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Muscle invasive bladder cancer (MIBC) is a widespread malignancy with a worse prognosis often related to a late diagnosis. For early-stage MIBC pts, a multidisciplinary approach is mandatory to evaluate the timing of neoadjuvant chemotherapy (NAC) and surgery. The current standard therapy is platinum-based NAC (MVAC-methotrexate, vinblastine, doxorubicin, and cisplatin or Platinum–Gemcitabine regimens) followed by radical cystectomy (RC) with lymphadenectomy. However, preliminary data from Vesper trial highlighted that dose-dense NAC MVAC is endowed with a good pathological response but shows low tolerability. In the last few years, translational-based research approaches have identified several candidate biomarkers of NAC esponsiveness, such as ERCC2, ERBB2, or DNA damage response (DDR) gene alterations. Moreover, the recent consensus MIBC molecular classification identified six molecular subtypes, characterized by different sensitivity to chemo- or targeted or immunotherapy, that could open a novel procedure for patient selection and also for neoadjuvant therapies. The Italian PURE-01 phase II Trial extended data on efficacy and resistance to Immune Checkpoint Inhibitors (ICIs) in this setting. In this review, we summarize the most relevant literature data supporting NAC use in MIBC, focusing on novel therapeutic strategies such as immunotherapy, considering the better patient stratification and selection emerging from novel molecular classification.

The azygos system is the most important pathway for decompression of the superior vena cava (SVC) when a blood flow obstruction to the right atrium is present. Thoracic and mediastinal malignancies, mainly lung cancers, are responsible for 60%-85% of superior vena cava syndrome (SVCS) cases. An uncommon origin of SVCS is primary malignant mediastinal germ cell tumor (PMMGCT) which represent 1%-4% of all mediastinal tumors and can be divided into two broad groups: seminomas and nonseminomatous germ cell tumors (NSGCTs). Primary mediastinal seminomas clinical presentation is often nonspecific, even if the majority of patients present with superior vena cava involvement. Here, we present the radiologic features of asymptomatic azygos system overflow in a patient with primary mediastinal seminoma.

Head and neck cancers (HNC) represent the seventh most frequent cancer worldwide, with squamous cell carcinomas as the most frequent histologic subtype. Standard treatment for early stage diseases is represented by single modality surgery or radiotherapy, whereas in the locally advanced and recurrent or metastatic settings a more aggressive multi-modal approach is needed with locoregional intervention and/or systemic therapies. Epidermal Growth Factor Receptor (EGFR) plays an important role in HNC biology and has been studied extensively in preclinical and clinical settings. In this scenario, anti-EGFR targeted agent cetuximab, introduced in clinical practice a decade ago, represents the only approved targeted therapy to date, while the development of immune-checkpoint inhibitors has recently changed the available treatment options. In this review, we focus on the current role of anti-EGFR therapies in HNCs, underlying available clinical data and mechanisms of resistance, and highlight future perspectives regarding their role in the era of immunotherapy.

Background: The introduction of immunotherapy has improved the prognosis of patients with Non-Small Cell Lung Cancer (NSCLC). However, data in poor ECOG Performance Status (PS) patients remain scant due to their exclusion from randomized trials. Material and methods: We analyzed data of patients with advanced NSCLC treated with immunotherapy in two Italian Centers, to evaluate the impact of PS (0-1 vs 2) on disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Chi-square test was used to compare clinical-pathological variables, their impact on survival was evaluated through Cox proportional hazard models. Results: Among 404 patients included, PS was 0 in 137 (33.9 %), 1 in 208 (51.5 %) and 2 in 59 (14.6 %) patients; 143 were female and 90 had squamous