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Contains fulltext : 229846.pdf (Publisher’s version ) (Closed access) BACKGROUND: Early reports on patients with cancer and COVID-19 have suggested a high mortality rate compared with the general population. Patients with thoracic malignancies are thought to be particularly susceptible to COVID-19 given their older age, smoking habits, and pre-existing cardiopulmonary comorbidities, in addition to cancer treatments. We aimed to study the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with thoracic malignancies. METHODS: The Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) registry is a multicentre observational study composed of a cross-sectional component and a longitudinal cohort component. Eligibility criteria were the presence of any thoracic cancer (non-small-cell lung cancer [NSCLC], small-cell lung cancer, mesothelioma, thymic epithelial tumours, and other pulmonary neuroendocrine neoplasms) and a COVID-19 diagnosis, either laboratory confirmed with RT-PCR, suspected with symptoms and contacts, or radiologically suspected cases with lung imaging features consistent with COVID-19 pneumonia and symptoms. Patients of any age, sex, histology, or stage were considered eligible, including those in active treatment and clinical follow-up. Clinical data were extracted from medical records of consecutive patients from Jan 1, 2020, and will be collected until the end of pandemic declared by WHO. Data on demographics, oncological history and comorbidities, COVID-19 diagnosis, and course of illness and clinical outcomes were collected. Associations between demographic or clinical characteristics and outcomes were measured with odds ratios (ORs) with 95% CIs using univariable and multivariable logistic regression, with sex, age, smoking status, hypertension, and chronic obstructive pulmonary disease included in multivariable analysis. This is a preliminary analysis of the first 200 patients. The registry continues to accept new sites and patient data. FINDINGS: Between March 26 and April 12, 2020, 200 patients with COVID-19 and thoracic cancers from eight countries were identified and included in the TERAVOLT registry; median age was 68.0 years (61.8-75.0) and the majority had an Eastern Cooperative Oncology Group performance status of 0-1 (142 [72%] of 196 patients), were current or former smokers (159 [81%] of 196), had non-small-cell lung cancer (151 [76%] of 200), and were on therapy at the time of COVID-19 diagnosis (147 [74%] of 199), with 112 (57%) of 197 on first-line treatment. 152 (76%) patients were hospitalised and 66 (33%) died. 13 (10%) of 134 patients who met criteria for ICU admission were admitted to ICU; the remaining 121 were hospitalised, but were not admitted to ICU. Univariable analyses revealed that being older than 65 years (OR 1.88, 95% 1.00-3.62), being a current or former smoker (4.24, 1.70-12.95), receiving treatment with chemotherapy alone (2.54, 1.09-6.11), and the presence of any comorbidities (2.65, 1.09-7.46) were associated with increased risk of death. However, in multivariable analysis, only smoking history (OR 3.18, 95% CI 1.11-9.06) was associated with increased risk of death. INTERPRETATION: With an ongoing global pandemic of COVID-19, our data suggest high mortality and low admission to intensive care in patients with thoracic cancer. Whether mortality could be reduced with treatment in intensive care remains to be determined. With improved cancer therapeutic options, access to intensive care should be discussed in a multidisciplinary setting based on cancer specific mortality and patients' preference. FUNDING: None.

In the randomized, active-controlled, multicenter Phase III open-label ALEX trial, alectinib showed superior efficacy and lower toxicity compared with crizotinib in the primary treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer (ALK-positive NSCLC). The aim of this economic evaluation was to assess the cost-utility of alectinib versus crizotinib from the perspective of the Italian National Health Service (INHS). A partitioned survival model with three health states (progression-free, post-progression, and death) was used. The clinical data (progression-free survival, overall survival and time to progression) was based on the ALEX trial. Utility values were derived from EQ-5D scores evaluated in the ALEX trial and literature. Costs included drug treatments, progression-free, post-progression and supportive care. Direct medical costs and benefits (quality-adjusted life-years, QALYs) were discounted at a 3.0% annual rate. Uncertainty was assessed using deterministic and probabilistic sensitivity analyses. Treatment with alectinib versus crizotinib led to a gain of 2.82 life-years, 1.86 QALYs, and incremental costs of €58,276, resulting in an incremental cost-utility ratio of €31,353 per QALY. The deterministic analysis showed that the most critical parameters in the model were the cost of post-progression and utility scores. From the probabilistic sensitivity analysis, alectinib had a 64.5% probability of being cost-effective at a willingness-to-pay threshold of €40,000 per QALY. Compared with crizotinib, alectinib increased the length of the progression-free state and the QALYs. The incremental overall cost increase was reflective of longer treatment durations in the progression-free state. Compared with crizotinib, alectinib can be considered a valid cost-utility option in the treatment of naive patients with ALK-positive NSCLC.

Background Nivolumab has shown a survival benefit compared with docetaxel as second-line treatment for patients with previously treated advanced squamous non-small cell lung cancer (NSCLC) in a randomized phase III trial. The experiences of patients and physicians in routine clinical practice are often different from those in a controlled clinical trial setting. We present data from the entire Italian cohort of patients with squamous NSCLC enrolled in a worldwide nivolumab NSCLC expanded access program. Patients and Methods Patients with pretreated advanced squamous NSCLC received nivolumab 3 mg/kg every 2 weeks for up to 24 months. Safety was monitored throughout; efficacy data collected included objective tumor response, date of progression, and survival information. Results The Italian cohort comprised 371 patients who received at least one dose of nivolumab. In the overall population, the objective response rate (ORR) was 18%, the disease control rate (DCR) was 47%, and median overall survival (OS) was 7.9 months (95% confidence interval 6.2–9.6). In subgroup analyses, ORR, DCR, and median OS were, respectively, 17%, 48%, and 9.1 months in patients previously treated with two or more lines of therapy (n = 209) and 8%, 40%, and 10.0 months in patients treated beyond disease progression (n = 65). In the overall population, the rate of any-grade and grade 3–4 adverse events was 29% and 6%, respectively. Treatment-related adverse events led to treatment discontinuation in 14 patients (5%). There were no treatment-related deaths. Conclusion To date, this report represents the most extensive clinical experience with nivolumab in advanced squamous NSCLC in current practice outside the controlled clinical trial setting. These data suggest that the efficacy and safety profiles of nivolumab in a broad, real-world setting are consistent with those obtained in clinical trials. Implications for Practice Nivolumab is approved in the U.S. and Europe for the treatment of advanced non-small cell lung cancer (NSCLC) after failure of prior platinum-based chemotherapy. In this cohort of Italian patients with previously treated, advanced squamous NSCLC treated in a real-world setting as part of the nivolumab expanded access program, the efficacy and safety of nivolumab was consistent with that previously reported in nivolumab clinical trials.

Computed tomography-guided lung biopsy is a valid and safe procedure for characterizing pulmonary nodules. In the past years, this technique has been mainly used to confirm the malignant nature of undetermined pulmonary lesions; however, today its role has been completely renewed. With the advent of target therapy and immunotherapy, it has arisen for lung cancer, in inoperable patients, the necessity to obtain adequate bioptical material to perform a correct molecular characterization of the lesion. Moreover, the possibility of acquired drug-resistance mechanisms makes it necessary in some cases to rebiopsy these lesions over time. For these reasons, it is likely that the request of computed tomography-guided lung biopsy will increase in the future, therefore every radiologist should be confident with its most important aspects.

