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Purpose:FGFR1 amplification (FGFR1amp) is recurrent in metastatic breast cancer (MBC) and is associated with resistance to endocrine therapy and CDK4/6 inhibitors (CDK4/6is). Multi-tyrosine kinase inhibitors (MTKIs) and selective pan-FGFR inhibitors (FGFRis) are being developed for FGFR1amp breast cancer. High-level FGFR amplification and protein expression by IHC have identified breast cancer responders to FGFRis or MTKIs, respectively.Experimental Design:Here, we used preclinical models and patient samples to identify predictive biomarkers to these drugs. We evaluated the antitumor activity of an FGFRi and an MTKI in a collection of 17 breast cancer patient–derived xenografts (PDXs) harboring amplification in FGFR1/2/3/4 and in 10 patients receiving either an FGFRi/MTKI. mRNA levels were measured on FFPE tumor samples using two commercial strategies. Proliferation and angiogenesis were evaluated by detecting Ki-67 and CD31 in viable areas by immunofluorescence.Results:High FGFR1–4 mRNA levels but not copy-number alteration (CNA) is associated with FGFRi response. Treatment with MTKIs showed higher response rates than with FGFRis (86% vs. 53%), regardless of the FGFR1–4 mRNA levels. FGFR-addicted PDXs exhibited an antiproliferative response to either FGFRis or MTKIs, and PDXs exclusively sensitive to MTKI exhibited an additional antiangiogenic response. Consistently, the clinical benefit of MTKIs was not associated with high FGFR1–4 mRNA levels and was observed in patients previously treated with antiangiogenic drugs.Conclusions:Tailored therapy with FGFRis in molecularly selected MBC based on high FGFR1–4 mRNA levels warrants prospective validation in patients with CDK4/6i-resistant luminal breast cancer and in patients with TNBC without targeted therapeutic options.

Background Reliable predictive imaging markers of response to immune checkpoint inhibitors are needed. Purpose To develop and validate a pretreatment CT-based radiomics signature to predict response to immune checkpoint inhibitors in advanced solid tumors. Materials and Methods In this retrospective study, a radiomics signature was developed in patients with advanced solid tumors (including breast, cervix, gastrointestinal) treated with anti-programmed cell death-1 or programmed cell death ligand-1 monotherapy from August 2012 to May 2018 (cohort 1). This was tested in patients with bladder and lung cancer (cohorts 2 and 3). Radiomics variables were extracted from all metastases delineated at pretreatment CT and selected by using an elastic-net model. A regression model combined radiomics and clinical variables with response as the end point. Biologic validation of the radiomics score with RNA profiling of cytotoxic cells (cohort 4) was assessed with Mann-Whitney analysis. Results The radiomics signature was developed in 85 patients (cohort 1: mean age, 58 years ± 13 [standard deviation]; 43 men) and tested on 46 patients (cohort 2: mean age, 70 years ± 12; 37 men) and 47 patients (cohort 3: mean age, 64 years ± 11; 40 men). Biologic validation was performed in a further cohort of 20 patients (cohort 4: mean age, 60 years ± 13; 14 men). The radiomics signature was associated with clinical response to immune checkpoint inhibitors (area under the curve [AUC], 0.70; 95% CI: 0.64, 0.77

BackgroundThe long-term sequelae of coronavirus disease 2019 (COVID-19) in children remain poorly characterised. This study aimed to assess long-term outcomes in children previously hospitalised with COVID-19 and associated risk factors.MethodsThis is a prospective cohort study of children (≤18 years old) admitted to hospital with confirmed COVID-19. Children admitted between 2 April 2020 and 26 August 2020 were included. Telephone interviews used the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) COVID-19 Health and Wellbeing Follow-up Survey for Children. Persistent symptoms (>5 months) were further categorised by system(s) involved.Results518 out of 853 (61%) eligible children were available for the follow-up assessment and included in the study. Median (interquartile range (IQR)) age was 10.4 (3–15.2) years and 270 (52.1%) were girls. Median (IQR) follow-up since hospital discharge was 256 (223–271) days. At the time of the follow-up interview 126 (24.3%) participants reported persistent symptoms, among which fatigue (53, 10.7%), sleep disturbance (36, 6.9%) and sensory problems (29, 5.6%) were the most common. Multiple symptoms were experienced by 44 (8.4%) participants. Risk factors for persistent symptoms were: older age “6–11 years” (OR 2.74, 95% CI 1.37–5.75) and “12–18 years” (OR 2.68, 95% CI 1.41–5.4), and a history of allergic diseases (OR 1.67, 95% CI 1.04–2.67).ConclusionsA quarter of children experienced persistent symptoms months after hospitalisation with acute COVID-19 infection, with almost one in 10 experiencing multisystem involvement. Older age and allergic diseases were associated with higher risk of persistent symptoms at follow-up.

Antibody–Drug Conjugates; Cancer treatment Conjugats anticossos-fàrmacs; Tractament contra el càncer Conjugados anticuerpo-fármaco; Tratamiento contra el cáncer Cross-reactivity with normal tissues is one of the key concerns for target selection for antibody–drug conjugates. Probody therapeutics are masked antibodies that can selectively be activated by proteases in the tumor. CX-2029, is a first-in-class Probody targeting CD71 with preliminary efficacy and a tolerable safety profile

BackgroundDuoBody-PD-L1×4-1BB (GEN1046) is a class-defining, bispecific immunotherapy designed to induce an antitumor immune response by simultaneous and complementary PD-L1 blockade and conditional 4-1BB stimulation. Encouraging clinical activity and manageable safety were observed during dose escalation in the ongoing phase 1/2a trial in patients with advanced solid tumors (NCT03917381). We report exploratory pharmacodynamic analyses and potential biomarkers of response in an expansion cohort of patients with PD-(L)1–R/R NSCLC.MethodsPatients with metastatic/unresectable NSCLC who had multiple lines of prior systemic therapy, including a checkpoint inhibitor, received flat-dose DuoBody-PD-L1×4-1BB (100 mg) intravenously every 3 weeks. Immunophenotyping of peripheral blood and measurements of soluble immune mediators were evaluated in serial blood samples in cycles 1–2. Tumor PD-L1 and 4-1BB expression and additional immune markers were evaluated by immunohistochemistry in core needle tumor biopsy specimens collected before treatment and at cycle 2.ResultsAs of May 2021, 40 patients with PD-(L)1–R/R NSCLC were enrolled (median age, 63 years). Treatment with DuoBody-PD-L1×4-1BB elicited pharmacodynamic modulation of immune endpoints within the first 2 cycles. Induction of peripheral IFN-y, CXCL9/10, and expansion of peripheral CD8+ effector memory T cells and activated NK cells were observed starting at cycle 1 (>2-fold from baseline) and maintained or increased through cycle 2. Based on 9 paired tumor biopsy samples, increased PD-L1 and 4-1BB expression and cytotoxic CD8+/GZMB+ cell density were detected following treatment. In a subset of patients with clinical response (n=5 confirmed PRs), a trend of greater induction of IFN-y, CXCL9/10, and activated NK cells was observed vs nonresponders. Disease control rates were higher in patients who had progressed on prior anti–PD-1 therapy within 8 months (64% [16/25]) from the first dose of DuoBody-PD-L1×4-1BB. As expected, among patients with evaluable baseline tumors (n=26), most with any degree of tumor reduction (best change, ConclusionsIn patients with NSCLC who progressed on PD-(L)1 therapy, DuoBody-PD-L1×4-1BB elicited pharmacodynamic effects consistent with its proposed mechanism of action. Relationships between disease control and PD-L1 tumoral expression, as well as time from last prior anti–PD-1 therapy, were observed. These findings support that patient selection and/or anti–PD-1 combination therapy may lead to improved clinical efficacy. Further analyses are ongoing and updated results will be presented.AcknowledgementsThe authors thank Hrefna Kristin Johannsdottir, Lei Pang, and Kate Sasser at Genmab A/S and Friederike Gieseke at BioNTech SE for their valuable contributions. This trial was funded by Genmab A/S and BioNTech SE.Trial RegistrationNCT03917381Ethics ApprovalThis trial is undertaken following full approval of the final protocol, amendments, informed consent form, applicable recruiting materials, and subject compensation programs by the Independent Ethics Committee/Institutional Review Board.ConsentWritten informed consent, in accordance with principles that originated in the Declaration of Helsinki 2013, current ICH guidelines including ICH-GCP E6(R2), applicable regulatory requirements, and sponsor policy, was provided by the patients.

