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Introduction Although standard doublet chemotherapy represents the upfront gold standard to increase survival and improve quality of life of gastric cancer patients, overall improvements in long-term outcomes are modest and novel treatments are urgently needed. Among these, immunotherapy is an increasingly attractive option. Areas covered A number of clinical trials have shown that checkpoint inhibitors may be of value, but many unclear issues remain controversial and should be promptly untangled. In our short review, we offer the current available data regarding immunotherapies in gastric cancers, discuss potential limits of the reported trials, compare outcomes of checkpoints inhibitor to those of standard chemotherapy or other novel treatments, and present basic principles of immune surveillance and immune escape that may be embraced in the near future with novel drug combinations. Expert opinion Gastric cancer patients may benefit from immunotherapy, both given alone in advanced lines or upfront in combination with chemotherapy. We believe that appropriate patients' and tumor's. selection are crucial issues to maximize its potential efficacy. In addition, we think that assay standardization, biomarker agreement, and translational studies will improve the benefit-to-risk ratio of these agents in the clinical practice.

Background Neuroendocrine differentiation has been extensively associated with worse prognosis and to mechanisms of therapy resistance in several epithelial cancers. A high prevalence of neuroendocrine differentiation was recently described in V600EBRAF-mutated (BRAFmt) metastatic colorectal cancers (mCRCs) but no data are available about its prognostic impact in this setting. Methods We assessed synaptophysin immunohistochemical expression in a multi-institutional series of 159 BRAFmt mCRCs with matched clinical and pathological information. Tumours were dichotomized as synaptophysin high and low. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan–Meier and log-rank tests. Results Thirty-five tumours (22.0%) showed any level of positivity for synaptophysin, and 18 (11.3%) were characterized by positivity in at least 20% of tumour cells. Four cases resulted 100% synaptophysin positive. The histotype of synaptophysin-positive tumours (i.e. ≥20%) was not otherwise specified in 11 cases (61.1%) and mucinous adenocarcinoma in 4 cases (22.2%). Four cases were DNA mismatch repair deficient (22.2%) and 7 (38.9%) were characterized by a high number of tumour-infiltrating lymphocytes. At multivariate analysis, high synaptophysin expression was a negative independent prognostic factor for both PFS (HR = 2.00, 95% confidence interval [CI] 1.21–3.33, p = 0.006) and OS (HR = 2.27, 95% CI 1.35–3.85, p = 0.001). Conclusions Among BRAFmt mCRCs, synaptophysin-positive tumours are characterized by worse PFS and OS. Further studies should investigate the molecular mechanisms involved in the acquisition of the neuroendocrine phenotype to identify novel-targeted treatment strategies.

Complex EGFR mutations are rare in non-small cell lung cancer (NSCLC). Limited clinical evidence is available on the efficacy of EGFR tyrosine kinase inhibitors (TKIs) in patients with NSCLC harbouring these uncommon EGFR mutations. Here, we reported the case of a complete metabolic response in a patient with advanced NSCLC carrying the uncommon EGFR G719A/V769M complex mutation treated with the first-line osimertinib.

The prognostic relevance of early immune-related adverse events (irAEs) in patients affected by non-small cell lung cancer (NSCLC) upon immunotherapy is not fully understood. The Leading to Treatment Discontinuation cohort included 24 patients experiencing severe irAEs after one of two administrations of single anti-PD-1/PD-L1 in any line setting for metastatic NSCLC between November 2015 and June 2019. The control cohort was composed of 526 patients treated with single anti-PD-1/PD-L1 in any line setting with no severe irAE reported. The primary end points were median progression-free survival, overall survival, objective response rate, risk of progression of disease and risk of death. The correlation of clinic pathological features with early severe irAEs represented the secondary end point. Median PFS was 9.3 and 8.4 months, median OS was 12.0 months and 14.2 months at a median follow-up of 18.1 and 22.6 months in the LTD cohort and in the control cohort, respectively. The ORR was 40% (95% CI 17.2–78.8) in the LTD cohort and 32.7% (95% CI 27.8–38.2) in the control cohort. The risk of disease progression was higher in the LTD cohort (HR 2.52 [95% 1.10–5.78], P = .0288). We found no survival benefit in LTD cohort compared to the control cohort. However, early and severe irAEs might underly an immune anti-tumor activation. We identified a significant association with first-line immune checkpoints inhibitors treatment and good PS. Further studies on risk prediction and management of serious and early irAEs in NSCLC patients are needed.

Background V600EBRAF mutated metastatic colorectal cancer (mCRC) is a subtype (10%) with overall poor prognosis, but the clinical experience suggests a great heterogeneity in survival. It is still unexplored the real distribution of traditional and innovative biomarkers among V600EBRAF mutated mCRC and which is their role in the improvement of clinical prediction of survival outcomes. Methods Data and tissue specimens from 155 V600EBRAF mutated mCRC patients treated at eight Italian Units of Oncology were collected. Specimens were analysed by means of immunohistochemistry profiling performed on tissue microarrays. Primary endpoint was overall survival (OS). Results CDX2 loss conferred worse OS (HR = 1.72, 95%CI 1.03–2.86, p = 0.036), as well as high CK7 expression (HR = 2.17, 95%CI 1.10–4.29, p = 0.026). According to Consensus Molecular Subtypes (CMS), CMS1 patients had better OS compared to CMS2-3/CMS4 (HR = 0.37, 95%CI 0.19–0.71, p = 0.003). Samples showing less TILs had worse OS (HR = 1.72, 95%CI 1.16–2.56, p = 0.007). Progression-free survival analyses led to similar results. At multivariate analysis, CK7 and CMS subgrouping retained their significant correlation with OS. Conclusion The present study provides new evidence on how several well-established biomarkers perform in a homogenousV600EBRAF mutated mCRC population, with important and independent information added to standard clinical prognosticators. These data could be useful to inform further translational research, for patients’ stratification in clinical trials and in routine clinical practice to better estimate patients’ prognosis.

