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Immune-checkpoint inhibitors and chimeric antigen receptor (CAR) T cells are revolutionizing oncology and haematology practice. With these and other immunotherapies, however, systemic biodistribution raises safety issues, potentially requiring the use of suboptimal doses or even precluding their clinical development. Delivering or attracting immune cells or immunomodulatory factors directly to the tumour and/or draining lymph nodes might overcome these problems. Hence, intratumoural delivery and tumour tissue-targeted compounds are attractive options to increase the in situ bioavailability and, thus, the efficacy of immunotherapies. In mouse models, intratumoural administration of immunostimulatory monoclonal antibodies, pattern recognition receptor agonists, genetically engineered viruses, bacteria, cytokines or immune cells can exert powerful effects not only against the injected tumours but also often against uninjected lesions (abscopal or anenestic effects). Alternatively, or additionally, biotechnology strategies are being used to achieve higher functional concentrations of immune mediators in tumour tissues, either by targeting locally overexpressed moieties or engineering ‘unmaskable’ agents to be activated by elements enriched within tumour tissues. Clinical trials evaluating these strategies are ongoing, but their development faces issues relating to the administration methodology, pharmacokinetic parameters, pharmacodynamic end points, and immunobiological and clinical response assessments. Herein, we discuss these approaches in the context of their historical development and describe the current landscape of intratumoural or tumour tissue-targeted immunotherapies., Limited penetration into tumour tissue can restrict the activity of systemically delivered cancer immunotherapies, whereas exposure of various non-malignant tissues to high levels of such agents can lead to problematic toxicities. Intratumoural administration and/or biotechnology strategies for selective targeting of tumour tissues have the potential to circumvent these issues and thereby increase the therapeutic index. Herein, the authors review the historical origins and current landscape of intratumoural and tumour tissue-targeted immunotherapies., Key points Repeated intratumoural injections with agents designed to enhance antitumour immune responses constitutes a feasible strategy to reduce the risk of systemic toxicities and achieve higher local bioactive drug concentrations. Spearheaded by the oncolytic virus talimogene laheparepvec, the first intratumoural immunotherapy approved by the FDA and EMA, and supported by a strong preclinical rationale, many intratumoural immunotherapies are now being developed in clinical trials. These immunotherapies include microorganisms (viruses or bacteria) and synthetic compounds mimicking infectious agents (such as pattern recognition receptor agonists), as well as immunomodulatory monoclonal antibodies, cytokines and chimeric proteins. Higher locoregional concentrations of immunotherapy agents can also be achieved through molecular engineering, for example, to target them towards moieties that are enriched in the tumour microenvironment. Increased specificity in tumour targeting can also be attained through the development of prodrug forms of immunotherapies that become functional only after entering tumour tissue (pro-immunodrugs). Procedural, pharmaceutical, regulatory and analytical challenges require multidisciplinary expert consensus and systematic research to maximize the potential of these modes of administration.

Background: Triple-negative breast cancer (TNBC) is associated with poor survival outcomes and treatment options are limited. These tumors lack therapeutic targets and become rapidly resistant to chemotherapy. The anti–PD-1 antibody pembrolizumab showed durable antitumor activity and manageable safety in patients with TNBC in the KEYNOTE-012, KEYNOTE-086, and KEYNOTE-119 studies. The combination of lenvatinib, an antiangiogenic multiple receptor tyrosine kinase inhibitor, with pembrolizumab has shown promising clinical outcomes in early-phase clinical trials across several cancer types. LEAP-005 (ClinicalTrials.gov, NCT03797326) is an ongoing study evaluating the efficacy and safety of lenvatinib combined with pembrolizumab in patients with previously treated advanced solid tumors. Here, we report the first results from the TNBC cohort of LEAP-005. Methods: This ongoing, multicohort, open-label, phase 2 study enrolled patients aged ≥18 y with previously treated, histologically or cytologically confirmed advanced TNBC. PD-L1 expression was assessed at a central laboratory using the PD-L1 IHC 22C3 pharmDx assay and measured using the combined positive score (CPS; number of PD-L1–positive tumor cells, lymphocytes, and macrophages divided by total number of tumor cells x 100). Patients received lenvatinib 20 mg once daily orally plus pembrolizumab 200 mg every 3 weeks intravenously for a maximum of 35 pembrolizumab doses, then lenvatinib alone until progressive disease or unacceptable toxicity. Primary endpoints were objective response rate (ORR) by blinded independent central review per RECIST version 1.1 and safety. Key secondary endpoints were disease control rate (DCR; defined as best overall response of complete response [CR], partial response [PR], or stable disease [SD] per RECIST v1.1), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Safety was monitored through 30 days after the last dose of study drug (90 days for serious AEs), with AEs graded using NCI CTCAE v4.0. Results: 31 patients have been enrolled in the TNBC cohort of LEAP-005. Median age was 56 y (range, 37 to 85), 58% had received ≥2 prior lines of therapy, and 26% had CPS ≥10 tumors. As of the April 10, 2020 data cutoff, median follow-up was 7 mo (range, 4 to 13). ORR was 29% (95% CI: 14–48), with 1 CR and 8 PRs. 9 pts had SD, and the DCR (CR + PR + SD) was 58% (95% CI: 39–76). 4 responses (1 CR and 3 PRs) were in patients with CPS ≥10 tumors (n=8) for an ORR of 50% (95% CI: 16–84), and 5 responses (all PRs) were in patients with CPS Citation Format: Hyun Cheol Chung, Esma Saada-Bouzid, Federico Longo Muñoz, Eduardo Yanez, Seock-Ah Im, Eduardo Castanon, Donna M. Graham, Javier Garcia-Corbacho, Juanita Lopez, Razi Ghori, Corina Dutcus, Alan Smith, Kevin Norwood, Carlos Gomez-Roca. Lenvatinib plus pembrolizumab for previously treated, advanced triple-negative breast cancer: Early results from the multicohort phase 2 LEAP-005 study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-07.

New patterns of progression under immune-oncology (IO) antibodies (mAb) have been described such as pseudoprogression. Except for melanoma, variations between studies reveal difficulties to establish their prevalence. This retrospective study enrolled patients participating in IO phase I trials at Gustave Roussy cancer center for solid tumors excluding melanoma. Radiological assessment according to iRECIST was correlated with prospectively registered patient characteristics and outcomes. Pseudoprogression (PsPD) was defined as RECIST-defined progression followed by stabilization or decrease at the next imaging, and dissociated response (DisR) as concomitant decrease in some tumor lesions and increase in others at a same timepoint. Among 360 patients included, 74% received IO mAb combination: 45% with another IO mAb, 20% with targeted therapy and 10% with radiotherapy. The overall response rate was 19.7%. PsPD were observed in 10 (2.8%) patients and DisR in 12 (3.3%) patients. Atypical responses (AR), including PsPD and DisR, were not associated with any patient’s baseline characteristics. Compare with typical responder patients, patients experiencing AR presented a shorter iPFS (HR 0.34; p

Resumen Introduccion y objetivos Diferentes estudios han demostrado el valor diagnostico y pronostico de la resonancia magnetica cardiaca (RMC) de estres en pacientes con cardiopatia isquemica. No obstante, la evidencia en ancianos es escasa, en parte por las limitaciones de las tecnicas diagnosticas disponibles para esta poblacion. El objetivo de este estudio es evaluar la utilidad de la RMC de estres en pacientes ancianos. Metodos Se estudio de manera prospectiva a los pacientes remitidos a una RMC de estres para descartar isquemia miocardica. Se considero paciente anciano a los mayores de 70 anos. El estudio de RMC de estres se realizo conforme a los protocolos internacionales. La gravedad de la hipoperfusion se clasifico en funcion de los segmentos afectados: ligera (1-2 segmentos), moderada (3-4 segmentos) o grave (> 4 segmentos). Se analizo la aparicion de eventos mayores durante el seguimiento (muerte, sindrome coronario agudo o revascularizacion). La supervivencia se analizo con el metodo de Kaplan-Meier y un modelo de regresion multivariante de Cox. Resultados De la cohorte inicial de 333 pacientes, 110 eran mayores de 70 anos. En el 40,9% de estos, la RMC de estres fue positiva para isquemia. La mediana de seguimiento fue de 26 [18-37] meses. En los pacientes ancianos se registraron 35 eventos: 15 fallecimientos, 10 sindromes coronarios agudos y 10 revascularizaciones. Los pacientes con isquemia moderada o grave tenian mayor riesgo de eventos ajustado por edad, sexo y riesgo cardiovascular (HR = 3,53; IC95%, 1,41-8,79; p = 0,01). Conclusiones La presencia de hipoperfusion moderada o grave detectada mediante RMC de estres predice de manera significativa la aparicion de eventos en mayores de 70 anos, sin que aparezcan efectos adversos relevantes.

