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Purpose of review In the current review, we will explore the molecular bases that have determined the design of clinical trials exploring the efficacy of antivascular agents in combination with chemotherapy, immune check point inhibitors and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with advanced nonsmall cell lung cancer. Recent findings Recent clinical trials have demonstrated the synergistic effect of antivascular agents with immune checkpoint inhibitors and EGFR-TKIs, despite no molecular marker has been identified yet to select patients. Summary Lung cancer remains one of the first causes of cancer-related death. However, thanks to the development of stratified molecular medicine and the introduction of immune checkpoint inhibitors, patients' survival has significantly improved. Due to the critical role of pro-angiogenic factors in cancer progression, antivascular agents targeting the vascular endothelial growth factor (VEGF) and its receptor (VEGFR) have been developed. Their efficacy has been explored in combination with chemotherapy, and immune checkpoint inhibitors, with promising but not definitive conclusions about their impact on prolonging patients' survival.

Immune-related adverse events (irAEs) due to immune checkpoint inhibitors are responsible for a considerable burden of morbidity and mortality. Predictors of severity of rheumatic irAEs have not been identified yet. The objective of this study was to test the hypothesis whether the presence of autoantibodies could be associated with a more severe and difficult-to-treat clinical phenotype of rheumatic irAEs.Patients referred to our centre due to the onset of rheumatic irAEs were prospectively recruited between June 2018 and December 2020. A pre-specified panel of autoantibodies was tested in each patient at baseline visit. All patients were started on glucocorticoids and then followed-up. Conventional or biologic immunosuppressants were started in case of steroid-refractory or relapsing disease. Logistic regression analysis was performed to evaluate the association between the baseline positivity of at least one autoantibody and the necessity of an add-on therapy.Fourty-three patients with rheumatic irAEs were enrolled. Twenty-five (58%) patients had positivity of at least one of the tested autoantibodies. Twenty-two (51%) patients required the start of an additional immunosuppressant during follow-up. The only factor associated with the necessity of an add-on therapy was autoantibody positivity (OR=9.65, 95% CI:2.09-44.56; p-value 0.004).The presence of autoantibodies in patients with cancer who develop rheumatic irAEs could predict their progression to difficult-to-treat clinical manifestations. This finding might prompt a future therapeutic approach based on a tailored and earlier immunosuppressive treatment in selected cases.

Small cell lung cancer (SCLC) accounts for approximately 15% (1) of new lung cancer cases. Conversely to the progresses in the field of non-small cell lung cancer (NSCLC), therapeutic options have not improved in the recent decades. Platinum-etoposide chemotherapy remains the cornerstone for first line treatment, while topotecan is the only approved agent for recurrent or progressive SCLC (2). Despite the initial sensitivity to chemotherapy and radiotherapy, responses are not durable, and patients develop tumor progression.

Stereotactic radiosurgery (SRS) in combination with immunotherapy (IT) is increasingly used in the setting of melanoma and non-small cell lung cancer (NSCLC) brain metastases (BM). The synergistic properties of this treatment combination are still not deeply understood. IT-SRS appropriate combination has been envisioned as a strategic point in patients' management. Authors performed a systematic review on current evidences up to December 2020. The impact of SRS-IT and different IT schedules on survival, local/distant intracranial control and toxicity, as well as predictive factors for relevant oncological and radiological outcomes has been analyzed. Authors retrieved 23 pertinent studies. Combining SRS with IT resulted in a significant improvement in OS and lesion response with no increase in radionecrosis, hemorrhage or other complications. The present review suggests that combining IT to SRS is safe and effective in providing a significant improvement in relevant clinical and radiological outcomes in melanoma and NSCLC BMs patients.

In previous studies, a clinical association between eruptive cherry angiomas(CAs) and cutaneous malignancies has been found.1-2 The presence of both lesions in the same individuals may suggest shared pathophysiology between eruptive CAs and other tumors.2 While the association of eruptive CAs with cutaneous melanoma has been well established, the rate of association with other rare melanocytic malignancies, such as uveal melanoma(UM) has not been yet explored.

Simple Summary The number of druggable tumor-specific molecular alterations in the treatment of non-small cell lung cancer (NSCLC) has grown significantly in the past decade. Emerging technologies such as liquid biopsy and single-cell methods allow for studying targetable drivers and develop personalized treatments. However, although new therapies confer prolonged disease control and high tumor response rates, most patients eventually progress on targeted treatments. Intratumoral heterogeneity is a frequent event in NSCLC, driving the tumor cells to develop adaptive or new resistance mechanisms within the drug environment. This review summarizes the current and upcoming research on the biological role of tumor heterogeneity, highlighting the link between early and acquired drug resistance and tumoral heterogeneity in targetable driver mutated NSCLC. Abstract Tailored therapies based on the identification of molecular targets currently represent a well-established therapeutic scenario in the treatment of non-small cell lung cancer (NSCLC) patients. However, while aiming to improve patients’ response to therapy, development of resistance is frequently observed in daily clinical practice. Intratumoral heterogeneity is a frequent event in NSCLC, responsible for several critical issues in patients’ diagnosis and treatment. Advances in single-cell sequencing technologies have allowed in-depth profiling of tumors and attributed intratumoral heterogeneity to genetic, epigenetic, and protein modification driven diversities within cancer cell populations. This review highlights current research on the biological role of tumor heterogeneity and its impact on the development of acquired resistance in NSCLC patients.

