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Malignant Pleural Mesothelioma (MPM) is a rare malignancy with an overall poor prognosis. The standard therapeutic strategy in early-stage disease is trimodality therapy. In this publication, we report the preliminary toxicity results of the first 20 patients treated with accelerated hypofractionated radiotherapy. Between July 2017 to June 2019, 20 MPM patients were enrolled and treated with accelerated hypofractionated radiotherapy using helical tomotherapy and intensity-modulated arc therapy. The prescription dose was 30 Gy in five daily fractions, while an inhomogeneous dose escalation to 40 Gy was prescribed based solely upon the presence of gross residual tumor. Only one case of G3 toxicity was reported, which was a bilateral pneumonitis that occurred two years after treatment probably due to superinfection. Median Time to Progression reached 18.2 months while one- and three-year Overall Survival rates were 85% (95% CI:60.4–94.9) and 49.5% (95% CI:26.5–68.9), respectively. Treatment of the intact lung with pleural intensity-modulated arc irradiation is a novel treatment strategy that appears to be safe, feasible, and without a high grade of lung toxicity. Survival rates and Time to Progression are encouraging.

Objectives Treatment options for malignant pleural mesothelioma (MPM) are limited but some studies on immune checkpoint inhibitors (ICIs) in MPM have reported antitumor activity. Very little is known about immune-related predictive factors. Materials and methods Here we report the case of a 45-year-old woman presenting with dyspnea and evidence of pleural effusion. She was diagnosed with malignant epithelioid pleural mesothelioma with brain metastasis and peritoneal carcinosis, refractory to initial standard chemotherapy treatment. Because of high PDL1 expression (100 %), she was treated with the anti-PD1 agent, pembrolizumab. Results Chemotherapy with cisplatin and pemetrexed was started, imaging studies showing stable disease after 3 treatment cycles. The patient underwent pleural decortication but rapidly progressed and thus started chemotherapy with carboplatin and gemcitabine. After 2 cycles she experienced seizures caused by a brain metastasis. This secondary lesion was surgically removed and confirmed as a metastasis from mesothelioma. Samples from both the primary tumor and the metastasis were molecularly characterized, the pleural sample proving ALK-positive and the brain sample, ALK-negative. PD-L1 was positive in 10 % of tumor cells in the pleural biopsy and 100 % in the brain lesion. Next generation sequencing analysis was negative for both samples. It was decided to start alectinib. Disease progression (peritoneal carcinosis and liver metastases) was documented after one month followed by complete bowel obstruction and recurrence in the site of the brain surgery. Alectinib was stopped and supportive care begun with parenteral nutrition via nasogastric tube. Pembrolizumab was started and after 15 days the patient’s condition had significantly improved, enabling recanalization and restoration of enteral nutrition. Imaging displayed complete response of the brain metastasis, peritoneal carcinosis, bone lesions and mediastinal nodal metastases. A partial response was documented in the pleural and pulmonary nodules, with stable liver metastases. The patient is still undergoing immunotherapy and has no cancer-related symptoms. Conclusions Our findings indicate that the use of immunotherapy in MPM warrants further investigation. Furthermore, the impressive clinical response obtained by our patient suggests that immune checkpoint inhibitors could help in the management of the disease after the failure of other treatments.

Immune checkpoint inhibition induced a great step forward in the treatment of non-small cell lung cancer patients. In cancer immune microenvironment many checkpoints were studied and their involvement could represent a mechanism of resistance to cancer immunotherapy. For this reason, the inhibition of multiple immune checkpoints is under development. However, myeloid-derived suppressor cells (MDSC) and exhausted immune cells could limit the efficacy of cancer immunotherapy. We analyzed the variation of circulating immune suppressive-like cell subsets and exhausted immune cells in three non-small cell lung cancer patients treated with the combination of anti-CTLA-4 plus anti-PD-1 plus anti-LAG-3 at T0 (baseline), T1 (after 2 months) and T2 (after 4 months). We also describe the clinical and radiological course of the disease during this treatment in all three patients. We observed both clinical differences and changes in the composition of immune suppressive-like cell subsets and exhausted immune cells between the patients receiving the same schedule of treatment with immune checkpoint inhibitors. The study on a wider patient population and experimental model design could help to clarify the kinetics of these cell subpopulations with the perspective to find new targets for treatment or new biomarkers for resistance to cancer immunotherapy.