Background: Characterization of tumor-related genetic alterations is promising for the screening of new predictive markers in non-small cell lung cancer (NSCLC). Aim of the study was to evaluate prognostic and predictive role of most frequent tumor-associated genetic alterations detected in plasma before starting immune checkpoint inhibitors (ICIs). Methods: Between January 2017 and October 2019, advanced NSCLC patients were prospectively screened with plasma next- generation sequencing (NGS) while included in two trials: VISION (NCT02864992), using Guardant360 (R) test, and MAGIC (Monitoring Advanced NSCLC through plasma Genotyping during Immunotherapy: Clinical feasibility and application), using Myriapod NGS-IL 56G Assay. A control group of patients not receiving ICIs was analyzed. Results: A total of 103 patients receiving ICIs were analyzed: median overall survival (OS) was 20.8 (95% CI: 16.7-24.9) months and median immune-related progression free disease (irPFS) 4.2 (95% CI: 2.3-6.1) months. TP53 mutations in plasma negatively affected OS both in patients treated with ICIs and in control group (P=0.001 and P=0.009), indicating a prognostic role. STK11 mutated patients (n=9) showed a trend for worse OS only if treated with ICIs. The presence of KRAS/STK11 co-mutation and KRAS/STK11/TP53 co-mutation affected OS only in patients treated with ICIs (HR =10.936, 95% CI: 2.337-51.164, P=0.002; HR =17.609, 95% CI: 3.777-82.089, P

Neuroendocrine differentiation has been extensively associated with worse prognosis and to mechanisms of therapy resistance in several epithelial cancers. A high prevalence of neuroendocrine differentiation was recently described inWe assessed synaptophysin immunohistochemical expression in a multi-institutional series of 159 BRAFmt mCRCs with matched clinical and pathological information. Tumours were dichotomized as synaptophysin high and low. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier and log-rank tests.Thirty-five tumours (22.0%) showed any level of positivity for synaptophysin, and 18 (11.3%) were characterized by positivity in at least 20% of tumour cells. Four cases resulted 100% synaptophysin positive. The histotype of synaptophysin-positive tumours (i.e. ≥20%) was not otherwise specified in 11 cases (61.1%) and mucinous adenocarcinoma in 4 cases (22.2%). Four cases were DNA mismatch repair deficient (22.2%) and 7 (38.9%) were characterized by a high number of tumour-infiltrating lymphocytes. At multivariate analysis, high synaptophysin expression was a negative independent prognostic factor for both PFS (HR = 2.00, 95% confidence interval [CI] 1.21-3.33, p = 0.006) and OS (HR = 2.27, 95% CI 1.35-3.85, p = 0.001).Among BRAFmt mCRCs, synaptophysin-positive tumours are characterized by worse PFS and OS. Further studies should investigate the molecular mechanisms involved in the acquisition of the neuroendocrine phenotype to identify novel-targeted treatment strategies.

Background: The susceptibility of advanced cancer patients treated with immune checkpoint inhibitors (ICI) for viral infections has not been investigated Currently, there are no robust data supporting the efficacy, safety and recommendation for influenza vaccination in cancer patients receiving ICI Methods: The prospective, multicenter, observational INVIDIa-2 study investigated the clinical efficacy of influenza vaccination in advanced cancer patients with solid tumors receiving ICI between October 2019 and January 2020 The incidence of influenza-like illness (ILI, primary endpoint) was observed until April 30, 2020 Secondary endpoints included a non-prespecified analysis for COVID-19 Results: The study enrolled 1279 patients;1188 were evaluable Of them, 11 patients developed ILI symptoms with confirmed diagnosis of COVID-19 (incidence of 0 9% and lethality of 72%, irrespective of the flu vaccination) Of the remaining 1177 patients, 574 received flu vaccination (48 8%) The ILI incidence was 7 7% (91 patients of 1177) Patients receiving the flu vaccine were significantly more frequently elderly (p

Background Targeted agents have improved the outcome of a subset of non-small cell lung cancer (NSCLC). Molecular profiling by next-generation sequencing (NGS) allows screening for multiple genetic alterations both in tissue and in plasma, but limited data are available concerning its feasibility and impact in real-world clinical practice. Methods Patients with advanced NSCLC consecutively referring to our Institution for potential eligibility to VISION trial (NCT02864992) were prospectively enrolled. They were already screened with standard method, and EGFR/ALK/ROS-1 positive cases were excluded. NGS was performed in plasma and tissue using the Guardant360 test covering 73 genes and the Oncomine Focus Assay covering 59 genes, respectively. Results The study included 235 patients. NGS was performed in plasma in 209 (88.9%) cases; 78 of these (37.3%) were evaluated also in tissue; tissue only was analyzed in 26 cases (11.1%). Half of the tissue samples were deemed not evaluable. Druggable alterations were detected in 13 (25%) out of 52 evaluable samples and 31 of 209 (14.8%) of plasma samples. Improved outcome was observed for patients with druggable alterations if treated with matched targeted agents: they had a longer median overall survival (not reached) compared with the ones who did not start any targeted therapy (9.1 months; 95% confidence interval, 4.6–13.6; p = .046). The results of NGS testing potentially also affected the outcome of patients treated with immunotherapy. Conclusion Systematic real-life NGS testing showed the limit of tissue analysis in NSCLC and highlighted the potentiality of genetic characterization in plasma in increasing the number of patients who may benefit from NGS screening, both influencing the clinical decision-making process and affecting treatment outcome. Implications for Practice Genetic characterization of cancer has become more important with time, having had positive implications for treatment specificity and efficacy. Such analyses changed the natural history of advanced non-small cell lung cancer (aNSCLC) with the introduction of drugs targeted to specific gene alterations (e.g., EGFR mutations, ALK and ROS-1 rearrangements). In the field of cancer molecular characterization, the applicability of the analysis of a wide panel of genes using a high-throughput sequencing approach, such as next-generation sequencing (NGS), is still a matter of research. This study used NGS in a real-world setting to systematically and prospectively profile patients with aNSCLC. The aim was to evaluate its feasibility and reliability, as well as consequent access to targeted agents and impact on clinical outcome whenever a druggable alteration was detected either in tumor tissue samples or through liquid biopsy.

The optimal management of gastric adenocarcinoma (GC) and gastroesophageal junction adenocarcinoma (GEJC) remains a critical challenge for medical oncologists. Indeed, this is a relevant burden since GC still stands fifth among the most common tumors and is the third leading cause of cancer-related death worldwide (1).