Aim: We investigated outcomes in patients with advanced non-small-cell lung cancer (NSCLC) and peritoneal involvement. Patients & methods: NSCLC patients with peritoneal carcinomatosis (PC) were included. We evaluated mOS1 (overall survival [OS] from NSCLC diagnosis) and mOS2 (OS from diagnosis of PC). Results: In total, 60 NSCLC patients were diagnosed with PC, 12 (20%) patients had a diagnosis of NSCLC and synchronous PC with a median OS of 9 months. Smokers had a shorter mOS1 and mOS2 compared with never-smokers; EGFR-mutated patients on tyrosine kinase inhibitors had longer mOS1 and mOS2 than EGFR wild-type patients. Conclusion: Metachronous PC is correlated to a short survival, irrespective of treatment line. Never-smokers and EGFR-mutated patients had improved mOS1 and mOS2 when compared with smokers and EGFR wild-type population.

Objective: To investigate the role of CTLA-4, PD-1 (programmed death-1), and PD-L1 (programmed death-ligand 1) single nucleotide polymorphisms (SNPs) in predicting clinical outcome of patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). Methods: A total of 166 consecutive patients were included. We correlated SNPs with clinical benefit, progression-free survival, time to treatment failure, and overall survival and evaluated the incidence of SNPs in nonresponder and long clinical benefit groups. Results: Considering the entire cohort, no correlation was found between SNPs and clinical outcome; however, PD-L1 rs4143815 SNP and the long clinical benefit group showed a statistically significant association ( p = 0.02). The nonresponder cohort displayed distinctive PD-L1 haplotype ( p = 0.05). Conclusion: PD-L1 SNPs seem to be marginally involved in predicting clinical outcome of NSCLC treated with ICI, but further investigations are required.

Rat sarcoma (RAS) oncogenes have intensively been investigated during the last decades. Taking into account all human tumours, Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene is the most frequently mutated (about 22%) among the three isoforms, followed by Neuroblastoma RAS Viral Oncogene Homolog (NRAS) (8%) and Harvey Rat Sarcoma Viral Oncogene Homolog (HRAS) (3%). In the last years, careful attention has been paid on KRAS and NRAS gene mutations in non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC) patients because of their prognostic and predictive roles. In particular, a large body of literature data has been generated investigating clinical outcomes of targeted treatments in NSCLC and CRC KRAS- and NRAS-mutated patients. The latest evidences are here reviewed, providing also an overview of the real-world RAS mutation testing practice across different Italian laboratories. On this basis, we propose a knowledge-based system, www.rasatlas.com, to support the healthcare personnel in the management of patients featuring RAS gene mutations in the landscape of precision oncology.

Introduction: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved as first-line therapy for advanced EGFR-mutated non-small cell lung cancer (NSCLC). Some osimertinib-related interstitial lung diseases (ILDs) were shown to be transient, called transient asymptomatic pulmonary opacities (TAPO)—clinically benign pulmonary opacities that resolve despite continued osimertinib treatment—and are not associated with the clinical manifestations of typical TKI-associated ILDs. Methods: In this multicentric study, we retrospectively analyzed 92 patients with EGFR-mutated NSCLC treated with osimertinib. Computed tomography (CT) examinations were reviewed by two radiologists and TAPO were classified according to radiologic pattern. We also analyzed associations between TAPO and patients’ clinical variables and compared clinical outcomes (time to treatment failure and overall survival) for TAPO-positive and TAPO-negative groups. Results: TAPO were found in 18/92 patients (19.6%), with a median follow-up of 114 weeks. Median onset time was 16 weeks (range 6–80) and median duration time 14 weeks (range 8–37). The most common radiologic pattern was focal ground-glass opacity (54.5%). We did not find any individual clinical variable significantly associated with the onset of TAPO or significant difference in clinical outcomes between TAPO-positive and TAPO-negative groups. Conclusions: TAPO are benign pulmonary findings observed in patients treated with osimertinib. TAPO variability in terms of CT features can hinder the differential diagnosis with either osimertinib-related mild ILD or tumor progression. However, because TAPO are asymptomatic, it could be reasonable to continue therapy and verify the resolution of the CT findings at follow-up in selected cases.

Novel treatment strategies incorporating PD-1/PD-L1 inhibitors in the first-line setting of advanced non-small-cell lung cancer (NSCLC) provided relevant improvements in survival outcomes. Among NSCLC patients with PD-L1 tumor proportion score ≥50%, identifying the ones to be addressed to pembrolizumab monotherapy or chemo-immunotherapy combinations is a matter of debate, taking into account the risks of overtreatment and toxicity. Here we report the clinical stories of four NSCLC patients with PD-L1 tumor proportion score ≥50% and good performance status, sharing high tumor burden including serosal involvement. After having rapidly progressed on first-line PD-1/PD-L1 inhibitors, they achieved major clinical and radiological response to pembrolizumab-chemotherapy combination. These cases prove the feasibility and effectiveness of salvage chemo-immunotherapy in pembrolizumab-refractory NSCLC patients.

BackgroundUntil now, no robust data supported the efficacy, safety and recommendation for influenza vaccination in patients with cancer receiving immune checkpoint inhibitors (ICIs).MethodsThe prospective multicenter observational INfluenza Vaccine Indication During therapy with Immune checkpoint inhibitors (INVIDIa-2) study investigated the clinical effectiveness of influenza vaccination in patients with advanced cancer receiving ICIs, enrolled in 82 Italian centers from October 2019 to January 2020. The primary endpoint was the time-adjusted incidence of influenza-like illness (ILI) until April 30, 2020. Secondary endpoints regarded ILI severity and vaccine safety.ResultsThe study enrolled 1279 patients; 1188 patients were evaluable for the primary endpoint analysis. Of them, 48.9% (581) received influenza vaccination. The overall ILI incidence was 8.2% (98 patients). Vaccinated patients were significantly more frequently elderly (pvs 29.8%, p=0.027). ILI lethality was, respectively, 0% in vaccinated and 4.3% in unvaccinated patients. Vaccine-related adverse events were rare and mild (1.5%, grades 1–2).ConclusionThe INVIDIa-2 study results support a positive recommendation for influenza vaccination in patients with advanced cancer receiving immunotherapy.

Aims: To assess prognostic value of pre-therapy carcinoembryonic antigen (CEA) and cytokeratin-19 fragments (CYFRA 21-1) blood levels in non-small cell lung cancer (NSCLC) patients treated with immune-checkpoint inhibitors (ICIs) and their early change as predictor of benefit. Materials and methods: This is a retrospective cohort study including patients with stage IIIB–IV NSCLC who received anti PD-1/PD-L1 in first or advanced lines of therapy in two institutions. A control cohort of patients treated only with chemotherapy has been enrolled as well. Results: A total of 133 patients treated with nivolumab or atezolizumab were included in the test set, 74 treated with pembrolizumab first line in the validation set and 89 in the chemotherapy only cohort. CYFRA 21-1 >8 ng/mL was correlated with overall survival (OS) in the test set, validation set and in univariate and multivariate analysis (pooled cohort hazard ratio (HR) 1.90, 95% confidence interval (CI) 1.24–2.93, p 0.003). Early 20% reduction after the third cycle was correlated with OS for CEA (HR 0.12; 95% CI 0.04–0.33; p Conclusions: CYFRA 21-1 pre-therapy assessment provides clinicians with relevant prognostic information about patients treated with ICI. CEA and CYFRA 21-1 repeated measures could be useful as an early marker of benefit.

