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Langerhans cell histiocytosis (LCH) is a rare disease that has a variable clinical presentation and unpredictable behavior. Until recently, therapeutic options were limited. Insights into the role of mitogen-activated protein kinase (MAPK) signaling have allowed the increased use of targeted treatments. Before the advent of drugs that interfere with this pathway, investigations concerning the tyrosine kinase inhibitor imatinib opened the way to a rationale-based therapeutic approach to the disease. Imatinib block the binding site of ATP in the BCR/ABL protein and is also a platelet-derived growth factor receptor (PDGFR) and a KIT (CD117) kinase inhibitor. A case of refractory LCH with brain involvement was reported to be successfully treated with imatinib. Thereafter, we further explored the role of this tyrosine kinase inhibitor. The present study is composed of an immunohistochemical evaluation of PDGFRβ expression and a clinical evaluation of imatinib in a series of LCH patients. In the first part, a series of 10 samples obtained from LCH patients was examined and a strong immunohistochemistry expression of PDGFRβ was found in 40% of the cases. In the clinical part of the study, five patients were enrolled. Long-lasting disease control was obtained. These results may suggest a potential role for this drug in the current age.

The cure rate of germ cell tumours (GCTs) has significantly increased from the late 1970s since the introduction of cisplatin-based therapy, which to date remains the milestone for GCTs treatment. The exquisite cisplatin sensitivity has been mainly explained by the over-expression in GCTs of wild-type TP53 protein and the lack of TP53 somatic mutations; however, several other mechanisms seem to be involved, many of which remain still elusive. The findings about the role of TP53 in platinum-sensitivity and resistance, as well as the reported evidence of second cancers (SCs) in GCT patients treated only with surgery, suggesting a spectrum of cancer predisposing syndromes, highlight the need for a deepened understanding of the role of TP53 in GCTs. In the following report we explore the complex role of TP53 in GCTs cisplatin-sensitivity and resistance mechanisms, passing through several recent genomic studies, as well as its role in GCT patients with SCs, going through our experience of Center of reference for both GCTs and cancer predisposing syndromes.

As widely acknowledged, 40–50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS–RAF–MEK–ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected stage III and IV melanoma therapy management. However, despite progress in BRAF-mutant melanoma treatment, the two different approaches approved so far for metastatic disease, immunotherapy and BRAF+MEK inhibitors, allow a 5-year survival of no more than 60%, and most patients relapse during treatment due to acquired mechanisms of resistance. Deep insight into BRAF gene biology is fundamental to describe the acquired resistance mechanisms (primary and secondary) and to understand the molecular pathways that are now being investigated in preclinical and clinical studies with the aim of improving outcomes in BRAF-mutant patients.

Immunotherapy based on anti PD-1/PD-L1 inhibitors has proven to be more effective than sunitinib in the first-line setting of advanced renal cell carcinoma (RCC). RCC patients with sarcomatoid histology (sRCC) have a poor prognosis and limited therapeutic options. We performed a systematic review and a meta-analysis of randomized-controlled trials (RCTs) of first-line anti PD-1/PDL-1 agents vs. sunitinib, presenting efficacy data in the sub-group of sRCC patients. The systematic research was conducted on Google Scholar, Cochrane Library, PubMed and Embase and updated until 31th January, 2020. Abstracts from ESMO and ASCO (2010−2019) were also reviewed. Full texts and abstracts reporting about RCTs testing first-line anti-PD-1/ PD-L1 agents vs. sunitinib in RCC were included if sRCC sub-group analyses of either PFS (progression-free survival), OS (overall survival) or radiological response rate were available. Pooled data from 3814 RCC patients in the ITT (intention-to-treat) population and from 512 sRCC patients were included in the quantitative synthesis. In the sRCC sub-group vs. the ITT population, pooled estimates of the PFS-HRs were 0.57 (95%: 0.45−0.74) vs. 0.79 (95% CI: 0.70−0.89), respectively, with a statistically meaningful interaction favoring the sRCC sub-group (pooled ratio of the PFS-HRs = 0.64; 95% CI: 0.50−0.82; p < 0.001). Pooled estimates of the difference in CR-R (complete response-rate) achieved with anti-PD-1/PDL-1 agents vs. sunitinib were + 0.10 (95% CI: 0.04−0.16) vs. + 0.04 (95% CI: 0.00−0.07) in the sRCC vs. the non-sRCC sub groups, with a statistically meaningful difference of + 0.06 (95% CI: 0.02−0.10; p = 0.007) favoring the sRCC sub-group. Sarcomatoid histology may be associated with improved efficacy of anti PD-1/PDL-1 agents vs. sunitinib in terms of PFS and CR-R.