Lung cancer remains the first cause of cancer-related deaths worldwide. Thanks to the improvement in the knowledge of the biology of non-small cell lung cancer (NSCLC), patients’ survival has significantly improved. A growing number of targetable molecular alterations have been identified. Next-generation sequencing (NGS) has become one of the methodologies entered in clinical practice and was recently recommended by the European society for medical oncology (ESMO) to perform a comprehensive molecular characterization in patients with cancer. The current review provides an overview of the clinical trials that have explored the impact of NGS in patients with cancer, its limits, and advantages.

Several immunotherapy agents are the standard of care of many solid malignancies. Nevertheless, the majority of patients do not benefit from the currently available immunotherapies. It is therefore of paramount importance to identify the prognostic and predictive factors of tumor response/resistance and to design effective therapeutic strategies to overcome primary resistance and improve the efficacy of immunotherapy. The aim of this review is to underline the influence of the tumor and host metabolism on the antitumor immune response and to discuss possible strategies to improve the efficacy of available treatments by targeting the specific metabolic pathways in tumors or immune cells and by modifying patients’ nutritional statuses. A systematic search of the Medline and EMBASE databases was carried out to identify scientific papers published until February 2020, which reported original research articles on the influence of tumor or host metabolism on antitumor immune response. The literature data showed the key role of glycolysis and mitochondrial oxidative phosphorylation, arginine, tryptophan, glutamine, lipid metabolism and microbiome on immune cell function. Moreover, specific nutritional behaviors, such as a low dietary intake of vitamin C, low glycemic index and alpha-linolenic acid, eicosapentenoic acid, docosahexaenoic acid, ornithine ketoglutarate, tryptophan and probiotic supplementation were associated with the potential clinical benefits from the currently available immunotherapies.

Background: Malignant melanoma (MM) is potentially the most dangerous form of skin tumor. In the last few years, the so-called TAM receptors, a unique family of tyrosine kinase (TK) receptors, have become increasingly important. Objectives: To evaluate Mer and Axl TAM receptor expression to find clinicopathological features that could explain the biological behavior of MM. Patients and Methods: Clinicopathological data were obtained from an MM electronic database at our Institute. We reviewed 24 cutaneous MM specimens. TAM receptor expression was assayed using immunohistochemistry. Combinative semiquantitative scoring was used for the evaluation of TAM receptor expression (MerTK and AxlTK). Appropriate statistical methods were used to evaluate a possible correlation between TAM receptor expression and the clinicopathological variables of the MM samples (univariate analysis and multivariate analysis). Results: MerTK and AxlTK were expressed differently in the MM samples, with a major expression of the first receptor. The cells of the tumor microenvironment contributed to the majority of the total score. A significant association was found between AxlScore and the site of the tumor and between AxlScore and the variable ulceration; another correlation was found between MerScore and the following characteristics: pathological stage of the tumor (pT), sex, ulceration, and tumor-infiltrating lymphocytes. Conclusions: All correlations between the expression of MerTK and AxlTK with the clinical and histological variables of MM should be validated in a large group of people in order to increase the validity and the impact of our observations, with subsequently therapeutic implications in the era of the “targeted therapy.”

Background Amelanotic and hypomelanotic melanoma (AHM) has a higher risk of delayed diagnosis and a significant lower 5-year melanoma-specific survival compared to pigmented melanoma. Our aim was the evaluation of the clinicopathological/dermoscopic features of amelanotic melanoma (AM) and hypomelanotic melanoma (HM). Methods All participants had a personal history of AHM. We defined HM as showing clinical/dermoscopic pigmentation in Results The most common phenotypic traits among the 145 AHM patients were as follows: phototype II, blue-grey eyes, and dark brown hair. Red hair was present in 23.8% AHM cases (AM = 22.60%; HM = 25.80%). The most affected area was the back (29.5%). A total of 67.1% were classified as AM and 32.9% as HM. The most represented hair colors in AM and HM were, respectively, blonde and dark brown hair. Median Breslow thickness was 1.7 mm, superficial spreading melanoma (SSM) and nodular melanoma (NM) were the most represented histotypes, and mitotic rate > 1 × mm2 was reported in 73.3% cases, and regression was significantly more present in HM. Dermoscopy showed high prevalence of white structureless zones (63.4%), linear looped vessels (58.8%), linear irregular vessels (50.0%), and arborizing vessels (47.2%). Multivariate logistic regression confirmed the association between the presence of pigmentation and the following: histological regression, dermoscopic globules, and arborizing vessels. Conclusions Predominance of red hair in AHM patients was not confirmed. AHM affects mostly intermittent sun-exposed body areas. The deeper median Breslow thickness (versus pigmented melanoma), the association of AM with the nodular histotype, and the high mitotic rate highlight the AHM's aggressiveness. HM's higher levels of regression can be explained by the presence of pigmentation, driving the underlying immune response. AHM showed a polymorphous vascular pattern and significant presence of arborizing vessels (especially HM).