Immunotherapy has significantly changed the treatment landscape for advanced non-small-cell lung cancer (NSCLC) with the introduction of drugs targeting programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1). In particular, the addition of the anti-PD-1 antibody pembrolizumab to platinum-pemetrexed chemotherapy resulted in a significantly improved overall survival in patients with non-squamous NSCLC, regardless of PD-L1 expression. In this preclinical study, we investigated whether chemotherapy can modulate PD-L1 expression in non-squamous NSCLC cell lines, thus potentially affecting immunotherapy efficacy. Among different chemotherapeutic agents tested, only pemetrexed increased PD-L1 levels by activating both mTOR/P70S6K and STAT3 pathways. Moreover, it also induced the secretion of cytokines, such as IFN-&gamma, and IL-2, by activated peripheral blood mononuclear cells PBMCs that further stimulated the expression of PD-L1 on tumor cells, as demonstrated in a co-culture system. The anti-PD-1/PD-L1 therapy enhanced T cell-mediated cytotoxicity of NSCLC cells treated with pemetrexed and expressing high levels of PD-L1 in comparison with untreated cells. These data may explain the positive results obtained with pemetrexed-based chemotherapy combined with pembrolizumab in PD-L1-negative NSCLC and can support pemetrexed as one of the preferable chemotherapy partners for immunochemotherapy combination regimens.

Background Despite sensitivity to first-line chemotherapy, most small-cell lung cancer (SCLC) patients relapse. In this setting, topotecan demonstrated modest activity with significant toxicity. Paclitaxel was also active. This study was designed to evaluate activity and safety of nab-paclitaxel in relapsed SCLC. Methods In this multicentre prospective Phase 2 trial, patients with refractory or sensitive SCLC progressed to first-line platinum-based chemotherapy received nab-paclitaxel 100 mg/smq on days 1, 8, 15 every 4 weeks up to six cycles, progressive disease or intolerable toxicity. Primary endpoint was investigator-assessed objective tumour response. Secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). Results Of the 68 patients treated, partial response was 8% in the refractory cohort and 14% in the sensitive cohort. Most common toxicities of any grade were fatigue (54%), anaemia (38%), neutropenia (29%), leukopenia (26%) and diarrhoea (21%). Median PFS was similar in both refractory (1.8 months) and sensitive cohorts (1.9 months), while median OS was longer in sensitive one (6.6 versus 3.6 months). Conclusions Although nab-paclitaxel has shown some modest anti-tumour activity in relapsed SCLC, associated with a favourable toxicity profile, the primary end-point of the study was not met. Clinical Trial registration Clinical Trial registration number is ClinicalTrials.gov Identifier: NCT03219762.

Background: Although immunotherapy with immune-checkpoint inhibitors (ICIs) has profoundly changed the therapeutic scenario in the treatment of advanced non-small cell lung cancer (NSCLC), trials of ICIs only enrolled NSCLC patients with common histology. Atezolizumab was approved by the United States Food and Drug Administration (US FDA) in October 2016 and by the European Medicines Agency (EMA) in September 2017 for the treatment of patients with metastatic NSCLC whose disease progressed during or following platinum-containing chemotherapy, regardless of PD-L1 expression. Methods: We designed a single-arm, multicenter, two-stage phase II study and plan to enroll 43 patients. The primary objective of the study is to evaluate the antitumor activity of atezolizumab in advanced NSCLC patients with rare histology subtypes. Patients with prior atezolizumab or ICI treatment and with untreated, symptomatic, or progressing brain metastases will be excluded. The primary endpoint is disease control rate. Secondary objectives are toxicity and safety, overall response rate, progression-free survival, overall survival, and time to progression. Diagnosis of NSCLC with rare histology will be confirmed by central pathology revision, and will include: colloid carcinoma, fetal adenocarcinoma, non-endocrine large cell carcinoma, sarcomatoid carcinoma, salivary gland-type tumor, lymphoepithelioma-like carcinoma, and NUT-nuclear protein in testis carcinoma. Archival tumor tissue is required for correlative studies of PD-L1 expression on tumor cells and tumor infiltrating lymphocytes. Conclusions: Therapeutic options in NSCLC with rare histology subtypes, to be assessed in specifically designed trials, are an unmet need. This trial will help elucidate the role of atezolizumab as a viable option in this setting.

Background Pembrolizumab is the first-line standard of care for advanced non–small cell lung cancer (NSCLC) with a PD-L1 tumour proportion score (TPS) ≥ 50%. Eastern Cooperative Oncology Group performance status (PS) 2 patients may receive pembrolizumab, despite the absence of sustaining evidence. Patients and methods GOIRC-2018-01 is a multicentre, retrospective, observational study. PS 2 NSCLC patients with a PD-L1 TPS ≥50% receiving first-line pembrolizumab from June 2017 to December 2018 at 21 Italian institutions were included. Clinical-pathological characteristics were correlated with disease response and survival outcomes; adverse events were recorded. The primary objective was 6-months progression-free rate (6-months PFR). Results One hundred fifty-three patients (median age 70 years) were enrolled. At a median follow-up of 18.2 months, median progression-free survival (PFS) and overall survival (OS) were 2.4 (95% confidence interval, 95% CI, 1.6–2.5) and 3.0 months (95% CI 2.4–3.5), respectively. 6-months PFR was 27% (95% CI 21–35%). Patients with a PS 2 determined by comorbidities (n = 41) had significantly better outcomes compared with disease burden-induced PS 2 (n = 112). Indeed, 6-months PFR was 49% versus 19%, median PFS 5.6 versus 1.8 months and OS 11.8 versus 2.8 months, respectively. Additional potential prognostic factors (radiotherapy, antibiotics, steroids received before pembrolizumab) correlated with clinical outcomes. The determinant of PS 2 resulted the only factor independently impacting on both PFS and OS. No toxicity issues emerged. Conclusions Outcomes of PS 2 NSCLC patients with PD-L1 TPS ≥50% receiving first-line pembrolizumab were globally dismal but strongly dependent on the reason conditioning the poor PS itself.

Epidermal growth factor receptor (EGFR) exon 20 insertions occur rarely among different cancer types, with the highest frequency reported among non-small-cell lung cancer (NSCLC) patients, particularly adenocarcinomas (ADCs). Exon 20 insertions fall back in the tyrosine kinase domain, and can be clustered into two principal groups represented by in frame insertions and three to 21 bp (corresponding to 1–7 amino acids) duplications within amino acids 762 and 774. The identification of these alterations is key for an adequate management of NSCLC patients due to the possibility to treat these patients with specific targeted therapies. Next generation sequencing (NGS) technology, able to detect several hotspot gene mutations for different patients simultaneously, is the best detection approach due to its higher sensitivity and specificity compared to other techniques. Here we reviewed the principal biological characteristics, the main detection technologies and treatment options for NSCLC patients harbouring EGFR exon 20 insertions.

Alectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system (CNS) efficacy in the treatment of ALK-positive non-small-cell lung cancer (NSCLC). We investigated alectinib as compared with crizotinib in patients with previously untreated, advanced ALK-positive NSCLC, including those with asymptomatic CNS disease. In a randomized, open-label, phase 3 trial, we randomly assigned 303 patients with previously untreated, advanced ALK-positive NSCLC to receive either alectinib (600 mg twice daily) or crizotinib (250 mg twice daily). The primary end point was investigator-assessed progression-free survival. Secondary end points were independent review committee-assessed progression-free survival, time to CNS progression, objective response rate, and overall survival. During a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression or death occurred in 62 of 152 patients (41%) in the alectinib group and 102 of 151 patients (68%) in the crizotinib group. The rate of investigator-assessed progression-free survival was significantly higher with alectinib than with crizotinib (12-month event-free survival rate, 68.4% [95% confidence interval (CI), 61.0 to 75.9] with alectinib vs. 48.7% [95% CI, 40.4 to 56.9] with crizotinib; hazard ratio for disease progression or death, 0.47 [95% CI, 0.34 to 0.65]; P