Background:This prospective, multicentre, observational INVIDIa-2 study is investigating the clinical efficacy of influenza vaccination in advanced-cancer patients receiving immune-checkpoint inhibitors (ICIs), enrolled in 82 Italian centres, from October 2019 to January 2020. The primary endpoint was the incidence of influenza-like illness (ILI) until 30 April 2020. All the ILI episodes, laboratory tests, complications, hospitalizations and pneumonitis were recorded. Therefore, the study prospectively recorded all the COVID-19 ILI events.Patients and methods:Patients were included in this non-prespecified COVID-19 analysis, if alive on 31 January 2020, when the Italian government declared the national emergency. The prevalence of confirmed COVID-19 cases was detected as ILI episode with laboratory confirmation of SARS-CoV-2. Cases with clinical-radiological diagnosis of COVID-19 (COVID-like ILIs), were also reported.Results:Out of 1257 enrolled patients, 955 matched the inclusion criteria for this unplanned analysis. From 31 January to 30 April 2020, 66 patients had ILI: 9 of 955 cases were confirmed COVID-19 ILIs, with prevalence of 0.9% [95% confidence interval (CI): 0.3–2.4], a hospitalization rate of 100% and a mortality rate of 77.8%. Including 5 COVID-like ILIs, the overall COVID-19 prevalence was 1.5% (95% CI: 0.5–3.1), with 100% hospitalization and 64% mortality. The presence of elderly, males and comorbidities was significantly higher among patients vaccinated against influenza versus unvaccinated ( p = 0.009, p Conclusion:COVID-19 has a meaningful clinical impact on the cancer-patient population receiving ICIs, with high prevalence, hospitalization and an alarming mortality rate among symptomatic cases. Influenza vaccination does not protect from SARS-CoV-2 infection.

Introduction: Immune checkpoint inhibitors have provided substantial benefit in non-small cell lung cancer (NSCLC) with unprecedented results in terms of survival. However, the identification of reliable predictive biomarkers to these agents is lacking and multiple clinicopathological factors have been evaluated. The aim of this study was to analyze the potential role of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lactate dehydrogenase (LDH) levels in patients with pretreated NSCLC receiving nivolumab. Methods: This was a retrospective multicenter study involving 14 Italian centers, evaluating the role of some laboratory results in patients with NSCLC treated with nivolumab in the second or later lines of therapy for at least four doses and with a disease re-staging. Results: A total of 187 patients with available pretreatment laboratory results were included. NLR levels below 5 were associated with an improvement in terms of both progression-free survival (PFS) (p = 0.028) and overall survival (OS) (p = 0.001), but not in terms of overall response rate (ORR) or disease control rate (DCR). Moreover, PLR levels below 200 were associated with longer PFS (p = 0.0267) and OS (p = 0.05), as well as higher ORR (p = 0.04) and DCR (p = 0.001). In contrast, LDH levels above the upper normal limit (UNL) were not associated with significant impact on patient outcomes. Conclusions: Patients with pretreated NSCLC and high pretreatment levels of NLR and PLR may experience inferior outcomes with nivolumab. Therefore, in this subgroup of patients with poor prognosis the use of alternative therapeutic strategies may be a valuable option, especially in programmed cell death ligand 1 (PD-L1)-negative patients and/or in the presence of other additional poor prognostic factors.

Background: Immune-checkpoint inhibitors have radically changed the treatment landscape of Non-Small-Cell Lung Cancer (NSCLC). It is still unclear whether specific clinical characteristics might identify those patients benefiting from immunotherapy more than others. The aim of this study was to identify clinical characteristics associated with disease-specific survival (DSS), time-to-treatment failure (TTF), objective responses (OR) and progressive disease (PD) in NSCLC patients treated with Nivolumab. Methods: This was a multicenter retrospective study conducted on 294 patients treated with Nivolumab for advanced NSCLC. Results: Of the more than 50 variables analyzed, five showed a significant correlation with DSS: ECOG PS, size of the biggest brain metastasis, number of metastatic sites, toxicity, and malignant pleural effusion. Three variables significantly correlated with TTF: malignant pleural effusion, number of metastatic sites, number of liver metastases. Malignant pleural effusion was the only variable showing a significant correlation with OR, as well as the only one correlating with all the endpoints of the study. Conclusions: This study identified clinical characteristics associated with survival and response during treatment with Nivolumab in NSCLC patients. The unfavorable association between malignant pleural effusion and objective response is a novel finding with important translational implications.

Introduction: Although sorafenib is the upfront standard of care for advanced hepatocellular carcinoma (HCC), molecular predictors of efficacy have not been identified yet. In the ALICE-1 study, rs2010963 of VEGF-A and VEGF-C proved to be independent predictive factors for progression-free survival (PFS) and overall survival (OS) in multivariate analysis. The ALICE-1 study results were confirmed in the ALICE-2 study, in which VEGF and VEGFR SNPs were analyzed. In the ePHAS study we analyzed the SNPs of eNOS. In univariate analysis, patients homozygous for an eNOS haplotype (HT1: T-4b at eNOS-786/eNOS VNTR) had significantly shorter median PFS and OS than those with other haplotypes. These data were confirmed in the validation set. Methods: This nonpharmacological, interventional, prospective multicenter study aims to determine whether eNOS, HIF-1, VEGF, Ang2 and VEGFR polymorphisms play a role in predicting the objective response rate, PFS, and OS of advanced HCC patients treated with sorafenib. The study will involve 160 advanced HCC patients with Child-Pugh class A disease. The primary aim is to validate the prognostic or predictive roles of eNOS, Ang2, HIF-1, VEGF and VEGFR polymorphisms in relation to the clinical outcome (PFS) of HCC patients treated with sorafenib. Conclusions: Overall, our data may suggest that polymorphism analysis of the VEGF, VEGFR-2, HIF and eNOS genes can identify HCC patients who are more likely to benefit from sorafenib.

