Search

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.

Although the role of epigenetic alterations in oncogenesis has been well studied, their prevalence in metastatic solid tumours is still poorly described. We therefore aimed at: (i) describing the presence of epigenetic gene alterations (EGA) - defined by an alteration in a gene encoding an epigenetic regulator; and (ii) evaluating their relationship with clinical characteristics and outcome in patients (pts) included in prospective molecular profiling trials.On-purpose tumour biopsies from pts with metastatic solid tumours enrolled in the Gustave Roussy-sponsored MOSCATO (NCT01566019) and MATCHR (NCT02517892) trials were molecularly profiled using whole exome sequencing (WES). Alterations in 176 epigenetic genes were assessed and classified as pathogenic variants (PV) or non-pathogenic variants by a molecular tumour board. Clinical characteristics and outcome were collected.Between Dec 2011 and Oct 2016, WES was successfully performed in 292 pts presenting various solid tumours. We found 496 epigenetic gene alterations in 134 patients (49%), including 237 pathogenic variants in 86 patients; 63 tumour samples (47%) presented ≥3 EGAs. The median number of previous treatment lines was 3 (1-10). The most frequently altered genes were KMT2D and KMT2C (16% each), ARID1A and SETD2 (10% each) and KMT2A (8%).; 31% of EGA co-occurred with a driver gene alteration (p amp;lt; 0.001). Outcome was not correlated with the presence of EGA.Epigenetic alterations occur frequently in metastatic solid tumours. With the current development of epigenetic modifiers, they increasingly represent actionable targets. Such genes should now be systematically analysed in molecular profiling studies.

Lysine-specific demethylase 1 (LSD1) inhibitor; Neuroendocrine tumor; Non-Hodgkin lymphoma Tumor neuroendocrino; Linfoma no Hodgkin; Inhibidores de desmetilasa-1 específica a lisina Tumor neuroendocrí; Limfoma no Hodgkin; Inhibidor de la desmetilasa-1 específica a la lisina Background CC-90011 is an oral, potent, selective, reversible inhibitor of lysine-specific demethylase 1 (LSD1) that was well tolerated, with encouraging activity in patients who had advanced solid tumors or relapsed/refractory marginal zone lymphoma. The authors present long-term safety and efficacy and novel pharmacodynamic and pharmacokinetic data from the first-in-human study of CC-90011. Methods CC-90011-ST-001 (ClincalTrials.gov identifier NCT02875223; Eudract number 2015–005243-13) is a phase 1, multicenter study in which patients received CC-90011 once per week in 28-day cycles. The objectives were to determine the safety, maximum tolerated dose, and/or recommended phase 2 dose (primary) and to evaluate preliminary efficacy and pharmacokinetics (secondary). Results Sixty-nine patients were enrolled, including 50 in the dose-escalation arm and 19 in the dose-expansion arm. Thrombocytopenia was the most common treatment-related adverse event and was successfully managed with dose modifications. Clinical activity with prolonged, durable responses were observed, particularly in patients who had neuroendocrine neoplasms. In the dose-escalation arm, one patient with relapsed/refractory marginal zone lymphoma achieved a complete response (ongoing in cycle 58). In the dose-expansion arm, three patients with neuroendocrine neoplasms had stable disease after nine or more cycles, including one patient who was in cycle 46 of ongoing treatment. CC-90011 decreased levels of secreted neuroendocrine peptides chromogranin A, progastrin-releasing peptide, and RNA expression of the blood pharmacodynamic marker monocyte-to-macrophage differentiation–associated. Conclusions The safety profile of CC-90011 suggested that its reversible mechanism of action may provide an advantage over other irreversible LSD1 inhibitors. The favorable tolerability profile, clinical activity, durable responses, and once-per-week dosing support further exploration of CC-90011 as monotherapy and in combination with other treatments for patients with advanced solid tumors and other malignancies. This study was supported by Bristol Myers Squibb, Princeton, New Jersey, USA. Writing and editorial assistance was provided by Bio Connections, LLC, funded by Bristol Myers Squibb.

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.

PURPOSE 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. MATERIAL AND METHODS 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. RESULTS 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 ( P = .0125). CONCLUSION Implementation of ESCAT classification for clinical decision making by Molecular Tumor Board is feasible and useful to better tailor therapies in patients with cancer.

Background: dNLR at the baseline (B), defined by neutrophils/[leucocytes-neutrophils], correlates with immune-checkpoint inhibitor (ICI) outcomes in advanced non-small-cell lung cancer (aNSCLC). However, dNLR is dynamic under therapy and its longitudinal assessment may provide data predicting efficacy. We sought to examine the impact of dNLR dynamics on ICI efficacy and understand its biological significance. Patients and methods: aNSCLC patients receiving ICI at 17 EU/US centres were included [Feb/13-Jun/18]. As chemotherapy-only group was evaluated (NCT02105168). dNLR was determined at (B) and at cycle2 (C2) [dNLR

Immunotherapy with immune checkpoint blockers (ICB) represents a valid therapeutic option in older patients for several solid cancer types. However, most of the data concerning efficacy and adverse events of ICB available are derived from younger and fitter patients. Reliable biomarkers are needed to better select the population that will benefit from ICB especially in older patients who may be at a higher risk of developing immune-related adverse events (irAEs) with a greater impact on their quality of life. The Lung Immune Prognostic Index (LIPI) is a score that combines pretreatment dNLR (neutrophils/[leukocytes − neutrophils]) and lactate dehydrogenase (LDH) and is correlated with outcomes in patients treated with ICB in non-small-cell lung cancer. We aimed to assess the impact of LIPI in ICB outcomes in a dedicated cohort of older patients. The primary objective was to study the prognostic role of LIPI score in patients aged 70 years or above in a real-life population treated with anti-programmed death-(ligand)1 (anti PD-(L)1). dNLR and LDH were collected in a prospective cohort of patients aged 70 years or above treated with PD-(L)1 inhibitors with metastatic disease between June 2014 and October 2017 at Gustave Roussy. LIPI categorizes the population into three different prognostic groups: good (dNLR ≤ 3 and LDH ≤ ULN—upper normal limit), intermediate (dNLR > 3 or LDH > ULN), and poor (dNLR > 3 and LDH > ULN). Anti PD-(L)1 benefit was analyzed according to overall survival (OS), progression free survival (PFS), and overall response rate (ORR) using RECIST v1.1. criteria. In the 191 older patients treated, most of them (95%) were ICB-naïve, and 160 (84%) had an ECOG performance status of 0–1 with a median age at ICB treatment of 77 (range, 70–93). The most common tumor types were melanoma (66%) and non-small-cell lung cancer (15%). The median follow-up duration was 18.8 months (95% CI 14.7–24.2). LIPI classified the population into three different groups: 38 (23%) patients had a good LIPI score, 84 (51%) had an intermediate LIPI score, and 43 (26%) had a poor LIPI score. The median OS was 20.7 months [95% CI, 12.6–not reached] compared to 11.2 months [95% CI, 8.41–22.2] and 4.7 months [95% CI, 2.2–11.3] in patients with a good, intermediate, and poor LIPI score, respectively (p = 0.0003). The median PFS was 9.2 months [95% CI, 6.2–18.1] in the good LIPI group, 7.2 months [95% CI, 5.4–13] in the intermediate LIPI group, and 3.9 months [95% CI, 2.3–8.2] in the poor LIPI group (p = 0.09). The rate of early death (OS < 3 months) was 37% in the poor LIPI group compared to 5% in the good LIPI group (

Aging is an important risk factor for cancers and is associated with poor prognosis. Weakness of the immune system, also called immunosenescence may occur with older age. The impact of aging on efficacy and safety of immune checkpoint blockers, such as anti-programmed death (ligand) PD-(L)1, remains undetermined. This study aims to evaluate the incidence of immune-related adverse events (irAEs) in patients aged 70 years or older than their younger counterparts.Patients with advanced solid tumors treated at Gustave Roussy with an anti-PD-(L)1 monotherapy between June 2014 and October 2017 were prospectively included within the dedicated irAEs pharmacovigilance registry REISAMIC (Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie). The incidence of irAEs of grade ≥II was compared between patients aged ≥70 (old patients, OP) versus patients aged 70 years (young patients, YP) using a chi-squared test. Survivals were estimated using the Kaplan-Meier method.Among the 603 patients treated by anti-PD(L)1, 191 were ≥70 y.o (OP) and 424 70 y.o (YP). The median (range) age of OP and YP were respectively 77 (70-93) and 59 years old (17-69). A total of 165 irAEs occurred in these patients (103 grade II and 58 grade III-IV). The overall incidence of grade ≥II irAEs was higher in OP than in YP (33% versus 25%, p = 0.03). In addition, OP were more prone of having multiples irAEs compared with YP (p = 0.037). Skin toxicities were more frequent in OP than in YP (p = 0.007) but endocrine toxicities were less frequent in OP than in YP (p = 0.044). This higher level of irAEs seems to be responsible for a higher rate of treatment discontinuation in OP (p = 0.2). There was no statistical difference in median time to toxicity, exposure to steroids or survival between the two groups.Although anti-PD-(L)1 immunotherapies remain an acceptable treatment option for older patients, prescribers should be aware that irAEs are more frequent in the elderly. Further translational studies are warranted to better understand the relationship between aging and irAEs.