A major limitation of circulating tumor DNA (ctDNA) for somatic mutation detection has been the low level of ctDNA found in a subset of cancer patients. We investigated whether using a combined isolation of exosomal RNA (exoRNA) and cell-free DNA (cfDNA) could improve blood-based liquid biopsy for EGFR mutation detection in non-small-cell lung cancer (NSCLC) patients.Matched pretreatment tumor and plasma were collected from 84 patients enrolled in TIGER-X (NCT01526928), a phase 1/2 study of rociletinib in mutant EGFR NSCLC patients. The combined isolated exoRNA and cfDNA (exoNA) was analyzed blinded for mutations using a targeted next-generation sequencing panel (EXO1000) and compared with existing data from the same samples using analysis of ctDNA by BEAMing.For exoNA, the sensitivity was 98% for detection of activating EGFR mutations and 90% for EGFR T790M. The corresponding sensitivities for ctDNA by BEAMing were 82% for activating mutations and 84% for T790M. In a subgroup of patients with intrathoracic metastatic disease (M0/M1a; n = 21), the sensitivity increased from 26% to 74% for activating mutations (P = 0.003) and from 19% to 31% for T790M (P = 0.5) when using exoNA for detection.Combining exoRNA and ctDNA increased the sensitivity for EGFR mutation detection in plasma, with the largest improvement seen in the subgroup of M0/M1a disease patients known to have low levels of ctDNA and poses challenges for mutation detection on ctDNA alone.NCT01526928.

Objectives Circulating cell-free tumor DNA (ctDNA) isolated from the peripheral blood of non-small-cell lung cancer (NSCLC) patients provides biomarkers for both therapeutic target selection, particularly when direct tumor biopsy is unfeasible, and also for drug resistance monitoring. This study evaluates the reliability and feasibility of ctDNA analysis in an in-house clinical molecular diagnostic workflow. Materials and methods Mutation profiling by both standard methods and Next-Generation sequencing (NGS) was carried out and compared on 2 independent lung cancer patient cohorts. Cohort 1 consisted of 50 EGFR-mutated NSCLC patients, established on tumour biopsy, for whom ctDNA was collected at disease progression after TKI-inhibitor treatment and could be used to monitor drug resistance. Cohort 2 consisted of 50 newly diagnosed lung cancer patients for whom tumour biopsy was not possible and only ctDNA was available, providing the possibility of biomarker identification. Results ctDNA analysis of Cohort 1 verified the persistence of the tumour-detected EGFR activating mutation at disease progression by both standard and NGS methods, in 84% and 92% of the cases respectively. The T790M EGFR resistance mutation was identified in 71% of the ctDNA EGFR mutated samples providing vital information for their disease management. In newly diagnosed Cohort 2 patients, EGFR activating mutations were detected in 16% of the patients by both standard and NGS analysis of ctDNA in peripheral blood, providing indication to targeted-therapy otherwise unavailable for this group of patients. Conclusion The presented study investigated lung cancer ctDNA analysis, comparing conventional methods versus NGS sequencing, and demonstrated the successful use of plasma ctDNA as a template for targeted NGS tumor gene panel in an in-house routine clinical practice. More importantly, these data underline the advantages of the clinical application of ctDNA NGS analysis for identification of therapeutic targets, real-time monitoring of therapy, and resistance mechanisms in lung cancer patients.

Background: In the field of oncological assistance, nowadays we have to deal with a complex scenario where patients got used to obtain a huge amount of information through internet or social media and to apply them in performing their health-related decisions. This landscape requires that clinicians become able to handle therapeutical approaches and adequate skills in communication tools to satisfy the current needs. Our project aimed to build a communication model based on clinical oncologists’ real experiences in order to find a simple way to share with patients all the innovative therapeutical opportunities today available in lung cancer. The final goal is to design a flexible and personalized model adaptable to clinician’s personal characteristics and to the specific patient he is facing. We applied both traditional educational tools and innovative techniques in order to make the results effective and applicable to support peer learning. Methods: The first step consisted in a Board synthesized the definition of the diagnostic process, the identification of treatment strategies and any potential communication barrier clinicians may face dealing with patients. The second step consisted in teamwork including a theoretical part and a training part. In the third step we produce five training videos and video interviews regarding communication praxis and a “Small communication manual”. The last step consisted in the publication of the produced material on website and its diffusion through the social media. Results: In medicine, the universal application of a single model of communication does not represent the optimal solution. By contrary, the availability of simple and practical suggestions to improve the communicative style could allow clinicians to abandon stereotyped formulas identically repurposed to all patients. The “from bottom to top” training, starting from real-life to take advantage of the clinician’s experience, give the clinicians the possibility to meditate about their own communicative style and to train in the context of a protected environment. Applying these rules, we design an effective communication model, based on healthcare humanization, which could represent a fundamental support for the patient in order to be gently driven by the clinician to the most appropriate therapeutical choice, balancing efficacy and quality of life. The relational training may improve the quality of clinician-patient communication and could be widespread to other clinicians through the media. Conclusions: Considering the innovative therapeutical options available, particularly for lung cancer patients, and the increasing access of health-related information through internet or social media the clinician-patient communication has become crucial to support the achievement of the most appropriate therapeutical choice for the patient, facing the intricate illness experience. Building a shareable and easy-to-apply communication model represents a challenge aimed to help clinicians and including technology not as a threat, but as a positive tool.