Background Immune-checkpoint inhibitors (ICIs) are now standard of care for advanced non-small cell lung cancer (NSCLC). Unfortunately, many patients experience immune-related adverse events (irAEs), which are usually mild and reversible, but they require timely management and may be life threatening. No predictive markers of irAEs are available. Materials and Methods The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were evaluated in patients with NSCLC consecutively treated with ICIs. Prespecified cutoff values of NLR and PLR were used and related to outcome and onset of irAEs. A control group of patients with advanced NSCLC not receiving ICIs was included. Results The study included 184 patients: 26 (14.1%) received pembrolizumab upfront, and 142 (77%) received ICIs (pembrolizumab, nivolumab or atezolizumab) after one or more lines of chemotherapy. The median number of ICIs cycles was six (range, 1–61). The median progression-free survival and overall survival were 4.8 (95% CI, 3.4–6.3) and 20.6 (95% CI, 14.7–26.5) months, respectively. Sixty patients (32.6%) developed irAEs, mainly grade 1–2 (65.0%), causing ICI interruption in 46 cases (25.0%). Low NLR and low PLR at baseline were significantly associated with the development of irAEs (odds ratio [OR], 2.2; p = .018 and OR, 2.8; p = .003, respectively). Multivariate analyses confirmed PLR as independent predictive marker of irAEs (OR, 2.3; p = .020). Conclusion NLR and PLR may predict the appearance of irAEs in non-oncogene-addicted aNSCLC, although this conclusion warrants prospective validation.

Introduction Gefitinib, erlotinib, and afatinib represent the approved first-line options for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Because pivotal trials frequently lack external validity, real-world data may help to depict the diagnostic-therapeutic pathway and treatment outcome in clinical practice. Methods MOST is a multicenter observational study promoted by the Veneto Oncology Network, aiming at monitoring the diagnostic-therapeutic pathway of patients with nonsquamous EGFR-mutant NSCLC. We reported treatment outcome in terms of median time to treatment failure (mTTF) and assessed the impact of each agent on the expense of the regional health system, comparing it with a prediction based on the pivotal trials. Results An EGFR mutation test was performed in 447 enrolled patients, of whom 124 had EGFR mutation and who received gefitinib (n = 69, 55%), erlotinib (n = 33, 27%), or afatinib (n = 22, 18%) as first-line treatment. Because erlotinib was administered within a clinical trial to 15 patients, final analysis was limited to 109 patients. mTTF was 15.3 months, regardless of the type of tyrosine kinase inhibitor (TKI) used. In the MOST study, the budget impact analysis showed a total expense of €3,238,602.17, whereas the cost estimation according to median progression-free survival from pivotal phase III trials was €1,813,557.88. Conclusion Good regional adherence and compliance to the diagnostic-therapeutic pathway defined for patients with nonsquamous NSCLC was shown. mTTF did not significantly differ among the three targeted TKIs. Our budget impact analysis suggests the potential application of real-world data in the process of drug price negotiation. Implications for practice The MOST study is a real-world data collection reporting a multicenter adherence and compliance to diagnostic-therapeutic pathways defined for patients with epidermal growth factor receptor-mutant non-small cell lung cancer. This represents an essential element of evidence-based medicine, providing information on patients and situations that may be challenging to assess using only data from randomized controlled trials, e.g., turn-around time of diagnostic tests, treatment compliance and persistence, guideline adherence, challenging-to-treat populations, drug safety, comparative effectiveness, and cost effectiveness. This study may be of interest to various stakeholders (patients, clinicians, and payers), providing a meaningful picture of the value of a given therapy in routine clinical practice.

Despite the well-known negative prognostic value of theTwo large retrospective series ofA total of 395These scoring systems are based on easy-to-collect data and defined specific subgroups with relevant differences in their life expectancy. These tools could be useful in clinical practice, would allow better stratification of patients in clinical trials and may be adopted for proper adjustments in exploratory translational analyses.

Background HER2 is the only validated predictive biomarker in gastro-oesophageal carcinoma (GOC). However, several factors, such as heterogeneity in protein expression, shortage of evaluable tumour tissue and need for quick target assessment, underline the usefulness of a pre-screening tool in order to anticipate HER2 status. Methods Data from 723 consecutive GOC analysed for HER2 at four Italian Institutions were collected. HER2 positivity was defined as 3+ by immunohistochemistry (IHC) or 2+ with gene amplification by in situ hybridisation (ISH). A multivariate logistic regression model was built using data from 413 cases, whereas 310 patients served as validation cohort. C-index, visual inspection of the calibration plot, Brier score and Spiegelhalter z-test were used to assess the performance of the nomogram. Results HER2 positive rate was 17.4%. Four variables were retained after adjustment in the final model: grading, Lauren’s histotype, pathologic material analysed (surgical specimen/biopsy) and site of tissue collection (primary tumour/metastases). Visual inspection of the calibration plot revealed a very good overlap between predicted and observed probabilities, with a Brier score of 0.101 and a non-significant Spiegelhalter z-test (P = 0.319). C-index resulted in 0.827 (95%CI 0.741–0.913). Conclusion A simple nomogram based on always-available pathologic information accurately predicts the probability of HER2 positivity in GOC.

Background Despite the well-known negative prognostic value of the V600EBRAF mutation in patients with metastatic colorectal cancer (mCRC), its outcome is quite heterogeneous, and the basis for this prognostic heterogeneity should be better defined. Methods Two large retrospective series of V600EBRAF-mutated mCRC from 22 institutions served as an exploratory and validation set to develop a prognostic score. The model was internally and externally validated. Results A total of 395 V600EBRAF-mutated mCRCs were included in the exploratory set. Performance status, CA19.9, lactate dehydrogenase, neutrophil/lymphocyte ratio, grading and liver, lung and nodal involvement emerged as independent prognostic factors for overall survival (OS). Two different scoring systems were built: a ‘complete’ score (0–16) including all significant covariates and a ‘simplified’ score (0–9), based only on clinicopathological covariates, and excluding laboratory values. Adopting the complete score, proportions of patients with a low (0–4), intermediate (5–8) and high (9–16) score were 44.7%, 42.6% and 12.6%, respectively. The median OS was 29.6, 15.5 (hazard ratio [HR] for intermediate vs low risk: 2.16, 95% confidence interval [CI]: 1.44–3.22, p Conclusions These scoring systems are based on easy-to-collect data and defined specific subgroups with relevant differences in their life expectancy. These tools could be useful in clinical practice, would allow better stratification of patients in clinical trials and may be adopted for proper adjustments in exploratory translational analyses.