Background We aimed to determine the safety and efficacy of nintedanib, an oral anti-angiogenic tyrosine kinase inhibitor, in combination with pembrolizumab, an anti-PD1 immunotherapy, in patients with advanced solid tumors (PEMBIB trial; NCT02856425). Methods In this monocentric phase Ib dose escalation cohort, we evaluated escalating doses of nintedanib (Dose level 1 (DL1) = 150 mg bid [bis in die, as twice a day]; DL2 = 200 mg bid, oral delivery) in combination with pembrolizumab (200 mg Q3W, IV). Patients received a 1-week lead-in dose of nintedanib monotherapy prior starting pembrolizumab. The primary objective was to establish the maximum tolerated dose (MTD) of the combination based on dose limiting toxicity (DLT) occurrence during the first 4 weeks. Secondary objectives were to assess the anti-tumor efficacy and to identify the associated immune and angiogenic parameters in order to establish the recommended nintedanib dose for expansion cohorts. Flow cytometry (FC), Immuno-Histo-Chemistry (IHC) and electrochemiluminescence multi-arrays were prospectively performed on baseline & on-treatment tumor and blood samples to identify immune correlates of efficacy. Results A total of 12/13 patients enrolled were evaluable for DLT (1 patient withdrew consent prior receiving pembrolizumab). Three patients at 200 mg bid experienced a DLT (grade 3 liver enzymes increase). Four patients developed grade 1–2 immune related adverse events (irAE). Eight patients died because of cancer progression. Median follow-up was 23.7 months (95%CI: 5.55–40.5). Three patients developed a partial response (PR) (ORR = 25%) and five patients (42%) had durable clinical benefit (DCB), defined as PR or stable disease (SD) ≥ 6 months. At baseline, patients with DCB had higher plasma levels of Tie2, CXCL10, CCL22 and circulating CD4+ PD1+ OX40+ T cells than patients without DCB. Patients with DCB presented also with more DC-LAMP+ dendritic cells, CD3+ T cells and FOXP3+ Tregs in baseline tumor biopsies. For DCB patients, the nintedanib lead-in monotherapy resulted in higher blood CCL3, Tregs and CCR4+ CXCR3+ CXCR5− memory CD4 T cells. After the first pembrolizumab infusion, patients with DCB showed lower IL-6, IL-8, IL-27 plasma levels. Conclusion Nintedanib 150 mg bid is the recommended dose for combination with pembrolizumab and is currently investigated in multiple expansion cohorts. Early tumoral and circulating immune factors were associated with cancer outcome under nintedanib & pembrolizumab therapy. Trial registration ClinicalTrials.gov, NCT02856425. Registered August 4, 2016 — Prospectively registered.

Background Patients with KRAS-mutant cancers have limited treatment options. Here we present a phase I study of JNJ-74699157, an oral, selective, covalent inhibitor of the KRAS G12C isoform, in patients with advanced cancer harboring the KRAS G12C mutation. Methods Eligible patients (aged ≥18 years) who had previously received or were ineligible for standard treatment received JNJ-74699157 once daily on a 21-day cycle. Dose escalation was guided by a modified continual reassessment method. Results Ten patients (100 mg: 9 and 200 mg: 1) were enrolled. Tumor types included non–small cell lung cancer (n = 5), colorectal cancer (n = 4), and carcinoma of unknown primary site (n = 1). The median age was 65 (range: 36-74) years and median treatment duration was 2.91 (range: 0.5-7.5) months. Dose-limiting toxicities of grades 3–4 increased blood creatinine phosphokinase (CPK) were observed in 100 mg and 200 mg dose levels. The most common adverse event was increased blood CPK (6 patients). No significant clinical benefit was observed; the best response was stable disease in 4 patients (40%). Conclusion Based on dose-limiting skeletal muscle toxicities and the lack of efficacy at the 100 mg dose, further enrollment was stopped. The safety profile of JNJ-74699157 was not considered favorable for further clinical development. ClinicalTrials.gov Identifier NCT04006301

Immune checkpoint blockers (ICBs) in combination with antiangiogenic drugs showed synergistic efficacy in several tumour types. New patterns of progression have recently been defined upon treatment with ICB alone including atypical responses such as pseudoprogression (PsPD), dissociated response and hyperprogressive disease (HPD). This study aimed to describe the patterns of response observed in patients treated with combination ICB with antiangiogenic drugs.We conducted a monocentric retrospective analysis of patients (pts) enrolled in phase I trials at Gustave Roussy assessing the combination of ICB and antiangiogenic drugs. Radiological CT scans were centrally reviewed by a senior radiologist according to iRECIST criteria including progressive disease (PD), partial response (PR) and stable disease (SD). HPD was defined as a progression at the first evaluation with a delta tumour growth rate exceeding 50%. PsPD was defined as initial progression followed by stabilisation or decrease of tumour size, DisR as a concomitant size decrease in some tumour lesions and size increase in others. Both PsPD and DisR are defined as atypical responses. Overall response rate included PR and complete response (CR) and disease control rate included PR, CR and SD.Between December 2016 and June 2020, 111 pts were included. The median follow up was 12.8 months (11.3-15.1). The most common tumour types were lung and pleura (20%), kidney (18%) and bladder (17%). The overall response rate and disease control rate were 21.6% (n = 24) and 59% (n = 65), respectively. Twenty-one patients (19%) experienced PD as the best response. PsPD, DisR and HPD were observed in 4 (3.6%), 11 (9.9%) and 7 (6.3%) pts, respectively. DisR and PsPD were associated with longer iProgression Free Survival (median: 6.9 and 18.9 months, respectively) and iOverall Survival (median: 28.4 and 31.1 months, respectively) than a median of SD in immune progression-free survival (median: 4.2 months) and immune overall survival (median: 12.7 months).Patients treated with ICBs and antiangiogenic agents display atypical responses. Survival might be longer in patients with DisR responses and PsPD disease than patients with HPD, PD and SD.

Immunotherapy has dramatically changed the treatment landscape for several tumor types. However, the impact of previous radiotherapy (RT) on response to immunotherapy is still unknown. We report the case of a 58-year-old female diagnosed with a squamous anal cell carcinoma previously treated with RT and having a dissociated response to anti-PD1 agent. An extensive analysis of the immune contexture performed on the tissue collected from both previously RT-treated and RT-untreated lesions confirmed differences on immune microenvironment, highlighting the potential impact of radiotherapy on the immune response.

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.

Aim Despite unprecedented results of anti-programmed death protein (ligand) 1 (PD-(L)1) immune checkpoint inhibitor in the oncology's armamentarium, immune-related adverse events (irAEs) represent a therapeutic hurdle. Currently, there is no consensual recommendation on a routinely monitored biomarker to early detect irAE. Biological markers such as serum creatine phosphokinase (CPK) are commonly used to measure muscular tissue injury. The potential of routine serum CPK monitoring to predict cardiac or neuromuscular irAE in patients treated with immunotherapy remains unknown. Methods In this retrospective study between January 2016 and December 2018 at Gustave Roussy Cancer Campus, 1151 cancer patients treated with anti-PD–(L)1 immunotherapy were systematically monitored with serum CPK measurements before each immunotherapy cycle. We considered significant CPK increases according to Common Terminology Criteria for Adverse Events v5.0 (CTCAEV5) of grade ≥2 severity. Comparisons were performed in patients with immune-related CPK (ir-CPK) elevations symptomatic versus asymptomatic. Results Overall, 53 of 1151 (4.6%) patients showed a CPK increase. Elevations of CPK were deemed to be immunotherapy-related in 31 of 1151 (2.7%) patients. Among them, 12 of 31 (38.7%) patients experienced symptomatic cardiac or neuromuscular irAE, whereas the other 19 of 31 (61.3%) patients remained asymptomatic. In patients with symptomatic irAE, the mean ir-CPK level was higher compared with asymptomatic patients (1271 versus 771 UI/L, P value = 0.02). In the asymptomatic group, all patients experienced a spontaneous resolution of the ir-CPK increase, and none required medical intervention. Conclusion Most patients with immune-related CPK increase remained asymptomatic. The CPK serum increase did not alter the clinical management of asymptomatic patients. The results of this study did not support a significant clinical interest for a systematic routine CPK monitoring in patients amenable to anti-PD-(L)1 immunotherapy.