NSCLC. Clinical-pathological variables were uniformly distributed except for higher prevalence of liver metastases in patients with poor PS. We found that PS2 patients showed worse outcomes in terms of DCR (21.8 % vs 50.3 %, p = 0.001), PFS [2.0 (95 % CI 1.6–3.0) vs 3.0 (95 % CI 2.7–4.0) months, p < 0.0001] and OS [4.0 (95 % CI 2.8–5.7) vs 13.2 (95 % CI 11.0−15.8) months, p < 0.0001]. PS2 status, negative PDL1 expression and early corticosteroids exposure as well as higher Neutrophil to Lymphocyte Ratio and LDH at baseline were associated with worse outcomes at univariate and multivariable analysis. Subgroup analysis confirmed poor outcomes in PS2 patients with high LDH and concomitant corticosteroid therapies. The incidence of Grade 3/4 adverse events was 11.3 % in PS 0−1 and 10.2 % in PS 2 patients (p = 0.81). Conclusion: Our data confirm reduced efficacy of immunotherapy in patients with poor PS even though a good safety. Despite PS remains the most powerful independent prognostic factor for NSCLC, LDH levels and steroids exposure could support the decision making in PS2 patients.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies: novel therapeutic approaches beyond conventional chemotherapy are still lacking and prognosis remains poor, even for resectable patients (pts). Furthermore, there is an almost complete absence of validated predictive factors. Consequently, robust biomarkers for the early diagnosis and the prognostic stratification are urgently needed in clinical practice, especially in the context of neoadjuvant and adjuvant settings. In the last years, evidence revealed the crucial role of miRNAs in cancer initiation and progression, as well as in the chemo-resistance mechanisms, suggesting their use as clinical biomarkers. Material and methods: In this pilot study, we performed a microarray analysis to characterize global miRNA expression profile from surgical tissue samples collected from 20 resected PDAC pts pooled into 4 groups according to different clinico-pathological features: nodal metastases (N+/N-) and tumor grading (G2/G3). Results: According to expression patterns, we identified, among 384 miRNAs, a significant different modulation for 11 miRNAs associated to G2 vs G3 and for 7 miRNAs in N+ vs N- disease, suggesting a possible specific signature reflecting histological grade and nodal metastasis occurrence, respectively. We focused on 2 up-regulated (miR-138-5p and miR-518-3p) and 3 down-regulated (miR-215-5p, miR-519a-3p and miR-576-5p) miRNAs in N+ pts, and on 3 up-regulated (miR-1-3p, miR-31-5p and miR-205-5p) in G3 pts, in order to verify their possible implication in the molecular changes behind tumor differentiation and spread, as well as their potential use for prognostic and therapeutic purpose. A bio-informatic analysis was also performed, using different in silico tools, to study both high affinity miRNA targets and cross-regulated pathways among the upand down-regulated miRNAs. The results identified several associated targets involved in multiple signaling pathways commonly dysregulated in cancer. Finally, BRCA1/2 and RB1 miRNAs-mediated-modulation is actually ongoing, considering the pivotal role of these genes in some PDAC pts. Conclusion: These preliminary data provide a strong rationale to further investigate miRNAs expression in larger cohorts of PDAC pts, possibly integrating validated tissue miRNAs data with circulating miRNAs, in order to identify strong (and easily accessible) potential biomarker(s) with prognostic and/or predictive significance. Citation Format: Luca Pompella, Michela Falco, Carlo Caputo, Anna Grimaldi, Giuseppe Tirino, Severo Campione, Francesca Sparano, Maria Lucia Iacovino, Chiara Carmen Miceli, Carlo Molino, Marco Montella, Renato Franco, Gennaro Galizia, Giovanni Conzo, Vincenzo Napolitano, Annamaria Auricchio, Francesca Cardella, Fortunato Ciardiello, Michele Caraglia, Angela Lombardi, Gabriella Misso, Ferdinando De Vita. A pilot study of miRNA expression profile in surgically resected pancreatic ductal adenocarcinoma: Initial report from a bi-institutional cohort [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-052.