e13617 Background: After the results of the Nurse-led Telephone Triage (NTT) study ( Calvetti L, et al. ASCO 2020), the system has been implemented to prevent unnecessary hospitalizations of cancer patients. With the pandemic outbreak, a dedicated SARS-CoV-2 2019 (COVID-19) NTT protocol was added to monitor cancer patients (CPs) receiving active medical treatment. We report on the impact of NTT in limiting accesses and minimizing the risk of spread of the infection through the Department of Oncology. Methods: CPs on active medical treatment were educated to call the NTT in case of any symptoms suspected for COVID-19 infection to the Oncology Department of Vicenza, Italy, during the COVID-19 pandemic (February 22 2020 to January 31, 2021). Each event assessment was performed by trained oncology nurses with the supervision of a medical oncologist on duty and in case of suspected COVID-19 infection a testing pathway for COVID-19 was activated. Primary endpoint of this study was to compare incidence of COVID-19 and related deaths in both CPs on active medical treatment and health workers with the rate in the overall population of Veneto region. Results: From February 22 2020 to January 31, 2021 1,154 patients received systemic anticancer treatment (versus 1,022 patients in the same 2019 – 2020 period). Total consultations at NTT were 587; 97 patients reported symptoms suspected for COVID-19 infections. The COVID-19 testing pathway was launched in 60 CPs and a positive test was reported in 25 CPs (2.2% incidence compared to 6.5% in the overall Veneto region population). Two COVID-19 related deaths were reported (8% death rate). In the same period, 2/54 (3.7%) health workers tested positive for COVID-19. Patients who tested positive had a median treatment delay of 25 days. Conclusions: The NTT system in the clinical practice provided a useful tool for monitoring and limiting hospital-acquired COVID-19 infection among both CPs on active treatment and health workers.

2002 Background: Novel organization models are needed to ensure early management of new treatment-related toxicity of anticancer treatments. Aim of this prospective observational study was to evaluate the impact of the introduction of NTT in reducing hospitalization of CPs. Methods: CPs on active medical treatment at the Department of Oncology of San Bortolo Hospital (Vicenza, Italy) were given instructions to refer to NTT in case of treatment-related adverse events (TRAEs). The service was opened Mon to Fri from 8am to 8pm. Assessment of TRAEs was performed by trained oncology nurses according to the CTCAE scale and subsequent actions were taken according to the severity of the events. The assessment was made under supervision of a medical oncologist in charge of the service while on duty. Primary endpoint of the study was to compare the rate of hospitalization of CPs on anticancer treatment after the introduction of NTT compared to 2017-2018 period. Results: From September 2018 to September 2019 1,075 patients received systemic anticancer treatment (versus 936 patients in the equivalent 2017 – 2018 period). Total consultations at NTT were 429; 581 TRAEs were reported. 117 patients reported more than one TRAE. CTCAE were graded as G1 237 (40.8%), G2 231 (39.8%) or G3-G4 113 (19.4%). The most common grade ≥ 3 TRAE was fever (38 events (33.6%) that resulted a febrile neutropenia in 7 cases) followed by cancer pain (15 (13.3%)) and fatigue (9 (8%)). In the observation period, 109 CPs on treatment were hospitalized versus 138 in the 2017-2018 period with a normalized hospitalization rate of 10.1% versus 14.7 % (p = 0.002, chi-square) with a reduction of normalized number of hospitalizations of 44 (estimated cost savings of 380.160 euros). Conclusions: Our results provided evidence of successful implementation of the NTT system in reducing rates of hospitalization through emergency room in cancer patients receiving modern medical treatments.

3046 Background: ICIs revolutionized aNSCLC treatment. The next challenge lays on the search for predictive markers. Detection of multiple tumor-related genetic alterations through NGS in cell free DNA is a promising tool, provided the limited availability of tumor tissue in most cases. Methods: Between January 2017 and October 2019, aNSCLC pts consecutively referring to our Institution were prospectively screened with plasma NGS while included in two clinical trials: VISION (NCT02864992) and MAGIC trial, an observational study. In VISION trial NGS was performed in plasma (Guardant360 test) and tissue (Oncomine Focus Assay). In MAGIC Myriapod NGS-IL 56G Assay was used. Aim of the study was to evaluate the impact of STK11, KRAS and TP53 mutations (muts) on outcome of ICI-treated pts, with overall survival (OS) as primary endpoint. A control group of pts not receiving ICIs was also analyzed. Results: A total of 235 NSCLC pts were enrolled and received ICIs. 93 pts were analyzed in plasma at the time of beginning ICIs: median OS was 18.9 m (95% CI: 13.7-24.1) and median immune-related progression free disease (irPFS) 3.8 m (95% CI: 2.5-5.1). 49 (52.7%), 22 (23.7%) and 8 (8.6%) pts carried TP53, KRAS and STK11 pathogenic alterations, respectively. STK11 mutated pts showed a trend for worse OS compared with wildtype counterpart (14.9 m, 95% CI: 6.5-23.3, versus 20.3, 95% CI: 13.4-27.2, p = 0.192) KRAS muts had no impact on outcome. Pts with TP53 or STK11/KRAS co-mut (n = 3) had worse OS (12.3 m, 95% CI: 9.2-15.4; HR = 3, 95% CI: 1.6-5.8, p = 0.001 and 5.9 m, 95% CI: 1.4-7.6; HR = 2.9, 95% CI: 1.4-6.3, p = 0.007) and worse irPFS (2.8 m, 95% CI: 1.7-3.9, HR = 1.8 95% CI: 1.1-3.1, p = 0.03 and 1.2 m, 95% CI: 0.9-1.5, HR = 2.2 95% CI: 1.2-4.1, p = 0.01). Number of muts negatively impacts pts’ OS (HR = 1.2, 95% CI: 1.1-1.3, p = 0.02) and was higher among TP53 mutated pts (p < 0.001, Mann-Whitney test). In multivariate analysis, TP53 and STK11/KRAS retained significance. A control group of pts not receiving ICIs was analyzed (n = 101): median OS was 16.8 m (95% CI: 13-20.6). Nor STK11 (n = 10), nor STK11/KRAS (n = 6) had impact on OS (HR = 1.8, 95% CI: 0.7-4.7, p = 0.267 and 1.4, 95% CI: 0.7-3.0, p = 0.293) while the presence of TP53 muts (n = 41) was associated with shorter OS (11.4 m, 95% CI: 7.3-15.5; HR = 2.2, 95% CI: 1.2-4.2, p = 0.009). Conclusions: NGS performed in plasma might be used to detect predictive markers. TP53 muts in plasma at baseline had prognostic value, while STK11/KRAS muts were associated with worse outcome to ICIs.