BackgroundIntratumoral immunotherapies are being tested in different solid tumors. They trigger local and systemic responses.1 2 BO-112 is a double stranded RNA nanoplexed with polyethyleneimine (PEI), which mimics a viral infection and mobilizes the immune system.In preclinical models and in a first in human clinical trial BO-112 activated dendritic cells, induced CD-8 infiltration, apoptosis and enhancement of immunogenic cell death and achieved an objective response in 2 out of 10 patients with melanoma with primary resistance to antiPD-1.3 4MethodsIn this phase 2 study, BO-112 plus pembrolizumab is evaluated in patients with advanced melanoma, who have developed progressive disease while on or within 12 weeks after anti-PD1/PD-L1 based therapy (either as first line or as adjuvant treatment). BO-112 is administered intratumorally once weekly in 1 to 8 tumor lesions, total dose 1 to 2 mg, for the first 7 weeks and thereafter every three weeks; pembrolizumab 200 mg is administered intravenously every three weeks. Overall response rate (ORR) is analyzed as primary endpoint by independent reviewer. Secondary objectives include disease control rate (DCR), duration of response and progression free survival (PFS); response assessment is done by RECIST 1.1 and iRECIST; in addition, CD-8 and PD-L1 IHC, NGS, itRECIST and radiomics signatures are prospectively assessed. Key eligibility criteria include cutaneous or mucosal melanoma with known BRAF status; at least one lesion RECIST 1.1 measurable and amenable for IT injection. Enrollment has been completed on 26th August.ResultsWith 26 evaluable patients with a first response assessment, seven have progressive disease (PD), five have partial response (PR) and fourteen patients show stable disease (SD). Preliminary ORR is 19.2% and DCR is 73.1% at week 8. Three patients with PR at week 8 have undergone a second assessment at week 16, with further decrease in sum of diameters (SOD) in both injected and non-injected lesions. Three out of five patients with SD and a second assessment maintain SD, showing a decrease in SOD in two cases (figure 1). In addition, two patients with only skin lesions have a pathological complete response. CD8 and PD-L1 have increased in 8 and 7 out of 13 patients with paired biopsies, being related with clinical benefit (figure 2).Abstract 961 Figure 1Swimmer plot, efficacy data for evaluable patients undergoing at least one response assessmentAbstract 961 Figure 2Immunohistochemistry data for CPS and CD8 data from paired biopsiesConclusionsDespite these data being preliminary, there is a trend for benefit in terms of ORR and also in long lasting stable diseases. BO-112 is able to increase PD-L1 expression in tumor cells and increase CD8-T cell infiltrates.AcknowledgementsMerck, Pivotal SLU, Quibim radiomics, Pangaea laboratories, all participating sites and patientsTrial RegistrationNCT04570332ReferencesAznar MA, Planelles L, Perez-Olivares M, et al. Immunotherapeutic effects of intratumoral nanoplexed poly I:C. J Immunother Cancer. 2019 May 2;7(1):116.5. Hamid O, Ismail R, Puzanov I. Intratumoral immunotherapy-update 2019. The Oncologist 2020;25:e423–438.Márquez-Rodas I, Longo F, Rodríguez-Ruiz M, et al. Intratumoral nanoplexed poly I:C BO-112 in combination with systemic anti-PD-1 for patients with anti-PD-1-refractory tumors. Sci Transl Med 2020 Oct 14;12(565):eabb0391.Kalbasi A, Tariveranmoshabad M, Hakimi K, Kremer S, et al. A. Uncoupling interferon signaling and antigen presentation to overcome immunotherapy resistance due to JAK1 loss in melanoma. Sci Transl Med 2020 Oct 14;12(565):eabb0152.Ethics ApprovalThe study obtained ethics approval by Spanish Health Agency (AEMPS), on 11th December 2020, and French Health Agency (ANSM) on 27th January 2021; study obtained approval from two Ethics Committee: Vall D’Hebron, Barcelona, Spain on 7th December 2020 (number 467), and Centre Léon Bérard, Lyon, France, CPP 20.11.10.38825 on 11th February 2021.For each study patient, written informed consent is obtained prior to any protocol-related activities. As part of this procedure, the principal investigator or one of his/her associates must explain orally and in writing the nature, duration, and purpose of the study, and the action of the study drug in such a manner that the patient is aware of the potential risks, inconveniences, or adverse effects that may occur. They should be informed that the patient may withdraw from the study at any time. They will receive all information that is required by the regulatory authorities and ICH guidelines. The ICF has been signed by the patient and a copy provided to them.ConsentN/A

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.

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: BO-112 is a double stranded synthetic RNA formulated with polyethyleneimine that mimics a viral infection. Through dendritic cells activation, increase in CD8 T-cell infiltration and interferons induction, it produces an immunogenic cell death. Phase 1 study (NCT02828098) showed ORR 20% in patients (pts) with anti PD-1 resistant melanoma (mel). Hence phase 2 trial was designed. Study design: Single arm study (NCT04570332) with intratumoral BO-112 plus intravenous pembrolizumab in pts with mel (cutaneous, acral or mucosal) and confirmed progressive disease (PD) while on anti-PD1 based therapy. Pts were treated with BO-112, 1-2 mg on a weekly basis for 7 weeks and thereafter Q3W in 1-8 different lesions. Pembrolizumab 200 mg was administered Q3W. Primary endpoint was overall response rate (ORR) by RECIST 1.1 by independent reviewer. Secondary endpoints included disease control rate (DCR), progression free survival (PFS) and safety. Exploratory objectives included radiomic signatures, itRECIST and evaluation of tumor microenvironment. At least 20% of pts had to achieve response in order to consider primary endpoint met. Results: Recruitment was completed 24th August 2021 with 42 pts; female 43%; median age 66 (rank 27-88). Table summarizes basal characteristics. With 40 evaluable for response pts, 10 achieved response (25%): 3 complete response (CR) and 7 partial response (PR). 17 pts (44%) achieved a stable disease (SD), meaning a DCR of 68% with 18 pts still on treatment. The 4 pts with a baseline LDH>3xULN developed PD no later than week 8. Responses per histology were: 66% mucosal, 28% cutaneous, 0% acral. Responses per BRAF/NRAS status were: BRAF mutant (Mut) 43%, NRAS Mut 31%, and BRAF/NRAS wild type (WT) 17%. 33 pts (79%) had at least one BO-112 related adverse event (AE) being only in 2 cases grade>3 (G4 infusion reaction and G3 myalgia). Most common related AEs were asthenia, pyrexia, diarrhea, vomiting and chills. Study treatment was not discontinued in any pts due to related AE. Conclusions: The primary efficacy endpoint has been met. Additionally, disease control (PR+CR+SD) is meaningful and durable in a population with no current standard treatment options. Very high LDH levels (LDH >3xULN) and acral mel could predict poor outcome. Safety profile was manageable without treatment discontinuation due to AEs. N (ITT pts, 42) (%) AJCC8 M1C/D 19 (45) BRAF Mut 7 (17) WT 35 (83) Previous treatment Ipilimumab-nivolumab 6 (15) Anti PD-1 monotherapy 33 (79) Other combo 3 (7) Prior line indication Adjuvant 11 (26) Advanced 31 (74) LDH >ULN 17 (41) Best ORR (IRCR evaluable pts, N=40) Global Mucosal Cutaneous Acral ORR 10 (25) 2 (66) 8 (28) 0 PR 7 (18) 1 (33) 6 (21) 0 CR 3 (8) 1 (33) 2* (7) 0 SD 17 (43) 1 (33) 13 (45) 3 (37) PD 13 (33) 0 8 (28) 5 (63) *2 pts had pathologic CR and RECIST SD Citation Format: Iván Márquez-Rodas, Caroline Dutriaux, Philippe Saiag, Luis de la Cruz Merino, Eduardo Castanon Álvarez, Caroline Robert, Juan F. Rodríguez-Moreno, Ana M. Arance, Pablo Cerezuela-Fuentes, Henry Montaudié, Miguel F. Sanmamed, María González Cao, Julie Charles, María Pilar López Criado, Alfonso Berrocal, Enrique de Miguel, Elisa Funk-Brentano, Sorilla Prey, María del Carmen Álamo de la Gala, Javier Sánchez López, Helena Escuin-Ordinas, Sonia Macia, Marisol Quintero, Marya F. Chaney, Stéphane Dalle. Efficacy of intratumoral BO-112 with systemic pembrolizumab in patients with advanced melanoma refractory to anti-PD-1-based therapy: Final results of SPOTLIGHT203 phase 2 study [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 CT014.