BackgroundCurrent therapy for non-small-cell lung cancer (NSCLC) frequently includes immune checkpoint inhibitors, such as pembrolizumab, and programmed death ligand 1 (PD-L1) positivity is mandatory for its use in this setting. Vimentin plays a role in carcinogenesis through the activation of the epithelial-to-mesenchymal transition (EMT) process. Its prognostic impact in NSCLC has been investigated in numerous studies but little data are available on its relation with PD-L1 expression.Patients and MethodsWe retrospectively retrieved data on patients with advanced NSCLC consecutively enrolled in a clinical trial at our institute. PD-L1 and vimentin expression were determined by immunohistochemistry. Correlations between variables were assessed using the Spearman correlation coefficient. The Kaplan-Meier method was used to estimate overall survival (OS) and the Log-rank test was used to compare survival curves. The association between demographic, clinical and biomarker information and survival was investigated with the Cox model.ResultsFifty-three patients were included in the study. A weak positive correlation was observed between the PD-L1 and vimentin (ρ=0.41, P=0.003). Patients with PD-L1 values P=0.080). No difference in overall survival (OS) was observed on the basis of vimentin expression (HR=1.25; 95% CI: 0.59–2.66; P=0.554). Patients harboring both vimentin and PD-L1 negative expression (P=0.093). No significant associations were observed between gender, age at diagnosis, stage at diagnosis, histology, KRAS or EGFR status, radical surgery or immunotherapy and OS.ConclusionsThe weak positive association between PD-L1 and vimentin suggests a potential interplay between these biomarkers. Further research is warranted to evaluate EMT and immune escape as two components of the same process.

Introduction: Among the oncogene-addicted non-small cell lung cancer patients, those bearing ALK rearrangement can be currently treated with next-generation ALK inhibitors. Brigatinib was first use...

PURPOSE Immunotherapy has revolutionized the treatment of advanced non–small-cell lung cancer (NSCLC). In two phase III trials (CheckMate 017 and CheckMate 057), nivolumab showed an improvement in overall survival (OS) and favorable safety versus docetaxel in patients with previously treated, advanced squamous and nonsquamous NSCLC, respectively. We report 5-year pooled efficacy and safety from these trials. METHODS Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG PS ≤ 1, and progression during or after first-line platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg once every 2 weeks) or docetaxel (75 mg/m2 once every 3 weeks) until progression or unacceptable toxicity. The primary end point for both trials was OS; secondary end points included progression-free survival (PFS) and safety. Exploratory landmark analyses were investigated. RESULTS After the minimum follow-up of 64.2 and 64.5 months for CheckMate 017 and 057, respectively, 50 nivolumab-treated patients and nine docetaxel-treated patients were alive. Five-year pooled OS rates were 13.4% versus 2.6%, respectively; 5-year PFS rates were 8.0% versus 0%, respectively. Nivolumab-treated patients without disease progression at 2 and 3 years had an 82.0% and 93.0% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression-free at 5 years, respectively. Treatment-related adverse events (TRAEs) were reported in 8 of 31 (25.8%) nivolumab-treated patients between 3–5 years of follow-up, seven of whom experienced new events; one (3.2%) TRAE was grade 3, and there were no grade 4 TRAEs. CONCLUSION At 5 years, nivolumab continued to demonstrate a survival benefit versus docetaxel, exhibiting a five-fold increase in OS rate, with no new safety signals. These data represent the first report of 5-year outcomes from randomized phase III trials of a programmed death-1 inhibitor in previously treated, advanced NSCLC.