BackgroundGrowth and differentiation factor 15 (GDF-15) is a TGF-β superfamily member physiologically expressed mainly in placenta and linked to feto-maternal tolerance. Under pathophysiologic conditions, prevention of excessive immune cell infiltration during tissue damage and cachexia induction have been ascribed to GDF-15. Recent research has though indicated a prominant role in modulation of the tumor microenvironment and the immune synapse, too1 2 indicating that GDF-15 may be a major tumor-derived immunosuppressant. Importantly, several cancer entities secrete high levels of GDF-15, correlating with poor prognosis and reduced overall survival [Front Immunol 2020 May 19;11:951]. To block this effect the GDF-15 neutralizing antibody CTL-002 was generated. In preclinical models CTL-002 demonstrated potent effector T cell shifting into tumor tissue by neutralizing GDF-15.MethodsThis is a phase 1, first-in-human (FIH), two-part, open-label clinical trial of intravenous (IV) administration of CTL-002 given as monotherapy and in combination with an anti-PD-1 antibody in subjects with advanced-stage, relapsed/refractory solid tumors who relapsed or were refractory to a prior anti-PD-1/PD-L1 therapy. Eligible subjects have exhausted all available approved standard treatments, including prior anti-PD1/-PD-L1 treatment, and present with a biopsy-accessible tumor for serial biopsy taking. The trial is termed GDFATHER, for ”GDF-15 Antibody-mediaTed Effector cell Relocation”.Main endpoints are safety of CTL-002 monotherapy and CTL-002 combination with an anti-PD-1 antibody, pharmacokinetics, pharmacodynamics (e.g. degree of GDF-15 neutralization achieved and change in immune-cell number and composition in the tumor tissue) as well as preliminary clinical efficacy (tumor mass reduction; anticachexia effect)In part A of the trial (dose escalation) up to 24 subjects will receive escalating doses of CTL-002 IV (0.3 – 20 mg/kg) in a ”mono-followed-by-combination”-design with CTL-002 given as monotherapy and followed by combination with an anti-PD-1 checkpoint inhibitor. In part B (expansion) up to 5 cohorts with up to 25 subjects per cohort with defined tumor entities expected to be GDF-15 dependent will be treated to determine the recommended phase 2 dose (RP2D) and further evaluate safety and preliminary efficacy of CTL-002 monotherapy and the combination.The study was initiated in December 2020 and enrolled the first patient on Dec 09, 2020. Cohort 4 is ongoing at time of submission (07/2021) and so far no DLT has occurred. Updated safety, biomarker and response assessments will be reported at the meeting. The ClinicalTrials.gov Identifier is NCT04725474. For more information please contact info@catalym.com.Trial RegistrationNCT04725474ReferencesWischhusen J, Wistuba-Hamprecht K, Harter PN, Cheng P, Martens A, Gogolla F, Nonomura Y, Romer P, Koch SD, Haake M, Schuberth-Wagner C, Rudiger M, Leo E, Mittelbronn M, Levesque MP, Hackl H, Dummer R, Weide B. Identifying GDF-15 as potential novel immunotherapeutic target linked to immune cell exclusion in tumors and resistance to anti-PD-1 treatment [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 2161.Hurt E, Thomas S, Mulgrew K, Blackmore S, Moynihan J, Cusdin F, Dodd R, Cariuk P, Sigurdardottir A, Brannigan E, Dobson C, Kumar R, Cobbold M. AZD8853: A novel antibody targeting GDF15 for immunotherapy refractory tumors [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 1828.Ethics ApprovalAll participants gave informed consent prior to participation. EC approval by Gobierno de Navarra, Departamento de Salud, EC_2020/30, Dated: Oct 13, 2020 in Pamplona, Spain. Respective additional national lead EC approvals for Germany (Ethikkommission der Universität Würzburg, 203–20ff of Oct 26, 2020) and Switzerland (Kantonale Ethikkommission Zürich, 2020–02308 of Nov 24, 2020).

BackgroundDespite recent advances in exome and RNA sequencing to identify tumor-rejection antigens including neoantigens, the existing techniques fail to identify the vast majority of antigens targeted by tumor-reactive cells. A growing number of studies suggest that HLA-I peptides derived from non-canonical (nonC) open reading frames or derived from allegedly non-coding regions can contribute to tumor immunogenicity. Here we use proteogenomics to identify personalized candidate canonical and non-canonical tumor-rejection antigens and to evaluate their contribution to cancer immune surveillance in patients.MethodsWhole exome sequencing was performed to identify the non-synonymous somatic mutations (NSM) and immunopeptidomics to identify the HLA-I presented peptides (pHLA) in 9 patient-derived tumor cell lines (TCL). Peptid-PRISM proteogenomics pipeline was used to identify both canonical and non-canonical pHLA, including those derived from NSM in coding regions. All peptides containing mutations and derived from either cancer-testis (CTA) or tumor-associated antigens (TAA) were selected as candidate tumor antigens. For nonC peptides, an immunopeptidomics healthy dataset containing several tissues and HLA-allotypes was used to eliminate those derived from normal ORFs and select nonC peptides preferentially expressed in tumor cells (nonC-TE). The selected candidate peptides were synthesized, pulsed onto autologous APCs and co-cultured with tumor-reactive ex vivo expanded lymphocytes to assess immune recognition (figure 1).ResultsNonC-TE peptides were identified in all TCL studied, ranging from 0.5% to 5.4% of the total HLA-I presented peptides (n= 506). As described previoulsy, 5’UTR were the main source. Of note, the tumor type did not have an impact on the frequency of presented nonC peptides, but rather the presence of HLA-A*11:01 and HLA-A*03:01 was a major determinant. T cell responses were detected against at least 13/33 putative neoantigens, 2/24 CTA and 2/61 TAA. On the contrary, none of the 471 nonC-TE candidate peptides tested thus far, including one containing a NSM were able to elicit a recall immune response. Nevertheless, T cells recognizing at least 3 of them were detected through in vitro sensitization of non-autologous PBMCs.Abstract 912 Figure 1Workflow diagramTumor biopsies and blood samples are obtained from cancer patients (left panel). Patient-derived tumor cell lines are generated in vitro, the peptides presented on HLA molecules are further isolated and analyzed in a mass-spectrometer (top panel). Whole exome sequencing (WES) from matched tumor and healthy tissue is performed to identify the non-synonymous somatic mutations (NSM) (middle panel). Peptide-PRISM proteogenomics pipeline combines the information from the immunopeptidomics data and WES to identify pHLA sequences from both canonical and non-canonical candidate tumor antigens (top right panel). Lymphocyte populations either TILs or sorted PBMCs are expanded and further screened for pre-existing T cell responses (bottom panel) against the candidate epitopes by co-culturing the T cells with peptide-pulsed autologous APC. The recognition is assessed by measuring IFNg release by elispot and the upregulation of activation surface markers by FACS (bottom right panel).ConclusionsOur results show that although HLA-I nonC peptides were frequently presented in all TCLs studied and they can be immunogenic, neoantigens derived from mutations in canonical coding regions were preferentially recognized by tumor-reactive lymphocytes, suggesting T cells targeting the latter are primed more efficiently. The identification of mutated nonC antigens using whole genome sequencing to identify mutations in non-coding regions warrants further examination. Still, the specificity of many tumor-reactive TILs remains unknown.Ethics Approval”This study was approved by the ”Comité de Ética de Investigación con Medicamentos del Hospital Universitario Vall d’Hebron” institution’s Ethics Board; approval number PR(AG)537/2019.”

Immunotherapy; Phase 1 trials; Prognostic model Inmunoterapia; Ensayos de fase 1; Modelo pronóstico Immunoteràpia; Assajos de fase 1; Model pronòstic Purpose Patient selection in phase 1 clinical trials (Ph1t) continues to be a challenge. The aim of this study was to develop a user-friendly prognostic calculator for predicting overall survival (OS) outcomes in patients to be included in Ph1t with immune checkpoint inhibitors (ICIs) or targeted agents (TAs) based on clinical parameters assessed at baseline. Methods Using a training cohort with consecutive patients from the VHIO phase 1 unit, we constructed a prognostic model to predict median OS (mOS) as a primary endpoint and 3-month (3m) OS rate as a secondary endpoint. The model was validated in an internal cohort after temporal data splitting and represented as a web application. Results We recruited 799 patients (training and validation sets, 558 and 241, respectively). Median follow-up was 21.2 months (m), mOS was 10.2 m (95% CI, 9.3–12.7) for ICIs cohort and 7.7 m (95% CI, 6.6–8.6) for TAs cohort. In the multivariable analysis, six prognostic variables were independently associated with OS – ECOG, number of metastatic sites, presence of liver metastases, derived neutrophils/(leukocytes minus neutrophils) ratio [dNLR], albumin and lactate dehydrogenase (LDH) levels. The phase 1 prognostic online (PIPO) calculator showed adequate discrimination and calibration performance for OS, with C-statistics of 0.71 (95% CI 0.64–0.78) in the validation set. The overall accuracy of the model for 3m OS prediction was 87.2% (95% CI 85%–90%). Conclusions PIPO is a user-friendly objective and interactive tool to calculate specific survival probabilities for each patient before enrolment in a Ph1t. The tool is available at https://pipo.vhio.net/. The research leading to these results has received funding from “la Caixa” Foundation (LCF/PR/CE07/50610001). Cellex Foundation for providing research facilities and equipment. This work was supported by the Accelerator Award (UpSMART) from Fundacion Científica – Asociacion Espanola Contra el Cancer (FC -AECC)/ Associazione Italiana per la Ricerca sul Cancro (AIRC) /Cancer Research United Kingdom (CRUK).