Mesenchymal–epithelial transition factor (MET) amplification has been suggested either as a de novo or acquired mechanism of resistance to anti-epidermal growth factor receptor (anti-EGFR) therapy. However, even if MET amplification has been widely described in the preclinical setting, only a few clinical data have confirmed the role of MET in the resistance to anti-EGFR treatment. A 60-year-old man presenting cholangiocarcinoma with EGFR amplification had a tumor response to anti-EGFR therapy. A new on-purpose tumor biopsy performed during tumor progression confirmed the known EGFR amplification as well as a new MET amplification. This clinical observation highlights the role of MET amplification as a mechanism of resistance to EGFR inhibitors.

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 (> 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.

105 Background: NRG1 fusions are rare oncogenic drivers that have been identified in a variety of solid tumors. These proteins bind HER3, leading to HER2/HER3 heterodimerization and oncogenic transformation. Zenocutuzumab (MCLA-128; Zeno) is a Biclonics antibody that overcomes HER3 mediated NRG1 (or NRG1 fusion) signaling in tumor cells. Zeno docks on HER2, then binds to and blocks the NRG1 fusion-HER3 interaction and HER3 heterodimerization with HER2. Zeno is being evaluated in patients (pts) with NRG1+ cancer in the ongoing pivotal phase 2 part of the eNRGy study and early access program (EAP). Methods: Pts with NRG1 + solid tumors previously treated with or not candidates for standard therapy, aged ≥ 18 years, with ECOG PS ≤ 2, and measurable (RECIST 1.1) or evaluable disease, were enrolled. NRG1 fusions were determined by next generation sequencing (NGS) before enrollment. Zeno (750 mg IV Q2W) was administered until disease progression or unacceptable toxicity. Tumor imaging was conducted every 8 weeks. The primary endpoint is investigator (INV)-assessed objective response rate (ORR) and secondary endpoints include duration of response (DOR) and safety. Results: As of 12 Jan 2022, 99 pts with NRG1 + cancer (85 eNRGy, 14 EAP) were enrolled. Efficacy was assessed in 73 pts who received ≥ 1 dose of Zeno and who were enrolled as of 12 Jul 2021 to allow for the opportunity to have ≥ 6 months (mo) follow-up and met the criteria for the primary efficacy population. Median age was 59 y (range 22–84), 58% were female, 47%/53% pts had ECOG PS 0/1. Tumor types were non-small cell lung cancer (NSCLC; 41 pts), pancreas cancer (18 pts), breast cancer (5 pts), cholangiocarcinoma (3 pts), colorectal cancer (2 pts), and 4 other tumor types (1 pt each), with a median 2 prior systemic therapies (range 0-9). The most frequent fusion partners were CD74 (27%), SLC3A2 (18%), and ATP1B1 (15%). Among the 71 pts with measurable disease, the INV-assessed confirmed ORR was 34% (90% CI, 25;44), including responses in NSCLC (35%; 14/40 pts), pancreas cancer (39%; 7/18 pts), breast cancer (2/4 pts), and cholangiocarcinoma (1/3 pts). Responses occurred at the first tumor assessment in 20/24 responders, and are ongoing in 13 pts. Treatment is ongoing in 22 pts (13 NSCLC, 6 pancreas, 3 other solid tumors). Median DOR was 9.1 mo (95% CI, 5.2-12.0). Kaplan-Meier estimate of DOR rate at 6 mo was 70%. Among the 208 pts treated with Zeno monotherapy across all dosing schedules in the phase 2 setting, for individual adverse events irrespective of causality, grade ≥ 3 events were reported in

Resume Cibler le systeme immunitaire de l’hote dans le traitement antitumoral a maintenant fait ses preuves dans de nombreux types tumoraux. Cependant le role de cette approche reste plus controverse dans les glioblastomes et de nombreux essais sont en cours pour determiner l’efficacite de l’immunotherapie dans cette indication. Le systeme nerveux central a longtemps ete considere comme un sanctuaire immunitaire mais de recents travaux ont montre la presence de reponses immunitaires meme en l’absence d’effractions au niveau de la barriere hemato-encephalique. Mieux comprendre le fonctionnement du systeme immunitaire permettra de developper des strategies therapeutiques efficaces. Les objectifs de cette revue sont de decrire le systeme immunitaire au sein du systeme nerveux central et d’evaluer les strategies therapeutiques en cours dans les glioblastomes.

Background: Baseline steroids before ICI have been associated with poor outcomes, particularly when introduced due to cancer symptoms. Methods: Retrospective analysis of advanced NSCLC patients treated with ICI. We collected the use of intercurrent steroids (&ge, 10 mg of prednisone-equivalent) within the first eight weeks of ICI. We correlated steroid use with patient outcomes according to the indications. Results: 413 patients received ICI, 299 were steroids-na&iuml, ve at baseline. A total of 49 patients received intercurrent steroids (16%), of whom 38 for cancer-related symptoms and 11 for other indications, such as immune-related events. Overall, median (m) progression-free survival (PFS) was 1.9 months (mo.) [95% CI, 1.8-2.4] and overall survival (OS) 10 mo. [95% CI, 8.1&ndash, 12.9]. Intercurrent steroids under ICI correlated with a shorter PFS/OS (1.3 and 2.3 mo. respectively, both p &lt, 0.0001). Intercurrent steroids for cancer-related symptoms correlated with poorest mPFS [1.1 mo., 95% CI, 0.9&ndash, 1.5] and mOS [1.9 mo., 95%CI, 1.5&ndash, 2.4, p &lt, 0.0001)]. No mOS and mPFS differences were found between cancer-unrelated-steroid group and no-steroid group. Steroid use for cancer-related symptoms was an independent prognostic factor for poor PFS [HR 2.64, 95% CI, 1.2&ndash, 5.6] and OS [HR 4.53, 95% CI, 1.8&ndash, 11.1], both p &lt, 0.0001. Conclusion: Intercurrent steroids during ICI had no detrimental prognostic impact if the indication was unrelated to cancer symptoms.

Purpose: Lysine-specific demethylase 1 (LSD1) is implicated in multiple tumor types, and its expression in cancer stem cells is associated with chemoresistance. CC-90011 is a potent, selective, and reversible oral LSD1 inhibitor. We examined CC-90011 in advanced solid tumors and relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). Patients and Methods: CC-90011-ST-001 (NCT02875223; 2015-005243-13) is a phase I, multicenter, first-in-human dose-escalation study. Nine dose levels of CC-90011 (1.25–120 mg) given once per week were explored. Primary objectives were to determine safety, maximum tolerated dose (MTD), and/or recommended phase II dose (RP2D). Secondary objectives were to evaluate preliminary efficacy and pharmacokinetics. Results: Fifty patients were enrolled, 49 with solid tumors (27 neuroendocrine tumors/carcinomas) and 1 with R/R NHL. Median age was 61 years (range, 22–75). Patients received a median of three (range, 1–9) prior anticancer regimens. The RP2D was 60 mg once per week; the nontolerated dose (NTD) and MTD were 120 mg once per week and 80 mg once per week, respectively. Grade 3/4 treatment-related toxicities were thrombocytopenia (20%; an on-target effect unassociated with clinically significant bleeding), neutropenia (8%; in the context of thrombocytopenia at the highest doses), and fatigue (2%). The patient with R/R NHL had a complete response, currently ongoing in cycle 34, and 8 patients with neuroendocrine tumors/carcinomas had stable disease ≥6 months, including bronchial neuroendocrine tumors, kidney tumor, and paraganglioma. Conclusions: CC-90011 is well tolerated, with the RP2D established as 60 mg once per week. The MTD and NTD were determined to be 80 mg once per week and 120 mg once per week, respectively. Further evaluation of CC-90011 is warranted.

Background Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy (CT) are the current standard of therapy in several cancer types. Patients (pts) with lung cancer display higher response rates to CT when given after ICIs. Although ICIs have failed to demonstrate antitumour activity in microsatellite stable (MSS) metastatic colorectal cancer (mCRC), little is known about CT effect after ICIs. We aimed to assess whether sequential ICIs followed by CT may be an alternative therapeutic approach in a population of pts with mCRC. Material and methods We retrospectively assessed CT after ICI (CAICI) failure in pts with mCRC. The ICI regimen consisted of anti-PD(L)1 alone or in combination. The primary end-point was objective response rate. Progression-free survival (PFS) and overall survival (OS) were secondary end-points. Results Between 2014 and 2018, 29 pts with mCRC received CAICI (MSS tumours, 27 pts [86%]). The median number of previous lines was 4 (range, 2–7). Regimens included TAS-102 (n = 14), FOLFIRI (irinotecan, leucovorin, and fluorouracil; n = 6) or FOLFOX (oxaliplatin, leucovorin, and fluorouracil; n = 4), regorafenib (n = 3) and carboplatin (1 pt with BRCA mutation). Partial response and stable disease were observed in 4 (19%) and 9 (43%) pts, respectively (disease control rate, 62%). The median PFS and OS were 3.8 months (95% confidence interval [CI] = 1.5–5.4) and 8.0 months (95% CI = 4.2–14.0), respectively. Conclusion ICIs administered before CT might enhance cytotoxic effects even in pts with immunorefractory MSS mCRC. The results of this small cohort need to be validated in independent prospective cohorts. The role of ICIs as modifiers of both tumour cells and microenvironment in mCRC deserves further research.