The mutational status of the epidermal growth factor receptor (EGFR) guides the stratification of non‐small cell lung cancer (NSCLC) patients for treatment with tyrosine kinase inhibitors (TKIs). A liquid biopsy test on cell‐free DNA is recommended as a clinical decision‐supporting tool, although it has limited sensitivity. Here, we comparatively investigated the extracellular vesicle (EV)‐RNA as an independent source for multidimensional and longitudinal EGFR profiling in a cohort of 27 NSCLC patients. We introduced and validated a new rapid, highly specific EV‐RNA test with wild‐type (WT) and mutant‐sensitive probes (E746‐A750del, L858R, and T790M). We included a cohort of 20 NSCLC patients with EGFR WT tumor tissues and systematically performed molecular EV‐RNA and circulating tumor DNA analyses with clinical data statistics and biophysical profiles of EVs. At the single‐patient level, we detected variegated tumor heterogeneity dynamics supported by combinations of driver EGFR mutations. EV‐RNA‐based mutation analysis showed an unprecedented sensitivity of over 90%. The resistance‐associated mutation T790M frequently pre‐existed at baseline with a gained EV‐transcript copy number at progression, while the general mutational burden was mostly decreasing during the intermediate follow‐up. The biophysical profile of EVs and the quantitative assessment of T790M revealed an association with tumor size determined by the sum of the longest diameters in target lesions. Vesicular RNA provides a validated tool suitable for use in clinical practice to investigate the dynamics of common driver EGFR mutations in NSCLC patients receiving TKIs., We applied a rapid and quantitative pipeline for detecting driver EGFR mutations in a retrospective cohort of NSCLC patients using circulating tumor DNA and extracellular vesicles' RNA (EV‐RNA) as independent longitudinal sources. The EV‐RNA provided sensitive and consistent dynamics of tumor heterogeneity with the potential to advance liquid biopsy tests in patients receiving tyrosine kinase inhibitors.

The identification of oncogenic driver mutations in non-small-cell lung cancer (NSCLC) has led to the development of targeted drugs. Tyrosine kinase inhibitors (TKIs) directed against the epidermal growth factor receptor (EGFR) target lung tumours bearing EGFR-activating mutations. This new therapeutic strategy has greatly improved tumour response rates. However, drug resistance invariably occurs during TKI-based treatment. Epithelial-to-mesenchymal transition (EMT) is one of the resistance mechanisms identified in EGFR-mutated NSCLC treated with TKIs. In this review we gather together the most important findings on this phenomenon in relation to cancer stem cells and cancer epigenetics. We also outline the correlation between the effects of stromal factors from the microenvironment, the transcription factors activated, the epigenetic changes in chromatin, and the evolution of cellular behaviour. Notably, EMT has already been shown to be the link between benign lung diseases such as chronic obstructive pulmonary disease and lung carcinogenesis. The various mechanisms of acquired resistance to EGFR-TKIs are also briefly described to provide background information on EMT. Our extensive review of the scientific literature serves to highlight the cellular and molecular events that lead to the onset of EMT in NSCLC cells treated with EGFR-TKIs. Finally, we put forward a hypothesis to explain why, in some cases, EMT rather than other known mechanisms is involved in resistance to TKIs.

Performing randomised clinical trials to address the clinical usefulness of predictive and prognostic tumour markers is a complex process for several reasons, and observational experiences may thus play an important role. The present study performed an observational retrospective analysis in Area Vasta Romagna, Italy, collecting information on tumour marker determination in 760 consecutive patients who started a new line of anticancer therapy between January and June 2010. The determination of well-known biomarkers was requested for all gastrointestinal stromal tumour (GIST) patients (n=13) and for almost all breast cancer patients (n=369), and targeted therapies were consequently prescribed. Conversely, Kirsten rat sarcoma viral oncogene homolog (KRAS) determination in colon cancer patients (n=177) was requested in ~50% of advanced cases, while epidermal growth factor receptor (EGFR) determination was required in slightly more than 30% of the same patients. EGFR and KRAS determinations were requested in only 15% and 7.5% of non-small cell lung cancer (NSCLC) patients (n=201), respectively. There would appear to be greater appropriateness of tumour marker determination for breast cancer and GISTs than for colon cancer and NSCLC. Resources can be further optimised by standardising tumour marker determinations in terms of the timing of requests and the consequent use of the results for tailored treatment planning.