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has overwhelmed the health systems worldwide. Data regarding the impact of COVID-19 on cancer patients (CPs) undergoing or candidate for immune checkpoint inhibitors (ICIs) are lacking. We depicted the practice and adaptations in the management of patients with solid tumors eligible or receiving ICIs during the COVID-19 pandemic, with a special focus on Campania region.MethodsThis survey (25 questions), promoted by the young section of SCITO (Società Campana di ImmunoTerapia Oncologica) Group, was circulated among Italian young oncologists practicing in regions variously affected by the pandemic: high (group 1), medium (group 2) and low (group 3) prevalence of SARS-CoV-2–positive patients. For Campania region, the physician responders were split into those working in cancer centers (CC), university hospitals (UH) and general hospitals (GH). Percentages of agreement, among High (H) versus Medium (M) and versus Low (L) group for Italy and among CC, UH and GH for Campania region, were compared by using Fisher’s exact tests for dichotomous answers and χ2 test for trends relative to the questions with 3 or more options.ResultsThis is the first Italian study to investigate the COVID-19 impact on cancer immunotherapy, unique in its type and very clear in the results. The COVID-19 pandemic seemed not to affect the standard practice in the prescription and delivery of ICIs in Italy. Telemedicine was widely used. There was high consensus to interrupt immunotherapy in SARS-CoV-2–positive patients and to adopt ICIs with longer schedule interval. The majority of the responders tended not to delay the start of ICIs; there were no changes in supportive treatments, but some of the physicians opted for delaying surgeries (if part of patients’ planned treatment approach). The results from responders in Campania did not differ significantly from the national ones.ConclusionOur study highlights the efforts of Italian oncologists to maintain high standards of care for CPs treated with ICIs, regardless the regional prevalence of COVID-19, suggesting the adoption of similar solutions. Research on patients treated with ICIs and experiencing COVID-19 will clarify the safety profile to continue the treatments, thus informing on the most appropriate clinical conducts.

Some commonly available patient or disease characteristics may be associated with progression-free survival (PFS) and overall survival (OS) in EGFR-mutant non-small cell lung cancer (NSCLC) patients receiving EGFR-TKIs (epidermal growth factor receptor - tyrosine kinase inhibitors). We performed a systematic review and meta-analysis of randomized control trials (RCTs) to explore differences in outcomes associated with EGFR-TKIs among subgroups of EGFR-mutant NSCLC patients. Pooled HRs for progression or death (PFS-HRs) and pooled HRs for death (OS-HRs) were compared among sub-groups defined according to baseline clinical and demographic variables as well as type of EGFR mutation. In the entire assessable population of 4465 EGFR-mutant NSCLC patients, significant interactions with PFS were found for gender (males vs. females; pooled ratio of the PFS-HRs = 1.2; 95% CI 1.12–1.56), smoking history (smokers vs. non-smokers; pooled ratio of the PFS-HRs = 1.26; 95% CI 1.05–1.51), and type of EGFR mutation (patients with exon 21 L858R mutation vs. exon 19 deletion; pooled ratio of the PFS-HRs = 1.39; 95% CI 1.18–1.63). Male patients, smokers and patients with EGFR exon 21 L858R mutation may derive less benefit from EGFR-TKIs compared to female patients, non-smokers and patients with EGFR exon 19 deletion.