Background: Gamma9 Delta2 (γ9δ2) T cells function at the crossroad of innate and adaptive immunity with important roles in immune responses against pathogens and carcinogenesis, making them an attractive target for cancer immunotherapy. Butyrophilin (BTN) 3A (CD277) is an immune checkpoint molecule expressed on tumors and cells of the immune system that is required for γ9δ2 T cell activation. These observations led to the design and development of ICT01, a humanized, monoclonal antibody that binds the extracellular domain of all 3 isoforms of BTN3A1/A2/A3 and induces pAg-independent γ9δ2 T cell activation and killing of multiple tumors in nonclinical settings. Methods: EVICTION (www.clinicaltrials.gov NCT04243499; EudraCT Number: 2019-003847-31) is a first-in-human, open-label clinical study to assess the safety, tolerability, and activity of a range of IV doses of ICT01 as monotherapy and in combination with pembrolizumab, in patients with advanced-stage, relapsed/refractory cancer. Following Regulatory and Ethics Committee approvals, the study is being conducted at cancer centers in France, Belgium, Spain, Germany, the UK and USA. Following signed informed consent, patients received ICT01 every 3 weeks with blood samples collected at multiple timepoints for immunophenotyping by flow cytometry and cytokine analysis (IFNγ, TNFα, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-13). Tumor biopsies are collected at baseline and on Day 28 for immunohistochemistry (e.g., BTN3A, γ9δ2 T cells) and expression profiling of cancer- and immunity-related genes. Results: Solid tumor (ST) dose cohorts 1-4 (total n=20) were enrolled and treated with ICT01 doses ranging from 20 μg to 20 mg, and dose cohort 1 of hematologic cancer patients (n=3, 200 μg) has been enrolled. ICT01 was well-tolerated, with no dose-limiting toxicities or related SAEs reported. Target occupancy on T cells at 30 min or 4 hours post first dose ranged from 34% (700 μg, n=2), 79% (2 mg, n=5), 93% (7 mg, n=4) and 100% (20 mg, n=1), with activated γ9δ2 T cells (CD69+) migrating from the blood within 30 min of dosing that led to a > 95% decrease from baseline in the number of circulating γ9δ2 T cells for all 4 doses by 24hrs. The 2nd dose of ICT01 induced a similar activation & migration of γ9δ2 T cells from the circulation. There were no effects on CD4/CD8 T cells, NK, or B cells. Available cytokine data from ST cohorts 1 & 2 showed no CRS although transient 2-3x increases in IFNγ, TNFα, & IL-2 were observed 4 hours post dose in patients with higher baseline γ9δ2 T cell counts. A 5-10x increase of IFNγ was observed on Days 7 & 28 in ST cohort 2, consistent with γ9δ2 T cell activation. Digital pathology analysis of tumor biopsies of a cohort 1 melanoma pt demonstrated a 25x and 8x increase of CD3-TCRgamma delta++ and CD3+ cell densities, respectively, as compared to baseline. Analyses of additional cohorts are ongoing and will be presented. Conclusion: The preliminary results demonstrate that ICT01 safely and potently activates the anti-tumor immune response of γ9δ2 T cells mediated by BTN3A. Citation Format: Aurelien Marabelle, Christiane Jungels, Johann De Bono, Norbert Vey, Martin Wermke, Elena Garralda, Steven Le Gouill, Patricia LoRusso, Aude De Gassart, Emmanuel Valentin, Patrick Brune, Marina Iche, Daniel Olive, Paul A. Frohna. Activation of the antitumor immune response of gamma9delta2 T cells in patients with solid or hematologic malignancies with ICT01, a first-in-class, monoclonal antibody targeting butyrophilin 3A: The EVICTION study [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 CT034.

Purpose: This study examined safety, pharmacokinetics, and efficacy of veliparib, a PARP inhibitor, combined with carboplatin and etoposide in patients with extensive-stage (ED) small cell lung cancer (SCLC) and other solid tumors. Patients and Methods: The 3 + 3 design was used for dose escalation of oral veliparib in combination with carboplatin (AUC 5 on day 1) and etoposide (100 mg/m2 on days 1–3) in 21-day cycles. Veliparib dose was explored from 80 to 240 mg b.i.d. on 7-day, 14-day, or continuous schedules. Patients without disease progression continued on maintenance monotherapy (veliparib 400 mg b.i.d.) until disease progression or unacceptable toxicity. Results: Thirty-nine patients were enrolled to determine the recommended phase II dose of 240 mg veliparib for 14 days combined with carboplatin and etoposide based on long-term tolerability. Dose-limiting toxicity occurred in 1 patient (grade 2 toxic motor polyneuropathy) at veliparib 240 mg b.i.d. for 7 days. Most common adverse events related to veliparib were nausea (39%), fatigue (39%), and hematologic toxicities. Continuous dosing of veliparib 240 mg b.i.d. with carboplatin and etoposide resulted in excessive chemotherapy dose delays due to hematologic toxicity (grade 3/4 neutropenia/thrombocytopenia). Etoposide pharmacokinetics was not affected by veliparib. Confirmed responses occurred in 17 of 39 (44%) and 16 of 25 (64%) of all enrolled and ED SCLC patients, respectively. At the RP2D, confirmed responses occurred in 6 of 13 (46%) and 5 of 6 (83%) of all enrolled and ED SCLC patients, respectively. Conclusions: Veliparib (240 mg b.i.d. 14 days) plus carboplatin/etoposide can be safely combined. Phase II of this study is ongoing in first-line patients with ED SCLC.

Previous studies have shown that metastatic colorectal carcinoma (mCRC) patients treated with bevacizumab, experience variation in the plasma levels of angiogenesis growth factors and related cytokines, called angiogenic switch (AS). The aim of the present study was to analyze the relationship between AS and the clinical response during standard chemotherapy-bevacizumab treatment.Patients with Eastern Cooperative Oncology Group 0-1 mCRC were eligible. Patients received treatment with standard dose capecitabine plus either oxaliplatin or irinotecan and bevacizumab for 6 cycles. Initial treatment was followed by maintenance therapy with bevacizumab plus capecitabine until progression. Plasma levels of angiogenic-related cytokines (hepatocyte growth factor, placental growth factor, macrophage chemoattractant protein-3, MM-9, eotaxin, basic fibroblast growth factor, and interleukin 18) were prospectively analyzed at baseline and every 8 weeks. Progression-free survival (PFS) was calculated using the Kaplan-Meier method.A total of 71 patients were enrolled. AS was observed in 45 patients (63.4%), 28 of whom experienced AS at the first evaluation after treatment start. Disease control, which includes partial/complete response and stable disease, was seen in 96% of AS patients (43/45), but only in 15/26 (58%) for the remaining patients without evidence of AS (P0.001). The median PFS of AS patients was 11.4 months (95% confidence interval, 8.6-15.8) versus 8.3 months for patients without AS (95% confidence interval, 5.6-16.4; P=0.04).Chemotherapy plus Bevacizumab combination in mCRC patients results in dynamic changes in plasma cytokines, which is associated with better disease control and longer PFS. These new findings support continuing studying AS as a potential marker of angiogenesis inhibitor effectiveness.

BackgroundThe long-term sequelae of coronavirus disease 2019 (Covid-19) in children remain poorly characterised. This study aimed to assess long-term outcomes in children previously hospitalised with Covid-19 and associated risk factors. MethodsThis is a prospective cohort study of children ([≤]18 years old) admitted with confirmed Covid-19 to Z.A. Bashlyaeva Childrens Municipal Clinical Hospital in Moscow, Russia. Children admitted to the hospital during the first wave of the pandemic, between April 2, 2020 and August 26, 2020, were included. Telephone interview using the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) Covid-19 Health and Wellbeing paediatric follow up survey. Persistent symptoms (>5 months) were further categorised by system(s) involved. FindingsOverall, 518 of 853 (61%) of eligible children were available for the follow-up assessment and included in the study. Median age was 10.4 years (IQR, 3-15.2) and 270 (52.1%) were girls; median follow-up since hospital discharge was 256 (223-271) days. At the time of the follow-up interview 126 (24.3%) participants reported persistent symptoms among which fatigue (53, 10.7%), sleep disturbance (36, 6.9%,) and sensory problems (29, 5.6%) were the most common. Multiple symptoms were experienced by 44 (8.4%) participants. Risk factors for persistent symptoms were: age "6-11 years" (odds ratio 2.74 (95% confidence interval 1.37 to 5.75) and "12-18 years" (2.68, 1.41 to 5.4), and a history of allergic diseases (1.67, 1.04 to 2.67). InterpretationA quarter of children experienced persistent symptoms months after hospitalization with acute covid-19 infection, with almost one in ten experiencing multi-system involvement. Older age and allergic diseases were associated with higher risk of persistent symptoms at follow-up. Our findings highlight the need for replication and further investigation of potential mechanisms as well as clinical support to improve long term outcomes in children. FundingNone. O_TEXTBOXResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSEvidence suggests that Covid-19 may result in short- and long-term consequences to health. Studies in children and adolescents are limited and available evidence is scarce. We searched Embase for publications from inception to April, 25, 2021, using the following phrases or combinations of phrases "post-covid condition" or "post-covid syndrome" or "covid sequalae" or "post-acute covid" or "long covid" or "long hauler" with "pediatric*" or "paediatric*" or "child*" or "infant*" or "newborn*" or "toddler*" or "neonate*" or "neonatal" or "adolescent*" or "teen*". We found small case series and small cohort studies looking at Covid-19 consequences in children. No large cohort studies of previously hospitalised children, assessing symptom duration, categorisation or attempting multivariable analyses to identify independent risk factors for long Covid development were identified. Added value of this studyTo our knowledge, this is the largest cohort study with the longest follow-up since hospital discharge of previously hospitalised children. We found that even months after discharge from the hospital, approximately a quarter of children experience persistent symptoms with one in ten having multi-system involvement. Older age and allergic diseases are associated with Covid-19 consequences. Parents of some children report emotional and behavioural changes in their children after Covid-19. Implications of all the available evidenceOur findings highlight the need for continued global research of Covid-19 consequences in the paediatric population. Older children admitted to the hospital should be carefully monitored upon discharge. Large, controlled studies aiming to identify risk groups and potential intervention strategies are required to fill knowledge gaps. C_TEXTBOX

OBJECTIVE: Health anxiety by proxy is a newly introduced term to describe parents' experience of excessive and unpleasant worries about their child's health. This article describes the development of a new measure, the Health Anxiety by Proxy Scale (HAPYS), for systematic assessment of health anxiety by proxy.METHOD: The development of the HAPYS was performed over three phases. (1) Patients clinically assessed to have health anxiety by proxy participated in semi-structured interviews to elaborate their experience of worries regarding their child's health and their related behaviours, and to examine the face validity of items in an existing questionnaire: 'Illness Worry Scale - parent version'. (2) Based on the findings from Phase 1 the project group and a panel of experts selected and formulated questionnaire items and scoring formats. (3) The HAPYS was pilot-tested twice using cognitive interviewing with healthy parents and parents with health anxiety by proxy followed by further adjustments.RESULTS: The final version of HAPYS consists of 26 items characteristic of health anxiety by proxy and of an impact section with five items.CONCLUSION: Based on the pilot testing the HAPYS showed good face and content validity. It holds the potential to be a valid questionnaire to help clinicians across health care settings assess parents suffering from health anxiety by proxy.