Simple Summary Small cell lung cancer (SCLC) remains the most aggressive form of neuroendocrine tumor of the lung, for which treatment options remain limited. The introduction of immune checkpoint inhibitors has modified for the first time the therapeutic strategies in patients with extensive disease after decades. New therapeutic approaches are required. Deeper knowledge of tumor biology is required to gain new insights into this complex disease. Abstract Several trials have tried for decades to improve the outcome of extensive disease small cell lung cancer (ED-SCLC) through attempts to modify the standard treatments. Nevertheless, platinum/etoposide combination and topotecan have remained respectively the first and the second line standard treatments for the last 40 years. With the advent of immunotherapy, this scenario has finally changed. Our review aims to provide an overview of the primary studies on the actual therapeutic strategies available for ED-SCLC patients, and to highlight emerging evidence supporting the use of immunotherapy in SCLC patients.

Background:Immune checkpoint inhibitors (ICIs) can induce a variety of rheumatic immune-related adverse events (Rh-irAEs). Few data are available on which features can predict the occurrence of long-lasting and severe Rh-irAEObjectives:To describe the serological features associated with long-lasting and severe Rh-irAE.Methods:ICI-treated patients were identified. Patients’ demographics, histotype of cancer, ICI, time interval from ICI start to Rh-irAE onset, characteristics of Rh-irAEs were recorded. Patients were tested for autoimmunity panel (a-IP): RF, ACPA, ANA, anti-SSA, anti-SSB, anti-Sm, anti-RNP, anti-Jo1, ANCA, ASMA, AMA, anti-dsDNA, anti-tireoglobulin, anti-tireoperoxidas, IgM and IgG anti-cardiolipin and anti-β2 glicoprotein I, crioglobulins. All patients were treated with steroids (CS). In case of flare of the Rh-irAE, csDMARDs or bDMARDs were started. Associations between a-IP status and need for DMARD start was evaluated. Non parametric tests were used.Results:22 Rh-irAE were included (see Table 1). Median age at Rh-irAE onset was 70 (50 – 84) years. 2 patients (9%) had a personal history of psoriasis. Median time from ICI start to Rh-irAE onset was 5 (1 – 26) months. 11 patients (50%) developed 1 Rh-irAE, 10 (45.4%) 2 and 1 (4.5%) 3. The most frequent were arthritis (A, 14, 63.6%), cutaneous vasculitis (CV, 5, 22.7%), PMR-like (4, 18.2%), polymyositis (PM, 4, 18.2%), myocarditis (Myo, 3, 13.6%) and dermatomyositis (DM, 2, 9.1%). Median initial prednisone dose was 25 (10 – 75) mg daily. In 14 patients (63.6%) a csDMARD was started upon steroids tapering. 9 patients (41%) were treated with methotrexate (MTX, 4, 18.2%) with hydroxychloroquine (HCQ, 2, 9.1%) with mycophenolate (MMF, 2, 9.1%) with colchicine (colch). 6 patients were treated with bDMARDs. 3 patients (50%) were treated with anakinra (ANK), 2 (33.3%) with IVIG and 3 (50%) with tocilizumab (TCZ). 13 patients (59.1%) were a-IP+. A significantly higher percentage of a-IP+ patients received DMARDs (11, 84.6%) compared to a-IP- patients (2, 22.2%,p = 0.0007). A significantly higher percentage of a-IP+ patients were treated with bDMARDs (5, 38.5%) compared to a-IP- patients (0, 0%, p = 0.05). We analysed whether in csDMARD-treated patients the need for bDMARDs was higher in a-IP+ but we found no statistical significance (45.4% vs 0%, p = 0.487).Table 1.Characteristics and treatment of Rh-irAEs patients.Age, SexCancerICIOnset (monts)Rhem-irAETreatmentResponseICI stopAutoAb169, MLung, adenoNivo3MyoCS, MMF, ANK, TCZLDAY, DpANCA270, MBladderAtezo1A,CS, MTXRemY, TNeg379, MLung SCCPembro1ACSRemNoRo52452, MLung, LCCNivo6A, CVCS, MTX, ANK, TCZLDANoANA 1:160 s582, MLung, LCCPembro3PMRCSRemNoNeg656, MMelanomaPembro26PMR, PMCS, MTXDeathY, DANA 1:160 s, pANCA772, MLung, adenoPembro5A, CVCS, MTX, TCZHDA (TCZ)Y, TANA 1:160 s874, MLung, adenoPembro1PMRCS, MTXLDANoANA 1:160 s975, MLung, adenoPembro1PM, MyoCSRemY, DNeg1075, MLung, adenoNivo9ACSRemNoNeg1168, FLung, adenoAtezo18ACS, MTXLDAY, TNeg1235, MMelanomaNivo2ACS, MTXLDANoANA 1:640 s1379, MLung, SCCNivo15A, PMRCS, MTX, ANKDeath (NR)Y, DRo521477, MLung, adenoPembro8DMCS, HCQ, IVIGLDAY, DANA 1:320 PCNA1567, MLung, adenoNivo13ACS, MTXLDANoASMA1674, MLung, SCCAtezo1A, CVCS, HCQ, ColchLDAY, DNeg1770, MLung, adenoNivo5A, CVCSRemY, DNeg1870, MLung, adenoPembro15ACSLDANoASMA1969, MLung, adenoNivo5DMCS, HCQ, MMF, IVIG, TacroMDAY, TANA 1:!60 s2084, MH&N, SCCNivo3PhCSRemY, DNeg2167, MLung, adenoDurva5A, PM, MyoCSLDAY, DANA 1:160 h2250, FLung, LCCNivo1A, CVCS, HCQRemY, DNegConclusion:The presence of serological autoimmunity might be helpful in detecting patients with Rh-irAEs refractory to steroid therapy.Disclosure of Interests:Corrado Campochiaro Speakers bureau: Novartis, Pfizer, Roche, GSK, SOBI, Alessandro Tomelleri: None declared, Roberto Ferrara: None declared, Chiara Lazzari: None declared, Giacomo De Luca Speakers bureau: SOBI, Novartis, Celgene, Pfizer, MSD, Diego Signorelli: None declared, Alessandra Bulotta: None declared, Vanesa Gregorc: None declared, Marina Garassino: None declared, Lorenzo Dagna Grant/research support from: Abbvie, BMS, Celgene, Janssen, MSD, Mundipharma Pharmaceuticals, Novartis, Pfizer, Roche, SG, SOBI, Consultant of: Abbvie, Amgen, Biogen, BMS, Celltrion, Novartis, Pfizer, Roche, SG, and SOBI