Background This is the first-in-human study of novel anti-angiopoietin-2 (Ang-2) monoclonal antibody LY3127804 as monotherapy and in combination with ramucirumab in advanced solid tumours. Methods Patients received intravenous LY3127804 monotherapy (4, 8, 12, 16, 20 and 27 mg/kg) in part A; LY3127804 (8, 12, 16, 20 and 27 mg/kg) with 8 mg/kg ramucirumab in part B; and LY3127804 (20 mg/kg) with 12 mg/kg ramucirumab in part C. Treatments were administered every 2 weeks (Q2W) during 28-day cycles. Dose-escalation was based on cycle 1 dose-limiting toxicities (DLTs). Results Sixty-two patients were treated in part A (n = 20), part B (n = 35) and part C (n = 7). Constipation, diarrhoea and fatigue were the most common treatment-emergent adverse events (TEAEs) in part A; hypertension and peripheral oedema were the most frequent TEAE in parts B and C. No DLT was observed and maximum tolerated dose for LY3127804 was not reached. Four patients achieved partial response with combination therapy (clear cell endometrial carcinoma, cervix squamous cell carcinoma, carcinoma of unknown primary and gastroesophageal junction carcinoma), 29 achieved stable disease, and 24 had progressive disease. Conclusions LY3127804 monotherapy and its combination with ramucirumab are well tolerated. LY3127804 20 mg/kg was the recommended Phase 2 dose.

Purpose We investigated the activities of an ImmunoTOX board, an academic, multidisciplinary group of oncologists and organ specialists that adopts a real-life, case-by-case approach in the management of patients with immune-related adverse events (irAEs). Experimental design The ImmunoTOX assessment board was set up in 2016 at Gustave Roussy in France. It meets every 2 weeks to discuss the case-by-case management of patients presenting with irAEs. Here, we describe the ImmunoTOX board's activities between 2016 and 2019. Results Over study period, 398 requests (concerning 356 patients) were submitted to the ImmunoTOX board. Most of the requests concerned the putative causal link between immunotherapy and the irAE (n = 148, 37%), followed by possible retreatment after temporary withdrawal because of an adverse event (n = 109, 27%), the clinical management of complex situations (n = 100, 25%) and the initiation of immunotherapy in patients with pre-existing comorbidities (n = 41, 10%). The ImmunoTOX board discerned 273 irAEs. The five organ systems most frequently involved by irAEs were lung (n = 58, 21%), gastrointestinal tract (n = 36, 13%), liver or biliary tract (n = 33, 12%), musculoskeletal system (n = 27, 10%), and nervous system (n = 23, 8%). The time to occurrence was shorter for severe irAEs (grade III and VI) than for mild irAEs (grades I and II), with medians of 47 and 91 days, respectively (p = 0.0216). Conclusion The main medical needs in the management of irAEs involved the lung organ. Severe irAEs were expected to occur earlier than mild irAEs. This real-life study can help to better estimate medical needs and therefore help to assess the management of irAEs.

Background PD(L)1 antibodies (anti‐PD(L)‐1) have been a major breakthrough in several types of cancer. Novel patterns of response and progression have been described with anti‐PD(L)‐1. We aimed at characterizing pseudoprogression (PSPD) among patients with various solid tumor types treated by anti‐PD(L)‐1. Methods All consecutive patients (pts) enrolled in phase 1 trials with advanced solid tumors and lymphomas treated in phase I clinical trials evaluating monotherapy by anti‐PD(L)‐1 at Gustave Roussy were analyzed. We aimed to assess prevalence and outcome of PSPD across tumor types. We also intended to describe potential clinical and pathological factors associated with PSPD. Results A total of 169 patients treated with anti‐PD(L)‐1 were included in the study. Most frequent tumor types included melanoma (n = 57) and non‐small cell lung cancer (n = 19). At first tumor evaluation 77 patients (46%) presented with immune unconfirmed progressive disease. Six patients (8%) experienced PSPD: 2 patients with partial response; 4 patients with stable disease. Increase in target lesions in the first CT‐scan was more frequently associated to PSPD (67% vs 33%; P = .04). Patients with a PSPD had a superior survival when compared to patients progressing (median OS: 10.7 months vs 8.7 months; P = .07). Conclusions A small subset of PSPD patients may experience response after an initial progression. Assessment of the current strategy for immune‐related response evaluations may require further attention., PD(L)1 antibodies (anti‐PD(L)‐1) have been a major breakthrough in several types of cancer. Novel patterns of response and progression have been described with these therapies. We aimed at characterizing pseudoprogression (PSPD) among patients with various solid tumor types treated by anti‐PD(L)‐1

In the expansion part of an ongoing phase 1 study, MCLA-158 is being investigated at the recommended phase 2 dose (RP2D) in patients (pts) with advanced solid tumors, including head and neck squamous cell carcinoma (HNSCC). Epidermal growth factor receptor (EGFR) and WNT signaling are known oncogenic and mitogenic drivers in several cancers, including HNSCC. MCLA-158 is a human common light chain IgG1 bispecific antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) activity. It targets EGFR and the leucine-rich, repeat-containing, G-protein coupled receptor 5 (LGR5), a transmembrane receptor associated with tumor initiating cells, particularly cancer stem cells. Potent antitumor activity was seen with MCLA-158 in pt-derived HNSCC xenograft models. The RP2D of MCLA-158 was determined to be 1500 mg every 2 weeks (q2w), with 4-week cycles, during the dose escalation part of the study, based on safety, PK and receptor occupancy prediction. A maximum tolerated dose was not reached. The primary objective of the expansion part is to characterize the safety and tolerability of single-agent MCLA-158 and confirm the RP2D. Secondary objectives include assessment of antitumor activity (investigator-assessed overall response rate [ORR] per RECIST 1.1 and duration of response). Key eligibility criteria include prior exposure to standard therapy, ECOG performance status (PS) 0-1, measurable disease (RECIST 1.1), and availability of a baseline tumor biopsy. At the interim data cutoff date of 15 June 2021, 7 pts with advanced recurrent/metastatic HNSCC were enrolled and treated in the expansion phase. Median age was 63 years (range 50-74), ECOG PS 0/1: 2/5. Primary tumor locations were oropharynx (2 pts), hypopharynx (1 pts), larynx (3 pts), and unknown primary (1 pt). All pts had a histology of squamous cell carcinoma. Prior treatment included platinum-based chemotherapy in all pts, and anti-PD-1/PD-L1 in 6 pts. No pts received prior cetuximab. A median of 3 treatment cycles (range 1-8) were administered to the 7 pts, 4 of whom were continuing with therapy at the cutoff. Of the 5 pts who had a postbaseline assessment, 2 had confirmed partial responses (5+ and 8 cycles initiated), and 2 pts had stable disease (reduction in the sum of target lesions of 7% and 17%; 4+ and 5 cycles initiated, respectively). Scheduled first postbaseline tumor assessments for 2 pts occurred after the data cutoff date. Among 26 pts who were treated at the RP2D in the dose escalation and expansion cohorts, the most frequent adverse events regardless of causality (all grades/grade 3) were infusion-related reactions (73%/8%), rash (39%/0%), asthenia (35%/4%), decreased appetite (27%/4%), nausea (27%/4%), and acneiform dermatitis (23%/4%). There were no treatment-related grade 4 or 5 adverse events. In conclusion, MCLA-158 shows promising signs of antitumor activity in pretreated HNSCC, and a well-tolerated and favorable safety profile. Citation Format: Antoine Hollebecque, Irene Brana, Lara Iglesias, Caroline Even, Kato Shumei, Marc Díez García, Mateo Bover, Patricia Martin-Romano, Rocio Garcia-Carbonero, Guillen Argilés, Josep Tabernero, Rajan Khanna, Viktoriya Stalbovskaya, Jeroen Lammerts van Bueren, Kees Bol, Mohamed Bekradda, Andrew Joe, Ernesto Wasserman, Ezra E.W. Cohen. Preliminary antitumor activity of MCLA-158, an IgG1 bispecific antibody targeting EGFR and LGR5, in advanced head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P185.