Summary Background Oncogenic alterations in RET represent important therapeutic targets in thyroid cancer. We aimed to assess the safety and antitumour activity of pralsetinib, a highly potent, selective RET inhibitor, in patients with RET-altered thyroid cancers. Methods ARROW, a phase 1/2, open-label study done in 13 countries across 71 sites in community and hospital settings, enrolled patients 18 years or older with RET-altered locally advanced or metastatic solid tumours, including RET-mutant medullary thyroid and RET fusion-positive thyroid cancers, and an Eastern Co-operative Oncology Group performance status of 0–2 (later limited to 0–1 in a protocol amendment). Phase 2 primary endpoints assessed for patients who received 400 mg once-daily oral pralsetinib until disease progression, intolerance, withdrawal of consent, or investigator decision, were overall response rate (Response Evaluation Criteria in Solid Tumours version 1.1; masked independent central review) and safety. Tumour response was assessed for patients with RET-mutant medullary thyroid cancer who had received previous cabozantinib or vandetanib, or both, or were ineligible for standard therapy and patients with previously treated RET fusion-positive thyroid cancer; safety was assessed for all patients with RET-altered thyroid cancer. This ongoing study is registered with clinicaltrials.gov , NCT03037385 , and enrolment of patients with RET fusion-positive thyroid cancer was ongoing at the time of this interim analysis. Findings Between Mar 17, 2017, and May 22, 2020, 122 patients with RET-mutant medullary and 20 with RET fusion–positive thyroid cancers were enrolled. Among patients with baseline measurable disease who received pralsetinib by July 11, 2019 (enrolment cutoff for efficacy analysis), overall response rates were 15 (71%) of 21 (95% CI 48–89) in patients with treatment-naive RET-mutant medullary thyroid cancer and 33 (60%) of 55 (95% CI 46–73) in patients who had previously received cabozantinib or vandetanib, or both, and eight (89%) of nine (95% CI 52–100) in patients with RET fusion-positive thyroid cancer (all responses confirmed for each group). Common (≥10%) grade 3 and above treatment-related adverse events among patients with RET-altered thyroid cancer enrolled by May 22, 2020, were hypertension (24 patients [17%] of 142), neutropenia (19 [13%]), lymphopenia (17 [12%]), and anaemia (14 [10%]). Serious treatment-related adverse events were reported in 21 patients (15%), the most frequent (≥2%) of which was pneumonitis (five patients [4%]). Five patients [4%] discontinued owing to treatment-related events. One (1%) patient died owing to a treatment-related adverse event. Interpretation Pralsetinib is a new, well-tolerated, potent once-daily oral treatment option for patients with RET-altered thyroid cancer. Funding Blueprint Medicines.

Summary Background Oncogenic alterations in RET have been identified in multiple tumour types, including 1–2% of non-small-cell lung cancers (NSCLCs). We aimed to assess the safety, tolerability, and antitumour activity of pralsetinib, a highly potent, oral, selective RET inhibitor, in patients with RET fusion-positive NSCLC. Methods ARROW is a multi-cohort, open-label, phase 1/2 study done at 71 sites (community and academic cancer centres) in 13 countries (Belgium, China, France, Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Taiwan, the UK, and the USA). Patients aged 18 years or older with locally advanced or metastatic solid tumours, including RET fusion-positive NSCLC, and an Eastern Cooperative Oncology Group performance status of 0–2 (later limited to 0–1 in a protocol amendment) were enrolled. In phase 2, patients received 400 mg once-daily oral pralsetinib, and could continue treatment until disease progression, intolerance, withdrawal of consent, or investigator decision. Phase 2 primary endpoints were overall response rate (according to Response Evaluation Criteria in Solid Tumours version 1·1 and assessed by blinded independent central review) and safety. Tumour response was assessed in patients with RET fusion-positive NSCLC and centrally adjudicated baseline measurable disease who had received platinum-based chemotherapy or were treatment-naive because they were ineligible for standard therapy. This ongoing study is registered with ClinicalTrials.gov, NCT03037385, and enrolment of patients with treatment-naive RET fusion-positive NSCLC was ongoing at the time of this interim analysis. Findings Of 233 patients with RET fusion-positive NSCLC enrolled between March 17, 2017, and May 22, 2020 (data cutoff), 92 with previous platinum-based chemotherapy and 29 who were treatment-naive received pralsetinib before July 11, 2019 (efficacy enrolment cutoff); 87 previously treated patients and 27 treatment-naive patients had centrally adjudicated baseline measurable disease. Overall responses were recorded in 53 (61%; 95% CI 50–71) of 87 patients with previous platinum-based chemotherapy, including five (6%) patients with a complete response; and 19 (70%; 50–86) of 27 treatment-naive patients, including three (11%) with a complete response. In 233 patients with RET fusion-positive NSCLC, common grade 3 or worse treatment-related adverse events were neutropenia (43 patients [18%]), hypertension (26 [11%]), and anaemia (24 [10%]); there were no treatment-related deaths in this population. Interpretation Pralsetinib is a new, well-tolerated, promising, once-daily oral treatment option for patients with RET fusion-positive NSCLC. Funding Blueprint Medicines.

Background Expression of LAG-3, an inhibitory immunoreceptor, has been linked to reduced T-cell proliferation and cytokine production. LAG525 is a humanized IgG4 anti-LAG-3 antibody which inhibits LAG-3 binding to MHC class II. Spartalizumab is a humanized IgG4 anti-PD-1 mAb which inhibits PD-1 binding with its ligands PD-L1 and PD-L2. Preclinical data have shown promising antitumor activity when blocking LAG-3 and PD-1. Methods The Phase II part of the first-in-human study (NCT02460224) explored LAG525 + spartalizumab in patients with advanced/metastatic non-small cell lung cancer (NSCLC), cutaneous and non-cutaneous melanoma, renal cell carcinoma (RCC), mesothelioma, or triple-negative breast cancer (TNBC). The dose/schedule of LAG525 and spartalizumab was 400 mg IV Q3W and 300 mg IV Q3W, respectively. Half of patients with TNBC naive to anti-PD-1/PD-L1 received LAG525 at 600 mg IV Q4W and spartalizumab at 400 mg IV Q4W. The primary endpoint was overall response rate (ORR) using RECIST v1.1. Results As of June 1, 2020, 235 patients were enrolled in the Phase II part of the study, including patients with NSCLC (n=42), melanoma (n=42), RCC (n=38), mesothelioma (n=57), or TNBC (n=56). In total, 142 patients were naive to, and 93 patients were pretreated with, PD-1/PD-L1 inhibitors. Overall, 232 patients (99%) discontinued treatment, 76% due to progressive disease.ORR and disease control rate by indication and prior anti-PD-1/PD-L1 treatment are summarized below (table 1). Best overall response was 3 (1.3%) CR, 23 (9.8%) PR, 84 (35.7%) SD, 95 (40.4%) PD, and 30 (12.8%) unknown. For patients naive to anti-PD-1/PD-L1, median progression free survival (mPFS) in months (90% CI) was 3.9 (1.7–5.6) for NSCLC, 2.2 (1.6–5.6) for melanoma, 4.4 (2.1–11.1) for RCC, 5.5 (3.5–6.4) for mesothelioma, and 1.9 (1.6–2.6) for TNBC. For patients pretreated with anti-PD-1/PD-L1, mPFS in months (90% CI) was 3.5 (1.9–4.9) for NSCLC, 1.9 (1.8–3.7) for melanoma, 3.0 (1.6–3.9) for RCC, 3.4 (1.8–3.8) for mesothelioma, and 1.7 (1.3–3.4) for TNBC. Adverse events of any grade, regardless of cause, were reported in 233 (99%) patients; the most common (occurring in >20%) were nausea (25%), fatigue (23%), and dyspnea (21%). Conclusions LAG525 + spartalizumab exhibited antitumor activity across different indications, including patients with melanoma, RCC, and mesothelioma who had been pretreated with PD-1/-L1 inhibitors, suggesting that this combination may salvage prior PD-1/-L1 resistance. The combination was well tolerated, and no new safety signals were observed. Biomarker analysis is ongoing. Trial Registration NCT02460224 Ethics Approval This study was approved by an independent ethics committee or institutional review board at each site.