Background: There is a lack of predictive biomarkers for immunotherapy in melanoma. Immunohistochemistry and gene sequencing are frequently assessed as part of clinical research. Radiomic signatures may also add valuable information, based on parameters which can be related to immune infiltration, therefore defining an imaging biomarkers panel for this clinical scenario. BO-112 is a double stranded synthetic RNA formulated with polyethyleneimine (PEI) that, by mimicking the effect of a viral infection, mobilizes the immune system. The role of imaging biomarkers is being explored in the present phase II clinical trial. Study design: Single arm study with BO-112 plus pembrolizumab (NCT04570332) in patients with advanced melanoma in progression to anti-PD1 therapy. As part of exploratory objectives, a radiomics analysis was performed to detect changes in lesion texture features. Quantitative features were obtained by using Quibim Precision 2.9 platform (Quibim, Valencia, Spain) after the manual delineation of lesions on the CT study of each subject at each timepoint to obtain information about injected/non-injected lesions. Images were normalized by taking into account Hounsfield Units (HU) bias across scanners in a cross-calibration phantom and the Z-score. The difference (Delta) in the features between baseline and week 8 was calculated. Results: Studies were assessed based on event (progression) and based on whether lesions had been injected. Patients with only cutaneous disease were not included in this analysis. Out of 23 patients who had at least two imaging assessments, 6 developed progressive disease by week 8, and 17 subjects had no event by that time. Due to the small sample size, the radiomic analysis was based on hypothesis testing. With regards to volume, 50% of the non-progressing lesions reduced their value from that of the baseline. Regarding injected versus non-injected changes, up to 50% of injected lesions decreased their volume after 8 weeks of injected treatment whereas in non-injected lesions volume decreased in less than 25% of lesions. From the independent sample t-test of delta radiomics features against the injected/non-injected lesions variable, there were 4 features with a statistically significant difference between groups; all of them related to the Low Grey-Level Zone Emphasis. Specifically, Delta original GLRLM Low Grey-Level Run Emphasis showed the highest significant difference between injected and non-injected lesions (p=0.004), with higher and positive delta values in the injected group (75% injected lesions were above 0). Conclusions: Imaging biomarkers provide a large number of quantitative image features with a wide span of information, from size to heterogeneity of the tissue which may be indicator of tumor progression and immune infiltrate. In the analysis of radiomics features, delta GLRLM low grey-level zone emphasis was sensitive to the tumoral changes happening in injected lesions at week 8. This might add insights into the imaging-based evaluation of immune infiltration in intratumoral immunotherapy and the creation of associated imaging biomarkers panels. Citation Format: Paula Moreno, Philippe Saiag, Luis de la Cruz Merino, Caroline Dutriaux, Eduardo Castanon Álvarez, Caroline Robert, Juan F. Rodríguez-Moreno, Pablo Cerezuela-Fuentes, Ana M. Arance, Henry Montaudié, Miguel F. Sanmamed, María González Cao, María Pilar López Criado, Julie Charles, Alfonso Berrocal, Enrique de Miguel, Elisa Funk-Brentano, Pablo Sau Llanas, Sorilla Prey, Eva Muñoz-Couselo, Delvys Rodríguez Abreu, Juan Martin-Liberal, Ángel Alberich-Bayarri, Javier Sánchez López, Sonia Macia, Marisol Quintero, Marya F. Chaney, Stéphane Dalle, Iván Márquez-Rodas. Radiomic features in tumor assessment, preliminary results from a phase 2 study of intratumoral administration of BO-112 with pembrolizumab in patients with anti PD1 refractory melanoma [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 CT109.

Background: There is a lack of predictive biomarkers for immunotherapy in melanoma. In terms of IHC, there is no strong rational to support the use of PD-L1 expression. BRAF mutations occur in 40-50% of melanomas and the MAPK pathway may also be activated by NRAS mutations. Patients harboring these mutations face usually a worse prognosis. BO-112 is a double stranded synthetic RNA formulated with polyethyleneimine (PEI) that, by mimicking the effect of a viral infection, mobilizes the immune system. Prior data from a phase I trial (NCT02828098) suggest that, when administered intratumorally, it causes an increase in CD8 infiltration and PD-L1 expression. The role of these and other biomarkers is being explored in the present phase II clinical trial. Study Design: Single arm study with BO-112 plus pembrolizumab (NCT04570332) in patients with advanced melanoma in progression to anti-PD1 therapy. Tumors were genotyped by next generation sequencing, whole exome sequencing and tumor mutation burden. Antitumor and immunological effects of the treatment in the tumor microenvironment were assessed by PDL1 and CD8 immunohistochemistry with a paired biopsy performed after 21 days of treatment. Results: A preliminary analysis has been performed, based on patients evaluable for clinical benefit (defined as response or stable disease>16 weeks). Samples from 35 patients have been analyzed, with 24 patients paired biopsies available. Patients with “cold” tumors (PD-L1 negative and CD8 low) at baseline had a trend to lack of clinical benefit. Only basal PD-L1 in the inflammatory component showed a statistically significant correlation with clinical outcome (4/20 (25%) tumors PDL1 IC negative had benefit versus 10/15 (67%) positive), p=0.0053. Fifteen patients had an increase in PD-L1 and 14 patients had increase in CD8 infiltrate after BO-112 treatment; the lack of increase in PDL1 and CD8 after treatment was also predictive of lack of response (p=0.04). BRAF/NRAS driver mutations correlated with positive outcome. Clinical benefit was observed in 4 of 17 (24%) patients not carrying activating mutations whereas 11 out of 18 (61%) patients with BRAF/NRAS activating mutations had clinical benefit (p=0.02), mainly in cutaneous histology (14% versus 65%, p=0.02). Mucosal melanoma patients (n=3) achieved an ORR 66.7% and DCR 100%. The two mucosal melanoma patients with partial response harbored SETD2 mutations and one of them showed extensive cyclic nucleotide-gated (CNGs), indicative of defects in DNA repair pathways. Regarding acral melanoma patients (n=9), no responses were observed, even in the single case with a NRAS mutation. The only patient achieving clinical benefit, with stable disease>16 weeks; had a unique mutation profile, with TP53 (inactivating) and KIT (activating) mutations. Conclusions: Patients basal mutant BRAF/NRAS could have more probability of benefit from BO-112 and pembrolizumab combination. PD-L1 and/or CD8 increase is an early marker of response. These findings could help to select patients in future clinical trials. Further investigation into predictive biomarkers is warranted. Citation Format: Ruth Roman, Philippe Saiag, Caroline Dutriaux, Luis de la Cruz Merino, Eduardo Castanon, Miguel F. Sanmamed, Caroline Robert, Juan F. Rodríguez-Moreno, Pablo Cerezuela-Fuentes, Ana M. Arance, María González Cao, Henry Montaudié, María Pilar López Criado, Julie Charles, Alfonso Berrocal, María del Carmen Álamo de la Gala, Enrique de Miguel, Elisa Funk-Brentano, Sorilla Prey, Eva Muñoz-Couselo, Delvys Rodríguez Abreu, Juan Martín-Liberal, Helena Escuin-Ordinas, Mark Branum, Sonia Macia, Marisol Quintero, Javier Sánchez López, Marya F. Chaney, Beatriz García-Peláez, Marta Vives-Usano, Miguel Ángel Molina, Stéphane Dalle, Iván Márquez-Rodas. Correlation of biomarkers and clinical benefit of intratumoral BO112 and pembrolizumab in patients with anti PD1 refractory melanoma [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 CT107.