Angiogenesis plays a pivotal role in the development and progression of tumors and it represents a crucial target for therapeutic strategies. Until now, regulatory agencies approved antiangiogenic agents targeting the VEGF and multi-target agents carrying antiangiogenic and anti-proliferative effects. They often provide only a modest survival benefit and their role in clinical practice is debated. The limited efficacy may be partially explained by the complexity of the molecular background of angiogenic processes, composed of several pathways interacting with both tumor cells and the microenvironment.Ramucirumab is a fully human monoclonal antibody selectively binding and inhibiting the VEGF receptor 2 (VEGFR-2), a crucial molecule involved in angiogenesis. A series of Phase I-II trials conducted in a wide spectrum of malignancies reported promising antitumor activity. In 2014, data from large Phase III clinical trials in gastrointestinal, lung and breast malignancies were released.Considering the evidences of efficacy emerging from the available Phase III trials, the antiangiogenic approach emerged as a promising strategy particularly for the treatment of gastric cancer. Nevertheless, the identification and validation of potentially predictive biomarkers are necessary to improve the selection of patients and the globally awaited clinical benefit.

Introduction: In the last few years, significant advances in molecular biology have provided new therapeutic options for colorectal cancer (CRC). The development of new drugs that target the immune response to cancer cells seems very promising and has already been established for other tumor types. In particular, the use of immune checkpoint inhibitors seems to be an encouraging immunotherapeutic strategy. Areas covered: In this review, the authors provide an update of the current evidence related to this topic, though most immunotherapies are still in early-phase clinical trials for CRC. To understand the key role of immunotherapy in CRC, the authors discuss the delicate balance between immune-stimulating and immune-suppressive networks that occur in the tumor microenvironment. Expert opinion: Modulation of the immune system through checkpoint inhibition is an emerging approach in CRC therapy. Nevertheless, selection criteria that could enable the identification of patients who may benefit from these agents are necessary. Furthermore, potential prognostic and predictive immune biomarkers based on immune and molecular classifications have been proposed. As expected, additional studies are required to develop biomarkers, effective therapeutic strategies and novel combinations to overcome immune escape resistance and enhance effector response.

Background NGS provides genetic information with potential impact on clinical practice. Plasma NGS has the advantage to reduce the need to repeat biopsy and provide information about tumor heterogeneity. Methods Since March 2018 we prospectively screened aNSCLCs consecutively referring to our institution for potential eligibility to VISION trial (NCT02864992). All the patients (pts) were previously screened for EGFR/ALK/ROS1 sensitizing alterations according to standard methods and positive cases were excluded. NGS was performed with METex14 Guardant360® covering 73 genes including all somatic alterations recognized as potential targets by NCCN. A parallel cohort of pts was also analysed with NGS in tissue by using METex14 Oncomine™ Focus Assay (MolecularMD) covering 59 genes. All identified druggable genetic alterations were tested for confirmation with a different method. Results We included 159 pts, 91 (57%) male, 37 (23,3%) smokers and 81 (50,9%) former smokers. Histology was: 144 adenocarcinoma, 7 squamous cell carcinoma, two sarcomatoid and 6 large cell/undifferentiated. 129 (81%) cases were analyzed in plasma and 63 (49%) had tissue NGS results for comparison. Median number of detected genetic alterations was 2 and maximum number was 17. No alterations were found in 14 cases (11%). Two of them were then retested and became positive. We found 34 (26%) potentially druggable genetic alterations and three of them showed discordant results between tissue and plasma. Among all druggable genetic alterations, till now we have treated 12 pts with targeted agents and six had already radiological response evaluable: five of them obtained control of disease. 18 pts with druggable alterations had already received immunotherapy (IT) and only two of them obtained objective response: METex14 mutation and RET rearrangement. We also found 5 cases of KRAS-STK11 co-mutations, three were treated with IT and no response was recorded. In parallel, 89 (56%) cases were analyzed in tissue and 44 (49%) were evaluable for NGS. Ten (23%) potentially druggable genetic alterations were found. Conclusions Plasma NGS was feasible and provided additional information: new druggable genetic alterations were found and potential impact of NGS on response to IT emerged. Legal entity responsible for the study Istituto Oncologico Veneto, IOV IRCCS. Funding Merck KGaA. Disclosure All authors have declared no conflicts of interest.