Background Patients with anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) have a higher risk of developing brain metastases (BMs) than patients with other NSCLC sub-types. ALK inhibitors have activity in BMs due to ALK+ NSCLC. We performed a systematic review of the literature with the aim of assessing the efficacy of ALK inhibitors on BMs. Material and methods A systematic search of the literature was performed using the databases Pubmed, EMBASE, Web of Science, The Cochrane Library, and SCOPUS. Relevant publications reporting activity of ALK inhibitors in NSCLC BMs were retrieved. Data were pooled using the number of events/number of evaluable patients according to fixed or random effect models. Intracranial tumour response was assessed through overall response rate (ORR), disease control rate (DCR: ORR + stable disease rate), median progression-free survival (PFS), and overall survival (OS). The primary endpoint was intracranial overall response rate (IC ORR). Results A total of 1,016 patients with BMs from 21 studies were analysed. In patients receiving ALK inhibitors in the first line setting, the pooled IC ORR was 39.17% (95%CI 13.1–65.2%), while the pooled IC ORR observed in further lines was 44.2% (95%CI 33.3–55.1%). Intracranial disease control rate (IC DCR) was 70.3% and 78.2% in naive and pre-treated patients, respectively. Patients who had not received brain radiation attained an IC ORR of 49.0%. Conclusions Based on these data, ALK inhibitors are effective in both naive and pre-treated patients with similar IC ORR and IC DCR, irrespective of the line of therapy.

Innovative therapeutic agents have significantly improved outcome with an acceptable safety profile in a substantial proportion of non-small cell lung cancer (NSCLC) patients, who depend on oncogenic molecular alterations for their malignant phenotype. Despite the survival improvement achieved with first-line chemotherapy, about 30% of patients do not obtain a tumor response. Moreover, those patients, initially sensitive to treatment, acquire resistance and develop tumor progression after a median of about 5 months. Approximately 60% of the patients progressing from first-line chemotherapy receive further systemic treatment in the second-line setting. Moreover, new options have emerged in the second-line armamentarium for the treatment of patients with NSCLC, including immune checkpoint inhibitors and antiangiogenic agents. The current review provides an overview on the clinical studies that gained the approval of chemotherapy agents (docetaxel and pemetrexed) and epidermal growth factor receptor gene–tyrosine kinase inhibitors as second-line treatment options for NSCLC patients, not carrying molecular alterations.