Probably it does.

Checkpoint inhibitors have improved the survival of patients with advanced tumors and show a manageable toxicity profile. However, auto-immune colitis remains a relevant side effect, and combinations of anti-PD1/PDL1 and anti-CTLA-4 increase its incidence and severity. Here, we report the case of a 50-year-old patient diagnosed with stage IV cervical cancer that relapsed following radical surgery, external radiation/brachytherapy and standard chemotherapy. She was subsequently treated with Nivolumab and Ipilimumab combination and developed grade 2 colitis presenting a dissociation between endoscopic and pathological findings. At cycle 10 the patient reported grade 3 diarrhea and abdominal discomfort, without blood or mucus in the stools. Immunotherapy was withheld and a colonoscopy was performed, showing normal mucosa in the entire colon. Puzzlingly, histologic evaluation of randomly sampled mucosal biopsy of the distal colon showed an intense intraepithelial lymphocyte infiltration with crypt loss and some regenerating crypts with a few apoptotic bodies set in a chronically inflamed lamina propria, consistent with the microscopic diagnosis of colitis. Treatment with methylprednisolone 2 mg/ kg was initiated which led to a decrease in the number of stools to grade 1. Additional investigations to exclude other causes of diarrhea rendered negative results. The patient experienced a major partial response and, following the resolution of diarrhea, she was re-challenged again with immunotherapy, with the reappearance of grade 2 diarrhea, leading to permanent immunotherapy interruption. We conclude and propose that performing random colonic biopsies should be considered in cases of immune checkpoint-associated unexplained diarrhea, even when colonoscopy shows macroscopically normal colonic mucosa inflammatory lesions.

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

Cytokines are soluble proteins that mediate cell-to-cell communication. Based on the discovery of the potent anti-tumour activities of several pro-inflammatory cytokines in animal models, clinical research led to the approval of recombinant interferon-alpha and interleukin-2 for the treatment of several malignancies, even if efficacy was only modest. These early milestones in immunotherapy have been followed by the recent addition to clinical practice of antibodies that inhibit immune checkpoints, as well as chimeric antigen receptor T cells. A renewed interest in the anti-tumour properties of cytokines has led to an exponential increase in the number of clinical trials that explore the safety and efficacy of cytokine-based drugs, not only as single agents, but also in combination with other immunomodulatory drugs. These second-generation drugs under clinical development include known molecules with novel mechanisms of action, new targets, and fusion proteins that increase half-life and target cytokine activity to the tumour microenvironment or to the desired effector immune cells. In addition, the detrimental activity of immunosuppressive cytokines can be blocked by antagonistic antibodies, small molecules, cytokine traps or siRNAs. In this review, we provide an overview of the novel trends in the cytokine immunotherapy field that are yielding therapeutic agents for clinical trials.

Phase I clinical trials in oncology primarily aim to assess the toxicity profile of new drugs and determine recommended phase II doses (RP2D). Since the cancer rate increases with age and our population is continually aging, RP2D must necessarily be assessed in older patients. Few clinical studies include older patients, however, and particularly few Phase I trials. We reviewed published data on the safety and efficacy of Phase I trials in older patients. The majority of studies included primarily young, fit patients, with age thresholds varying widely from 65 to 80years. However, age does not seem to be associated with more toxicity or less efficacy. While Phase I trials seem feasible in fit older patients, geriatric-medicine score systems should be included in the clinical trial design in order to better characterize this population.

// Roger Sun 1, 2 , Ines Koubaa 3 , Elaine Johanna Limkin 1, 2 , Isabelle Dumas 4 , Enrica Bentivegna 5 , Eduardo Castanon 6 , Sebastien Gouy 5 , Cynthia Baratiny 1 , Fyo Monnot 1 , Pierre Maroun 1 , Samy Ammari 3 , Elise Zareski 3 , Corinne Balleyguier 3 , Eric Deutsch 1, 2, 7 , Philippe Morice 5, 7 , Christine Haie-Meder 1 and Cyrus Chargari 1, 2, 8, 9 1 Department of Radiotherapy, Gustave Roussy Cancer Campus, Villejuif, France 2 INSERM U1030 Molecular Radiotherapy, Gustave Roussy Cancer Campus, Villejuif, France 3 Department of Radiology, Gustave Roussy Cancer Campus, Villejuif, France 4 Department of Medical Physics, Gustave Roussy Cancer Campus, Villejuif, France 5 Department of Surgery, Gustave Roussy Cancer Campus, Villejuif, France 6 Department of Drug development, Gustave Roussy Cancer Campus, Villejuif, France 7 Universite Paris Sud, Universite Paris-Saclay, Le Kremlin-Bicetre, France 8 Institut de Recherche Biomedicale des Armees, Bretigny-sur-Orge, France 9 French Military Health Service Academy, Ecole du Val-de-Grace, Paris, France Correspondence to: Cyrus Chargari, email: cyrus.chargari@gustaveroussy.fr Keywords: cervical cancer; locally advanced; brachytherapy; bladder invasion; vesicovaginal fistula Received: August 29, 2017 Accepted: January 01, 2018 Published: January 18, 2018 ABSTRACT Objective: We report outcomes of cervical cancer patients with bladder invasion (CCBI) at diagnosis, with focus on the incidence and predictive factors of vesicovaginal fistula (VVF). Results: Seventy-one patients were identified. Twenty-one (30%) had para-aortic nodal involvement. Eight had VVF at diagnosis. With a mean follow-up time of 34.2 months (range: 1.9 months–14.8 years), among 63 patients without VVF at diagnosis, 15 (24%) developed VVF. A VVF occurred in 19% of patients without local relapses (9/48) and 40% of patients with local relapse (6/15). Two-year overall survival (OS), disease-free survival (DFS) and local control rates were 56.4% (95% CI: 44.1–67.9%), 39.1% (95% CI: 28.1–51.4%) and 63.8% (95% CI: 50.4–75.4%), respectively. Para-aortic nodes were associated with poorer OS (adjusted HR = 3.78, P -value = 0.001). In multivariate analysis, anterior tumor necrosis on baseline MRI was associated with VVF formation (63% vs 0% at 1 year, adjusted-HR = 34.13, 95% CI: 4.07–286, P -value = 0.001), as well as the height of the bladder wall involvement of >26 mm (adjusted-HR = 5.08, 95% CI: 1.38–18.64, P -value = 0.014). Conclusions: A curative intent strategy including brachytherapy is feasible in patients with CCBI, with VVF occurrence in 24% of the patients. MRI patterns help predicting VVF occurrence. Methods: Patients with locally advanced CCBI treated with (chemo)radiation ± brachytherapy in our institute from 1989 to 2015 were analyzed. Reviews of baseline magnetic resonance imaging (MRI) scans were carried out blind to clinical data, retrieving potential parameters correlated to VVF formation (including necrosis and tumor volume).