Background Immune checkpoint inhibitors (ICIs) have changed the treatment of pts with aNSCLC and mMel. No predictive markers of development of irAEs are available. Aim of the study is to evaluate the role of circulating markers in predicting irAE onset. Methods We reviewed clinical data of aNSCLC and mMel pts treated with ICIs at Istituto Oncologico Veneto (Padova, Italy) and San Bortolo Hospital (Vicenza, Italy) between January 2012 and January 2019. We collected data on type and grading (G) of irAEs and calculated neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) before first ICI administration and at irAE onset. Values were dichotomized in: high (H) and low (L) NLR and H- and L-PLR, using pre-identified cut-offs of 3 and 180 for aNSCLC, 3 and 120 for mMel. Results Analysis included 377 pts (252 aNSCLC and 125 mMel). In aNSCLC cohort, median PFS and OS were 4.9 months (m) (95% CI: 3.6-6.1) and 8.6m (95% CI: 6.3-10.8). Ninety-seven pts (38%) developed irAEs, mainly G1-2 (72%), with permanent ICI discontinuation in 29 (29.9%) cases; 26 pts (26.8%) experienced more than one irAE. Pts with baseline L-NLR or L-PLR had a higher risk of irAE (OR = 2.3, 95% CI: 1.3-3.9, p = 0.002 | OR = 2.4, 95% CI: 1.3-4.1, p = 0.02). Multivariate analysis confirmed NLR and PLR as independent predictive markers (OR = 1.8, 95%CI: 1.0-3.2, p = 0.04 | OR = 1.9, 95%CI: 1.0-3.4, p = 0.03). L-PLR at irAE onset was associated with risk of irAE recurrence or second irAE development (OR = 4.2, 95% CI: 1.4-12.9, p = 0.01). In mMel pts, median PFS and OS were 5.1m (95% CI: 3.6-6.5) and 18.1m (95% CI: 11-25.2). Fifty-four pts (43%) developed irAEs, mainly G1-2 (76%), with permanent ICI discontinuation in 10 (18.5%) cases; 14 pts (25.9%) had multiple irAEs. Pts with baseline L-NLR had higher risk of irAE (OR = 2.2, 95% CI: 1.1-4.6, p = 0.04). NLR and PLR at time of irAE onset were not associated with the risk of irAE recurrence or second irAE development. Conclusions Baseline NLR and PLR may be reliable and inexpensive predictive tools of irAE risk. For aNSCLC pts L-PLR at irAE onset correlates with risk of further toxicity. If validated, these biomarkers may help pts’ management during ICIs and treatment handling after a first irAE. Legal entity responsible for the study IRCCS Istituto Oncologico Veneto - IOV - Padua – Italy. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Axitinib is an oral angiogenesis inhibitor, currently approved for treatment of metastatic renal cell carcinoma (mRCC) after failure of prior treatment with Sunitinib or cytokine. The present study is an Italian Multi-Institutional Retrospective Analysis that evaluated the outcomes of Axitinib, in second-line treatment of mRCC. The medical records of 62 patients treated with Axitinib, were retrospectively reviewed. The Progression Free Survival (PFS), the Overall Survival (OS), the Objective Response Rate (ORR), the Disease Control Rate (DCR), and the safety profile of axitinib and sunitinib–axitinib sequence, were the primary endpoint. The mPFS was 5.83 months (95% CI 3.93–7.73 months). When patients was stratified by Heng score, mPFS was 5.73, 5.83, 10.03 months according to poor, intermediate, and favorable risk group, respectively. The mOS from the start of axitinib was 13.3 months (95% CI 8.6–17.9 months); the observed ORR and DCR were 25 and 71%, respectively. When stratified patients by subgroups defined by duration of prior therapy with Sunitinib (≤ vs. >median duration), there was a statistically significant difference in mPFS with 8.9 (95% CI 4.39–13.40 months) vs. 5.46 months (95% CI 4.04–6.88 months) for patients with a median duration of Sunitinib >13.2 months. DCR and ORR to previous Sunitinib treatment was associated with longer statistically mPFS, 7.23 (95% CI 3.95–10.51 months, p = 0.01) and 8.67 (95% CI 4.0–13.33 months, p = 0.008) vs. 2.97 (95% CI 0.65–5.27 months, p = 0.01) and 2.97 months (95% CI 0.66–5.28 months, p = 0.01), respectively. Overall Axitinib at standard schedule of 5 mg bid, was well-tolerated. The most common adverse events of all grades were fatig (25.6%), hypertension (22.6%), gastro-intestinal disorders (25.9%), and hypothyroidism (16.1%). The sequence Sunitinib–Axitinib was well-tolerated without worsening in side effects, with a median OS of 34.7 months (95% CI 18.4–51.0 months). Our results are consistent with the available literature; this retrospective analysis confirms that Axitinib is effective and safe in routine clinical practice.

Background: In metastatic colorectal cancer (mCRC), BRAFV600E mutation has been variously associated to specific clinico-pathological features. Methods: Two large retrospective series of mCRC patients from two Italian Institutions were used as training-set (TS) and validation-set (VS) for developing a nomogram predictive of BRAFV600E status. The model was internally and externally validated. Results: In the TS, data from 596 mCRC patients were gathered (RAS wild-type (wt) 281 (47.1%); BRAFV600E mutated 54 (9.1%)); RAS and BRAFV600E mutations were mutually exclusive. In the RAS-wt population, right-sided primary (odds ratio (OR): 7.80, 95% confidence interval (CI) 3.05–19.92), female gender (OR: 2.90, 95% CI 1.14–7.37) and mucinous histology (OR: 4.95, 95% CI 1.90–12.90) were independent predictors of BRAFV600E mutation, with high replication at internal validation (100%, 93% and 98%, respectively). A predictive nomogram was calculated: patients with the highest score (right-sided primary, female and mucinous) had a 81% chance to bear a BRAFV600E-mutant tumour; accuracy measures: AUC=0.812, SE:0.034, sensitivity:81.2% specificity:72.1%. In the VS (508 pts, RAS wt: 262 (51.6%), BRAFV600E mutated: 49 (9.6%)), right-sided primary, female gender and mucinous histology were confirmed as independent predictors of BRAFV600E mutation with high accuracy. Conclusions: Three simple and easy-to-collect characteristics define a useful nomogram for predicting BRAF status in mCRC with high specificity and sensitivity.

639 Background: BM mCRCs account around 10% of mCRCs, with a dismal prognosis. Intra-group heterogeneity has been recently studied, however, an extensive prognostic clinical analysis has not been provided yet. Methods: BM mCRCs tested on primary tumor (T) or on metastases (mets) were collected from 13 Italian Oncology Units. A prognostic score was derived by an internal cross-validation procedure: the whole population was splitted in a training (67%) and in a testing (33%) sample; this process was repeated 10 times. Primary endpoint was OS. Multivariate analysis (MA) was performed on each training sample, and covariates with independent prognostic value were included in the scoring system, assigning rounded scores to the covariates. Results: A total of 395 BM mCRC patients were included. At MA, independent prognosticators for OS were ECOG PS (1 vs 0; 2-3 vs 0), Ca19.9 (high vs normal); LDH (≥300 vs low); neutrophil/lymphocyte ratio ( > 3 vs low); T grading (3-4 vs 1-2); liver mets (yes vs no); lung mets (yes vs no); lymphnode mets (yes vs no). Two different scoring systems were built: a «complete» score (0-18) with all significant covariates; a «simplified» score (0-11), selecting only significant clinico-pathological covariates, excluding laboratory values. With «complete» score, proportion of patients with low (0-4), intermediate (5-8) and high (9-18) score was 39%, 46% and 15%, respectively. Median OS was 27.6, 18.7 (HR interm. vs low 1.89, 95%CI 1.25 – 2.86, p = 0.003) and 6.6 months (HR high vs low 4.95, 95%CI 2.89 – 8.47, p < 0.0001), respectively. Similar results were observed adjusting for type of first-line treatment. Median PFS was 11.1, 8.6 (HR interm. vs low 1.36, 95%CI 0.94 – 1.97, p = 0.11) and 4.1 months (HR high vs low 3.50, 95%CI 1.98 – 6.20, p < 0.0001). Similar results were obtained with the «simplified» score. Conclusions: A simple and ready-to-use prognostic score for BM mCRC was developed. The robustness of the internal cross-validation justifies the effort of a validation study. Identification of specific prognostic factors in distinct molecular subgroups is crucial for adjusting exploratory translational analyses and future clinical trial design.