Fibroblast Growth Factor Receptors (FGFR1-4) have a critical role in the progression of several human cancers, including Squamous Non-Small-Cell Lung Cancer (SQCLC). Both non-selective and selective reversible FGFR inhibitors are under clinical investigation for the treatment of patients with tumors harboring FGFR alterations. Despite their potential efficacy, the clinical development of these drugs has encountered several challenges, including toxicity, and the appearance of drug resistance. Recent efforts have been directed at development of irreversible FGFR inhibitors, which have the potential to exert superior anti-proliferative activity in tumors carrying FGFR alterations. With this in mind, we synthetized, and investigated a set of novel inhibitors possessing a warhead potentially able to covalently bind a cysteine in the P-loop of FGFR. Among them, the chloroacetamide UPR1376 resulted able to irreversible inhibit FGFR1 phosphorylation in FGFR1 over-expressing cells generated from SQCLC SKMES-1 cells. In addition, this compound inhibited cell proliferation in FGFR1-amplified H1581 cells with a potency higher than the reversible inhibitor BGJ398 (infigratinib), while sparing FGFR1 low-expressing cells. The anti-proliferative effects of UPR1376 were demonstrated in both 2D and 3D systems and were associated with the inhibition of MAPK and AKT/mTOR signaling pathways. UPR1376 inhibited cell proliferation also in two BGJ398-resistant cell clones generated from H1581 by chronic exposure to BGJ398, although at concentrations higher than those effective in the parental cells, likely due to the persistent activation of the MAPK pathway associated to NRAS amplification. Combined blockade of FGFR1 and MAPK signaling, by UPR1376 and trametinib respectively, significantly enhanced the efficacy of UPR1376, providing a means of circumventing resistance to FGFR1 inhibition. Our findings suggest that the insertion of a chloroacetamide warhead on a suitable scaffold, as exemplified by UPR1376, is a valuable strategy to develop a novel generation of FGFR inhibitors for the treatment of SQCLC patients with FGFR alterations.

Background Recent evidence suggested a potential correlation between overweight and the efficacy of immune checkpoint inhibitors (ICIs) in cancer patients. Patients and methods We conducted a retrospective study of advanced cancer patients consecutively treated with anti-PD-1/PD-L1 inhibitors, in order to compare clinical outcomes according to baseline BMI levels as primary analysis. Based on their BMI, patients were categorized into overweight/obese (≥ 25) and non-overweight (

Background Bone metastases (BoM) are a negative prognostic factor in non-small-cell lung cancer (NSCLC). Beyond its supportive role, bone is a hematopoietic organ actively regulating immune system. We hypothesized that BoM may influence sensitivity to immunotherapy. Methods Pretreated non-squamous (cohort A) and squamous (cohort B) NSCLCs included in the Italian Expanded Access Program were evaluated for nivolumab efficacy according to BoM. Results Cohort A accounted for 1588 patients with non-squamous NSCLC, including 626 (39%) with (BoM+) and 962 (61%) without BoM (BoM-). Cohort B accounted for 371 patients with squamous histology including 120 BoM+ (32%) and 251 (68%) BoM- cases. BoM+ had lower overall response rate (ORR; Cohort A: 12% versus 23%, p

BRAF Mutant NSCLC and Immune Checkpoint Inhibitors: Results From a Real-World Experience

Purpose No effective salvage treatments are available for patients with advanced/recurrent thymoma (T) or thymic carcinoma (TC) who have progressed after platinum-based chemotherapy. This study evaluated the activity of everolimus in patients with advanced/recurrent T or TC previously treated with cisplatin-containing chemotherapy. Patients and Methods This was a single-arm, single-stage, open-label, multicenter, phase II trial. Patients received oral everolimus 10 mg/d until disease progression, unacceptable toxicity, or patient refusal. A Fleming phase II trial was designed. The null hypothesis of a true disease control rate (DCR) of 40% was tested against a one-sided alternative of a true DCR of 60% (α = β = 0.10): If disease control were achieved in ≥ 21 of the first 41 evaluable patients, everolimus could be recommended for further evaluation. Progression-free survival, overall survival, and safety were also evaluated. Results From 2011 to 2013, 51 patients were enrolled (T, n = 32; TC, n = 19). Complete remission was observed in one patient with TC, partial response in five patients (T, n = 3; TC, n = 2), and stable disease in 38 patients (T, n = 27; TC, n= 11), with a DCR of 88% (T,: 93.8%; TC, 77.8%). With a median follow up of 25.7 months, median progression-free survival was 10.1 months (T,: 16.6 months; TC, 5.6 months), and median overall survival was 25.7 months (T, not reached; TC, 14.7 months). Fourteen patients had a serious drug-related adverse event; of these patients, nine permanently discontinued treatment. Three patients died of pneumonitis while in the study. Immunohistochemical positivity for p4E-BP1 or insulin-like growth factor-1 receptor was statistically significantly related to a shorter survival. Conclusion Everolimus may induce durable disease control in a high percentage of patients with T or TC, albeit with a potential high risk of fatal pneumonitis.

Summary Background Malignant pleural mesothelioma is an aggressive cancer with highly vascularised tumours. It has poor prognosis and few treatment options after failure of first-line chemotherapy. NGR-hTNF is a vascular-targeting drug that increases penetration of intratumoral chemotherapy and T-cell infiltration by modifying the tumour microenvironment. In this trial, we aimed to investigate the efficacy and safety of NGR-hTNF in patients with malignant pleural mesothelioma who had progressed during or after a first-line treatment. Methods NGR015 was a randomised, double-blind, placebo-controlled phase 3 trial done in 41 centres in 12 countries. Eligible participants had malignant pleural mesothelioma of any histological subtype (epithelial, sarcomatoid, or mixed), were aged 18 years or older, and had an Eastern Cooperative Oncology Group performance status of 0–2 and radiologically documented progressive disease after one pemetrexed-based chemotherapy regimen. Participants were randomly assigned to receive weekly NGR-hTNF 0·8 μg/m2 intravenously plus best investigator choice (n=200), or placebo plus best investigator choice (n=200). Best investigator choice was decided before random assignment and could be single-agent gemcitabine (1000–1250 mg/m2 intravenously), vinorelbine (25 mg/m2 intravenously or 60 mg/m2 orally), doxorubicin (60–75 mg/m2 intravenously), or best supportive care only. Patients were randomised (1:1) with a block size of four after stratification for performance status and best investigator choice. The primary study endpoint was overall survival in the intention-to-treat population. The trial is closed to new participants and is registered with ClinicalTrials.gov (NCT01098266). Findings Between April 12, 2010 and Jan 21, 2013, we enrolled 400 eligible participants. 381 (95%) of 400 patients were selected to receive chemotherapy before all participants were randomly assigned to receive NGF-hTNF plus best investigator choice (n=200) or placebo plus best investigator choice (n=200). At the cutoff date (April 29, 2014), the median follow-up was 18·7 months (IQR 15·1–24·4), and overall survival did not differ between the two treatment groups (median 8·5 months [95% CI 7·2–9·9] in the NGR-hTNF group vs 8·0 months [6·6–8·9] in the placebo group; hazard ratio 0·94, 95% CI 0·75–1·18; p=0·58). Grade 3 or worse study-emergent adverse events occurred in 136 (70%) of patients receiving NGR-hTNF versus 118 (61%) of patients receiving placebo, with the most common being neutropenia (35 [18%] of 193 patients vs 36 [19%] of 193 patients), pain (11 [6%] vs 16 [8%]), dyspnoea (nine [5%] vs seven [4%]), and chills (nine [5%] vs none). 50 (26%) patients in the NGR-hTNF group had a serious adverse event, compared with 47 (24%) in the placebo group. Treatment-related serious adverse events occurred in 17 (9%) patients in the NGR-hTNF group and 20 patients (10%) in the placebo group. There were 12 deaths in the NGR-hTNF group and 13 deaths in the placebo group, but none were treatment related. Interpretation The study did not meet its primary endpoint. The hypothesis-generating findings from the subgroup analyses deserve a confirmatory randomised trial because patients who rapidly progress after first-line treatment have a poor prognosis. Funding MolMed.