23 Background: Early phase clinical trials usually include patients (pts) with advanced disease who have failed to standard therapies. Early palliative care (EPC) for these pts has shown to improve quality of life and even survival. Pallia 10 score (from 1 to 10) is a tool developed by the French Palliative Care Society to identify the best time to introduce palliative care. Methods: We assessed the Pallia 10 score and other prognostic factors (age, ECOG, Royal Marsden Hospital (RMH) score, LDH and albumin levels, number (nb) of prior systemic treatments and metastatic sites) in pts enrolled in phase I trials (P1CT) prospectively during 2 periods of time (cohort 1 (C1) and 2 (C2)). A double-blind assessment of the Pallia 10 score was done during 15 days by a member of the palliative care unit in C2. A Pallia 10 > 3 motivated a dedicated palliative care consultation. Results: From 01/07/2018 to 01/11/2018 (C1) and from 01/12/2020 to 16/04/2021 (C2), a total of 85 pts were assessed in C1 and 302 in C2. Gastro-intestinal (23%), hematological (14%) and lung (11%) cancer were the most frequent tumor types. Pallia 10 score and prognostic factors were similar between both cohorts (Table). On C1 and C2, 12% and 4% of pts had a dedicated palliative consultation with median time of referral of 18 and 2 months (m) after the P1CT onset (p = 0.003), with a median Pallia 10 score of 1.5 and 2 (p = 0.65), respectively. Overall, 75% and 76% of pts in C1 and C2 were still alive beyond 3m after discontinuation of the P1CT (p = 0.91), followed by at least one subsequent treatment in 56% and 54% of pts. In C2, assessment of Pallia 10 score was significantly different between palliative care physician (median 5, range 3-8), phase I physician (median 1, range 1 -6) and phase I nurse (median 3, range 1-8) (p < 0.001). Conclusions: Only a few patients included in P1CT were referred to the palliative care unit. Median Pallia 10 score was low when assessed by the phase I physician which suggests the need for a better tool to implement EPC in clinical practice and trials.[Table: see text]

BACKGROUND: Preliminary data has highlighted inherited predisposition to lung cancer related to certain genes. The frequency of pathogenic germline variants (PGV) PGV in patients (pts) with lung cancer according to the presence of an oncogenic driver is unknown. We studied the PGV of genes predisposing to cancer in pts with non-small cell lung cancer (NSCLC), and the somatic molecular profile of lung tumors. METHODS: Retrospective study of whole exome sequencing (WES) from tissue biopsies performed in pts with advanced NSCLC enrolled, after signature of the inform consent, in the MOSCATO/MATCH-R trials between 2012 and 2018. Variants were considered as PGVs in the cancer predisposing genes (PMID: 29625052) if they satisfied the following criteria: (i) they had a “PASS” flag in HaplotypeCaller, (ii) were annotated as “Pathogenic” or “Likely Pathogenic” in ClinVar (PMID: 29165669) or InterVar (PMID: 28132688), or (iii) were truncating variants. Somatic driver mutations and Loss of Heterozygocity (LOH) of PGV harboring genes were further evaluated. The overlap to loss of heterozygocity regions was reported only when the variant allele frequency of the PGV was significantly higher than in the normal tissue. Cancer history, clinical and molecular data were retrospectively collected. The somatic mutations (m) in EGFR/BRAF/MET/HER2/KRAS and fusions in ALK/ROS1/RET were also considered for analysis. RESULTS: Among 134 pts, 48% were women, median age was 61 (range 24-83), 45% were nonsmokers, 74% had adenocarcinoma. The most common somatic oncogenic driver alterations were: EGFRm in 44 pts (33%), KRASm in 19 pts (14%), BRAFm in 12 pts (9%) and ALK in 12 pts (9%).PGV were found in 22 out of 152 (15%) cancer-predisposing genes; 4 pts had additional somatic mutations (2) or LOHs (2) in the same genes. 77% of PGVs were in genes which are part of DNA repair pathways including 3.6% nucleotide excision repair (ERCC1/2/3, XPA), 6.5% homologous recombination/Fanconi Anemia: (FANC/A/C/M/D2, BRCA1, RECQL), 2.1% base excision repair (MUTYH, NTHL1), while the others were represented by genes related to cell signaling and metabolism (NF1, MET, ELANE, PRDM9, TRIM37).In the 22 PGV-carriers, 68% had a somatic oncogene-driven alteration (15/22) : EGFRm (n=7; 5 ex19del, 2 ex21(L858R)), KRASm (n=3; 2 G12D, 1 G12V), METm (n=2), HER2m (n=1), ROS1 (n=1) and RET (n=1). PGV were observed in 16% of EGFRm (7/44), 67% of METm (2/3), 15% in KRASm (3/19), 33% of HER2m (1/3), 25% of ROS1 (1/4), 50% of RET (1/2); but no PGV was identified in pts with BRAFVm (12) or ALK (12). CONCLUSION: In our cohort, 15% of pts with NSCLC were PGV-carriers; 68% of PGV-carriers had oncogene-driven tumors, particularly with somatic EGFR mutations. PGV and oncogene-driven lung carcinogenesis need further evaluation. Citation Format: Laura Mezquita, Andrei Iurchenko, Jose Carlos Benitez, Maria Baz, Sergey Nikolaev, David Planchard, Felix Blanc-Durand, Mihaela Aldea, Patricia Martín-Romano, Yohann Loriot, Claudio Nicotra, Maud Ngocamus, Jean-Yves Scoazec, Stefan Michiels, Sophie Postel-Vinay, Julien Viot, Luc Friboulet, Antoine Italiano, Fabrice Andre, Christophe Massard, Jean-Charles Soria, Etienne Rouleau, Daniel Gautheret, Benjamin Besse. High prevalence of pathogenic germline variants in patients with oncogene-driven non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 448.

3003 Background: NRG1 fusion proteins are oncogenic drivers in pancreas cancer and other solid tumors. They bind HER3, leading to HER2/HER3 heterodimerization and oncogenic transformation. The activity of zenocutuzumab (MCLA-128; zeno), a bispecific antibody targeting NRG1 fusion signaling in NRG1 fusion positive ( NRG1+) cancers, is being evaluated in the ongoing global multicenter phase 2 part of the eNRGy study and a global early access program (EAP). Methods: Enrolled patients (pts) have advanced NRG1+ pancreas cancer, non-small cell lung cancer (NSCLC), and other solid tumors previously treated with standard therapy, are ≥ 18 years-old, have ECOG ≤1, adequate organ function, and measurable disease (RECIST v1.1). Zeno dosing: 750 mg IV every 2 weeks until progression or unacceptable toxicity. Primary endpoint: investigator (INV)-assessed objective response rate (ORR). Secondary endpoints: ORR per central independent radiologist review, duration of response (DOR), and safety. Tumor imaging is conducted every 8 weeks. Results: 51 pts with NRG1+ cancer have received zeno, 37 in the eNRGy study and 14 pts in the EAP. As of 12 Jan 2021, treatment is ongoing in 27/51 pts (8/13 pancreas, 10/25 NSCLC, 9/13 other solid tumors). Among the 51 pts, 10 pts with pancreas cancer, 18 pts with NSCLC, and 5 pts with other solid tumors had measurable disease and had the opportunity for ≥1 tumor assessment (TA) and are included in this analysis. Among the 10 pts with pancreas cancer, median age was 49 y (range 34-72), 50% were male, 6/4 pts had ECOG 0/1, and all had metastatic disease and were KRAS wild-type. The median number of prior therapies was 3 (range 1-6). The INV-assessed confirmed ORR was 40% (4/10; 90% CI, 15;70), and for this cohort of pts, responses occurred at the first TA. Tumor regression was seen in 7/10 pts, and the disease control rate was 90% (90% CI, 61-100). A CA 19-9 decline of ≥ 50% was observed in 9/9 (100%) pts. DOR is pending. In the overall NRG1+ population, tumor regression was observed in 25 of 33 pts and confirmed INV-assessed responses were seen in 9 of 33 pts (ORR 27%; 90% CI, 15;43), including in pts who previously received afatinib. Zeno was well tolerated with no pts requiring dose reduction for toxicity. Across all cohorts, for individual AEs, grade 3 events were reported in ≤5% of pts, and there was a notable lack of cardiotoxicity and severe gastrointestinal or skin toxicity. Updated data from all cohorts (pancreas, NSCLC, other solid tumors) will be presented. Conclusions: Zeno induces rapid and major radiologic tumor regression and biomarker responses in heavily-pretreated metastatic KRAS wild-type NRG1+ pancreas cancer, with minimal toxicity. Zeno is a promising novel targeted therapeutic option for pts with NRG1+ cancers. Clinical trial information: NCT02912949.