e20595 Background: The association between thymoma (T) and immunological dysregulations is well acknowledged. Good’s syndrome (GS), which occurs in approximately 6% to 11% of T patients, is characterized by hypogammaglobulinemia, few or absent B-cells (CD19+), CD4 T cells lymphopenia, abnormal CD4/CD8 T ratio and impaired T cell mitogenic response. Patients with GS have increased susceptibility to bacterial, opportunistic and viral infections related to both humoral and cell-mediated immunodeficiency. The recent Sars-Cov-2 pandemic drew attention to the clinical condition of fatal viral pneumonitis and cytokines storm. Here we reported our monocentric experience of pneumonitis in patients with T and GS before the Sars-Cov-2 pandemic. Methods: We conducted a retrospective analysis of T patients with associated GS referred to the Rare Tumours Reference Center of University Federico II of Naples over a 10-year period (from 2009 to 2019). All the patients with radiological and/or clinical pneumonitis diagnosis were evaluated for this report. Immunological features, histopathological diagnosis and clinical outcome were registered. Results: A total of 41 patients with T and GS were identified, including 17 patients with local disease (stage I-II according to Masaoka-Koga) and 24 with advanced disease (stage III-IV). The majority (56.3%) had B2 T diagnosis. Radiological and/or clinical pneumonitis diagnosis was assessed in 23 cases (56%). Viral pneumonitis was detected in 8 patients: 3 patients with H1N1 infection, 3 patients with CMV infection, 2 patients with EBV infection. Bacterial pneumonitis was diagnosed in 9 patients (3 patients with K. pneumoniae, 4 patients with S. aureus, 2 patients with H. influenza). Opportunistic pneumonitis was found in 2 patients with Aspergillosis infection. In 2 cases no pathogenic agent was identified. The immunophenotyping, assessed in 4 patients with viral pneumonitis, displayed very low/undetectable levels of B cells, with median % value of CD3+T cells and NKT of respectively 9.8% and 0.4% of the total leukocytes. The median % of Treg was 4.7%. CD4+/CD8+ ratio was variable, ranging from 1,2 to 0,6. Interestingly the number of B cells was extremely low, independent of CD4+/CD8+ ratio. Blood levels of cytokines, chemokines and growth factors revealed elevated IL-4, Eotaxin, CCL2 / MCP-1 and CCL5 / RANTES ad strong reduction of IL-10. PDGF-BB levels were also elevated. 15 patients required admission to intensive care Six patients died for fatal pneumonitis. Conclusions: The management of T patients with GS is extremely challenging. Clear diagnostic algorithms do not yet exist and immune-profiling and quantitative immunoglobulins should be considered a part of diagnostic search in these patients. The coexistence of cancer, infections and immunosuppression may trigger life-threatening conditions, such as fatal pneumonitis, which often require intensive care and multidisciplinary approach.

9074 Background: Platinum based regimens are used in the first line setting for advanced Thymic Epithelial Tumors (TETs). Angiogenesis plays an important role in TETs: VEGF is overexpressed in TETs, and associated with aggressiveness and advanced stage. Etoposide inhibits angiogenesis in vitro and in vivo by decreasing VEGF production and microvessel density. The aim of this study is to assess the activity of metronomic oral etoposide, with identification of circulating predictive and pharmacodynamics biomarkers. Methods: Patients with advanced platinum pretreated TET referred from 2014 to 2019 at Rare Tumors Reference Center of Naples, were prospectively enrolled in this study. Oral etoposide 50 mg daily for 3 weeks on and 1 week off every 28 days, has been delivered until progression of disease, complete response or unacceptable toxicity. Response rate (RR), progression free survival (PFS), toxicity and ratio between time to etoposide progression (TTPe) and time to previous best treatment progression (TTPp) were evaluated. Serum samples were prospectively obtained from ten patients with simultaneously radiological assessment. cfDNA quantification was assessed using Qubit Fluorometric Quantitation. Results: 21 patients were enrolled: median age 59 years range (41 - 88); 70% male, 60% T (4 B1, 3 B2, 4 B3, 1 B1-B2); 40% had TC. A median of 5 (range 1-9) prior therapy regimens had been administered. Median follow-up since etoposide was 5 years (range 0.5-5). Obtaining an overall response rate of 85%, 3 patients achieved complete response and 15 partial response. Median PFS was 16 months [95%CI 3-60] with respectively a median PFS of 12 for T (95%CI 3-38) and 19 for TC (95%CI 6-60). No grade 3-4 related events occurred, G1-2 myelotoxicity has been registered in 20% of patients. Therapy is still ongoing for 15 patients and all are still alive. Median TTPe was 16 months, TTPp was 9 months and TTPe / TTPp ratio equal to 1.7. The median cfDNA of 8 responder patients, before starting therapy, was 2.2 ng/μl (0.178-5.24), dropping dramatically at radiological response to 0.5 ng/μl (0.323-2.56). 2 out of 3 non-responder patients had a median baseline value of 2.49 ng/μl, increasing to 4.6 ng/μl at progression. Variation of circulating VEGF correlates with radiological response. Conclusions: Taking into account that other antiangiogenic drugs, showing some activity in second and further lines treatment, are very expensive and associated with several side effects, we suggest that low dose oral etoposide might become the preferred treatment option in heavily pretreated TETs.