To demonstrate the advantages of using curved needles in fine needle aspiration (FNA) with CT-guided, for analyzing abdominal and/or retroperitoneal small lesions which are impossible to reach with conventional non-surgical biopsy techniques, particularly in cases in which the cytology sample was not possible to obtain by means of US or CT guide with axial images. An authorization for CT-guided FNA in patients with neoplasms is not required by the institutional review board of our Institute. From April 2012 to November 2014, the study included retrospectively 25 patients (16 M, 9 F) who underwent CT-guided FNA of abdominal and/or retroperitoneal small lesions (

The ICARUS trial is a phase II, open label, multicenter, single arm study conducted to investigate the efficacy, safety, and tolerability of a rechallenge treatment with the first-generation tyrosine kinase inhibitor (TKI) gefitinib in advanced non-small-cell lung cancer (NSCLC) patients carrying activating mutations of the epidermal growth factor receptor (EGFR). The ICARUS trial enrolled 61 patients who were rechallenged with gefitinib at progression after second-line chemotherapy. Serum-derived circulating cell-free DNA (cfDNA) collected before the rechallenge from a cohort of 29 patients, was retrospectively analyzed for the EGFR exon 19 deletions and for the p.L858R and p.T790M single nucleotide variants (SNV). The analysis of cfDNA detected the same EGFR activating mutation reported in the tumor tissue in 20/29 patients, with a sensitivity of 69%. Moreover, a p.T790M variant was found in 14/29 patients (48.3%). The median progression-free survival (PFS) was 2.7 months for p.T790M positive patients (CI 95% 1.4&ndash, 3.1 months) versus 3.5 months for the p.T790M negative patients (CI 95% 1.6&ndash, 5.3 months), resulting in a statistically significant difference (Long rank test p = 0.0180). These findings confirmed the role of the p.T790M mutation in the resistance to first-generation TKIs. More importantly, our data suggest that TKI rechallenge should be guided by biomarker testing.

Background: Programmed cell death 1 (PD-1) and PD-ligand 1 (PD-L1) inhibitors represent novel therapeutic options for advanced non-small cell lung cancer (NSCLC). However, approximately 50% of patients do not benefit from therapy and experience rapid disease progression. PD-L1 expression is the only approved biomarker of benefit to anti-PD-1/PD-L1 therapy. However, its weakness has been evidenced in many studies. More recently, tumor mutational burden (TMB) has proved to be a suitable biomarker, but its calculation is difficult to obtain for all patients. Methods: We tested specific NSCLC genetic alterations as potential immunotherapy biomarkers. Tumor DNA was obtained from advanced NSCLC patients treated with anti-PD-1 monoclonal antibody nivolumab ( n = 44) or pembrolizumab ( n = 3). The mutational status of 22 genes was assessed by targeted next-generation sequencing and the association with survival was tested in uni- and multivariate models. The association between gene mutations and clinical benefit was also investigated. Results: The most frequently mutated genes were TP53 (49%), KRAS (43%), ERBB2 (13%), SMAD4 (13%), DDR2 (13%), STK11 (9%), ERBB4 (6%), EGFR (6%), BRAF (6%), and MET (6%). We confirmed that KRASmut patients have a better response to PD-1 inhibitors, showing a longer progression-free survival (PFS) and overall survival (OS) than KRASwt patients. In addition, we observed that patients with ERBB-family mutations, including EGFR, ERBB2, and ERBB4 all failed to respond to PD-1 antibodies, independently of KRAS status. Conclusions: This study suggests that the analysis of KRAS and ERBB-family gene mutational status is valuable when assessing the clinical practice for the selection of NSCLC patients to treat with PD-1 inhibitors.

Objectives Although patients with advanced non-small cell lung cancer (NSCLC) and an activating epidermal growth factor receptor (EGFR) mutation benefit from the use of EGFR-tyrosine kinase inhibitors (TKI), most of them progress within 12 months from treatment start due to acquired resistance. In clinical practice, many physicians frequently offer these patients retreatment with EGFR-TKIs after a chemotherapy break, based on small or retrospective studies. Materials and methods A phase II trial was conducted in patients with stage III/IV NSCLC, to assess the efficacy, safety and impact on quality of life (QoL) and disease-related symptoms of gefitinib rechallenge. Eligible patients had initially responded to first-line gefitinib and progressed after second-line chemotherapy. Results Of 61 enrolled patients, 73.8% were female, 100% had EGFR-mutated adenocarcinoma and 67.2% were never-smokers. Thirty-two (52.5%) patients obtained a clinical benefit, with 3 (4.9%) achieving a partial response and 29 (47.5%) having stable disease. Median progression-free survival was 2.8 months, overall survival 10.2 months and duration of gefitinib treatment 3.6 months. The most common all grade-adverse events were diarrhea (27.6%), nausea and/or vomiting (20.3%), rash (14.7%) and dyspnea (10.3%); no new toxicities were apparent. Conclusion Findings from this study indicate that gefitinib rechallenge offers modest benefit and may be taken into consideration only for patients for whom no other treatment option exists.

3067Background: Nivolumab is the first checkpoint inhibitor approved for the treatment of squamous non small cell lung cancer (Sq-NSCLC) to show a survival benefit in a randomised phase III trial. ...

Gefitinib, an inhibitor of epidermal growth factor receptor tyrosine kinase, has been developed and approved for treatment of advanced non-small cell lung cancer (NSCLC). In this study, we investigated the uptake of gefitinib in gefitinib-sensitive and -resistant NSCLC cell lines. The transport system was temperature-dependent, indicative of an active process and sodium- and potential-independent. Moreover, high cell densities and low extracellular pH significantly reduced the uptake of gefitinib. Inhibitors of the human organic cation transporter 1 (hOCT1) significantly decreased gefitinib uptake; however, gefitinib was not a substrate for hOCT1 or hOCT2 in overexpressing HEK293 cells. Interestingly, gefitinib significantly reduced uptake of the hOCT prototypical substrate MPP suggesting that gefitinib may exert an inhibitory effect on the intracellular accumulation of drugs transported by hOCT1 and hOCT2. After 15min of treatment at 1microM (the maximum plasma concentration of gefitinib obtained at the clinically relevant dose) gefitinib accumulated within the cell in resistant-cell lines at concentrations similar or even higher than in gefitinib-sensitive cells tending to rule out an alteration in drug uptake as a mechanism of resistance to gefitinib treatment. Moreover, our results suggest that the extrusion of lactate by crowded cells may contribute in decreasing the pH, which in turn can influence the uptake of gefinitib and as a result the inhibition of EGFR autophosphorylation.