Background IL-15 is a member of the common y-chain family of cytokines that shares functional activities with IL-2. SO-C101is a superagonist fusion protein of IL-15 and the IL-15 receptor α sushi+ domain. SO-C101 stimulates the proliferation and the cytotoxic activity of NK cells and memory CD8+ T cells. In pre-clinical studies SO-C101 promoted expansion and activation of human, murine and cynomolgus monkey NK and CD8+ T cells. NK and CD8+ T cell activation correlated with potent monotherapy anti-cancer activity of SO-C101 in metastatic and solid tumor models. The combination of an anti-PD-1 or of anti-cancer monoclonal antibodies with SO-C 101 augmented the anti-tumor responses in mouse models. First clinical study was initiated in June 2019 to investigate SO-C101 as monotherapy and in combination with pembrolizumab. Methods The phase 1/1 b study currently on-going is a multicenter, open-label, dose escalation study for patients with selected advanced/metastatic solid tumors. The study consists of 2 parts: Part A - dose escalation of SO-C101 as monotherapy; Part B - dose escalation of SO-C101 in combination with pembrolizumab. Study objectives are to define the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of SO-C101 in both parts. Results As of September 22nd, 19 subjects were treated in part A in 6 escalating dose levels, and 3 subjects were treated in part B, at dose level 1. SO-C101 was well tolerated. No DLT was observed, the main AEs related to SO-C101 were injection site reactions, fever, chills, flu-like syndrome, all G1- G2, and transient lymphopenia in 5 subjects, Grade 2 to 4, all resolved within few days. Preliminary PK results showed the PK profile to be dose-proportional, with a Tmax of approx. 5 – 6 hours after administration and T½ approx. 4 hours. Preliminary PD analysis showed dose dependent NK and CD8+ T cell activation. A preliminary efficacy signal has been observed in a patient refractory to anti-PD1 therapy, who showed a RECIST PR with initial 20% shrinkage of target lesions at 6 weeks and 49% shrinkage at 12 weeks on CT-scans. Conclusions To date, SO-C101 has been well tolerated, with a manageable toxicity and encouraging signs of clinical activity. The study will proceed to reach a RP2D in both monotherapy and combination with Pembrolizumab. Expansion of the study in selected indications is warranted. Trial Registration https://clinicaltrials.gov/ct2/show/NCT04234113?term=sotio&draw=3&rank=12 The study was approved to proceed by FDA – IND 140011 -and by the sites ECs. Ethics Approval The NCT04234113 clinical trial was approved by each investigational site health agency and ethical committee. Consent Written informed consent of patients was obtained prior enrollment in the NCT04234113 clinical trial.

Background Activation of the STING pathway in intratumoral immune cells leads to increased type I interferon production, promoting recruitment and priming of T-cells against tumor antigens, and providing anti-tumor activity.1 Intratumoral administration of STING agonists has resulted in notable therapeutic activity in animal models.1 STING agonists have also shown clinical activity in patients, which was more pronounced when combined with an anti-PD-1 antibody.2,3 BI 1387446 potently and highly selectively activates the STING pathway; BI 754091 is a humanized IgG4 anti-PD-1 monoclonal antibody. Intratumoral administration of BI 1387446 resulted in tumor regression, and enhanced the activity of anti-PD-1 therapy in syngeneic tumor models.4 Methods NCT04147234 is a first-in-human, Phase I, open-label, multicenter trial of BI 1387446 in patients aged ≥18 years with advanced, unresectable and/or metastatic malignant solid tumors. Patients (up to ~122) will be enrolled from ~six sites across Europe and the USA. The main objectives are to characterize safety and determine the maximum tolerated dose (MTD) for BI 1387446 ± BI 754091. BI 1387446 will be administered intratumorally at increasing doses as monotherapy in Arm A, and in combination with BI 754091 (240 mg every three weeks, intravenously) in Arm B. In both arms, BI 1387446 will be administered in superficial lesions. In a potential third arm, Arm C, BI 1387446 will be administered in deep/visceral lesions in combination with intravenous BI 754091. Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control.For trial eligibility, patients must have exhausted standard treatment options, have ≥1 tumor lesion suitable for injection, ≥1 additional tumor lesion amenable to biopsy, and ECOG performance status of 0/1. Treatment will continue until progressive disease, unacceptable toxicity, other withdrawal criteria, or a maximum treatment duration of 34 cycles (for cycle 19 and onwards, administration of BI 1387446 is applicable for patients with a partial response), whichever occurs first. Primary endpoints are the MTD based on number of dose-limiting toxicities (DLTs), and number of patients with DLTs in the MTD evaluation period. Secondary endpoints are objective response based on RECIST 1.1, and best percentage change from baseline in size of target and injected lesions. Paired pre- and post-treatment biopsies of injected- and non-injected lesions and peripheral blood will be collected to assess pharmacodynamic changes associated with treatment. The trial is currently open for recruitment. Results N/A Conclusions N/A Acknowledgements Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Steven Kirkham, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this abstract. Trial Registration NCT04147234 Ethics Approval Not applicable. Consent Not applicable. References Corrales L, et al. J Clin Invest 2016;126:2404–2411. Meric-Bernstam F, et al. 33rd Ann Mtg and Pre-Conf Programs of the Society for Immunotherapy of Cancer (SITC), Washington, November 7–11 Nov 2018 (Poster #P309). 2018. Harrington K, et al. 43rd Ann Cong of the European Society for Medical Oncology (ESMO), Munich, 19–23 Oct 2018 (Poster #5475). 2018. Gremel G, et al. American Association for Cancer Research (AACR), Virtual Meeting, 22–24 Jun 2020 (Poster #4522). 2020.

Background Gamma9 Delta2 (γ9δ2) T cells are an important component of the innate anti-tumor immune response whose infiltration into solid tumors has been associated with a positive prognosis, making γ9δ2 T cells an attractive target for the next generation of cancer immunotherapy. Butyrophilins (BTNs) are a family of immune checkpoint molecules that regulate γ9δ2 T cell activity, including BTN3A that is a potent endogenous activator of γ9δ2 T cells following phosphoantigen (pAg) binding to the intracellular domain of BTN3A1. This observation led to the design and development of ICT01, a humanized, monoclonal antibody that binds all 3 isoforms of BTN3A1/A2/A3 and induces pAg-independent γ9δ2 T cell activation, for the treatment of patients with solid or hematologic tumors. Methods EVICTION (www. clinicaltrials.gov NCT04243499; EudraCT Number: 2019-003847-31) is a first-in-human, two-part, open-label, clinical study to assess the safety, tolerability and activity of intravenous doses of ICT01 as monotherapy and in combination with pembrolizumab, in patients with advanced-stage, relapsed/refractory cancer. Following Competent Authority and Ethics Committee approvals, the study is being conducted at cancer centers in France, Belgium, Spain, Germany, and the UK. Patients provide signed informed consent prior to screening. Eligible patients receive ICT01 (Range: 20 µg to 200 mg) every 3 weeks with blood samples collected at multiple timepoints for immunophenotyping and cytokine analysis (IFNγ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-13, TNFα). Tumor biopsies are collected at baseline and Day 28 and stained by immunohistochemistry for BTN3A, γ9δ2 T cells and other markers of anti-tumor immunity. Results Cohort 1 comprising 6 patients with solid tumors (3 Colorectal, 1 Pancreatic, 1 Ovarian, 1 Melanoma) has been enrolled and treated with ICT01 doses ranging from 20 to 700 µg. No dose-limiting toxicities or related SAEs have been reported. Target occupancy on T cells at 4 hours post first dose was 10% at 70 µg (n=1), 31% at 200 µg (n=2) and 34% at 700 µg (n=2), which was reflected at 24 hours post dose by a 73%, 91% and 97% decrease from baseline in the number of circulating γ9δ2 T cells, respectively. On Day 7, γ9δ2 T cells remained decreased by 37%, 75% and 76%, respectively. There were no effects on CD4 or CD8 T cells, NK cells, or B cells. Transient increases in IFNγ, secreted by activated γ9δ2 T cells, were observed in 4/6 patients. No cytokine release syndrome was observed. Data from the paired tumor biopsies are still being generated and will be presented. Conclusions The preliminary results demonstrate that ICT01 has the potential to safely activate the innate anti-tumor potential of γ9δ2 T cells through BTN3A. Acknowledgements . Trial Registration www.clinicaltrials.gov NCT04243499; EudraCT Number: 2019-003847-31 Ethics Approval This study was approved by the following Ethics Committees: COMITE DE PROTECTION DES PERSONNES, Sud-Mediterranee V (Gustave Roussy, IPC), Comite d’Ethique Institut Jules Bordet, COMITE DE ETICA DE INVESTIGACION CLINICA CON MEDICAMENTOS del Hospital Universitari Vall d’Hebron, Ethikkommission an der TU Dresden, HRA London-Surrey Borders Research Ethics Committee. Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

BACKGROUND: RET fusions are oncogenic drivers in 1 to 2% of non–small-cell lung cancers (NSCLCs). In patients with RET fusion–positive NSCLC, the efficacy and safety of selective RET inhibition are unknown. METHODS: We enrolled patients with advanced RET fusion–positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1–2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS: In the first 105 consecutively enrolled patients with RET fusion–positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event. CONCLUSIONS: Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion–positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.)

Functional or unexplained medical symptoms (physical symptoms that are not adequately explained by organic factors and where a major role for psychological factors is assumed) are common amongst children in the general population but can also be an expression of somatisation and somatoform disorders. Co-morbid psychopathology is common. We describe measures mostly used in research into problems related to somatisation in children and adolescents that may be helpful to clinical researchers. Some address the nature and severity of physical symptoms, others document illness attitudes, beliefs and functional impairment, and a third group assesses emotional symptoms. Questionnaires can be helpful for clinicians in quantifying (i) the nature and severity of somatic symptoms and associated functional impairment, (ii) contributory health attitudes and illness beliefs and (iii) co-morbid or primary anxiety and depressive disorders. Together with pain and activity diaries and careful documentation of school attendance, these measures may also be helpful in monitoring treatment response.