International audience; BACKGROUND:Paraneoplastic syndromes (PNS) are autoimmune disorders specifically associated with cancer. There are few data on anti-PD-1 or anti-PD-L1 immunotherapy in patients with a PNS. Our objective was to describe the outcome for patients with a pre-existing or newly diagnosed PNS following the initiation of anti-PD-1 or anti-PD-L1 immunotherapy.METHODS:We included all adult patients (aged ≥18) treated with anti-PD-1 or anti-PD-L1 immunotherapy for a solid tumor, diagnosed with a PNS, and registered in French pharmacovigilance databases. Patients were allocated to cohorts 1 and 2 if the PNS had been diagnosed before vs. after the initiation of immunotherapy, respectively.FINDINGS:Of the 1304 adult patients screened between June 27th, 2014, and January 2nd, 2019, 32 (2.45%) had a PNS and were allocated to either cohort 1 (n = 16) or cohort 2 (n = 16). The median (range) age was 64 (45-88). The tumor types were non-small-cell lung cancer (n = 15, 47%), melanoma (n = 6, 19%), renal carcinoma (n = 3, 9%), and other malignancies (n = 8, 25%). Eleven (34%) patients presented with a neurologic PNS, nine (28%) had a rheumatologic PNS, eight (25%) had a connective tissue PNS, and four (13%) had other types of PNS. The highest severity grade for the PNS was 1-2 in 10 patients (31%) and ≥ 3 in 22 patients (69%). Four patients (13%) died as a result of the progression of a neurologic PNS (encephalitis in three cases, and Lambert-Eaton syndrome in one case). Following the initiation of immunotherapy, the PNS symptoms worsened in eight (50%) of the 16 patients in cohort 1.INTERPRETATION:Our results show that PNSs tend to be worsened or revealed by anti-PD-1 or anti-PD-L1 immunotherapy. Cases of paraneoplastic encephalitis are of notable concern, in view of their severity. When initiating immunotherapy, physicians should carefully monitor patients with a pre-existing PNS.

Background: The degree of histopathological response after neoadjuvant therapy in locally advanced gastric cancer (GC) is a key determinant of patients' long-term outcome. We aimed to assess the pattern of histopathological regression after two neoadjuvant approaches and its impact on survival times. Methods: Regression grade of the primary tumour (Becker criteria) and the degree of nodal response by a 4-point scale (grades A–D) were assessed. Grade A—true negative lymph nodes (LNs); grade B and C—infiltrated LNs with any or little evidence of nodal response; and grade D—complete pathological response in a previously infiltrated LN. A favourable pathological response was defined as Becker Ia–b and grade D. Results: From 2004 to 2014, 80 patients with GC (cT3–4/N+ by CT-scan/EUS) were treated with either preoperative chemotherapy (ChT, n=34) or chemoradiation (CRT, n=46). Patients in the CRT group had a higher likelihood of achieving a Becker Ia–b response (58 vs 32%, P=0.001), a grade D nodal regression (30 vs 6%, P=0.009) and a favourable pathological response (23 vs 3% P=0.019). Patients with a grade D nodal response had a longer 5-year PFS and OS compared with those with a grade B or C response. Patients with a baseline negative LN status had similar outcomes irrespective of the preoperative therapy received (5-year OS; ChT vs CRT, 58 vs 51%, P=0.92). Conclusions: Preoperative chemoradiation increases the likelihood of achieving favourable histopathological features that correlate with a 5-year OS>70% in GC patients.

Introduction: Higher levels of TILs after neoadjuvant chemotherapy (NAC) in the residual tumor have been related to a better outcome in BC patients. According to International TILs working group (2014), we have quantified stromal TILs in a cohort of patients treated with NAC plus dendritic cell vaccines (cohort V) (NCT01431196 plus an expanded cohort) and in an historic cohort of patients treated with the same NAC without V (cohort C) in order to assess if the addition autologous dendritic cell vaccination pulsed with patient´s tumor lysates helps to increase TILs in the residual BC specimen. Our previous data with these cohorts of patients have shown an improved pCR and the stimulation of lymphocytes population in the peripheral blood from cohort V. Methods: Classification of molecular subtypes was performed by IHC. We evaluated percentage of TILs by three different pathologists using stained HE core biopsy sections in paired samples taken at diagnosis (preNAC) and after surgery (postNAC) in a prospectively defined retrospective analysis. Results: 79 patients were evaluated (cohort C 42; cohort V 37). Patients from V cohort were younger (p=0.01). Cohorts were well balanced for AJCC staging, molecular subtypes (cohort C: LA 26%, LB 45%, TN 29%; cohort V: LA 24%, LB 40%, TN 35%), stromal TILs preNAC [cohort C: median 9 (range, 1-24); cohort V: 6 (1-34); p=0.38] and stromal TILs postNAC [cohort C: 9 (2-52); cohort V 8 (4-50); p=0. 94]. Seventy-seven patients (97%) underwent surgery (cohort C 41; cohort V 36). Pathologic CR was higher in Cohort V (27% vs 7%; p=0.02). However a superior pCR rate was detected in TNBC subtype (cohort C 27%; cohort V 58%; p=0.15). Patients from Cohort V experienced an increment of stromal TILs after NAC plus autologous dendritic cell vaccination (preNAC: 6 (1-34); postNAC 8 (4-50); p=0.03), especially in TNBC [preNAC 14 (1-34); postNAC 30 (10-50); p=0.2]. A correlation analysis by Pearson´s R coefficient stated a strong association in V cohort between stromal TILs preNAC and postNAC (R=0.83) as well as a moderate correlation between stromal TILs postNAC and and molecular subtypes (R=0.6). Table 1. Differences in Stromal TILs between studied cohorts PreNAC (median, range)PostNAC (median, range)P valueCohort C9 (1-66)9 (2-52)0.22Cohort V6 (1-34)8 (4-50)0.03*Cohort C LA LB TN5 (1-10) 9 (1-24) 12 (10-24)6 (3-12) 10 (2-40) 13 (5-52)0.69 0.17 1Cohort V LA LB TN5 (2-17) 6 (1-15) 14 (1-347 (4-12) 7 (4-27) 30 (10-50)0.18 0.08 0.2 Conclusion: Pathological complete responses were higher in BC patients treated with neoadjuvant chemotherapy plus active immunotherapy. The addition of autologous dendritic cell vaccines to NAC increases significantly stromal TILs in breast cancer patients. Citation Format: Baraibar I, Martin-Romano P, Mejías L, Perez Solans B, Ceniceros L, Legazpi J, Gardeazabal I, Inoges S, Lopez-diaz A, Idoate M, Cordoba A, Santisteban M. Increased stromal lymphocytes in breast cancer patients with autologous dendritic cell vaccination plus neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-04-01.

Introduction: Precision medicine has shown to improve outcomes of cancer patients by identifying oncogenic alterations and actionable mutations. Yet, most tests perform DNA sequencing and are not able to discriminate which tumor driving signaling pathways (SP) are functionally active. OncoSignal pathway analysis tests quantitatively measure activity of SP such as estrogen receptor, androgen receptor, PI3K, MAPK, TGF-β, Notch on fresh frozen and formalin-fixed paraffin-embedded (FFPE) tissue samples, while mutation analysis provides complementary information related to the genomic alteration in the SP. Combined information is expected to improve choice of the optimal effective targeted therapy to improve patients' outcome and quality of life as well as to reduce unnecessary side effects/costs due to unnecessary therapy. In this study OncoSignal pathway analysis was performed on a series of samples from the Moscato trial (1), with the aim of assessing clinically actionable SP activity. Methods: OncoSignal pathway analysis (ER, AR, PI3K, MAPK, HH, Notch, TGF-β) was performed blinded by Molecular Pathway Dx (Philips, Eindhoven) on tumor tissue samples from 5 breast and 31 prostate tumors, all proven to be hard to treat and obtained from the Moscato study. Results were sent back to Institut Gustave Roussy for clinical annotation and analysis. For breast and prostate cancer, pathway activity scores were determined for each SP in healthy breast (n=7) and prostate (n=9) tissues (GEO datasets: GSE17951 and GSE10780) and compared with pathway activity scores in cancer tissue samples (multiple GEO datasets: n=133 and n=1712). Increased activity of a pathway in cancer tissue (>95th percentile of healthy tissue pathway activity) was considered as tumor-driver function for the respective pathway and thus clinically actionable. Subsequently, for each individual Moscato sample, alterations were considered as tumor driving pathways if the sample pathway activity score exceeded the 95th percentile of normal (primary) tissue pathway activity. Results: Identified tumor driving SP in breast cancer were ER, AR, MAPK-AP1, HH, and PI3K pathway whereas in prostate cancer identified SP were the AR and PI3K pathway. Of the 5 breast cancer metastasis samples (lung, head/neck, skin, liver, lymph node; average tumor content 40%), all had at least one clinically actionable tumor driving pathway. Of the 30 prostate cancer metastasis samples (bone, liver, lymph nodes; average tumor content 62%), 29 (97%) had a clinically actionable tumor driving pathway. Conclusion: OncoSignal pathway analysis enabled identification of clinically potentially actionable signaling pathway activity in 97-100% of analyzed breast and prostate cancer samples. Citation Format: Patricia Martin-Romano, Sieglinde Neerken, Anja Van de Stolpe, Eveline Den Biezen-Timmerman, Maud Ngo, Claudio Nicotra, Martijn Akse, Alexander Eggermont, Paul Van de Wiel, Christophe Massard, Fabien Calvo. First results of the EIT PACMAN Study: OncoSignal pathway analysis to identify clinically actionable signal transduction pathway activity in a variety of cancer types [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1331.