A number of different clinical characteristics and molecular markers related to epidermal growth factor receptor (EGFR) activation have been reported to singly correlate with therapeutic activity of EGFR tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC). This study was designed to evaluate the predictive value on gefitinib outcomes of a comprehensive panel of molecular parameters in advanced NSCLC patients EGFR and K-ras mutations were detected by direct sequencing on tumor DNA from paraffin embedded samples EGFR and HER2 gene copy number was assessed by FISH EGFR protein expression was quantified by immunohistochemistry. EGFR gene intron 1 polymorphism was assessed on genomic DNA isolated from venous whole blood samples Ninety-one patients were prospectively enrolled and the overall gefitinib response rate was 18 7% (2 complete and 15 partial responses) Sex (p = 0005), non-smoking status (p = 0010). skin toxicity (p = 0020). EGFR gene mutations (p

The epidermal growth factor receptor(EGFR) is a validated target for therapy in non-small cell lung cancer (NSCLC). Most patients, however, either do not benefit or develop resistance to specific inhibitors of the EGFR tyrosine kinase activity, such as gefitinib or erlotinib. The mammalian target of rapamycin (mTOR) is a key intracellular kinase integrating proliferation and survival pathways and has been associated with resistance to EGFR tyrosine kinase inhibitors. In this study, we assessed the effects of combining the mTOR inhibitor everolimus (RAD001) with gefitinib on a panel of NSCLC cell lines characterized by gefitinib resistance and able to maintain S6K phosphorylation after gefitinib treatment. Everolimus plus gefitinib induced a significant decrease in the activation of MAPK and mTOR signaling pathways downstream of EGFR and resulted in a growth-inhibitory effect rather than in an enhancement of cell death. A synergistic effect was observed in those cell lines characterized by high proliferative index and low doubling time. These data suggest that treatment with everolimus and gefitinib might be of value in the treatment of selected NSCLC patients that exhibit high tumor proliferative activity. (C) 2009 Elsevier Inc. All rights reserved. RI goldoni, matteo/E-9153-2011; Mutti, Antonio/C-1095-2011

Despite high response rates to first-line standard treatment, the great majority of patients with small cell lung cancer (SCLC) will relapse and succumb to their disease rather quickly. In the context of salvage therapy, symptom palliation and quality-of life improvements, besides survival prolongation, are primary treatment endpoints. A variety of single-agent and multi-agent chemotherapy regimens have been tested with limited success in patients with recurrent SCLC. A number of combination regimens have demonstrated high response rates in second-line settings, but these can be considered only for patients with good performance status. Treatment outcome depends on many factors, including type of response to first-line therapy, treatment-free interval, and performance status. Currently, topotecan represents an effective, tolerable therapeutic option and is the only agent approved for this indication. The management of patients with recurrent disease remains an area of active research. This review provides an update of clinical research on second-line chemotherapy of SCLC and of recent results obtained with novel molecular targeted approaches in both first- and second-line therapy.

Radical surgery remains the only treatment with curative potential for patients with operable non-small cell lung cancer (NSCLC). However, despite complete surgical resection, long-term survival is still disappointing with an average 5-year survival rate lower than 60%. Thoracic post-operative radiotherapy trials demonstrated a possible impact in reducing loco-regional recurrence but not overall survival. Moreover, the majority of post-surgical failures are represented by distant metastases, indicating a possible role for adjuvant systemic therapies. The role of adjuvant chemotherapy has now been clearly established in many solid tumors and the role of last generation platinum-based chemotherapy has now being considered as standard of care in advanced NSCLC. However, the role of adjuvant chemotherapy for completely resected NSCLC remains highly controversial. After the meta-analysis published in 1995, which showed a non-statistically significant 5% improvement in 5-year survival with second generation platinum-based adjuvant chemotherapy, several randomized clinical trials addressing the role of last generation adjuvant chemotherapy in patients with completely resected stage I, II and IIIA NSCLC have been completed with conflicting results. The available scientific evidence is reviewed and strengths/weaknesses of each trial are discussed in this article. Although most of the available evidence points to a possible survival benefit in long-term survival improvement ranging from 4% to 15%, the introduction of adjuvant chemotherapy as standard of care in the treatment of resected NSCLC is still a matter of debate. Practical issues and clinical aspects which may help clinicians in the decision making process about prescription of adjuvant treatment are also discussed. (c) 2005 Elsevier Ltd. All rights reserved.

PURPOSE: We aimed to assess the correlation between pulmonary hemorrhage and pneumothorax in computed tomography (CT)-guided transthoracic fine needle aspiration (TTFNA), particularly its possible value as protection against the development of pneumotorax. MATERIALS AND METHODS: We reviewed the CT images of 538 patients (364 males and 174 females, mean age 70 years, range 36-90 years) who underwent CT-guided TTFNA of pulmonary nodules between January 2008 and September 2013. The following CT findings were assessed: pulmonary hemorrhage (type 1, along the needle track; type 2, perilesional; low-grade, ≤6 mm; high-grade, >6 mm), pneumothorax, distance between the target nodule and the pleural surface, and emphysema. RESULTS: Pneumothorax occurred in 154 cases (28.6%) and pulmonary hemorrhage occurred in 144 cases (26.8%). The incidence of pneumothorax was lower in patients showing type 1 and high-grade pulmonary hemorrhage pattern. The incidence of pneumothorax in biopsies ≥30 mm from pleural surface was 26% (12/46) in cases showing this pattern, while it was 71.4% (30/42) when this pattern was not seen. Similarly, the incidence of pneumothorax in biopsies

Background Epidermal growth factor receptor (EGFR) gene copy number has been proposed as predictor of response to epidermal growth factor receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer (NSCLC). Methods Cytologic and matched histologic samples from 33 primary non-small cell lung cancers were analyzed by fluorescence in situ hybridization (FISH) for epidermal growth factor receptor gene. Results FISH was positive in 52% and negative in 35% of the 31 matched evaluable samples. Four of 31 (13%) cases were discordant ( K = 0.736; p Conclusion Our data support the feasibility and reliability of epidermal growth factor receptor gene assessment by FISH on cytology.

Lung neuroendocrine tumors are catalogued in four categories by the World Health Organization (WHO 2004) classification. Its reproducibility and prognostic efficacy was disputed. The WHO 2010 classification of digestive neuroendocrine neoplasms is based on Ki67 proliferation assessment and proved prognostically effective. This study aims at comparing these two classifications and at defining a prognostic grading system for lung neuroendocrine tumors. The study included 399 patients who underwent surgery and with at least 1 year follow-up between 1989 and 2011. Data on 21 variables were collected, and performance of grading systems and their components was compared by Cox regression and multivariable analyses. All statistical tests were two-sided. At Cox analysis, WHO 2004 stratified patients into three major groups with statistically significant survival difference (typical carcinoid vs atypical carcinoid (AC),P=0.021; AC vs large-cell/small-cell lung neuroendocrine carcinomas,PP=0.021; and G2 vs G3,P≤0.001), mitotic count (G1 ≤2, G2 >2–47, G3 >47; G1 vs G2,P≤0.001; and G2 vs G3,P≤0.001), and presence of necrosis (G1 absent, G2 10% of sample; G1 vs G2,P≤0.001; and G2 vs G3,P≤0.001) at uni and multivariable analyses. The combination of these three variables resulted in a simple and effective grading system. A three-tiers grading system based on Ki67 index, mitotic count, and necrosis with cutoffs specifically generated for lung neuroendocrine tumors is prognostically effective and accurate.

Background: The FAST was a factorial trial in first-line treatment of advanced non-small-cell lung cancer (NSCLC), addressing the role of replacing cisplatin with a non-platinum agent. The prognostic and predictive effect of ERCC1/BRCA1 expression and ERCC1/XPD/XRCC1-3 gene polymorphisms on outcomes of patients was examined.Methods:Patients were randomised to receive treatment with or without cisplatin. ERCC1/BRCA1 expression was determined by immunohistochemistry. ERCC1 (C8092A, C118T), XPD (Lys751Gln), XRCC1 (Arg399Gln) and XRCC3 (Thr241Met) gene polymorphisms were evaluated on tumour DNA by TaqMan allelic discrimination assay.Results:Tumour samples were available from 110 of 433 patients enrolled: 54.7% were ERCC1 positive and 51.4% were BRCA1 positive. Overall, ERCC1-negative patients had better response rate (P=0.004), progression-free survival (P=0.023) and overall survival (P=0.012) compared with positive ones, with no statistically significant treatment interaction. The BRCA1-positive patients showed numerically better outcomes, although not statistically significant, with no treatment interaction. Among DNA repair gene polymorphisms, only XRCC1 Gln/Gln genotype evidenced a potential prognostic role (P=0.036).Conclusion:This study confirms the prognostic role of ERCC1 expression and XRCC1 (Arg399Gln) polymorphism in advanced NSCLC treated with first-line chemotherapy. None of these biomarkers was shown to be a specific predictive factor of cisplatin efficacy. © 2013 Cancer Research UK. All rights reserved.