Background: BO-112 is a double stranded synthetic RNA formulated with polyethyleneimine (PEI), that acts as an agonist to toll-like receptor 3 and targets the cytosolic helicase melanoma differentiation-associated gene 5 and retinoic acid-inducible gene I. By mimicking the effect of a viral infection, it mobilizes the immune system, including activation of dendritic cells, CD8 T-cell infiltration, induction of interferons (IFNs), induction of apoptosis and enhancement of immunogenic cell death. Clinical data are available from the first-in-human study (NCT02828098) which evaluated single intratumoral (IT) BO-112 (Part 1; N = 16) and the combination of IT BO-112 with pembrolizumab or nivolumab (Part 2; N = 28). Part 2 showed an ORR of 11% and DCR of 46% in patients with multiple tumor types. Of them, 2 out of 10 (20%) patients with melanoma resistant to anti PD-1 achieved a partial response. Safety profile of BO-112, both as single agent and in combination with anti-PD-1, is manageable and currently characterized by Grade 1 fever and other flu-like symptoms. A phase 2 clinical study of IT BO-112 in combination with pembrolizumab in patients with liver metastases from colorectal or gastric/gastro-esophageal junction cancer patients is currently ongoing. Methods: Phase 2, single arm, open label study of IT BO-112 in combination with pembrolizumab in patients with advanced and/or metastatic melanoma that have progressed on anti-PD-1-containing treatment (NCT04570332). BO-112 will be administered once weekly (QW) in 1 to 8 tumor lesions, total dose 1-2 mg (depending on the number of injected lesions), for the first 7 weeks and then once every three weeks (Q3W); pembrolizumab 200 mg will be administered Q3W. Key eligibility criteria include histologically confirmed, unresectable cutaneous or mucosal melanoma with known BRAF status. Patients must have progressed on or after treatment with an anti-PD-1/L1 mAb. At least one lesion RECIST 1.1 measurable and amenable for weekly IT injection is needed. Primary efficacy variable is ORR by RECIST 1.1, assessed by independent central radiologist (by QUIBIM Precision platform). Secondary efficacy variables include clinical activity in terms of DCR, DOR, PFS, OS, iRECIST, safety and PKs. Exploratory objectives include itRECIST and evaluation of tumor microenvironment (by Pangaea laboratory). A 1-sided alpha of 4.19% and power of 81.8% are used. A total of 40 patients will be enrolled. If less than 8 patients out of 40 have ORR, the study will not meet the statistical bar. Study was approved on 14 December in Spain; enrollment is open; two sites are active as of 18 December 2020. Nineteen sites (12 in Spain and 7 in France) are planned to be activated. Citation Format: Iván Márquez-Rodas, Miguel Fernández de Sanmamed Gutiérrez, María González Cao, Ana M. Arance, Alfonso Berrocal, Eduardo Castañon, Sofía España, Pablo Cerezuela-Fuentes, Juan F. Rodríguez-Moreno, Pilar López Criado, Juana Oramas, Luis de la Cruz Merino, Stéphane Dalle, Caroline Dutriaux, Julie Charles, Caroline Robert, Brigitte Dréno, Henri Montaudié, Philippe Saiag, Javier Sánchez-López, María Rojas, Helena Escuin-Ordinas, Vanesa Pons Sanz, Sonia Maciá, Marisol Quintero. Phase 2 clinical study to evaluate the efficacy and safety of intratumoral BO-112 in combination with pembrolizumab in patients with advanced melanoma that have progressive disease on anti-PD-1-based therapy [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 CT233.

Background BO-112 is a dsRNA (poly I:C) formulated with polyethylenimine, that upon Intratumoral (IT) injection acts by activating TLR3, RIG-1 and MDA-5. This induces immunogenic cell death and potentiate systemic therapy with checkpoint inhibitors in animal models. In patients (pts), single-agent BO-112 IT increases necrosis, apoptosis and expression of pro-immune genes in solid cancers, with a manageable safety. 1 mg was the dose combined with anti-PD-1 in the current clinical trial (NCT02828098). Methods BO-112 was combined with anti PD-1 in 28 pts with solid tumors primarily resistant to anti PD-1 (nivolumab or pembrolizumab). A lesion >1 cm amenable to IT injection was required. 28 pts were treated with 1 mg IT BO-112 qw x 2 or 3 doses before continuing the previous anti PD-1 combined with BO-112, until progression, limiting toxicity or up to 1y. Pre & post BO-112 biopsies from injected lesion were analysed. Response was first assessed by RECIST 1.1 at week 8-12. Results BO-112 related AEs and biological effects at interim analysis are summarized in the table. The combination was well tolerated. No deaths were associated with BO-112. Of 18 evaluable pts for response, at first assessment: 2 have achieved an objective partial response (PR) (1 melanoma and 1 renal carcinoma), with 1 of them continuing treatment; 11 patients had stable disease (SD); 5 patients progressed (PD). Additionally 6 patients progressed prior to the first evaluation, 3 died before efficacy assessments and 1 received palliative radiotherapy and was considered not evaluable. Table . 100P All G3-5 TEAEs (%) G3-4 BO-112 related TEAEs (%) Necrosis (D > 5%) (%)* CD8+ T cell infiltrate (D > 5%) (%)* *evaluable All N = 28 18 (64) 1 (4) 10 (50) 7 (35) Melanoma N = 10 7 (70) 0 5 (56) 4 (44) Non-Small lung cancer N = 13 8 (62) 1 (8) 3 (38) 1 (13) Other N = 5 3 (60) 0 2 (67) 2 (67) Conclusion BO-112 combined with anti PD-1 shows a manageable safety profile, direct antitumor effects and innate and adaptive immune system activation. Efficacy analyses suggest potential to reverse primary resistance to anti-PD1 treatment. Studies in other indications, including combination with radiotherapy, are planned. Clinical trial identification NCT02828098. Legal entity responsible for the study Bioncotech Therapeutics. Funding Bioncotech Therapeutics. Disclosure I. Marquez-Rodas: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pierre Fabre; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bioncotech; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Regeneron; Advisory / Consultancy, Research grant / Funding (institution): Incyte; Non-remunerated activity/ies: Biosequence; Research grant / Funding (institution): Idera. P. Lopez-Casas: Full / Part-time employment: Bioncotech. M. Martin: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Puma; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy: Tahio; Advisory / Consultancy: Pharmamar; Advisory / Consultancy: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Daiichi. D. Tersago: Full / Part-time employment: Bioncotech. M. Quintero: Full / Part-time employment, Officer / Board of Directors: Bioncotech. I. Melero: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Alligator; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Genentech; Advisory / Consultancy: Genmab; Advisory / Consultancy: Incyte; Advisory / Consultancy: Tusk; Advisory / Consultancy: Numab; Advisory / Consultancy: Molecular Partners; Advisory / Consultancy: F Star; Advisory / Consultancy: Bayer; Advisory / Consultancy: AstraZeneca. All other authors have declared no conflicts of interest.

New patterns of progression under immune-oncology (IO) antibodies (mAb) have been described such as pseudoprogression. Except for melanoma, variations between studies reveal difficulties to establish their prevalence.This retrospective study enrolled patients participating in IO phase I trials at Gustave Roussy cancer center for solid tumors excluding melanoma. Radiological assessment according to iRECIST was correlated with prospectively registered patient characteristics and outcomes. Pseudoprogression (PsPD) was defined as RECIST-defined progression followed by stabilization or decrease at the next imaging, and dissociated response (DisR) as concomitant decrease in some tumor lesions and increase in others at a same timepoint.Among 360 patients included, 74% received IO mAb combination: 45% with another IO mAb, 20% with targeted therapy and 10% with radiotherapy. The overall response rate was 19.7%. PsPD were observed in 10 (2.8%) patients and DisR in 12 (3.3%) patients. Atypical responses (AR), including PsPD and DisR, were not associated with any patient's baseline characteristics. Compare with typical responder patients, patients experiencing AR presented a shorter iPFS (HR 0.34; p 0.001) and OS (HR 0.27; p = 0.026). Among the 203 patients who progressed in 12 weeks, 80 (39.4%) patients were treated beyond progression. PD was confirmed in 80% of cases, while 10% of patients presented a response.Pseudoprogression and dissociated response are uncommon patterns of progression. Their prevalence should be balanced with the rate of real progressing patients treated beyond progression. Prognosis or on-treatment biomarkers are needed to identify early patients who will benefit from immunotherapy.