Introduction: The treatment of lung cancer has radically changed over the last few years. The discovery of druggable oncogenic alterations and the introduction of immunotherapy have provided lung cancer patients with the possibility of more efficient and less toxic therapeutic alternatives than chemotherapy. In the case of lung squamous cell carcinoma (LSCC), the treatment progress is slower than adenocarcinoma, for which several targeted agents have been already approved. The standard first-line therapy for LSCC, in most sites of the world, is platinum-based chemotherapy. After disease progression, these patients now have novel treatment options, including antiangiogenic agents and immune checkpoint blockade.Areas covered: We provide a summary of the recent novelties for the second-line therapy of LSCC, emphasizing on the results of the most important clinical trials that have led to regulatory approvals.Expert commentary: Immune checkpoint inhibitors have changed the therapeutic algorithm for LSCC patients. Other treatment options in the second-line setting include ramucirumab in combination with docetaxel and afatinib. However, we still lack biomarkers to predict which patients could respond better to each treatment. Despite the identification of several actionable molecular alterations, there are no approved targeted agents specific for advanced LSCC. Results from ongoing biomarker-driven studies are eagerly awaited to establish effective treatments for molecularly selected subgroups of patients.

Summary Background An established multivariate serum protein test can be used to classify patients according to whether they are likely to have a good or poor outcome after treatment with EGFR tyrosine-kinase inhibitors. We assessed the predictive power of this test in the comparison of erlotinib and chemotherapy in patients with non-small-cell lung cancer. Methods From Feb 26, 2008, to April 11, 2012, patients (aged ≥18 years) with histologically or cytologically confirmed, second-line, stage IIIB or IV non-small-cell lung cancer were enrolled in 14 centres in Italy. Patients were stratified according to a minimisation algorithm by Eastern Cooperative Oncology Group performance status, smoking history, centre, and masked pretreatment serum protein test classification, and randomly assigned centrally in a 1:1 ratio to receive erlotinib (150 mg/day, orally) or chemotherapy (pemetrexed 500 mg/m 2 , intravenously, every 21 days, or docetaxel 75 mg/m 2 , intravenously, every 21 days). The proteomic test classification was masked for patients and investigators who gave treatments, and treatment allocation was masked for investigators who generated the proteomic classification. The primary endpoint was overall survival and the primary hypothesis was the existence of a significant interaction between the serum protein test classification and treatment. Analyses were done on the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00989690. Findings 142 patients were randomly assigned to chemotherapy and 143 to erlotinib, and 129 (91%) and 134 (94%), respectively, were included in the per-protocol analysis. 88 (68%) patients in the chemotherapy group and 96 (72%) in the erlotinib group had a proteomic test classification of good. Median overall survival was 9·0 months (95% CI 6·8–10·9) in the chemotherapy group and 7·7 months (5·9–10·4) in the erlotinib group. We noted a significant interaction between treatment and proteomic classification (p interaction =0·017 when adjusted for stratification factors; p interaction =0·031 when unadjusted for stratification factors). Patients with a proteomic test classification of poor had worse survival on erlotinib than on chemotherapy (hazard ratio 1·72 [95% CI 1·08–2·74], p=0·022). There was no significant difference in overall survival between treatments for patients with a proteomic test classification of good (adjusted HR 1·06 [0·77–1·46], p=0·714). In the group of patients who received chemotherapy, the most common grade 3 or 4 toxic effect was neutropenia (19 [15%] vs one [ vs 22 [16%]) was the most frequent in the erlotinib group. Interpretation Our findings indicate that serum protein test status is predictive of differential benefit in overall survival for erlotinib versus chemotherapy in the second-line setting. Patients classified as likely to have a poor outcome have better outcomes on chemotherapy than on erlotinib. Funding Italian Ministry of Health, Italian Association of Cancer Research, and Biodesix.

The advent of immune checkpoint inhibitors gave rise to a new era in oncology and general medicine. The increasing use of programmed death-1 (PD-1) inhibitors in non-small cell lung cancer and in other malignancies means clinicians have to face up to new challenges in managing immune-related adverse events (irAEs), which often resemble autoimmune diseases. Neurological irAEs represent an emerging toxicity related to immunotherapy, and it is mandatory to know how to monitor, recognize, and manage them, since they can rapidly lead to patient death if untreated. Guidelines for the diagnosis and treatment of these irAEs have been recently published but sharing some of the most unusual clinical cases is crucial, in our opinion, to improve awareness and to optimize the approach for these patients. A literature review on the diagnosis and treatment of immune-related neurotoxicity’s has been conducted starting from the report of four cases of neurological irAEs regarding cases of polyneuropathy, myasthenia gravis, Bell’s palsy, and encephalopathy, all of which occurred in oncological patients receiving PD-1 inhibitors (pembrolizumab and nivolumab) for the treatment of non-oncogene addicted advanced non-small cell lung cancer. The exclusion of other differential diagnoses and the correlation between the suspension of immunotherapy and improvement of symptoms suggest that immunotherapy could be the cause of the neurological disorders reported.

The discovery of several molecular alterations that underlie non-small cell lung cancer (NSCLC) pathogenesis has led to the development of targeted therapies. In particular, gefitinib and erlotinib have become the standard of care in patients harboring epidermal growth factor receptor mutations, while crizotinib showed an impressive efficacy in patients with ALK-positive NSCLC. Nevertheless, the occurrence of clinical resistance limits the long term results of these novel agents. The identification of the molecular mechanisms responsible for acquired resistance to targeted therapy is crucial in order to pursue the creation of rational strategies to overcome resistance. In the current review, we will focus on the acquired resistance mechanisms to EGFR-TKIs and crizotinib and the therapeutic strategies currently under study to overcome resistance.

