCA) is a rare tumor accounting for less than 2% of all human malignancies. Mutations in the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex have been identified in approximately 20% of all human cancers and more than 40% of CCA. If the role of SWI/SNF on the tumor biology and microenvironment is being uncovered in other tumor types, it remains vastly unknown in CCA. Here, we wanted to investigate, using clinical samples, the association between SWI/SNF defects, the molecular landscape and tumor immune microenvironment in CCA. Material and Methods: Mutation profiling of 103 patients with CCA from Gustave Roussy (GR) was assessed with FoundationOne® CDx 324-gene NGS panel. Formalin-fixed paraffin-embedded tumor tissues from 11 patients with CCA were analyzed for SWI/SNF (PBRM1, ARID1A, SMARCB1 and SMARCA4) and Polycomb-DUB (BAP1) subunits, as well as lymphocytic markers (CD4 and CD8). Stainings were performed using a VENTANA BenchMark ULTRA. Absolute count of positive cells per mm2 was determined by digital image analysis with the Definiens Developer XD™ by selecting at least 5 independent tumoral zones. Pairwise comparisons were performed using the Mann-Whitney test. Results: Among the patients for whom NGS data was available, the most frequently altered genes were TP53 (27%), CDKN2A (17%), KRAS (16%), ARID1A (12%), FGFR2 (12%) and PBRM1 (10%). Subunits of the SWI/SNF complex and BAP1 were mutated in 25% and 10% of cases, respectively. Tumor samples with ARID1A mutations (n=5) showed strongly decreased ARID1A expression compared to WT tumor samples (n=2) (mean = 308.03 positive nuclei (p.n)/mm2 versus 6096.82 p.n/mm2 respectively; P&amp;lt;0.0001) but unchanged PBRM1, SMARCB1 and SMARCA4 expression. PBRM1 mutations (n=4) were associated with decreased expression of PBRM1 (mean = 309.6 p.n/mm2 versus 4980.2 p.n/mm2 in WT samples; P&amp;lt;0.0001) and ARID1A (mean=1196.15 p.n/mm2; P&amp;lt;0.001), but unchanged SMARCB1 and SMARCA4 expression. BAP1 mutations (n=3) were also associated with decreased BAP1 and ARID1A expression (ARID1A mean = 457.70 p.n/mm2; P&amp;lt;0.001). ARID1A and PBRM1-altered tumor samples showed a poorly infiltrated microenvironment, with decreased CD4+ T cell (159.48 positive cells (p.c)/mm2 and 188.66 p.c/mm2 respectively versus 1126.52 p.c/mm2 for WT; P&amp;lt;0.0001) and CD8+ T cell density (72.38 and 76.54 p.c/mm2 versus 548.58 p.c/mm2 for WT; P&amp;lt;0.0001). Conclusion: Mutations in the ARID1A and PBRM1 subunits of the SWI/SNF complex are associated with a loss of protein expression. In contrast to what reported in other tumor types, ARID1A and PBRM1 mutations correlated with poorly lymphocytic TIME in CCA. Decreased PBRM1 expression is further associated with decreased ARID1A expression. Independent revalidation and further study in larger tumor series are warranted. Citation Format: Clémence Astier, Jean-Yves Scoazec, Virginie Marty, Olivia Bawa, Nicolas Signolle, Carine Ngo, Francesco Facchinetti, Antoine Hollebecque, Sophie Postel-Vinay. Characterization of SWI/SNF complex gene mutations, protein expression and tumor immune microenvironment in cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5714.

Abstract 3413: Clinical utility of circulating tumor DNA sequencing with a large panel: The experience of Gustave Roussy/National Center for Precision Medicine (PRISM)