Immunotherapy has emerged in recent years and has revolutionized the treatment of cancer. Immune checkpoint inhibitors, including anti-cytotoxic T lymphocyte antigen-4 (CTLA-4), anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) agents, are the first of this new generation of treatments. Anti-PD-1/PD-L1 agents target immune cells by blocking the PD-1/PD-L1 pathway. This blockade leads to enhancement of the immune system and therefore restores the tumour-induced immune deficiency selectively in the tumour microenvironment. However, this shift in the balance of the immune system can also produce adverse effects that involve multiple organs. The pattern of toxicity is different from traditional chemotherapy agents or targeted therapy, and there is still little experience in recognizing and managing it. Thus, toxicity constitutes a real clinical management challenge and any new alteration should be suspected of being treatment-related. The most common toxicities occur in the skin, gastrointestinal tract, lungs, and endocrine, musculoskeletal, renal, nervous, haematologic, cardiovascular and ocular systems. Immune-mediated toxic effects are usually manageable, but toxicities may sometimes lead to treatment withdrawal, and even fulminant and fatal events can occur. Oncologists need to collaborate with internists, clinical immunologists and other specialists to understand, manage and prevent toxicity derived from immunotherapy. This review focuses on the mechanisms of toxicity of anti-PD-1/PD-L1 agents, and its diagnosis and management.

BackgroundPerioperative chemotherapy (CT) or neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced gastric (GC) or gastroesophageal junction cancer (GEJC) has been shown to improve survival compared to an exclusive surgical approach. However, most patients retain a poor prognosis due to important relapse rates. Population pharmacokinetic-pharmacodynamic (PK/PD) modeling may allow identifying at risk-patients. We aimed to develop a mechanistic PK/PD model to characterize the relationship between the type of neoadjuvant therapy, histopathologic response and survival times in locally advanced GC and GEJC patients.MethodsPatients with locally advanced GC and GEJC treated with neoadjuvant CT with or without preoperative CRT were analyzed. Clinical response was assessed by CT-scan and EUS. Pathologic response was defined as a reduction on pTNM stage compared to baseline cTNM. Metastasis development risk and overall survival (OS) were described using the population approach with NONMEM 7.3. Model evaluation was performed through predictive checks.ResultsA low correlation was observed between clinical and pathologic TNM stage for both T (R = 0.32) and N (R = 0.19) categories. A low correlation between clinical and pathologic response was noticed (R = -0.29). The OS model adequately described the observed survival rates. Disease recurrence, cTNM stage ≥3 and linitis plastica absence, were correlated to a higher risk of death.ConclusionOur model adequately described clinical response profiles, though pathologic response could not be predicted. Although the risk of disease recurrence and survival were linked, the identification of alternative approaches aimed to tailor therapeutic strategies to the individual patient risk warrants further research.

Background: The development of immune checkpoint blocker development brings new hope in older patients (OPs) because of clinical efficacy and low toxicity. Clinical indications are rising steadily, but very few data are available in the geriatric population where comorbidities, reduced functional reserve and immunosenescence may affect efficacy and tolerance. Methods: All cases of patients enrolled in immunotherapy phase I trials between January 2012 and December 2016 in the Drug Development Department (DITEP) at Gustave Roussy were retrospectively reviewed. Case–control analysis was performed in OPs (patients ≥ 70 years) matched to younger patients (YPs) (patients < 70 years) by trial and treatment dose. We compared cumulative incidence, grade and type of immune-related adverse events (IrAEs) and survival outcomes. Results: Among the 46 OPs and the 174 YPs enrolled in 14 phase I/II trials, 10 (22%) and 23 (13%) patients experienced grade III–IV IrAEs. Cumulative incidence of grade I–II IrAEs was significantly higher in OPs than YPs (p < 0.05). No significant difference was observed between the two groups for grade III–IV IrAEs (p = 0.50). Older age was not associated with lower dose intensity of treatment (p = 0.14). No significant difference was observed between OPs and YPs in median progression-free survival (hazards ratio 1.41, 95% confidence interval [CI] [0.94–2.11] p = 0.09) or median overall survival (HR 0.92, 95% CI [0.61–1.39] p = 0.77). Conclusion: Immune checkpoint blockade appears to be an acceptable treatment option for OPs in the setting of phase I trials.

Surgically resectable synchronic and metachronic liver metastases of colon cancer have high risk of relapse in spite of standard-of-care neoadjuvant and adjuvant chemotherapy regimens. Dendritic cell vaccines loaded with autologous tumor lysates were tested for their potential to avoid or delay disease relapses (NCT01348256). Patients with surgically amenable liver metastasis of colon adenocarcinoma (n = 19) were included and underwent neoadjuvant chemotherapy, surgery and adjuvant chemotherapy. Fifteen patients with disease-free resection margins were randomized 1:1 to receive two courses of four daily doses of dendritic cell intradermal vaccinations versus observation. The trial had been originally designed to include 56 patients but was curtailed due to budgetary restrictions. Follow-up of the patients indicates a clear tendency to fewer and later relapses in the vaccine arm (median disease free survival –DFS-) 25.26 months, 95% CI 8.74-n.r) versus observation arm (median DFS 9.53 months, 95% CI 5.32–18.88). Electronic supplementary material The online version of this article (10.1186/s40425-018-0405-z) contains supplementary material, which is available to authorized users.

In the last decade, the tyrosine kinase receptor cMET, together with its ligand hepatocyte growth factor (HGF), has become a target in non-small cell lung cancer (NSCLC). Signalization via cMET stimulates several oncological processes amongst which are cell motility, invasion and metastasis. It also confers resistance against several currently used targeted therapies, e.g., epidermal growth factor receptor (EGFR) inhibitors. In this review, we will discuss the basic structure of cMET and the most important signaling pathways. We will also look into aberrations in the signaling and the effects thereof in cancer growth, with the focus on NSCLC. Finally, we will discuss the role of cMET as resistance mechanism.

Background: Our objective was to develop a prognostic stratification tool that enables patients with cancer and pulmonary embolism (PE), whether incidental or symptomatic, to be classified according to the risk of serious complications within 15 days. Methods: The sample comprised cases from a national registry of pulmonary thromboembolism in patients with cancer (1075 patients from 14 Spanish centres). Diagnosis was incidental in 53.5% of the events in this registry. The Exhaustive CHAID analysis was applied with 10-fold crossvalidation to predict development of serious complications following PE diagnosis. Results: About 208 patients (19.3%, 95% confidence interval (CI), 17.1-21.8%) developed a serious complication after PE diagnosis. The 15-day mortality rate was 10.1%, (95% CI, 8.4-12.1%). The decision tree detected six explanatory covariates: Hestia-like clinical decision rule (any risk criterion present vs none), Eastern Cooperative Group performance scale (ECOG-PS; = 2), O-2 saturation (= 90%), presence of PE-specific symptoms, tumour response (progression, unknown, or not evaluated vs others), and primary tumour resection. Three risk classes were created (low, intermediate, and high risk). The risk of serious complications within 15 days increases according to the group: 1.6, 9.4, 30.6%; P