The analysis of circulating cell-free tumor DNA (ctDNA), which can be obtained from plasma by non-invasive procedures, was proven useful to provide biomarkers in the management of non-small-cell lung cancer (NSCLC) patients. Several studies assessed ctDNA prognostic and predictive value as source of key data for therapeutic target selection and drug resistance in such patients. The purpose of the present study was to compare the assessment of NSCLC common hot spot mutations in ctDNA samples using the NGS Oncomine cfDNA Lung Cancer assay (ThermoFisher) to the standard clinical tests (i.e. real-time quantitative PCR and droplet digital PCR), performed in both FFPE tumor and ctDNA samples. In particular we aimed to evaluate the feasibility and accuracy of this assay for (1) the detection of EGFR/KRAS mutations in 50 patients with newly diagnosed lung cancer and no possibility to obtain tissue samples and (2) the identification of anti-EGFR treatment acquired resistance mutations in 50 NSCLC EGFR-mutated patients with disease progression. The Oncomine cfDNA Lung assay is a multiplexed sequencing test, designed to detect 150 hotspot mutations in 11 lung cancer-related genes (ALK, BRAF, EGFR, ERBB2, KRAS, MAP2K1, MET, NRAS, PIK3CA, ROS1, and TP53) with a limit of detection as low as 0.1%. We analyzed a total of 100 ctDNAs which were sequenced using the Ion S5 system. Libraries were templated using the Ion Chef and multiplexed as 8 libraries on a 520 chip. Data analysis was performed in Torrent Suite using the variant Caller plugin. The total process time, from ctDNA isolation to result reporting, was as short as 4 days, supporting a workflow where blood samples are received early on day 1 and final variant calls are available on day 4. ctDNA NGS analysis for the newly diagnosed patients with no available tumor sample identified KRAS mutations (7%) and more importantly, targetable EGFR mutations (10%). For the patients with progression disease, EGFR acquired resistance mutations were found in 78% of the cases. Overall, the most frequently mutated genes were EGFR (85%), TP53 (26%), PIK3CA (18%), ALK (10%), and MET (8%). Taken the EGFR mutation detected by routine methods as the gold standard, the concordance with EGFR variants detected by NGS was 97%. Interestingly, the NGS approach detected the same EGFR mutations with the same allelic frequency of standard methods. These preliminary data confirm the potential of the Oncomine cfDNA lung assay for plasma genotyping which allows both noninvasive multiplexed detection of targetable genomic alterations and monitoring of acquired resistance mutations in lung cancer. Citation Format: Ilaria Francaviglia, Gilda Magliacane, Greta Grassini, Salvatore Girlando, Daniela Medicina, Chiara Lazzari, Alessandra Bulotta, Lorenza Pecciarini, Claudio Doglioni, Maria Giulia Cangi. Identification and monitoring of somatic mutations in circulating cell-free DNA by next-generation sequencing in patients with lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5580.

8567Background: NGR-hTNF is a vascular-targeting agent able to increase intratumoral chemotherapy penetration and T-cell infiltration by modifying tumor microenvironment. MPM patients failing first...

Immune checkpoint inhibitors have significantly improved overall survival with an acceptable safety profile in a substantial proportion of non-small cell lung cancer (NSCLC) patients. However, not all patients are sensitive to immune checkpoint blockade and, in some cases, programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors accelerate tumor progression. Several combination strategies are under evaluation, including the concomitant or sequential evaluation of chemotherapy or radiotherapy with immunotherapy. The current review provides an overview on the molecular rationale for the investigation of combinatorial approaches with chemotherapy or radiotherapy. Moreover, the results of completed clinical studies will be reported.