This paper addresses child and adolescent psychopathology as it presents to general practitioners and paediatricians, and explores psychosocial aspects of unexplained medical symptoms in children and adolescents. High rates of psychopathology have been identified amongst children and adolescents attending general practice and paediatric services, most of it ‘‘hidden’’ at presentation and emotional in nature. It is often linked to poor physical well being and to maternal stress focused on the child. It may be of special relevance to medical help seeking in socio-economically advantaged areas. Co-morbid psychopathology, mainly emotional disorders, is common amongst children with unexplained medical symptoms. However, there are specific psychosocial aspects that differentiate these children from those with emotional disorders. They involve disease beliefs, illness behaviour and predicament. The latter may be characterised by special reactivity to stress in children with personality vulnerability, in a context of parents with high levels of mental distress, unexplained medical symptoms and emotional over-involvement with the child. There is comparatively little interface work between CAMHS and primary health care. An important research priority would seem to lie in the development of interventions that can be adapted for use by primary care staff. Similarly, there are few dedicated CAMHS paediatric liaison teams. Their more extensive development should help attend in a more informed and focused way than at present to children and adolescents suffering from unexplained physical symptoms and disorders. Further research is needed into vulnerability mechanisms and maintaining factors, health beliefs, treatment engagement and interventions.

Oncologia de precisió; Assaigs clínics; Preselecció molecular Oncología de precisión; Ensayos clínicos; Preselección molecular Precision oncology; Clinical Trials; Molecular prescreening Most academic precision oncology programs have been designed to facilitate enrollment of patients in early clinical trials with matched targeted agents. Over the last decade, major changes were seen both in the targetable molecular alteration landscape and in drug development trends. In this article, we describe how the Vall d’Hebron Institute of Oncology molecular prescreening program adapted to a dynamic model of biomarker-drug codevelopment. We started with a tumor-agnostic hotspot mutation panel plus in situ hybridization and immunohistochemistry of selected markers and subsequently transitioned to tumor-specific amplicon-based next-generation sequencing (NGS) tests together with custom copy number, fusion, and outlier gene expression panels. All assays are optimized for archived formalin-fixed paraffin-embedded tumor tissues without matched germline sequencing. In parallel, biomarker-matched trials evolved from a scenario of few targets and large populations (such as PI3K inhibitors in PIK3CA mutants) to a complex situation with many targets and small populations (such as multiple targetable fusion events). Recruitment rates in clinical trials with mandatory biomarkers decreased over the last 3 years. Molecular tumor board meetings proved critical to guide oncologists on emerging biomarkers for clinical testing and interpretation of NGS results. The substantial increase of immunotherapy trials had a major impact in target prioritization and guided clinical implementation of new markers, such as tumor mutational burden, with larger exon-based NGS assays and gene expression signatures to capture microenvironment infiltration patterns. This new multiomics era of precision oncology is expected to increase the opportunities for early clinical trial matching.

According to the NCI experimental Therapeutics Program (NeXT) definition pharmacodynamic biomarkers (PD) are molecular indicators of the drug’s effect on the target in an organism.

Purpose: Despite the wide use of antiangiogenic drugs in the clinical setting, predictive biomarkers of response to these drugs are still unknown. Experimental Design: We applied whole-exome sequencing of matched germline and basal plasma cell-free DNA samples (WES-cfDNA) on a RAS/BRAF/PIK3CA wild-type metastatic colorectal cancer patient with primary resistance to standard treatment regimens, including inhibitors to the VEGF:VEGFR2 pathway. We performed extensive functional experiments, including ectopic expression of VEGFR2 mutants in different cell lines, kinase and drug sensitivity assays, and cell- and patient-derived xenografts. Results: WES-cfDNA yielded a 77% concordance rate with tumor exome sequencing and enabled the identification of the KDR/VEGFR2 L840F clonal, somatic mutation as the cause of therapy refractoriness in our patient. In addition, we found that 1% to 3% of samples from cancer sequencing projects harbor KDR somatic mutations located in protein residues frequently mutated in other cancer-relevant kinases, such as EGFR, ABL1, and ALK. Our in vitro and in vivo functional assays confirmed that L840F causes strong resistance to antiangiogenic drugs, whereas the KDR hot-spot mutant R1032Q confers sensitivity to strong VEGFR2 inhibitors. Moreover, we showed that the D717V, G800D, G800R, L840F, G843D, S925F, R1022Q, R1032Q, and S1100F VEGFR2 mutants promote tumor growth in mice. Conclusions: Our study supports WES-cfDNA as a powerful platform for portraying the somatic mutation landscape of cancer and discovery of new resistance mechanisms to cancer therapies. Importantly, we discovered that VEGFR2 is somatically mutated across tumor types and that VEGFR2 mutants can be oncogenic and control sensitivity/resistance to antiangiogenic drugs. Clin Cancer Res; 24(15); 3550–9. ©2018 AACR.

The receptor tyrosine kinase rearranged during transfection (RET) is an oncogenic driver activated in multiple cancers, including non–small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and papillary thyroid cancer. No approved therapies have been designed to target RET; treatment has been limited to multikinase inhibitors (MKI), which can have significant off-target toxicities and limited efficacy. BLU-667 is a highly potent and selective RET inhibitor designed to overcome these limitations. In vitro, BLU-667 demonstrated ≥10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants. In vivo, BLU-667 potently inhibited growth of NSCLC and thyroid cancer xenografts driven by various RET mutations and fusions without inhibiting VEGFR2. In first-in-human testing, BLU-667 significantly inhibited RET signaling and induced durable clinical responses in patients with RET-altered NSCLC and MTC without notable off-target toxicity, providing clinical validation for selective RET targeting. Significance: Patients with RET-driven cancers derive limited benefit from available MKIs. BLU-667 is a potent and selective RET inhibitor that induces tumor regression in cancer models with RET mutations and fusions. BLU-667 attenuated RET signaling and produced durable clinical responses in patients with RET-altered tumors, clinically validating selective RET targeting. Cancer Discov; 8(7); 836–49. ©2018 AACR. See related commentary by Iams and Lovly, p. 797. This article is highlighted in the In This Issue feature, p. 781

Purpose: Vanucizumab is an investigational antiangiogenic, first-in-class, bispecific mAb targeting VEGF-A and angiopoietin-2 (Ang-2). This first-in-human study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of vanucizumab in adults with advanced solid tumors refractory to standard therapies. Experimental Design: Patients received escalating biweekly (3–30 mg/kg) or weekly (10–30 mg/kg) intravenous doses guided by a Bayesian logistic regression model with overdose control. Results: Forty-two patients were treated. One dose-limiting toxicity, a fatal pulmonary hemorrhage from a large centrally located mediastinal mass judged possibly related to vanucizumab, occurred with the 19 mg/kg biweekly dose. Arterial hypertension (59.5%), asthenia (42.9%), and headache (31%) were the most common toxicities. Seventeen (41%) patients experienced treatment-related grade ≥3 toxicities. Toxicity was generally higher with weekly than biweekly dosing. A MTD of vanucizumab was not reached in either schedule. Pharmacokinetics were dose-linear with an elimination half-life of 6–9 days. All patients had reduced plasma levels of free VEGF-A and Ang-2; most had reductions in KTRANS (measured by dynamic contrast-enhanced MRI). Two patients (renal cell and colon cancer) treated with 30 mg/kg achieved confirmed partial responses. Ten patients were without disease progression for ≥6 months. A flat-fixed 2,000 mg biweekly dose (phamacokinetically equivalent to 30 mg/kg biweekly) was recommended for further investigation. Conclusions: Biweekly vanucizumab had an acceptable safety and tolerability profile consistent with single-agent use of selective inhibitors of the VEGF-A and Ang/Tie2 pathway. Vanucizumab modulated its angiogenic targets, impacted tumor vascularity, and demonstrated encouraging antitumor activity in this heterogeneous population. Clin Cancer Res; 24(7); 1536–45. ©2017 AACR.

Background Exploratory research showed that female oncologists are frequently under-represented in leadership roles. European Society for Medical Oncology (ESMO) Women for Oncology (W4O) therefore implemented gender equality programs in career development and established international studies on female representation at all stages of the oncology career pathway. Methods For 2017-2019, data were collected on (i) first and last authorship of publications in five major oncology journals and (ii) representation of women in leadership positions in oncology—as invited speakers at National/International congresses, board members or presidents of National/International societies and ESMO members. The 2015/2016 data from the first published W4O Study were incorporated for comparisons. Results Across 2017-2019, female oncologists were significantly more likely to be first than last authors (P < 0.001). The proportion of female first authors was similar across years: 38.0% in 2017, 37.1% in 2018, 41.0% in 2019 (P = 0.063). The proportion of female last authors decreased from 30.4% in 2017 to 24.2% in 2018 (P = 0.0018) and increased to 28.5% in 2019 (P = 0.018). Across 2015-2019, invited speakers at International/National oncology congresses were significantly less likely to be female than male (P < 0.001; 29.7% in 2015 to 36.8% in 2019). Across 2016-2019, board members of International/National oncology societies were significantly less likely to be female than male (P < 0.001; 26.8% in 2016 to 35.8% in 2019). There were statistically significant increasing trends in female speakers and board members across the study periods (P < 0.001 for both). Societies with a female president had a higher proportion of female board members across these periods (P = 0.026). Conclusions Reported progress towards gender equality in career development in oncology is real but slow. Women in leadership positions are essential for encouraging young women to aspire to and work towards similar or greater success. Therefore, continued monitoring is needed to inform ESMO W4O initiatives to promote gender balance at all stages of the career pathway., Highlights • Across 2017-2019, female oncologists were significantly more likely to be first than last authors (P < 0.001). • Across 2015-2019, invited speakers at International/National oncology congresses were significantly less likely to be female. • Across 2016-2019, board members of International/National oncology societies were significantly less likely to be female. • Societies with a female president had a higher proportion of female board members across these periods. • Reported progress towards gender equality in career development in oncology is real but slow.