AIM: To assess the prevalence and prognostic significance of additional intrathoracic findings (AIFs) in patients with cancer and pulmonary embolism (PE). AIFs were considered alterations other than the characteristic ones intrinsic to PE or changes in cardiovascular morphology. METHODS: Subjects have been taken from a Spanish national multidisciplinary and multicenter study of PE and cancer who were treated between 2004 and 2015. The endpoint was the appearance of serious complications or death within 15 days. RESULTS: The registry contains 1024 eligible patients; 41% diagnosed by computed tomography pulmonary angiography versus 59% by non-angiographic CT. Serious complications occurred within 15 days in 18.9%, [95% confidence interval (CI), 16.6-21.4%] and 9.5% (95% CI 7.9-11.5%) died. At least one AIF was seen in 72.6%. The most common AIFs were as follows: pulmonary nodules (30.9%), pleural effusion (30.2%), tumor progression (28.3%), atelectasis (19.0%), pulmonary infarct (15.2%), emphysema (13.4%), pulmonary lymphangitic carcinomatosis (4.5%), and pneumonia (6.1%). Patients with AIF exhibited a higher complication rate at 15 days: 21.9% versus 13.0%, odds ratio (OR) 1.8 (95% CI 1.2-2.8), P = 0.03, and 15-day mortality: 15.0% versus 7.3%, OR 1.9 (95% CI 1.1-3.2), P = 0.020. Patients with pneumonia, pneumothorax, pulmonary edema, pulmonary nodules, tumor progression, pulmonary fibrosis, and pleural effusion showed an excess of adverse events. CONCLUSIONS: Additional intrathoracic findings are highly prevalent and significantly impact prognosis in patients with PE and cancer, making them germane to the classification of this population.

Background The limited efficacy of neoadjuvant schedules to obtain pCR in breast cancer together with a prompt relapse of triple negative breast cancers has opened up the development of new strategies involving the immune system, which is essential in cancer control. We have elaborated an autologous vaccine with dendritic cells loaded with patients' own tumor antigens. Based on the synergistic effect between immunotherapy and chemotherapy our hypothesis is that the combination of both strategies could improve pCR with an excellent tolerance and could increase DFS and OS. Methods Two centers are enrolling patients from February 2011. Twenty-one patients with stage II-III HER2 negative breast cancer have started on sequential neoadjuvant chemotherapy based on dose dense antracyclines (E 100mg/m2 and C 600 mgr/m2) × 4 cycles plus GM-CSF followed by taxanes (DOC 75–100 mgr/m2) × 4 cycles plus vaccination. Vaccine calendar was started after the 4th EC and alternated with taxane schedule and after chemotherapy up to a maximum of a 2 year-period. SNB biopsy was performed before neoadjuvant chemotherapy. pCR in the breast and the axilla is the main endpoint, measured by Miller&Paine classification. Data were analyzed using SPSS and alpha was set at 0.05 (two-tailed). We have compared these results in the vaccinated cohort (V) with our historic cohort (C) of 19 patients treated in the same way but without the vaccine. Results Both cohorts (V and C) were well balanced for age, histologyc type, differentiation grade, Ki67>15%, tumor size ≤ 5 cm, stage and expression of hormone receptors. All patients except one in the vaccine cohort achieved 8 cycles of chemotherapy. According to grade ¾ toxicities we did not find significant differences except for hand-foot syndrome in the V cohort (19% vs 0%; p = 0.04) and vomiting in the C cohort (0% vs 21%; p = 0.02). Lymphopenia was the most common adverse event (81% in V vs 89.5% in C; p = 0.45). Other toxicities were anemia (0% vs 5.3%; p = 0.28), thrombopenia (0% vs 10% p = 0.12), leukopenia (9.5% vs 15.8% p = 0.55) and neutropenia (14% vs 21%, p = 0.57). Gastrointestinal toxicity was similar in both groups: mucositis (0% vs 5.3%, p = 0.28); gastritis (5% in both cohorts), nausea (19% vs 16%, p = 0.78), diarrhea (5% in both cohorts), constipation (0% vs 15% in C, p = 0.06). Myalgias were seen in 19% in V vs 11% in C (p = 0.45). We did not see any local grade ¾ toxicity related to the intradermal vaccines. Regarding efficacy data, clinical complete response by MRI was shown in 38% in the V as compared to 16% in the C (p = 0.06). Breast-conserving surgery was more common in the V cohort (62% vs 53%, p = 0.55). Total pCR (T plus N) was superior with the addition of the vaccine (24% vs 5% p = 0.014). Moreover in three more patients in the V group we find isolated tumor cells in the breast (Titc). Conclusions The addition of autologous dendritic cell vaccines to neoadjuvant chemotherapy significantly increased the rate of pathological complete responses among patients with HER2-negative breast cancer. Vaccination does not seem to add any toxicity to the schedule. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-16-03.

Anti-PD1 antibodies have led to a therapeutic shift in cancer treatment. Although classically described as "well tolerated," these drugs can lead to severe immune-related adverse events. Using CT scan imaging, Nishino and colleagues describe different radiologic patterns and their possible relation to severity of several cases of anti-PD1–induced pneumonitis. Clin Cancer Res; 22(24); 5956–8. ©2016 AACR. See related article by Nishino et al., p. 6051

OBJECTIVE: To analyze the prognostic value of pulmonary artery obstruction versus right-ventricle (RV) dysfunction radiologic indices in cancer-related pulmonary embolism (PE). METHODS: We enrolled 303 consecutive patients with paraneoplastic PE, evaluated by computed tomography pulmonary angiography (CTPA) between 2013 and 2014. The primary outcome measure was serious complications at 15days. Multivariate analyses were conducted by using binary logistic and robust regressions. Radiological features such as the Qanadli index (QI) and RV dysfunction signs were analyzed with Spearman's partial rank correlations. RESULTS: RV diameter was the only radiological variable associated with an adverse outcome. Subjects with enlarged RV (diameter>45mm) had more 15-day complications (58% versus 40%, p=0.001). The QI correlated with the RV diameter (r=0.28, p

Trastuzumab significantly improves overall survival (OS) when added to cisplatin and fluoropyrimidine as a treatment for HER2-positive advanced gastric cancers (AGC). The aim of this study was to evaluate the impact of the gradual implementation of HER2 testing on patient prognosis in a national registry of AGC. This Spanish National Cancer Registry includes cases who were consecutively recruited at 28 centers from January 2008 to January 2016. The effect of missing HER2 status was assessed using stratified Cox proportional hazards (PH) regression. The rate of HER2 testing increased steadily over time, from 58.3 % in 2008 to 92.9 % in 2016. HER2 was positive in 194 tumors (21.3 %). In the stratified Cox PH regression, each 1 % increase in patients who were not tested for HER2 at the institutions was associated with an approximately 0.3 % increase in the risk of death: hazard ratio, 1.0035 (CI 95 %, 1.001-1.005), P = 0.0019. Median OS was significantly lower at institutions with the highest proportions of patients who were not tested for HER2. Patients treated at centers that took longer to implement HER2 testing exhibited worse clinical outcomes. The speed of implementation behaves as a quality-of-care indicator. Reviewed guidelines on HER2 testing should be used to achieve this goal in a timely manner.

Objectives Liver metastases appear in 20–30% of patients diagnosed with non-small cell lung cancer (NSCLC) and represent a poor prognosis feature of NSCLC and a possibly more treatment-resistant condition. Potential clinical outcome differences in NSCLC patients with liver metastases harboring molecular alterations in EGFR, KRAS and EML4-ALK genes are still to be determined. This study aims to evaluate the incidence of liver metastasis in a single population and look for potential correlations between EGFR mutations, liver infiltration and clinical outcomes. Methods A total of 236 consecutive stage IV NSCLC patients treated at the Clínica Universidad de Navarra were analyzed. Results At onset, liver metastases were present in 16.9% of patients conferring them a shorter overall survival (OS) compared to those with different metastatic locations excluding liver infiltration (10 vs. 21 months; p = 0.001). Patients with EGFR wild-type tumors receiving standard chemotherapy and showing no liver involvement presented a superior median OS compared to those with liver metastases (23 vs. 13 months; p = 0.001). Conversely, patients with EGFR-mutated tumors treated with EGFR tyrosin-kinase inhibitors (TKI’s) presented no significant differences in OS regardless of liver involvement (median OS not reached vs. 25 months; p = 0.81). Conclusion Overall, liver metastases at onset negatively impact OS of NSCLC patients. EGFR TKIs however, may reverse the effects of an initial negative prognosis of liver metastasis in first-line treatment of EGFR mutated NSCLC patients. Electronic supplementary material The online version of this article (doi:10.1186/s12967-015-0622-x) contains supplementary material, which is available to authorized users.