Small-cell lung cancer has a high chemotherapeutic sensitivity but with disappointing outcome results. Patients with “sensitive disease” are those who respond to treatment with a long relapse-free interval (RFI): in these cases rechallenge with first-line chemotherapy might represent a therapeutic opportunity. Our largest retrospective experience confirmed that rechallenge is feasible with interesting outcome results; there are no statistical differences between RFI and outcome.Patients with small-cell lung cancer (SCLC) that progresses after first-line (FL) chemotherapy have a poor prognosis and second-line (SL) chemotherapy has limited efficacy. Patients whose disease relapses/progresses90 days after FL platinum-based treatment are considered platinum-sensitive and could be rechallenged with a similar regimen. We conducted a multicenter retrospective analysis to evaluate outcomes of SCLC patients rechallenged with platinum/etoposide.Records of all SCLC patients treated in 7 institutions between January 2007 and December 2011 were reviewed. The primary end point was overall survival from the time of rechallenge (OS-R); secondary end points were progression-free survival (PFS) and overall survival from the time of diagnosis (OS-D). Survival curves were calculated using the Kaplan-Meier method.Of the 2000 SCLC patients identified, 112 (5.6%) had sensitive disease treated with rechallenge platinum/etoposide; 65% were men with a median age of 64 years. At the time of diagnosis, 44% of patients had limited disease, 82% had an Eastern Cooperative Oncology Group performance status of 0 to 1. A median of 4 cycles of rechallenge was administered. Tumor response was 3% for complete response and 42% for partial response, 19% of patients maintained stable disease, 27% progressive disease, and 9% were not evaluable. Median PFS from the time of rechallenge was 5.5 months (95% confidence interval [CI], 4.4-6.3). Median OS-R and OS-D were 7.9 months (95% CI, 6.9-9.7) and 21.4 months (95% CI, 19.8-24.1), respectively. Subgroup analysis according to relapse-free interval (90-119 vs. 120-149 vs.150 days) did not show any statistically significant difference in PFS or OS-R.The outcome for SL chemotherapy for SCLC is poor. Rechallenge platinum/etoposide is a reasonable option with potentially better outcomes than standard chemotherapy.

Purpose To test the efficacy of adding cisplatin to first-line treatment for elderly patients with advanced non–small-cell lung cancer (NSCLC) within a combined analysis of two parallel phase III trials, MILES-3 and MILES-4. Patients and Methods Patients with advanced NSCLC who were older than age 70 years with Eastern Cooperative Oncology Group performance status 0 to 1 were randomly assigned to gemcitabine or pemetrexed, without or with cisplatin. In each trial, 382 events were required to detect a hazard ratio (HR) of death of 0.75, with 80% power and two-tailed α of .05. Trials were closed prematurely because of slow accrual, but the joint database allowed us to analyze the efficacy of cisplatin on the basis of intention-to-treat and adjusted by trial, histotype, non-platinum companion drug, stage, performance status, sex, age, and size of the study center. Results From March 2011 to August 2016, 531 patients (MILES-3, 299; MILES-4, 232) were assigned to gemcitabine or pemetrexed without (n = 268) or with cisplatin (n = 263). Median age was 75 years, 79% were male, and 70% had nonsquamous histology. At a median 2-year follow-up, 384 deaths and 448 progression-free survival events were recorded. Overall survival was not significantly prolonged with cisplatin (HR, 0.86; 95% CI, 0.70 to 1.05; P = .14) and global health status score of quality of life was not improved, whereas progression-free survival (HR, 0.76; 95% CI, 0.63 to 0.92; P = .005) and objective response rate (15.5% v 8.5%; P = .02) were significantly better. Significantly more severe hematologic toxicity, fatigue, and anorexia were found with cisplatin. Conclusion The addition of cisplatin to single-agent chemotherapy does not significantly prolong overall survival, and it does not improve global health status score of quality of life in elderly patients with advanced NSCLC.