Abstract Background: Circulating tumor DNA (ctDNA) sequencing is a promising approach for testing gene alterations and tailoring therapy in cancer patients given, its limited invasiveness, high sensitivity and potential to comprehensively represent tumor heterogeneity. Here, we report the results from a single-center study conducted at Gustave Roussy (Villejuif, France) where we investigated the impact of comprehensive molecular profiling of ctDNA in patients with advanced solid tumors. Methods: Genomic analysis was performed using the Foundation One Liquid CDx Assay (324 genes, tumor mutational burden [TMB], microsatellite instability status). Each individual genomic report was reviewed and discussed weekly by a multidisciplinary tumor board (MTB) dedicated to precision medicine, attended by experts in clinical oncology, molecular biology, and clinical genetics. Actionable targets were defined by the MTB according to the existing level of evidence (classified by ESCAT tier), and molecular-based treatment suggestions were proposed where possible. Results: Between December 2020 and November 2021, 1772 patients with metastatic solid tumors underwent molecular profiling. Median time to assay results was 12 days. Results were contributive for 1658 patients (94%). At least one actionable target was detected in 1059 patients (64%) with a total of 1825 theragnostic alterations including : high blood TMB (&amp;gt; 16 mutations/Mb) (N= 243, 13%), alteration of the DNA damage repair response pathway (N=336, 18%), PIK3CA mutations (N=150, 8%), FGFR alterations (N= 67, 4%), MET activations (N=13, 0.7%), ERBB family pathway alterations (N=127, 7%) and PTEN mutations (N=95, 5%). Overall, the MTB recommended a matched therapy for 597 patients (56%) with a total of 819 therapeutic orientations: clinical trials (N= 639, 78%), off label/compassionate use (N=81, 10%), drug with a market authorization (N=51, 6%) and drug within an early access program (N=48, 6%). MTB did not recommend treatment for 462 patients (44%) with targetable molecular alterations for the following reasons: no clinical trial (N=421, 65%), matched treatment was already received (N=169, 26%), worsening of performance status (N= 49, 8%). Conclusions: This large-scale study demonstrates that liquid biopsy with a large NGS ctDNA panel is an efficient approach to match patients to genomically directed clinical trials/targeted therapies. Outcomes of patients treated with matched therapy will be presented at the meeting. Citation Format: Arnaud Bayle, Laila Belcaid, Miha Aldea, Florent Peyraud, Patricia Martin Romano, Félix Blanc-Durand, Rebecca Clodion, Santiago Ponce, Claudio Nicotra, Antoine Hollebecque, Yohann Loriot, Benjamin Besse, Damien Vasseur, Ludovic Lacroix, Etienne Rouleau, Jean-Charles Soria, Fabrice Barlesi, Geoffrey R. Oxnard, Fabrice Andre, Antoine Italiano. Clinical utility of circulating tumor DNA sequencing with a large panel: The experience of Gustave Roussy/National Center for Precision Medicine (PRISM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3413.

Abstract CT126: A phase 2 trial of first-line AZD0171 + durvalumab and chemotherapy (CT) in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and CD8+ T cell infiltration

Abstract Background: Leukemia inhibitory factor (LIF) is an immunosuppressive cytokine linked to tumor growth and metastasis. LIF overexpression correlates with poor prognosis and chemoresistance in multiple tumor types including PDAC. Preclinical data show that LIF promotes an immunosuppressive tumor microenvironment, hindering cytotoxic CD8+ T cell recruitment; low T cell infiltration also correlates with mortality in patients with PDAC. Preclinical studies show LIF-blocking antibodies sensitize tumors to PD-1/PD-L1 inhibition, inhibit epithelial-mesenchymal transition, and prolong survival in combination with CT. In patients with PDAC, higher LIF levels correlate with more aggressive pathology, elevated CA19-9 (a PDAC biomarker), and lower response and survival rates. AZD0171 (formerly MSC-1), a first-in-class, humanized, IgG1 monoclonal antibody, binds specifically and potently to LIF, preventing downstream signaling. In a phase 1 dose escalation study (NCT03490669), AZD0171 monotherapy had manageable safety and led to stable disease (SD) in 34.2% of patients with advanced solid tumors across all dose levels. AZD0171 + CT may improve survival outcomes vs CT alone. Based on preclinical data, AZD0171 may function to stimulate antitumor immune response, and combination with the PD-L1 inhibitor durvalumab could prolong that response and overcome peripheral tolerance in patients with metastatic PDAC. Methods: This is a phase 2, open-label, single-arm, multicenter study of AZD0171 + durvalumab and CT in treatment-naive patients with metastatic PDAC (NCT04999969). Eligible patients must have an ECOG performance status 0 or 1, a Gustave Roussy Immune Score 0 or 1, ≥1 measurable target lesion per RECIST v1.1, and confirmed presence of tumoral CD8+ T cells. Patients with central nervous system metastasis, history of leptomeningeal disease or cord compression, a thromboembolic event ≤3 months prior to study treatment, unresolved grade ≥2 toxicities from prior therapy, or a sensitizing mutation or tumor characteristic for which there is a preferred treatment, are excluded. As PDAC is poorly immune infiltrated, a novel clinical trial assay will be used to select for patients who have existing resident CD8+ T cells and may therefore be more likely to respond. About 115 patients will receive intravenous AZD0171, durvalumab and CT until disease progression or unacceptable toxicity. The primary endpoints are safety and overall survival (OS) rate at 12 months. Secondary endpoints include objective response rate, disease control rate (confirmed response or SD ≥16 weeks), duration of response, median progression-free survival (PFS), PFS rate at 4 months, median OS, pharmacokinetics, pharmacodynamics (changes in serum CA19-9 level and tumor CD8+ T cell infiltration) and immunogenicity. The trial is currently recruiting. Citation Format: Grainne O'Kane, Teresa Macarulla, Fiyinfolu Balogun, Antoine Hollebecque, Matthew J. Reilley, Sreenivasa R. Chandana, Jim Eyles, Oluwaseun Ojo, Philip Overend, Douglas C. Palmer, Nadia Luheshi, Mayukh Das, Antoine Italiano, Joan Seoane. A phase 2 trial of first-line AZD0171 + durvalumab and chemotherapy (CT) in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and CD8+ T cell infiltration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT126.