BACKGROUND: We studied whether thymidylate synthase (TS) genotype has an independent prognostic/predictive impact on a European population of advanced non-small cell lung cancer (NSCLC) patients receiving pemetrexed. METHODS: Twenty-five patients treated with pemetrexed-based regimens were included. Genomic DNA was isolated prior to treatment. The variable number of tandem repeat (VNTR) polymorphisms, the G > C single nucleotide polymorphisms (SNP) and the TS 6-bp insertion/deletion (6/6) in the 3' untranslated region (UTR) polymorphisms were analyzed and correlated with overall response rate (ORR), progression-free survival (PFS), overall-survival (OS) and toxicity. RESULTS: The genotype +6/+6 predicted a higher ORR among active/former smokers compared to +6/-6 genotype (100% vs. 50%; p = 0.085). Overall, the 3R/3R genotype predicted a higher ORR (100%) over the rest VNTR polymorphisms (p = 0.055). The presence of 3R/3R genotype significantly correlated with a superior ORR in patients without EGFR activating mutations (100%) compared to 2R/2R, 2R/3R and 3R/4R genotype (77.8%, 33.3% and 0% respectively; p = 0.017). After a median follow-up of 21 months, a trend towards a better PFS, although not significant, was found among subjects showing 3R/3R polymorphisms (p = 0.089). A significantly superior OS was found in patients showing 3R/3R genotype rather than other VNTR polymorphisms (p = 0.019). No significant correlation with the toxicity was observed. CONCLUSION: In our series, 3R/3R polymorphism correlated with a superior OS. Also, this polymorphism, when associated to wild type EGFR, was related to a higher ORR to pemetrexed. Toxicity was not significantly correlated with a specific TS genotype.

Review on ID1 (inhibitor of DNA binding 1, dominant negative helix-loop-helix protein), with data on DNA, on the protein encoded, and where the gene is implicated.

Background: Liver metastasis (LM) occurs in 30% of non-small cell lung cancer patients but the contribution of the patient's genetic background to the hepatic metastasis development is unclear. Previously, we reported that inflammation contributes to the prometastatic microenvironment of the liver. Upregulation of transcriptional regulator Id1 gene has been associated with inflammation while ablation of Id1 in mice reduced inflammation. In this study Id1 deficient mice were used to analyze the role of host Id1 in the hepatic colonization of an experimental lung cancer. Methods: Lewis lung carcinoma cells were used for the experimental production of hepatic metastasis via intrasplenic injection of cancer cells in C57BL/6 wild-type and Id1-knockout (KO) mice. Animals were splenectomized to avoid flank tumor formation and weekly FDG-micro-positron emission tomographies (PET) were performed to monitor LM formation. Animals were sacrificed at the time of LM occurrence and total RNA was purified from LM. A microarray gene expression analysis (Affymetrix) with the support of Ingenuity Pathways Analysis (IPA) was performed to evaluate the potential impact of Id1 deficiency on the regulation of genes mediating cancer cell invasion and proliferation, angiogenesis and metastasis. Results: By week two after cancer cell injection, 70% wild-type and 10% Id1-KO mice had detectable hepatic metastasis by FDG-PET (p=0.02). Three weeks after injection, when 100% wild-type had LM, still just 20% Id1-KO mice had LM (p=0.015). Moreover, 50% Id1-KO mice remained LM-free >4 weeks after cancer cell injection. No other metastasis sites were detected at necropsy. A microarray gene expression analysis of LM from Id1-KO animals uncovered a remarkable downregulation (p Conclusion: Our results demonstrate that Id1 expression deficiency impaired the metastatic process of lung cancer cells to the liver through the specific downregulation of key metastasis-associated genes and suggest that Id1-dependent mechanisms are new targets for hepatic metastasis therapeutic. This study has been partially funded by “UTE project CIMA” and an ISCIII-FIS grant 2011. Citation Format: Ignacio Gil-Bazo, Eduardo Castanon, Inés López, Victor Segura, Mariano Ponz-Sarvise, José M. López-Picazo, Maria Collantes, Margarita Ecay, Isabel Gil-Aldea, Alfonso Calvo, Fernando Vidal-Vanaclocha. Inhibitor of differentiation-1 (Id1) expression deficiency in the tumor microenvironment impairs experimental hepatic metastasis of lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1996. doi:10.1158/1538-7445.AM2014-1996

Aim: In the present study, we aimed to assess the prognostic factors and outcomes of apparently stable febrile neutropenia (ASFN) episodes. Methods: FINITE is a prospective, multicenter study to assess prognostic factors and patterns of care in patients with ASFN defined by the absence of hemodynamic instability, acute organ failure, specific sources of infection (e.g. pneumonia) or inability to take oral medication. We used a binary logistic regression model with bootstrap resampling to identify prognostic factors for serious complications in stable patients. Results: From Sep/12 to Mar/14, 921 patients with ASFN were included from 24 centers. The rates of serious complicatios and mortality were:14.6% (95%CI, 12.5 to 17%) and 2.1% (95%CI, 1.4 to 3.3%). Signifficant clinical and microbiological differences were observed in patients with or without complications. In the multivariate analysis, nine variables were independent risk factors for serious complications: European Cooperative Oncology Group performance status >1, cardiovascular disease, chronic obstructive pulmonary disease, mucositis NCI grade >1, monocytes Multivariate and bootstrap analysis of risk factors for serious complications Parameter Coeff. OR 95% CI p-value ECOG ≥2 1.39 4 1.33-3.37 0.001 Cardiovascular disease 0.81 2.2 1.15-4.47 0.01 COPD 1.01 2.7 1.68-6.77 0.001 Mucositis ≥2 1.08 2.9 1.78-4.96 0.001 Monocytes 0.99 2.6 1.66-4.96 0.001 Lymphocytes 450/mm3 0.85 2.3 1.45-4.1 0.002 Rigors 0.75 2.1 1.33-3.37 0.002 Previous treatment with corticoids 0.71 2 1.05-3.95 0.02 Malnutrition 1.20 3.3 1.68-6.46 0.01 Conclusions: This study identified risk factors for serious complications in patients with solid cancers and ASFN episodes, with potential implications on individualized therapy. Disclosure: All authors have declared no conflicts of interest.

Background Inhibitor of DNA binding 1 (Id1) and 3 (Id3) genes have been related with the inhibition of cell differentiation, cell growth promotion and tumor metastasis. Recently, Id1 has been identified as an independent prognostic factor in patients with lung adenocarcinoma, regardless of the stage. Furthermore, Id1 may confer resistance to treatment (both, radiotherapy and chemotherapy). Methods We have studied, using monoclonal antibodies for immunohistochemistry, the Id1 and Id3 tumor epithelial expression in 17 patients with stage III-N2 non-small cell lung cancer (NSCLC) treated with definitive chemoradiotherapy. Results Id1 expression is observed in 82.4% of the tumors, whereas Id3 expression is present in 41.2% of the samples. Interestingly, Id1 and Id3 expression are mutually correlated (R = 0.579, p = 0.015). In a subgroup analysis of patients with the most locally advanced disease (T4N2 stage), co-expression of Id1 and Id3 showed to be related with a worse overall survival (45 vs 6 months, p = 0.002). A trend towards significance for a worse progression free survival (30 vs 1 months, p = 0.219) and a lower response rate to the treatment (RR = 50% vs 87.5%, p = 0.07) were also observed. Conclusions A correlation between Id1 and Id3 protein expression is observed. Id1 and Id3 co-expression seems associated with a poor clinical outcome in patients with locally advanced NSCLC treated with definitive chemoradiotherapy.