BACKGROUND: The FAST is a 2 × 2 factorial trial addressing two questions: (1) the role of replacing cisplatin (P) with a non-platinum agent, vinorelbine (N), and (2) the role of adding a third agent, ifosfamide (I), in a doublet based on gemcitabine (G). METHODS: A total of 433 stage IIIB-IV non-small cell lung cancer (NSCLC) patients were randomised to one of four arms: gemcitabine-cisplatin (GP), gemcitabine-vinorelbine, gemcitabine-ifosfamide- cisplatin or gemcitabine-ifosfamide-vinorelbine. Two comparisons were performed: N- vs P-containing regimens and I-triplets vs non-I doublets. RESULTS: For N- vs P-containing regimens, adjusted overall survival was 9.7 vs 11.3 months (P=0.044), progression-free survival was 4.9 vs 6.4 months (P=0.020) and response rate was 24% vs 31% (P=0.124), respectively. No statistically significant difference was observed between doublets and triplets. Grade 3-4 haematological toxicity was significantly more frequent in P-containing therapy; grade 3-4 leucopenia was significantly more common in triplets. Concerning non-haematological toxicity, grade 3-4 nausea-vomiting was significantly increased in P-containing regimens. CONCLUSIONS: This trial provides evidence of a slight survival superiority of GP-containing regimens over platinum-free N-containing chemotherapy. This trial also confirms that the addition of a third chemotherapy agent (I) to a standard G-based doublet does not improve treatment outcome. © 2012 Cancer Research UK. All rights reserved.

The fusion gene EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) was recently identified as a novel genetic alteration in non-small cell lung cancer (NSCLC). EML4-ALK translocations correlate with specific clinical and pathological features, in particular lack of EGFR and K-ras mutations, and may be associated with resistance to EGFR tyrosine-kinase inhibitors (TKIs). Here, we report a case of a patient with a concomitant EGFR mutation and ALK translocation resistant to erlotinib. Considering this report, ALK status should be investigated in unexplained cases of EGFR-TKI-resistance of EGFR mutated NSCLCs. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Background: Histological typing of non-small cell lung cancer (NSCLC) has an increasing clinical relevance due to the emerging differences in medical treatment between squamous and nonsquamous tumors. However, most NSCLCs are diagnosed in an advanced stage, and the diagnosis is often obtained exclusively by cytology either exfoliative or following fine needle aspiration. We investigated the accuracy of fine needle aspiration cytology (FNAC) in NSCLC typing as compared with histology. Methods: Over the period 2000-2009, 1182 transbronchial needle aspirate or transthoracic needle aspirate samples were obtained from patients with suspicious thoracic lesions. In 474 patients, a cytological diagnosis of primary NSCLC was obtained, and 186 (39%) of them (108 transbronchial needle aspirates and 78 transthoracic needle aspirates) received a parallel or subsequent histologic diagnosis on endoscopic biopsy (112) or surgery (74). Results: At cytology, 158 (85%) NSCLC cases were typed (89 adenocarcinoma and 69 squamous cell carcinoma), while 28 (15%) were classified as NSCLC not otherwise specified. At histology, 183 (98%) cases were typed (109 adenocarcinoma, 69 squamous cell carcinoma, 3 adenosquamous carcinoma, and 2 large cell carcinoma), and only 3 (2%) were classified as NSCLC not otherwise specified. Cytological and histological typing was concordant in 137 of 156 (88%) cases (K = 0.755; p < 0.001). The positive predictive value of FNAC in typing NSCLC was 92% for adenocarcinoma and 82% for squamous cell carcinoma. Conclusion: FNAC in expert hands is fairly accurate for typing NSCLC and can be regarded as an acceptable procedure for diagnostic and medical treatment planning purposes in most NSCLC cases, especially when more invasive approaches are unfeasible. In poorly differentiated and doubtful cases, the use of ancillary techniques, such as immunocytochemistry, may be required to improve the diagnostic yield.

Malignant pleural mesothelioma (MPM) is a very important public health issue. A large amount of data indicates a relationship between mesothelioma and asbestos exposure. The incidence has both considerably and constantly increased over the past 2 decades in the industrialized countries and is expected to peak in 2010-2020. In Italy, a standardized-rate incidence in 2002 among men was 2.98 per 100,000 and 0.98 per 100,000 among women, with wide differences from one region to another. Stage diagnosis and definition may be difficult. Management of patients with MPM remains complex, so an optimal treatment strategy has not yet been clearly defined. The First Italian Consensus Conference on Malignant Pleural Mesothelioma was held Bologna (Italy) in May 20, 2008. The Consensus Conference was given the patronage of the Italian scientific societies AIOM, AIRO, AIPO, SIC, SICO, SICT, SIAPEC-IAP, AIOT, GOAM, and GIME. This Consensus did not answer all of the unresolved questions in MPM management, but the Expert Opinions have nonetheless provided recommendations, presented in this report, on MPM management for clinicians and patients.

Background: Erlotinib demonstrated significantly prolonged survival versus placebo in patients with advanced NSCLC who had progressed after standard chemotherapy. TRUST is a phase IV trial initiated to provide erlotinib access to patients with advanced NSCLC. We report the interim analysis for patients enrolled in the TRUST trial in Italy. Patients and methods: Eligible patients had stage IIIB/IV NSCLC and had failed or were unsuitable for chemotherapy. Erlotinib (150 mg/day orally) was given until disease progression or unacceptable toxicity. Patients were monitored monthly. Results: At time of this analysis, data from 651 patients were available. Patient characteristics were: median age 66 years (range 30-87), male 69%, former or current smoker 71%, ECOG PS 0-1 81%, adenocarcinoma histology 52% and stage IV 82%. Erlotinib was administered as first-, second-, third- or other-line in 12, 45,43 and

Purpose Epidermal growth factor receptor ( EGFR ) gene copy number obtained by fluorescence in situ hybridization (FISH) has been recently found to predict treatment outcome in non-small cell lung cancer (NSCLC) patients receiving EGFR tyrosine kinase inhibitors. However, it is still unknown whether EGFR status differs in metastases compared with primary NSCLC. In all studies FISH have been performed on histologic material. The possibility to perform FISH analysis on cytologic material obtained by fine-needle aspiration from superficial and visceral metastases would allow us to know the real EGFR status avoiding invasive diagnostic procedures. Methods EGFR gene copy number was analyzed by FISH on fine-needle aspirates obtained from 31 patients with metastatic NSCLC and the results were compared with those obtained on corresponding paraffin histologic sections from the primary tumor. Results The feasibility of EGFR FISH on cytology was 90% (28 of 31 patients). EGFR FISH was positive in 61% (17 of 28 patients) of the metastases and in 36% (10 of 28 patients) of the primary tumors. Nine of the 28 cases (32%) were EGFR positive on both primary tumor and metastatic site and 10 (36%) were negative on both primary tumor and metastasis. Nine of the 28 cases (32%) showed discordance of primary tumor versus metastasis (McNemar test; p = 0.041). Conclusions EGFR FISH can be reliably assessed on fine-needle aspirates obtained from NSCLC metastases. We found that EGFR gene copy number is discordant between primary NSCLC and the corresponding distant metastatic sites in a significant proportion of cases. These findings should be considered in future studies designed to elucidate the predictive role of EGFR FISH in NSCLC.