Background: Cabazitaxel is a second-generation taxane that is approved for use with concomitant low dose daily prednisone in metastatic castration resistant prostate cancer (mCRPC) after docetaxel failure. Since the role of daily corticosteroids in improving cabazitaxel efficacy or ameliorating its safety profile has not been adequately investigated so far, we compared outcomes of patients receiving cabazitaxel with or without daily corticosteroids in a retrospective single-Institution cohort of mCRPC patients. Patients and methods: Medical records of deceased patients with documented mCRPC treated with cabazitaxel following prior docetaxel between January, 2011 and January, 2017 were reviewed at the single participating center. Patients who were receiving daily doses of systemic corticosteroids other than low dose daily prednisone or prednisolone (30% PSA decline at 12 weeks. Prednisone use was not significantly prognostic for overall survival or PSA decline ≥30% rates on regression analyses. Importantly, a >30% PSA decline at 12, but not at 3, 6, 9 weeks, was prognostic for improved survival at multivariate analysis Conclusions: The data presented here support the hypothesis that omitting daily corticosteroids in cabazitaxel-treated patients has no negative impact on either survival or safety profile. In the large prospective trial CABACARE, cabazitaxel-treated patients will be randomized to receive or not receive daily prednisone. The CABACARE (EudraCT n. 2016-003646-81) study is currently ongoing at University Federico II of Naples and at other multiple participating centers in Italy.

8567 Background: Thymic epithelial tumors (TETs), show a high rate of EGFR immunohistochemistry (IHC) positivity, however, the prognostic and predictive role of EGFR has not yet been well defined, and contradictory data have emerged regarding the delivering of anti-EGFR monoclonal antibodies in TETs. The outcomes of the largest series of thymoma patients treated with cetuximab, and its hypothetic immune-modulatory role, are here described. Methods: Seven patients with diagnosis of pre-treated advanced thymoma and score positivity 2+ and 3+ at EGFR-IHC, were treated with cetuximab as off-label modality, with a dose of 400 mg/m2 in the first cycle and 250 mg/m2 in the following cycles every 7 days, until disease progression, unacceptable toxicity, withdrawal of consent. Primary endpoint was Overall Response Rate ORR, assessed radiologically. Secondary endpoints were progression Free Survival (PFS), safety, and relationship between time to cetuximab progression (TTPc) and time to previous treatment progression (TTP1). During treatment with cetuximab lymphocyte subpopulations have been carefully monitored in 4 patients affected by both thymoma and Good syndrome (GS) defined as B-cell lymphocyte counts (CD19+)

TPS345 Background: In the TROPIC trial, cabazitaxel (CAB) plus daily prednisone (PDN) was associated with a significant advantage in OS and PFS in docetaxel (DOC)-pretreated patients (Pts). Whether daily PDN may significantly contribute to CAB efficacy or improve its safety profile is unknown. In the CHARTEED trial, DOC was administered without daily PDN with no concerns about the lack of efficacy or greater toxicity. Safety data about CAB without PDN are scarce. Corticosteroids present multiple biological effects, which may potentially be either positive, such as those mediated by adrenal androgen and cytokine suppression, or detrimental, such as those associated with the activation of the glucocorticoid receptor (GR) and of the androgen receptor (AR). Furthermore, PDN is a CYP3A4 inducer and can potentially negatively affect CAB clearance. Finally, AR-V7 positivity in circulating tumor cells and retinoblastoma (RB) loss/inactivation have been identified as potential mechanisms of resistance to hormonal and chemotherapy treatments in prostate cancer. For this reason, we also aim to evaluate if CAB activity is related to such biomarkers. Methods: CABACARE (EudraCT 2016-005251-25) is a randomized, phase II, open label, multi-center study comparing CAB at 25 mg/m2 q21 plus daily PDN (10 mg) vs CAB at 25 mg/m2 q21 alone in mCRPC pts progressed during or after DOC treatment. The study is designed to test non inferiority in terms of PFS, according PCWG-2, of CAB alone vs CAB plus PDN assuming that the two arms are equally effective (non-inferiority HR = 1.4). Main secondary objectives are: safety, QoL, pain assessment, overall response rate (ORR), PSA response, time to PSA progression, Time to radiological progression; OS; time to skeletal related events . The influence of AR-V7 and RB status measured in circulating epithelial cells at baseline on CAB activity will also be evaluated. A total of 35 Italian centers have started / will start recruiting pts in the CABACARE trial. Of the 220 pts required by the trial design, 43 pts have been enrolled since 30th Nov , 2017 until 2nd Oct, 2018 in 10 different Italian Institutions. Clinical trial information: 2016-005251-25.