Background: Homozygous deletion of MTAP, the gene encoding the metabolic enzyme methylthioadenosine phosphorylase, occurs in ~15% of human malignancies. Tumor cells with this deletion are selectively vulnerable to decreases in the methyl donor S-adenosylmethionine (SAM). AG-270 is a first-in-class, oral, potent, reversible inhibitor of methionine adenosyltransferase 2A (MAT2A), the key enzyme responsible for SAM synthesis. We report preliminary results from an ongoing, first-in-human, phase 1 trial of AG-270 (ClinicalTrials.gov Identifier: NCT03435250). Aims: The primary objective of this study is to determine the maximum tolerated dose (MTD) of AG-270. Secondary objectives include safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Methods: Eligibility requires homozygous deletion of cyclin dependent kinase inhibitor 2A (CDKN2A) in the patient’s tumor (as MTAP is usually co-deleted with CDKN2A), or loss of MTAP by IHC. Patients receive AG-270 daily in 28-day cycles, with intensive PK/PD sampling after the first dose and after 2 weeks of treatment. Paired tumor biopsies are collected at baseline and at the end of cycle 1. Disease evaluation is performed every 2 cycles. Results: As of 20 May 2019, 39 patients had been treated with AG-270: 50 mg once daily (QD; n=3), 100 mg QD (n=7), 150 mg QD (n=6), 200 mg QD (n=11), 400 mg QD (n=6), or 200 mg twice daily (BID; n=6). AG-270 was well absorbed. Plasma concentrations increased in a dose-proportional manner except at 400 mg QD, where exposure was lower than anticipated. The geometric mean area under the curve from 0-24 h at steady state (AUC0-24,ss) in the QD cohorts ranged from 33200 to 199085 ng*h/mL, and the geometric mean AUC0-24,ss in the 200 mg BID cohort was 254616 ng*h/mL. The median half-life of AG-270 ranged from 16.1 to 38.4 h. Decreases in plasma [SAM] were exposure-dependent. After 2 weeks of dosing, maximal reductions in plasma [SAM] ranged from 51% to 71% across the tested cohorts. Analysis of 9 paired tumor biopsies by IHC showed decreases in levels of symmetrically di-methylated arginine (SDMA) residues, consistent with MAT2A inhibition; the average H-score reduction compared to baseline was 36.4% [-98.8%, +21.4%]. Asymptomatic, exposure-dependent increases in unconjugated bilirubin were observed starting at 100 mg QD, consistent with the known potential of AG-270 to inhibit UGT1A1. Three patients (at 100 mg QD, 150 mg QD, and 200 mg BID) developed grade 2 and 3 diffuse erythematous rashes during the second week of dosing that resolved within 1 week of stopping treatment. Exposure-dependent, reversible decreases in platelet counts were first observed at 200 mg QD and were grade 3 and 4 in severity at 200 mg BID. Two patients treated at 200 mg BID developed reversible but dose-limiting grade 3 and 4 increases in liver enzymes. The MTD of AG-270 is 200 mg QD. An unconfirmed partial response has been observed in a patient with a high-grade neuroendocrine carcinoma of the lung. Seven patients have achieved radiographically confirmed stable disease of 2.0 to 9.9 months’ duration. Conclusions: AG-270 causes reductions in plasma [SAM] and in tumor SDMA levels at well-tolerated doses. This trial will next evaluate the combination of AG-270 with taxane-based chemotherapy, given preclinical data demonstrating enhanced antitumor activity with AG-270 and taxanes in MTAP-deleted cancer models. Citation Format: Rebecca S Heist, Mrinal M Gounder, Sophie Postel-Vinay, Frederick Wilson, Elena Garralda, Khanh Do, Geoffrey I Shapiro, Patricia Martin-Romano, Gerburg Wulf, Michael Cooper, Caroline Almon, Salah Nabhan, Varsha Iyer, Yanwei Zhang, Kevin Marks, Elia Aguado-Fraile, Frank Basile, Keith Flaherty, Howard A Burris. A phase 1 trial of AG-270 in patients with advanced solid tumors or lymphoma with homozygous MTAP deletion [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PR03. doi:10.1158/1535-7163.TARG-19-PR03

Background Reliable evaluation of treatment benefit in early phase clinical trials is necessary. The time to progression ratio (TTPr), which compares successive TTP in a single patient, is a powerful criteria for determining targeted or immune therapies efficacy. Methods We evaluated 205 TTPr in a large cohort of 177 advanced cancer patients enrolled in at least two Phase 1/1b trials (out of 2827 phase 1/1b-treated patients) at Gustave Roussy. Results This first wide description of TTPr showed that, under the hypothesis of overall absence of treatment line effect, the median TTPr was 0.7 and that 25% of patients presented a TTPr above the conventional efficacy threshold of 1.3. Conclusions A higher median TTPr and a larger proportion of patients above the 1.3 threshold should therefore be achieved to conclude to drug efficacy. New guidelines for TTPr interpretation and calibration are proposed, which warrant independent prospective validation.

Background: Antiangiogenic drugs can synergize with immunotherapy in preclinical models. However some molecules have shown unacceptable levels of toxicity when combined with anti-PD-1. We aimed to determine the safety and activity of the nintedanib+pembrolizumab combination. Nintedanib is an oral angiokinase inhibitor aiming the vascular endothelial growth factor receptors 1,2,3, platelet-derived growth factor receptors α,β, fibroblast growth factor receptors 1,2,3 as well as RET. Pembrolizumab is a highly selective, humanized monoclonal IgG4-kappa isotype antibody against PD-1 designed to block the negative immune regulatory signaling of the PD-1 receptor expressed by T cells. Methods: PEMBIB is a monocentric phase Ib trial which evaluated escalating doses of continuous oral intake of nintedanib (Dose level 1 (DL1) = 150 mg BID; DL2 =200 mg BID) in combination with intravenous flat dose of pembrolizumab at 200 mg every 21 days in patients with advanced solid tumors using the rolling 6 design. A lead-in monotherapy of nintedanib was performed 7 days prior starting the C1D1 of pembrolizumab with the aim of modifying the tumor microenvironment. The primary objective was to establish the MTD of nintedanib in combination with pembrolizumab based on the assessment of DLT occurrence during the first 4 weeks (28 days since C1D1) and to determine the recommended phase II dose (RP2D). Secondary objectives included antitumor activity assessed by both RECIST v1.1 and irRECIST. The clinical activity of the combination is being further evaluated in the expansion part of this trial. Results: As of November 24, 2016, 13 patients (12 evaluable for DLT) have been enrolled in the escalation part with the following pathology: 2 squamous cervical carcinoma, 1 MSI colorectal cancer, 1 triple negative breast cancer, 2 thymic carcinoma, 1 malignant pleural mesothelioma, 1 peritoneal mesothelioma, 1 gastric adenocarcinoma, 1 clear cell renal carcinoma, 1 neuroendocrine tumor, 1 nasopharyngeal cancer. 50% patients were male, ECOG 0 (83%) or 1. There were no grade 4-5 toxicities. The most frequent adverse events reported for more than 2 patients were alanine & aspartate aminotransferase increase, fatigue, decreased appetite, diarrhea, nausea, vomiting, hypothyroidism. Three dose-limiting toxicities of liver enzymes elevation were observed in 200 mg BID nintedanib thus recommending 150 mg BID nintedanib for the phase II part. One nasopharyngeal carcinoma, 1 squamous cervical carcinoma and 1 thymic carcinoma developed an objective RECIST partial response (ORR=25%). Conclusions: Toxicity was consistent with the drugs profile and no unexpected events have been seen with the combination. Nintedanib at 150 mg BID with 200 mg flat dose of Pembrolizumab was well tolerated. Additional data for safety and efficacy is further evaluated in the expansion part. Citation Format: Andreea Varga, Capucine Baldini, Patricia Martin-Romano, Antoine Hollebecque, Anas Gazzah, Rastislav Bahleda, Jessica Menis, Stephane Champiat, Yolla El-Dakdouki, Xavier Paoletti, Vincent Ribrag, Jean-Marie Michot, Saloomeh Rafie, David Planchard, Benjamin Besse, Christophe Massard, Jean-Charles Soria, Aurelien Marabelle. Safety and efficacy results from a phase I dose-escalation trial of Nintedanib in combination with Pembrolizumab in patients with advanced solid tumors (PEMBIB trial) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT141.

3080Background: We aimed to determine the safety and activity of the nintedanib+pembrolizumab combination. Nintedanib is an oral angiokinase inhibitor targeting the vascular endothelial, platelet-d...