The analysis of circulating cell-free tumor DNA (ctDNA), which can be obtained from plasma by non-invasive procedures, is expected to provide useful biomarkers in the management of non-small-cell lung cancer (NSCLC) patients. Indeed, several studies have assessed ctDNA prognostic and predictive value as source of key data for therapeutic targets and drug resistance in carcinoma patients. The expanding number of targeted therapeutics for NSCLC always expects a real-time wider tumor genotyping, and the use of ctDNA as either a complement or an alternative to tumor tissue DNA (ttDNA) could be a valid option for Next-Generation Sequencing (NGS) of key cancer genes. However, isolation and enrichment of ctDNA is a big challenge because of its high degree of fragmentation and its low concentration against the normally occurring background of cell-free DNA derived from healthy cells. Therefore standardized methods for ctDNA extraction and analysis are crucial aspects in the setting-up of a molecular diagnostic approach. In this study we aimed to evaluate the ctDNA use for molecular profiling, also analyzing the impact of both pre-analytical and analytical variables on DNA yield and mutation detection. Matched ttDNA and ctDNA from 30 NSCLC patients were extracted, quantified and quality-controlled, and then investigated by different standard methods (real-time PCR, digital PCR, Mass Spectrometry genotyping) for EGFR, KRAS, BRAF, PIK3CA status. Mutational screening of ctDNA samples by IonTorrent NGS (Oncomine™ Lung cfDNA Assay, ThermoFisher) was also performed. Further, we extended ctDNA evaluation to additional 30 lung cancer patients with no available tumor sample. We found that cell free DNA concentration in plasma correlated with both stage and number of metastatic sites. Analyzing matched ttDNA and ctDNA by standard methods, we identified mutations in EGFR, KRAS, PIK3CA genes, with an overall concordance of 77%. Interestingly, Oncomine Lung cfDNA assay detected these same mutations with the same allelic frequency of standard methods; mutations in TP53 and ALK genes were also found. In the 30 patients with no available tumor sample, we found EGFR (10%) and KRAS (7%) mutations on ctDNA by standard methods; NGS analysis is under evaluation. This study evaluated the use of multiple different methods to detect mutations in NSCLC and showed that ctDNA can be a feasible option for clinical monitoring of lung cancers, including for those patients who cannot undergo invasive diagnostic procedures, due to either comorbidities or absence of biopsable tumor lesions. Citation Format: Gilda Magliacane, Greta Grassini, Ilaria Francaviglia, Elena DalCin, Chiara Lazzari, Alessandra Bulotta, Monika Ducceschi, Vanesa Gregorc, Lorenza Pecciarini, Claudio Doglioni, Maria Giulia Cangi. ctDNA use in molecular diagnostics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 744. doi:10.1158/1538-7445.AM2017-744

e20077Background: In the NGR015 trial, patients failing a pemetrexed-based regimen were randomly assigned to weekly NGR-hTNF (N; n = 200) or placebo (P; n = 200), both given with BIC that included ...

e20075Background: NGR-hTNF selectively binds to CD13-expressing blood vessels and improves intratumor T-lymphocyte infiltration and CT uptake. CD13 expression is upregulated by tumor hypoxia/angiog...

Bone disease (BD) is the hall-mark clinical feature of multiple myeloma (MM), accounting up to 60% of patients with bone pain at diagnosis and 60% with a pathologic fracture during the course of their disease. Experimental models, which recapitulate in vivo the human bone marrow microenvironment (HBMM) in immunodeficient mice have been recently developed as valuable tool for the study of MM pathophysiology as well as the experimental treatment of BD. At present, bisphosphonates are the mainstay treatment of MM-related BD. The growing information on the cellular and molecular bases of BD as well as the availability of novel anti-resorptive agents, such as the IgG1-anti-RANKL (AMG 161) Denosumab, are now depicting a new scenario where the treatment will be afforded by the use of different agents. Furthermore the availability of highthroughput molecular profiling approaches, including DNA microarrays and proteomics, is likely to provide new platforms for patients stratification and treatment individualization on specific targets. It is now the right time for a therapeutical approach which is rationally based on the complexity of the biopathology of MM-related BD.

Gemcitabine (GEM) is presently the standard option for the treatment of advanced pancreatic cancer (PC). We investigated the in vitro and in vivo antitumor potential of GEM-loaded PEGylated liposomes (L-GEM) as a novel agent for the treatment of PC. In vitro analysis of antitumor activity against human PC cell lines, BXPC-3 and PSN-1, showed a significant time- and dose-dependent reduction of cell viability following exposure to L-GEM as compared to free GEM [at 72 h, IC50: 0.009 vs. 0.027 μM (P = 0.003) for BXPC-3 and 0.003 vs. 0.009 μM (P

Valproic acid (VPA) is a well-tolerated anticonvulsant that exerts anti-tumour activity as a histone deacetylase inhibitor. This study investigated the in vitro and in vivo activity of VPA against multiple myeloma (MM) cells. In vitro exposure of interleukin-6-dependent or -independent MM cells to VPA inhibited cell proliferation in a time- and dose-dependent manner and induced apoptosis. In a cohort of severe combined immunodeficiency mice bearing human MM xenografts, VPA induced tumour growth inhibition and survival advantage in treated animals versus controls. Flow cytometric analysis performed on MM cells from excised tumours showed increase of G(0)-G(1) and a decreased G(2)/M- and S-phase following VPA treatment, indicating in vivo effects of VPA on cell cycle regulation. Gene expression profiling of MM cells exposed to VPA showed downregulation of genes involved in cell cycle progression, DNA replication and transcription, as well as upregulation of genes implicated in apoptosis and chemokine pathways. Pathfinder analysis of gene array data identified cell growth, cell cycle, cell death, as well as DNA replication and repair as the most important signalling networks modulated by VPA. Taken together, our data provide the preclinical rationale for VPA clinical evaluation as a single agent or in combination, to improve patient outcome in MM.

7558 Background: NGR-hTNF, a tumor-targeted antivascular agent, promotes a vessel normalization that improves intratumor T-cell infiltration and chemotherapy uptake. The prognostic role of baseline...

7557 Background: Historically, the TFI (time from end of first-line to start of second-line therapy) has been reported as a prognostic factor and predictive marker of benefit of next treatment line...