e21601 Background: The introduction of Immunotherapy (IO) has dramatically improved the prognosis of patients (pts) with advanced Non-Small Cell Lung Cancer (NSCLC). However, data regarding the role of IO in ECOG Performance Status (PS) 2 pts are generally limited in randomized trials, and real-world evidences could support clinical decision-making. Methods: We retrospectively analyzed data about pts with stage IV NSCLC treated with IO between April 2013 and December 2019 in two Italian Centers. The aim of our study was to assess the impact of PS status (0-1 vs 2) on disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Response was classified according to RECIST v1.1 criteria. PFS and OS were estimated by the Kaplan-Meier method. Chi-square test was used to compare clinical-pathological variables: gender, age ( < 70, 70-79, ≥80 years-old), smoking status, histology (squamous, non-squamous), PDL1 expression ( < 1%, ≥1%), IO line (1°, ≥2°), number (N) of metastatic sites (1, ≥2), presence of liver and/or brain metastasis. Their impact on survival was evaluated through Cox proportional hazard models. Results: Four-hundred-one pts (35.7% female) with median age of 65.4 years (range 27-88) were studied. Baseline PS was 0 in 134 pts (33.4%), 1 in 209 pts (52.1%) and 2 in 58 pts (14.5%). 312 pts had non-squamous NSCLC, 89 squamous NSCLC. Clinical-pathological variables were uniformly distributed across PS groups except for a higher rate of liver metastasis in PS2 pts ( p= 0.046). Response evaluation was available for 386 pts. DCR was 49.7% in PS0-1 pts and 25.9% in PS2 pts ( p= 0.006). At a median follow-up of 29 months (mos), median PFS was 3.0 mos (95% CI 2.63-4.00) and 2.04 mos (95% CI 1.84-3.00) in pts with PS0-1 and 2 ( p< 0.0001). Median OS was 13.2 mos (95% CI 11.18-15.78) and 4.0 mos (95% CI 2.66-5.62) in pts with PS 0-1 and 2 respectively ( p< 0.0001). Univariate analysis showed significant correlation of PS2 status, negative PDL1, IO line ≥2, N of metastatic sites ≥2 and liver metastasis, for both PFS and OS. Multivariate analysis confirmed an independent association of PS ( p= 0.0013 for PFS, p< 0.0001 for OS), PDL1 ( p= 0.0002 for PFS, p= 0.02 for OS) and liver metastasis ( p= 0.017 for PFS, p= 0.02 for OS). The incidence of Grade 3/4 adverse events was 10.5% in PS 0-1 pts and 13.7% in PS 2 pts ( p= 0.41). Conclusions: Our data confirm reduced efficacy of IO in pts with poor PS, regardless of the N of prior therapy lines or PDL1 expression. Despite IO appears to be safe and tolerable its role remains uncertain in PS2 pts based on worse survival outcomes.

Background Antibody-dependent cell-mediated cytotoxicity (ADCC) may mediate antitumour activity of IgG1-isotype monoclonal antibody (mAb), suggesting as potential treatment combination of IgG1-mAbs, anti-epidermal growth factor receptor cetuximab and anti-programmed death-ligand-1 avelumab. Methods We evaluated ADCC induction in lung cancer cells by lactate dehydrogenase (LDH) release assay. Antitumour activity and safety of cetuximab plus avelumab were explored in a single-arm proof-of-concept study in pre-treated non-small cell lung cancer (NSCLC) patients (pt) (Cetuximab-AVElumab-lung, CAVE-Lung). Search for predictive biomarkers of response was done. Results Avelumab plus cetuximab induced ADCC in NSCLC cells in vitro in presence of natural killers (NK) from healthy donors (HD) or NSCLC pt, as effectors. Sixteen relapsed NSCLC pt were treated with avelumab plus cetuximab. Antitumour activity was observed in 6/16 pt, defined by progression free survival (PFS) ≥8 months, with 4 of them still on treatment at data lock time (range, 14–19 months). Of note, 3/6 responders had received as previous line anti-programmed death-1 therapy. In responders, clinical benefit was accompanied by significant increase in LDH release over baseline at the first radiological evaluation (8 weeks) (p=0.01) and by early skin toxicity; while in the 10 non-responders, that had PFS ≤5 months, LDH release tends to reduce. Baseline circulating DNA levels were higher in non-responders compared with responders and HD (p=0.026) and decrease in responders during therapy. Mutations in DNA damage responsive family genes were found in responders. Conclusion Cetuximab and avelumab activates NSCLC pt NK cells. Ex vivo evaluation of ADCC, circulating DNA levels and early skin toxicity may predict response to cetuximab plus avelumab in NSCLC. EUDRACT 2017-004195-58