Introduction: Epidermal growth factor receptor (EGFR) gene intron I contains a polymorphic single sequence dinucleotide repeat (CA), whose length has been found to inversely correlate with transcriptional activity. This study was designed to assess the role of (CA)(n) polymorphism in predicting the outcome of gefitinib treatment in advanced non-small cell lung cancer (NSCLC). Methods: Blood and tumor tissue from 58 patients with advanced NSCLC submitted to gefitinib were collected. EGFR intron I gene polymorphism, along with EGFR gene mutation, gene copy number and immunohistochemistry expression were determined. Moreover, a panel of lung cancer cell lines characterized for EGFR intron I polymorphism was also studied. Results: EGFR intron I polymorphism showed a statistically significant correlation with the gefitinib response (response rate 25 versus 0%, for patients with a (CA)(16) and with a (CA)(else) genotype, respectively; p = 0.044). Patients with a (CA)(16) genotype had a longer survival compared with those with a (CA)(else) genotype (11.4 versus 4.8 months, respectively; p = 0.037). In addition, cell lines lacking the (CA)(16) allele showed a statistically significant higher IC50 compared with cell lines bearing at least one (CA)(16) allele (p = 0.003). Conclusions: This study supports a potential role of EGFR intron I polymorphism in predicting the outcome of gefitinib treatment in advanced NSCLC. RI goldoni, matteo/E-9153-2011

BACKGROUND Because the efficacy of carboplatin and cisplatin in the treatment of advanced non-small-cell lung cancer (NSCLC) has not been proven to be equivalent, an individual patient data meta-analysis comparing the two treatments was performed. METHODS Randomized trials comparing carboplatin to cisplatin in first-line treatment of advanced NSCLC were identified and their electronic databases obtained. A general variance-based method was used to estimate the summary hazard ratios (HRs), odds ratios (ORs), and their 95% confidence intervals (CIs) for mortality, objective response, and toxicity. Cochran's chi-square test (Q test) was used to test for heterogeneity among trials, and the I2 index, which expresses the proportion of variability of the results due to heterogeneity, was calculated. A random-effects model that takes into account interstudy variation was also applied. All statistical tests were two-sided. RESULTS Nine trials that included a total of 2968 patients were analyzed; overall median follow-up was 1021 days. The objective response rate was higher for patients treated with cisplatin than for patients treated with carboplatin (30% versus 24%, respectively; OR = 1.37; 95% CI = 1.16 to 1.61; P

7548 Background: In order to assess the validity of objective response to chemotherapy (CT) as a surrogate endpoint of survival in advanced non-small cell lung cancer (NSCLC), we applied the four Prentice criteria to the data collected in the CISCA meta-analysis, comparing the efficacy of carboplatin and cisplatin in the first-line treatment of advanced NSCLC. Methods: Nine trials including 2,968 patients (pts) were analyzed in the CISCA meta-analysis. The prognostic effect of tumor response on survival was analyzed setting a landmark at two months after randomization (time of response recording), in order to eliminate early death from the analysis. After this landmark correction, pts included in the validation analysis were 2,525 with complete data on tumor response and survival. Results: Cisplatin-based CT was associated with a significantly higher tumor response rate compared with carboplatin-based CT (OR = 1.39; 95% CI: 1.18–1.64; p < 0.001). Carboplatin regimens also led to a numerically higher risk of death as compared to cisplatin (HR = 1.06; 95% CI: 0.98–1.16; p = 0.15). Tumor response was a highly significant predictor of survival (HR = 0.50; 95% CI: 0.46–0.55; p < 0.001). When tumor response was introduced in the Cox model (as a four level variable), the hazard ratio in favour of cisplatin treatment changed from 1.06 to 1.004 (95% CI: 0.922–1.093; p = 0.94), indicating that no residual effect of the cisplatin treatment on survival was present once tumor response was adjusted for. This suggests that the overall survival benefit of cisplatin CT was a result of the increase in response rate. The median survival time of patients with complete and partial response was 19.5 months (95% CI: 11.5–27.5 months) and 14.0 months (95% CI: 13.1–14.9 months), respectively; whereas, the median survival time of patients with no response was 7.8 months (95% CI: 7.5–8.1 months). Conclusions: These results support the hypothesis that the achievement of an objective response to CT in advanced NSCLC is associated with a survival benefit. The potential role of objective response as a surrogate endpoint for survival in CT trials of advanced NSCLC warrants further investigation. No significant financial relationships to disclose.

Purpose: To evaluate the role of pretreatment and posttreatment expression in buccal mucosa cells of signal transduction proteins activated by epidermal growth factor receptor, including phosphorylated epidermal growth factor receptor (p-EGFR), phosphorylated mitogen-activated protein kinase (p-MAPK), and phosphorylated AKT (p-AKT), in predicting gefitinib activity in advanced non–small cell lung cancer patients. Expression of the same proteins was also assessed on corresponding tissue samples for comparison. Moreover, EGFR gene mutations and copy number were analyzed. Experimental Design: Protein expression was evaluated by standard immunocytochemistry in buccal smears, obtained by scraping immediately before and after 2 weeks of gefitinib treatment, and in the available archival tumor specimens. EGFR gene mutations were evaluated by direct sequencing and gene copy number was determined by fluorescence in situ hybridization. Data were correlated with gefitinib toxicity and objective response. Results: Fifty-eight patients with pretreated advanced non–small cell lung cancer were enrolled and nine of these patients (15%) showed an objective response to gefitinib (including two complete responses). Toxicity (P = 0.025) and baseline p-AKT expression in buccal mucosa cells (P = 0.061) showed a potential predictive role. On the contrary, the probability of achieving an objective response was not affected by pretreatment expression of EGFR, p-EGFR, and p-MAPK, either in buccal mucosa or in tumor tissue. Responders showed a nonstatistically significant trend toward a more pronounced reduction in the expression of p-EGFR, p-MAPK, and p-AKT after gefitinib treatment. Among responders, five of six (83%) tumors showed EGFR gene mutation, whereas none of the tumors from patients with stable or progressive disease did (P < 0.001). Conclusions: Epithelial cells obtained from buccal mucosa may be used to assess the pharmacodynamic effect of EGFR-targeted agents, and pretreatment p-AKT expression may be a possible predictive biomarker of in vivo gefitinib activity.

BACKGROUND. The authors assessed the predictive and prognostic role of decline in the serum levels of carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1) during chemotherapy in patients with advanced nonsmall cell lung cancer (NSCLC). METHODS. Changes in serum levels of CEA and CYFRA 21-1 during first-line, conventional chemotherapy were studied prospectively with an immunometric assay at baseline and every 2 courses in 117 patients with advanced NSCLC. Data were correlated with radiologic objective response (OR) and survival. RESULTS. One hundred seven patients were evaluable for radiologic and serologic response assessment after 2 chemotherapy courses. The radiologic OR rate was 44% overall. The CEA and CYFRA 21-1 responses (≥20% reduction over baseline level; assessed after the second course of chemotherapy) were 38% and 61%, respectively. Statistically significant correlations were observed between CEA and CYFRA 21-1 responses and OR (P = .01 and P = .004, respectively). The median survival from response assessment (landmark analysis) was 9 months. In a univariate analysis, disease stage, performance status, baseline lactate dehydrogenase level (LDH), OR, CEA response, and CYFRA 21-1 response were correlated significantly with survival. In particular, the median survival was 13 months for patients who had a CEA response and 11 months for patients who had a CYFRA 21-1 response compared with 8 months and 6 months for patients who did not respond, respectively. In a multivariate analysis, performance status (P = .005), baseline LDH level (P = .02), CEA response (P = .03) and CYFRA 21-1 response (P = .01) were confirmed as independent prognostic factors for survival. CONCLUSIONS. CEA and CYFRA 21-1 responses appeared to be reliable surrogate markers of chemotherapy efficacy in patients with advanced NSCLC. Cancer 2006. © 2006 American Cancer Society.