3555 Background: GONO-FOLFOXIRI demonstrated higher activity and efficacy compared to FOLFIRI. P with oxaliplatin- or irinotecan-based doublets is feasible and associated with improved activity in KRAS codon 12-13 wild-type pts. BRAF and other RAS rare mutations have been suggested as additional potential biomarkers for anti-EGFR agents. Methods: Pts with untreated unresectable mCRC and wild-type BRAF-RAS genes were enrolled in this GONO multicenter phase II trial of biweekly P 6 mg/kg d1 with a modified FOLFOXIRI regimen (IRI 150 mg/m2 d1, OXA 85 mg/m2 d1, l-LV 200 mg/m2 d1 and 5FU 3000 mg/m2 48-h continuous infusion d1, reduced to 2400 mg/m2 due to grade 3-4 toxicity in 2 of first 3 pts enrolled). Primary end-point was response rate (RR, RECIST Criteria). Based on a two stage Simon’s Minimax design (p0=60%, p1=80%; a=0.05, β =0.2) at least 26 responses on 36 evaluable pts should be observed to satisfy the primary end-point. Results: 37 out of 87 screened pts were enrolled (M/F, 57/43%; median age 63 years, range 33-72; ECOG PS 0/1-2, 76/24%; primary colon/rectum, 70/30%; primary on site, 42%; sites of disease single/multiple, 54/46%; liver only mts, 35%). Among the first 3 pts treated with 5FU 3000 mg/m2, 2 experienced SAEs (1 grade 4 diarrhea and neutropenia; 1 grade 3 diarrhea). Grade 3-4 toxicities observed among the 34 pts treated at the amended dose were: neutropenia 53% (2 febrile neutropenia); diarrhea 32%; stomatitis 15%; neurotoxicity (grade 2-3) 30%; cutaneous rash 24%. Delays or dose reductions were needed only in 9% and 10% of the total 310 cycles, respectively. One SAE (febrile neutropenia and sepsis) resulting in pt death occurred after amendment. 32 partial responses, 4 disease stabilizations and 1 progression were observed, with a RR of 86% (95% CI: 75-97%). 9 pts underwent local procedures on metastases, achieving an R0 resection in 8 and a pathologic complete response in 3 of them. At a median follow-up of 7.4 months mPFS has not been reached. Conclusions: In molecularly selected unresectable pts adding P to FOLFOXIRI resulted in high activity and interesting resection rate. The regimen appears feasible. Further follow-up is needed to assess long-term outcome.

e14040 Background: Data on B for elderly patients with advanced CRC are scarce, although recent analyses demonstrated safety for its use. To investigate the efficacy and safety of treating older pts with B and chemotherapy in the clinical practice a national cohort was analyzed. Methods: In this observational cohort study 213 elderly patients from 9 Italian centers who received first-line B combined with chemotherapy were enrolled. Demographics and comorbidities were captured, along with efficacy and toxicity results. Predefined endpoints were response rate, progression-free, overall survival, and safety. Survival curves were generated with Kaplan-Maier methodology. Results: Median age was 72 (66-84), PS was 0-1 in 96%. Comorbidities at study entry were reported in 153 pts (72%): cardiovascular (including hypertension) 107, diabetes 32, respiratory 15, endocrine 10, neurological 10, renal 7, other diseases 51. Comprehensive geriatric evaluation with ADL, IADL and CIRS scores was available for only 64 pts (29%) reporting median values of 6, 8 and 20 respectively. Companion chemotherapy was 5-FU alone for 27 (12.6%), oxaliplatin-based doublet for 75 (35.2%) and irinotecan-based combination for 111 (52.1%). 81 pts had chemotherapy dose reduction, and 23 interrupted B before progression. Disease control was achieved in 86%, with median PFS/OS of 8.8/18.9 months. 76 pts were maintained on B alone or B plus 5-FU. Main toxicities were neutropenia (44%), anemia (37.5%), diarrhea (40.8%), mucositis (25.8%) and hand-foot syndrome (14.1%). Sensorial neurotoxicity was frequent among pts receiving oxaliplatin. Specific B-induced toxicities were induced or worsened hypertension in 48 pts (22.5%), proteinuria in 24 (11%), and venous or artherial thromboembolism in 16 (7.5%). Conclusions: To treat elderly CRC pts with B and chemotherapy is safe and major efficacy endpoints did not differ from expected. Geriatric evaluation is underused in the common practice and better tools are required to select elderly to be treated with antiangiogenics.

Pancreatic cancer is the only human malignancy for which patients' survival has not improved substantially during the past 30 years. Despite advances in the comprehension of the molecular mechanisms underlying pancreatic carcinogenesis, current systemic treatments offer only a modest benefit in tumor-related symptoms and survival. Over the past decades, gemcitabine and its combination with other standard cytotoxic agents have been the reference treatments for advanced pancreatic cancer patients. The recent introduction of the three-drug combination regimen FOLFIRINOX or the new taxane nab-paclitaxel represent key advances for a better control of the disease. Novel agents targeting molecular mechanisms involved in cancer development and maintenance are currently under clinical investigation. This review describes the most important findings in the field of systemic combination therapies for the treatment of pancreatic cancer. We discuss the emerging evidences for the clinical activity of combination treatments with standard chemotherapy plus novel agents targeting tumor cell-autonomous and tumor microenvironment signaling pathways. We present some of the most important advances in the comprehension of the molecular mechanisms responsible for the chemoresistance of pancreatic cancer and the emerging therapeutic targets to overcome this resistance.