Background Immune checkpoint inhibitors (ICIs) in patients with pretreated advanced NSCLC (aNSCLC) showed an overall survival (OS) benefit over standard chemotherapy in phase III randomized clinical trials (RCTs). Nevertheless, a significant portion of patients do not benefit from ICIs. The identification of biomarkers to select patients most likely to respond to ICIs is greatly needed in clinical practice. The role of baseline clinical and blood biomarkers as prognostic of response to ICIs was investigated in patients with aNSCLC and a prognostic ImmunoScore is defined. Methods We retrospectively reviewed clinical data of aNSCLC patients consecutively treated with single agents anti PD-1 or anti PD-L1 as 2nd (81.8%) or ≥ 3rd (18.2%) line at University Hospitals of Valencia and Naples. ECOG PS, sites of metastases, neutrophil to lymphocyte ratio (NLR), LDH and albumin levels were recorded at baseline. The impact of these variables on PFS and OS was assessed through survival analyses (Kaplan Meier method), univariate (log rank test) and multivariate analyses (Cox proportional hazard model). Results The analysis included 132 pts. Median PFS and OS were 3 (95% CI 2.74-3.26) and 9 (95% CI 5.90-12.02) months respectively. The univariate analysis for PFS showed that baseline NLR>4 (p = 0.001), albumin 1 (HR 2.96, p 400 U/l (p = 0.089). The multivariate analysis for PFS confirmed as statistically significant independent negative prognostic factors PS > 1 (p = 0.001) and liver metastases (p = 0.011). Finally, according to PS, liver metastases, NLR and albumin three different prognostic groups at high (3-4 RF), intermediate (1-2 RF) and low (0 RF) risk for OS were defined. Median OS was respectively 5 (95% CI 3.45-6.55), 7 (95% CI 4.98-9.02) and 23 (95% CI 16.53-29.47) months (p Conclusion Baseline evaluation of clinical and blood biochemical parameters can be a tool to predict outcome in patients treated with ICIs for aNSCLC. Moreover, combining them in ImmunoScore may help to identify pts candidates to second or subsequent Iines of therapy who most likely will benefit from ICIs. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background cfDNA analysis could represent an alternative to invasive biopsy in patients with NSCLC to better understand disease profile. We report a real-world experience of genomic assessment of an Italian patients’ cohort. Methods We evaluated 58 non-oncogene-addicted aNSCLC patients treated at our Institution from January 2018 to May 2019. All patients were characterized using cfDNA NGS Guardant360® platform (Guardant Health, Redwood City, CA). Association between a positive result (defined as cfDNA detected) and clinical features was assessed using logistic regression test. Using online library dataset (mycancergenome.org) and literature data, we divided patients in genomic clusters and performed a descriptive analysis. Results The median age of patients was 67 (range 38-85), 44 men and 14 women, 8.6% never smokers, 41.4% former and 50% current smokers. 14 patients (24.2%) had squamous cell carcinoma and 44 (75.8%) had non-squamous NSCLC, 50 of 58 at stage IV at the time of testing. Most patients were PS 0-1 per ECOG scale and has been treated with at least one systemic regimen before performing NGS. 47 of 58 patients (81%) has been considered positive at the analysis. No targetable genomic alterations per local authority has been found. More than 40 different mutated genes were detected, the most common alterations involved TP53 (60% of patients), KRAS (34%), PDGFRα (17%), EGFR (15% - not-TKI-sensitive), PI3KCA (15%), CDKN2A (15%). Chemotherapy (but not immunotherapy) and extra-thoracic radiotherapy before testing increased the probability to result positive at NGS of 4.5 and 2 folds respectively. Six mutational clusters have been identified. Most patients had genomic alterations in Replication Stress - DNA damage/repair, cell cycle - (72%) and Tyrosine Kinase Receptor/Growth Factor pathway (62%), less common mutations affected PI3K/AKT/mTOR and Hormone signaling (26% and 9% respectively). Conclusions Our experience demonstrated the feasibility of NGS-based NSCLC patients genomic profiling. The widespread of NGS platforms (and the subsequent reduction of costs) should encourage clinicians to use these methods with all patients to guarantee access to developing therapeutics and clinical trials. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure F. Ciardiello: Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Ipsen; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: BMS; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Servier; Advisory / Consultancy: Celgene; Advisory / Consultancy: Lilly; Advisory / Consultancy: Pfizer. F. Morgillo: Advisory / Consultancy: MSD; Advisory / Consultancy: Lilly; Research grant / Funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.