Purpose Nivolumab, a programmed death-1 inhibitor, prolonged overall survival compared with docetaxel in two independent phase III studies in previously treated patients with advanced squamous (CheckMate 017; ClinicalTrials.gov identifier: NCT01642004) or nonsquamous (CheckMate 057; ClinicalTrials.gov identifier: NCT01673867) non–small-cell lung cancer (NSCLC). We report updated results, including a pooled analysis of the two studies. Methods Patients with stage IIIB/IV squamous (N = 272) or nonsquamous (N = 582) NSCLC and disease progression during or after prior platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks). Minimum follow-up for survival was 24.2 months. Results Two-year overall survival rates with nivolumab versus docetaxel were 23% (95% CI, 16% to 30%) versus 8% (95% CI, 4% to 13%) in squamous NSCLC and 29% (95% CI, 24% to 34%) versus 16% (95% CI, 12% to 20%) in nonsquamous NSCLC; relative reductions in the risk of death with nivolumab versus docetaxel remained similar to those reported in the primary analyses. Durable responses were observed with nivolumab; 10 (37%) of 27 confirmed responders with squamous NSCLC and 19 (34%) of 56 with nonsquamous NSCLC had ongoing responses after 2 years’ minimum follow-up. No patient in either docetaxel group had an ongoing response. In the pooled analysis, the relative reduction in the risk of death with nivolumab versus docetaxel was 28% (hazard ratio, 0.72; 95% CI, 0.62 to 0.84), and rates of treatment-related adverse events were lower with nivolumab than with docetaxel (any grade, 68% v 88%; grade 3 to 4, 10% v 55%). Conclusion Nivolumab provides long-term clinical benefit and a favorable tolerability profile compared with docetaxel in previously treated patients with advanced NSCLC.

ABSTRACT Non-small-cell lung cancer (NSCLC) treatment has led to improved efficacy and compliance due to individual tailoring of the therapeutic options and the use of strategies based on both clinical characteristics and histological and biological features of the disease. In nonsquamous NSCLC, novel agents, such as pemetrexed and bevacizumab, have improved survival in the first-line setting. Maintenance therapy with pemetrexed and erlotinib resulted in improved progression-free survival compared with second-line therapy at disease progression. In the second-line setting, pemetrexed improves survival in nonsquamous NSCLC compared with docetaxel, and erlotinib has shown a survival benefit compared with best supportive care in patients who did not previously receive an EGF receptor inhibitor. Although the benefit of first- and second-line treatment over best supportive care alone has been firmly established, the role of further-line treatment remains controversial. This article summarizes the state-of-the-art treatments in this setting.

Background Platinum-based chemotherapy is the cornerstone of treatment of advanced non-small-cell lung cancer (NSCLC) patients, but the efficacy of adding cisplatin to single-agent chemotherapy remains to be demonstrated in prospective phase III trials dedicated to elderly patients. Furthermore, the superiority of cisplatin/pemetrexed over cisplatin/gemcitabine in non-squamous NSCLC has not been confirmed prospectively. We present the rationale and design of two open-label, multicenter, randomized phase III trials for elderly patients with advanced NSCLC∶ Multicenter Italian Lung cancer in the Elderly Study (MILES)-3 and MILES-4. The aim is to evaluate the efficacy of adding cisplatin to single-agent chemotherapy (both trials) and the efficacy of pemetrexed versus gemcitabine in non-squamous tumors (MILES-4). Patients and Methods Both trials are dedicated to first-line therapy of patients older than 70 years with advanced NSCLC, ECOG performance status 0-1. In the MILES-3 trial, patients are randomized in a 1∶1 ratio to gemcitabine or cisplatin/gemcitabine. In the MILES-4 study patients with non-squamous histology are randomized, in a factorial design with 1∶1∶1∶1 ratio, to four arms: gemcitabine (A), cisplatin/gemcitabine (B), pemetrexed (C), cisplatin/pemetrexed (D). Two comparisons are planned∶ A+C vs B+D to test the role of cisplatin; A+B vs C+D to test the role of pemetrexed. Primary endpoint of both trials is overall survival. Secondary and exploratory endpoints include progression-free survival, response rate, toxicity, and quality of life. Conclusions MILES-3 and MILES-4 results will add important evidence about the role of cisplatin-based doublets and pemetrexed in the first-line therapy of elderly patients with advanced NSCLC.