BackgroundWe presented EVICTION Trial data from patients with solid tumors that showed microgram doses of ICT01 rapidly activate γ9δ2 T cells that release inflammatory cytokines (e.g., IFNγ) and traffic from the circulation (Abstract #316, SITC 2020). Confirming tumor infiltration of activated γ9δ2 T cells and the subsequent clinical benefit are the next steps in characterizing the therapeutic potential of ICT01.MethodsEVICTION is an ongoing Phase 1/2a, EU and US trial assessing ICT01 monotherapy (IV Q3W) in advanced/refractory solid and hematologic cancers, and ICT01 in combination with pembrolizumab (200mg IV Q3W) in solid tumor patients who failed ≥1 CPI. Pharmacodynamic activity was monitored by immunophenotyping and cytokine level analysis. Tumor biopsies (baseline, Day 28) were used for immunohistochemistry of BTN3A and tumor-infiltrating lymphocytes, and gene expression profiling. Efficacy evaluations were conducted every 8 weeks.ResultsICT01 monotherapy dose escalation (20µg to 200mg IV ICT01 Q3W) in solid tumor patients (Group A, n=32) has been completed, and 3 dose cohorts of ICT01 (700µg, 2 and 7 mg) plus Pembro (Group C, n=12) were completed; both without any DLTs. First-dose fever and chills (Grade 1/2) were the most common AEs that increased in frequency but not severity with dose and did not recur.ICT01 induced trafficking of >95% of circulating γ9δ2 T cells within 30 min post ICT01 (≥2mg), which was sustained for 21 days at doses ≥75mg. Transient, dose-dependent increases in serum cytokines at 30 min (TNFα) or 4h (IFNγ) post-dose were correlated with baseline γ9δ2 T cell counts and with activation and migration of NK and CD8 T cells out of the blood at doses ≥7mg. Higher baseline circulating γ9δ2 T cells and lower TILs were associated with more robust intra-tumoral increases in total γδ(3–34x increase), CD3 (3–55x increase) and CD8 T cells (1.3–66x increase), which demonstrated the potential to transform an immune desert tumor phenotype. Disease control by ITT analysis of RECIST1.1 data was observed in 6/32 (SD) and 4/7 patients (3 SD (bladder, melanoma, NSCLC), 1 PR (bladder)) in Groups A and C, respectively, with 5/6 patients at 7mg in Group C not yet evaluable.ConclusionsThese results show a broad antitumor immune response in the blood and tumors comprising γ9δ2, CD8 T cell, and NK cell activation and tumor-infiltration following ICT01 alone and in combination with pembrolizumab. Preliminary efficacy data suggest low-dose ICT01 plus pembrolizumab may be more effective than ICT01 monotherapy for advanced/refractory solid tumors, which requires confirmation.AcknowledgementsLena Daher for her medical/scientific writing support.Trial Registration www.clinicaltrials.gov NCT04243499; EudraCT Number: 2019-003847-31Ethics ApprovalThis study was approved by the following Ethics Committees: COMITE DE PROTECTION DES PERSONNES, Sud-Méditerranée V (Gustave Roussy, IPC, Nantes), Comité d’Ethique Institut Jules Bordet, COMITÉ DE ÉTICA DE INVESTIGACIÓN CLÍNICA CON MEDICAMENTOS del Hospital Universitari Vall d’Hebron, Ethikkommission an der TU Dresden, HRA London-Surrey Borders Research Ethics Committee.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

BackgroundTransforming growth factor beta (TGFβ) is a bifunctional regulator of tumor growth playing a role in tumor immune evasion and resistance to checkpoint blockade. Increased activation of TGFβ pathway correlated with reduced overall survival in patients with PD-1 resistance/refractory tumors. Therefore, the combination of a TGFβ inhibitor with an anti-PD-1 agent may benefit patients who are resistant to checkpoint blockade. SAR439459 is a ”second generation” human anti-TGFβ IgG4 monoclonal antibody. Here we report the preliminary PD results and patient selection strategy (mesenchymal CRC) of SAR439459 ± anti-PD-1 cemiplimab in patients with advanced tumors from an on-going phase 1 study (NCT03192345).MethodsPeripheral blood, serum and tumor biopsies from patients were collected for the assessment of both predictive and PD biomarkers. A consensus molecular subtyping 4 (CMS4) gene classifier was developed and used to identify mesenchymal CRC tumors based on an in-silico experiment followed by a validation using ~200 procured CRC tumor biopsy samples with customized NanoString assay. TGFβ level in plasma and tumor was measured by ELISA to assess target engagement of SAR439459. Well-known immune modulation events as the PD readout were measured: 1) immunophenotyping of circulating immune cells ; 2) cytokine/chemokine production by MSD assay; 3) PD-L1, CD8+ T cells and FoxP3+ Tregs in tumor micro-environment (TME) by immunohistochemistry; 4) TGFβ pathway activation gene signature in TME by RNAseq.ResultsSAR439459 ± cemiplimab, induced inhibition of plasma TGFβ level ≥ 90% at doses ≥ 0.25mg/kg Q2W, together with a clear trend of decrease in intra-tumoral TGFβ. RNAseq data from paired biopsies revealed concomitant down-regulation of TGFβ pathway. In periphery, SAR439459 ± cemiplimab increased proliferating T and NK cells. Concomitantly, enhanced production of pro-inflammatory cytokines/chemokines confirmed peripheral immune activation. In TME, a trend of increased CD8+ T cell infiltration and conversion from ”immune-excluded” to ”immune-inflamed” phenotype was observed following the combination treatment in several cases. No significant modulation of PD-L1 or FoxP3 was observed from the available paired biopsies. Out of 137 pre-screened CRC patients, 58 (42%) were identified as carrying the CMS4 phenotype based on the gene classifier.ConclusionsClinical modulation of TGFβ level and the related pathway demonstrated SAR439459’s target engagement. Further analysis confirmed the peripheral immune activation in patients treated with SAR439459 ± cemiplimab. Coupled with CD8+ T cell modulation in TME, these findings suggest the identification of early PD biomarkers impacted by SAR439459 which is consistent with the mechanism of action and biological activity of TGFβ blockade therapy.Trial RegistrationNCT03192345Ethics ApprovalThe study protocols were approved by the institutional review board or independent ethics committee of each participating institution. All patients provided written informed consent priorto enrollment.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

BackgroundT-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory domains (TIGIT), and costimulatory receptor CD226 competitively bind 2 ligands, CD155 and CD112, which are expressed by tumor cells and antigen-presenting cells in the tumor microenvironment.1 2 Dual TIGIT/programmed cell death protein-1 (PD-1) blockade increased tumor antigen-specific CD8+ T-cell expansion and function in vitro and promoted potent antitumor response in vivo.3 4 TIGIT/PD-1 dual blockade using a TIGIT monoclonal antibody (mAb) with intact Fc produced clinical responses in advanced cancer.5 SEA-TGT is an investigational, human, nonfucosylated mAb directed against TIGIT. SEA-TGT binds to TIGIT, blocking inhibitory checkpoint signals directed at T cells. SEA-TGT enhances binding to activating FcγRIIIa and decreases binding to inhibitory FcγRIIb; this depletes immunosuppressive regulatory T cells and amplifies naive and memory T cells, potentially augmenting PD-1 inhibition effects. Preclinically, at suboptimal doses, SEA-TGT plus anti-PD-1 mAbs had superior antitumor activity than either agent alone.6MethodsSafety and antitumor activity of SEA TGT in ~377 adults (≥18 years) will be evaluated in this phase 1, multicenter, open-label, dose-escalation/expansion study. Part A will assess the safety/tolerability of SEA TGT to determine maximum tolerated and recommended doses. Part B will assess the safety and antitumor activity of the recommended dose in disease-specific expansion cohorts. Part C will assess SEA-TGT plus sasanlimab in dose-expansion cohorts after an initial safety run-in. Patients with histologically/cytologically confirmed relapsed/refractory/progressive metastatic solid tumors including non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), gastric/gastroesophageal junction carcinoma, cutaneous melanoma, bladder, cervical, ovarian or triple-negative breast cancer, or selected lymphomas will be eligible for Parts A and B. Part C will enroll patients with histologically confirmed advanced NSCLC (high [tumor proportion score (TPS) ≥50%] and low [TPS=1–49%] PD ligand 1 [PD-L1] expression), cutaneous melanoma, and HNSCC without previous anti–PD-1/PD-L1 therapy exposure. SEA TGT will be administered on Day 1 of 21-day cycles.Laboratory abnormalities, adverse events, dose-limiting toxicities, and dose-level safety and activity are primary endpoints. Secondary endpoints are objective response (OR) and complete response (CR) rates, duration of OR/CR, progression-free survival, overall survival, pharmacokinetics (PK), and antidrug antibodies. Exploratory analysis will include pharmacodynamics (PD), PK/PD relationships, biomarkers, and resistance to SEA-TGT. This trial is recruiting in Europe and North America.Trial RegistrationNCT04254107ReferencesBlake SJ, Dougall WC, Miles JJ, et al. Molecular pathways: Targeting CD96 and TIGIT for cancer immunotherapy. Clin Cancer Res 2016;22(21):5183–5188.Chauvin JM, Zarour HM. TIGIT in cancer immunotherapy. J ImmunoTher Cancer 2020;8:e000957.Johnston RJ, Comps-Agrar L, Hackney J, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell 2014;26(6):923–937.Chauvin JM, Pagliano O, Fourcade J, et al. TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J Clin Invest 2015;125(5):2046–2058.Rodriguez-Abreu D, Johnson ML, Hussein MA, et al. Primary analysis of a randomized, double-blind, phase 2 study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). J Clin Oncol 2020;38(15 suppl):9503.Smith A, Zeng W, Lucas S, et al. Poster 1583. SEA-TGT is an empowered anti-TIGIT antibody that displays superior combinatorial activity with several therapeutic agents. Presented at: American Association for Cancer Research Annual Meeting; April 9–14, 2021; Virtual Meeting.Ethics ApprovalInstitutional review boards or independent ethics committees of participating sites approved the trial, which will be conducted in compliance with the Declaration of Helsinki and International Conference on Harmonisation Guidelines for Good Clinical Practice. All patients will provide written informed consent.