1081Background: Levels of tumor infiltrating lymphocytes (TILs) at diagnosis have shown to improve survival in TNBC and HER2 overexpressing breast cancer (BC) patients. Indeed, high levels of TILs ...

579 Background: Preoperative chemotherapy is an alternative approach undergoing active clinical research in patients (pts) with locally advanced colon cancer (LACC). The aim of this study was to assess the feasibility and preliminary evidence of activity of a direct monitoring of 5-FU levels based on pharmacokinetically (PK) guided dose adjustments. Methods: LACC pts (T4 or T3 with extramural depth >5mm) diagnosed after a colonoscopy and spiral CT were scheduled to receive 4 cycles of Oxalipatin (85mg/m²), Leucovorin (400 mg/m²), bolus 5-FU (400 mg/m2) and infusional 5-FU (initial dose of 2400mg/m² in 46h and then tailored according to PK monitoring to reach an area under the curve (AUC) between 25-30 mg·h·L-1). Surgery was planned 4 to 6 weeks after the completion of chemotherapy treatment. All pts were staged at baseline and before surgery. Pathological tumor regression was graded according to the MSKCC classification. Toxicity was reported according to the NCI-CTCAE 4.0. Results: From March 2011 to April 2013, 16 pts (M/F: 10/6; median age 56) with LACC were evaluated. Median dose of 5-FU was 4750 mg. 70.6% pts required a 5-FU dose increase to reach the target AUC. Median 5-Fu plasma clearance was 199,58 L/h. Side effect profile included G3 neutropenia (6 pts), G2 diarrhea (5 pts), G2 nausea (3 pts) and G2 asthenia (4 pts). Neoadjuvant treatment was discontinued in 2 pts due to small bowell obstruction requiring surgery. No progressive disease was observed during preoperative chemotherapy. A radiological dowstaging was achieved in 9 pts (56.25%). All pts underwent surgery (laparoscopy-assisted 50%) with an R0 resection rate of 93.75%. There were no treatment-related deaths. Pathological responses (MSKCC score) included grades 4, 3+ and 3 in 12.5%, 12.5% and 25% of pts, respectively. Median number of harvested nodes was 23.5 (7-51) with a ypN0 rate of 75%. Median time to hospital discharge was 7 days. After a median follow-up of 7 months (3-27), the 2-year actuarial median PFS and OS were 67.5% and 100%. Conclusions: Preoperative PK-adjusted FOLFOX in LACC pts achieves major pathological responses in almost 50% the pts and a remarkable R0 resection rate. Further research seems warranted.

e19114 Background: Adrenal gland is a common site of metastasis in lung cancer. Adrenal metastasis (AM) can occur at the time of diagnosis (synchronous AM) or later (metachronous AM). When an AM appears as an isolated site of dissemination it is considered a good-prognosis metastatic disease. Nevertheless few data are available about the prognosis and the optimal management of these patients. Methods: Retrospective analysis of the historical series of adrenalectomies in patients treated of lung cancer at our institution. Results: From April 2002 to April 2011, 30 patients (27m/3f) diagnosed of AM of lung cancer (16 non-squamous, 8 squamous, 6 small-cell; 21 metachronous AM, 9 synchronous AM) were treated with adrenalectomy (26 laparoscopic, 4 open surgery). Median age was 55 years old (range: 42-71). Median size of the AM was 35 mm (range: 12-140). There were no severe complications of surgery in any patient. All the patients had received radical treatment for the primary tumour and for other metatatic sites (8 patients brain metastases, 3 patients other sites) before adrenalectomy. Median overall survival (OS) and disease-free survival from adrenalectomy for the entire group were 44 (95% CI: 10-78) and 15 (95%CI: 7,6-22.3) months respectively. We found an statistical trend (p=0.087) of better OS from adrenalectomy for patients with non-squamous histology compared with squamous histology: 57 (95%CI: 38.4-75.6) and 21 (18.3-23.8) months respectively. The percentage of alive patients at 2 and 5 years was 59.1% and 36% respectively. Conclusions: These results add new data about the prognosis of patients with adrenal metastases into the context of low-tumor-burden metastatic lung cancer. Adrenalectomy is a tolerable procedure which plays a role in the management of these patients.

122 Background: In recent years many drug combinations have demonstrated clinical activity in heavily pretreated patients (pts) with metastatic breast cancer (MBC). Eribulin (E) in monotherapy has shown a beneficial effect in overall survival (OS) with slight rate of objective responses (OR) and poor effect in progression free survival (PFS). The Eribulin – Carboplatin (Cb) combination has been studied in other types of tumors in a phase Ib with promising results. We initiated an exploratory program with an off-label combination of E – Cb in pts with visceral disease and ECOG < 2. Methods: We retrospectively analyzed pts with MBC previously treated with anthracyclines, taxanes, and Capecitabine. Chemotherapy regimen consisted of E 1.1mg/m2 on days 1 and 8 and Cb AUC: 5 on day 1 every 21 days. Toxicity was assessed according to CTC criteria v 4.0. OR, PFS and OS rates were also evaluated. RECIST criteria were used to appraise radiological response. Results: Treatment was delivered in 10 pts. Median (M) age was 56 (range, 39-65). Pts characteristics were defined as follows: ECOG 0 (1 pt), 1 (6 pts) and 2 (3 pts); histological subtypes: luminal 9 pts and Her-2, 1 pt. M of previous lines was 7 (3-11). M of metastatic localizations were 3 (1-4). M of administered cycles was 6’5 (1-10). Grade 2 toxicity was asthenia 40%, peripheral neuropathy 10% and nausea - vomiting 10%. G 3 anemia and thrombopenia were noted in 20%. G 3-4 neutropenia was observed in 5 pts. Two pts required hospital admission due to febrile neutropenia. OR rate: complete response 10%, partial response 50% and stable disease 40%. Biochemical response rate was 80%. M of follow-up was 11 months, with M PFS and OS of 8 (4-11) and 18 months (4-18) respectively. Conclusions: Eribulin and Carboplatin is feasible, achieving remarkable response and survival rates with an acceptable toxicity profile in heavily pretreated patients with metastatic breast cancer. Preliminary results are promising and encourage us to continue recruiting patients.

e15220 Background: The aim of this study was to evaluate the feasibility and efficacy of FOLFOXIRI induction chemotherapy (ICT) with pharmacokinetic (PK) dose adjustment of 5-FU followed by chemo-r...

356 Background: Neoadjuvant therapy is an increasingly used approach in LAPC patients (pts) but the optimal sequence remains to be defined. We evaluated the feasibility and efficacy of induction chemotherapy (ICT) with pharmacokinetic (PK) monitoring, chemo-radiotherapy (CRT) and surgery. Methods: Borderline resectable and unresectable LAPC pts with EUS stages T3-4/N+ were included. Pts were planned to receive 4 cycles of biweekly ICT with Oxalipatin (85mg/m²), Leucovorin (400mg/m²), Irinotecan (150mg/m²) and 5-FU (initial dose of 3200mg/m² in 46h and then tailored according to PK monitoring to reach an area under the curve (AUC) between 25-30 mg·h·L-1.) After ICT, pts with no progressive disease received CRT (50.4 Gy, daily concurrent Capecitabine and weekly Oxaliplatin). Surgery was planned 4 to 6 weeks after the completion of CRT. Pathological response was graded according to the CAP classification. Toxicity was recorded according to the NCI-CTCAE 4.0. Results: From November 2011 to February 2013, 13 LAPC treatment-naïve (M/F: 11/2) pts were enrolled (T4; 30.8%, N+; 61.5%, 8 borderline resectable, 5 unresectable due to celiac abutment (2 pts), SMA and celiac encasement (1 pt), unreconstructible SMV and portal occlusion (2 pts). Median age was 63. During ICT, 5- FU dose had to be increased from baseline in 30.7% pts. Grade 3-4 ICT-related toxicities were neutropenia (6 pts) and diarrhea (1 pt). During CRT, grade 3 toxicity included neutropenia (2 pts), thrombocytopenia (1 pt), diarrhea (1 pt), asthenia (1 pt) and mucositis (1 pt); three pts required hospital admission in hospital. Twelve pts completed the whole neoadjuvant program. Ten pts proceeded to surgery with an R0 resection rate of 76.9%. Pathological response was CAP 0 (no viable cells) and CAP 1 (small groups of cancer cells) in 20% and 50% of pts, respectively; ypT0 and ypN0 rates were 20 and 60%. After a median follow-up of 12 months, the 12-month actuarial median PFS and OS were 80% and 75%, respectively. Conclusions: This neoadjuvant strategy seems feasible and promising although a longer follow-up is required. 5-FU PK modulation may contribute to a better therapeutic index.

e12015 Background: The combination of Pegylated Liposomal Doxorubicin (PDL) plus Gemcitabine (GEM) has been previously investigated in the treatment of recurrent metastatic breast cancer (RMBC) pat...