BackgroundSO-C101 (IL 15/IL-15Rα sushi + domain fusion protein) was investigated in a multicenter, open-label, dose escalation study as monotherapy and in combination with pembrolizumab in patients with selected advanced/metastatic tumors (NCT04234113). Synergistic effects of SO-C101 and an anti-programmed cell death protein 1 (PD-1) antibody have been validated in various tumor mouse models inducing a protective memory response.MethodsThe combination part of the study follows a classical 3+3 dose escalation design. Study objectives are to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). The evaluation period for dose-limiting toxicities in each dose step is 21 days. The RP2D is defined as MTD or a dose below, taking into consideration pharmacokinetic and pharmacodynamic parameters.The study is ongoing (data cut-off 21 June 2021).ResultsA total of 12 patients with a median of 2 (range 1–6) lines of previous systemic therapies were treated at SO-C101 dose levels 1.5 µg/kg (3 patients), 3.0 µg/kg (3 patients), and 6.0 µg/kg (6 patients) together with 200 mg of pembrolizumab. One dose-limiting toxicity of grade (G) 3 cytokine release syndrome (CRS) was observed in one patient at 6.0 µg/kg. The MTD has not yet been reached.Of the treated patients, 2 had long-term stable disease (anal squamous cell carcinoma patient at 1.5 µg/kg, duration 25 weeks; gastric carcinoma patient at 3.0 µg/kg, duration 14 weeks) and 3 achieved a partial response (thyroid gland cancer patient at 3.0 µg/kg, target lesion decrease by 36%; skin squamous cell carcinoma patient at 6.0 µg/kg, target lesion decrease by 40%; and melanoma patient at 6.0 µg/kg, target lesion decrease by 58%). The patients with skin squamous cell carcinoma and melanoma had previously progressed on anti-PD-1 therapy, while the patient with thyroid cancer was anti-PD-1 naïve.The most common study drug-related adverse events were lymphopenia, local injection site reactions, transaminase increase, fever, chills as well as CRS-related symptoms (all mainly G1 or G2 and resolved). The only study drug-related adverse event >G2 that occurred in more than one patient was lymphopenia. No treatment-related death was reported.ConclusionsAlthough the MTD of SO-C101 in combination with pembrolizumab has not been reached yet, clinical efficacy signals were already observed in 5 patients. Available safety data indicate good tolerability. SO-C101 in combination with pembrolizumab has already shown the potential to provide an additional clinical benefit to patients with solid tumors.Trial RegistrationNCT04234113Ethics ApprovalThis study was approved by the FDA (IND 140011) and by the Ethics Boards of participating institutions

Background: Toll-like receptors (TLRs), including TLR7, are involved in innate immune signaling. LHC165 is a TLR7 agonist which activates signaling pathways, increases cytokine release and promotes effector T-cell antitumor activity. In mouse models LHC165 treatment led to inhibition of tumor growth, and combination with an anti-PD-1 agent had more effective inhibition than either treatment alone. Methods: LHC165X2101 is a Phase I/Ib open-label dose-escalation/-expansion trial of LHC165 single agent (SA) ± spartalizumab, an anti-PD-1 mAb (NCT03301896). Eligible pts (≥18 yrs, ECOG 0-2) with advanced/metastatic solid tumors were treated with LHC165 SA (100-600 µg, Q2W intratumoral injection) ± spartalizumab (400 mg, Q4W IV). Primary objective was to assess safety and tolerability. Dose-escalation data are presented. Results: As of the data cutoff Sept 18, 2020, 39 pts enrolled; 20 pts received LHC165 SA and 19 pts combination. Median age 56 y, ECOG ≤1, median prior IO therapies: 2 (1-8) in SA pts, 3 (1-7) in combination pts. 37 (95%) pts discontinued: 27 (69%) progressive disease; 4 (10%) pt decision; 2 (5%) AEs; 2 (5%) completed treatment; and 2 (5%) pts died, treatment unrelated. 1 DLT of Gr 3 reversible pancreatitis was observed (LHC165 400 µg + spartalizumab 400 mg). AEs suspected to be treatment related observed in 22 (56%) pts; Gr ≥3 in 2 (5%) pts, 1 pt with lymphopenia and neutropenia, and 1 pt with pancreatitis. BOR in all pts was 3 PRs (all IO pretreated) and 4 SDs (1 IO pretreated). DCR (95%) was 18% (7.5%-33.5%). Median DOE (wks) was 4.5 (1.1-25.0) for SA pts, 11.9 (4.0-48.3) for combination pts. RDE was declared LHC165 600 µg ± spartalizumab 400 mg, with promising results in pts with melanoma and HNSCC. Systemic cytokine increases (CXCL10, IFNγ, IL6) were notable in a subset of pts following LHC165 ± spartalizumab. Immunohistochemistry tended to show higher baseline tumoral levels of CD8 and CD68 in pts with PR and on-treatment increases in pts with PR/SD. Tumoral RNA-sequencing showed higher T-cell inflammation at baseline in pts with PR and a consistent increase in T-cell inflammation in pts with PR/SD after treatment. Dose response relationships were not observed with available data. In most pts maximum LHC165 concentration was reached at around 1 hr, the first PK sampling time. Exposure of LHC165 ± spartalizumab increased with increasing dose of LHC165. Terminal half-life of LHC165 600 µg ranged from 9.4-58.9 hrs. No evidence of LHC165 accumulation over time or interaction between LHC165 and spartalizumab was noted. Conclusions: LHC165 ± spartalizumab demonstrated safety, tolerability, and evidence of preliminary antitumor activity. Exposure to LHC165 increased with dose, no interaction was observed with spartalizumab. Increased systemic cytokines and T-cell inflammation after LHC165 suggests active TLR7 agonism. Biomarker data suggest an active immune microenvironment at baseline is required for a response. Citation Format: Giuseppe Curigliano, Miguel Martin Jimenez, Toshio Shimizu, Bhumsuk Keam, Funda Meric-Bernstam, Annemie Rutten, John Glaspy, Nehal S. Parikh, Mary Ising, Nadia Hassounah, Jincheng Wu, Kun Xu, Somesh Choudhry, Elena Garralda. Phase I study of LHC165 ± spartalizumab (PDR001) in patients (pts) with advanced solid tumors [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 CT103.

Background/Purpose Activation of the stimulator of interferon genes (STING) pathway in intratumoral immune cells leads to increased type I interferon production, promoting recruitment and priming of T-cells against tumor antigens and triggering anti-tumor activity. In patients with cancer, STING agonists have shown clinical activity, with effects increased when combined with an anti-programmed cell death [PD]-1 antibody. BI 1387446 potently and highly selectively activates the STING pathway; ezabenlimab (BI 754091) is a humanized IgG4 anti-PD-1 monoclonal antibody. Tumor regression and enhanced activity of anti-PD-1 therapy was observed after BI 1387446 administration in syngeneic tumor models. Methods NCT04147234 is a first-in-human, Phase I, open-label, multicenter trial of BI 1387446 recruiting a planned 122 patients from six sites across Europe and the USA. Patients will have advanced, unresectable and/or metastatic solid tumors. The main objectives are to characterize safety and determine the maximum tolerated dose (MTD) of BI 1387446 alone and in combination with ezabenlimab. BI 1387446 will be administered intratumorally at escalating doses as monotherapy in Arm A (~34 patients), and + ezabenlimab (240 mg every 3 weeks, IV) in Arm B (~44 patients); BI 1387446 will be administered in superficial lesions in both Arms. In a potential Arm C (~44 patients), BI 1387446 will be administered in deep/visceral lesions + ezabenlimab, IV. Arm B will open at the starting dose level once the starting dose level in Arm A is considered safe by the safety monitoring committee; Arm C may open at the starting dose level once this dose level is considered safe in Arm B. Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control. Patients (≥18 years of age) must have exhausted standard treatment options, have ≥1 tumor lesion suitable for injection, ≥1 additional tumor lesion amenable to biopsy, and ECOG performance status ≤1. Treatment will continue until progressive disease, unacceptable toxicity, other withdrawal criteria, or for a maximum of 34 cycles (for cycles 19–34, only patients with partial response will receive BI 1387446), whichever occurs first. Primary endpoints are the MTD based on number of dose-limiting toxicities (DLTs) and number of patients with DLTs. Secondary endpoints are objective response rate (based on RECIST 1.1 criteria) and best change from baseline in size of target and injected (and uninjected) lesions. Plasma, blood, and tumor tissue will be collected at baseline and on-therapy for pharmacodynamic analyses. The trial is actively recruiting, and eight patients have been treated as of December 2020. Citation Format: Kevin Harrington, Eileen Parkes, Jared Weiss, Mathew Ingham, Andrés Cervantes, Emiliano Calvo, Ute Klinkhardt, Patricia Sikken, Michael Schmohl, Elena Garralda. Phase I, first-in-human trial evaluating BI 1387446 (STING agonist) alone and in combination with ezabenlimab (BI 754091; anti-PD-1) in solid tumors [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 CT217.