Background: Historically, 5-y overall survival (OS) with chemotherapy for pts with metastatic lung cancer was ~5%; with the advent of immunotherapy, this has increased to ~15%. CheckMate (CM) 017, 057, 063, and 003 are NIVO studies with extensive follow-up in pts with previously treated advanced NSCLC. Using pooled data from these studies, we evaluated the long-term benefit (up to 4 y) of NIVO and impact of early response or disease control on subsequent long-term OS. Methods: Progression-free survival (PFS) and OS were estimated for pts with NSCLC across histologies treated with NIVO in pooled analyses of CM 017, 057, 063, and 003 (n=664), and for pts randomized to NIVO (n=427) or docetaxel (DOC; n=427) in pooled analyses of CM 017/057. Other analyses for CM 017/057 included estimation of OS in pts alive at 6 mo by response status at 6 mo, and OS in all responders (complete or partial response [CR/PR]) from time of response. Results: In pooled analyses of the 4 studies, 4-y OS rates for NIVO in all pts and those with PD-L1 ≥1% and Conclusions: These large pooled analyses show pts with CR/PR or SD with NIVO at 6 mo derived marked OS benefit; this long-term benefit was improved vs pts with DOC with the same response status at 6 mo. The NIVO safety profile was consistent with prior reports. Table.6-Month Landmark Analysis of OS by Response Status at 6 months in Pooled CM 017/057aPts alive at mo 6Response status at 6 mo, %bPost-landmark 1-y OS rate, %Post-landmark 2-y OS rate, %Post-landmark 3-y OS rate, %Post-landmark 4-y OS rate, %NIVO 3 mg/kg Q2W (n = 280)CR/PR, 2581636158SD, 2458352419PD, 51401384DOC 75 mg/m2 Q3W (n = 264)CR/PR, 1362382612SD, 39351872PD, 48221285aThe 6-month landmark timepoint was used to allow sufficient time for the majority of responses with NIVO to occur, while allowing meaningful time to assess OS post landmark: median time to response, 2.1 mo; 75th quartile, 3.5 mo.b% of pts alive at 6 mo. Citation Format: Julie Brahmer, Hossein Borghaei, Suresh S. Ramalingam, Leora Horn, Esther Holgado, Adam Pluzanski, Marco A. Burgio, Marina Garassino, Laura Q. Chow, Scott Gettinger, Lucio Crino, David Planchard, Charles Butts, Alexander Drilon, Joanna Wojcik-Tomaszewska, Gregory Otterson, Vinny Hayreh, Ang Li, John R. Penrod, Scott J. Antonia. Long-term survival outcomes with nivolumab (NIVO) in pts with previously treated advanced non-small cell lung cancer (NSCLC): Impact of early disease control and response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT195.

e20688 Background: The immune modulation is emerging as a key strategy in non-small cell lung cancer (NSCLC) patients management. PD-L1 has been the only biomarker validated for immunotherapy but it holds many limitations. Vimentin is one of the marker for epithelial-to-mesenchymal transition (EMT), a biological process which favors immune escape. We explored two issues: the correlation between PD-L1 and Vimentin expression in NSCLC samples and the prognostic value of PD-L1 and vimentin concordance in NSCLC patients. Methods: We collected all the NSCLC samples evaluable for both PD-L1 and Vimentin and recorded the relative available clinical and survival data, if written informed consent was present. PD-L1 and Vimentin were retrospectively assessed through immunohistochemistry (IHC) by using prediluted antibodies clones SP263 (Ventana Medical Systems, Tucson, AZ, USA) and anti Vimentin V9 (Ventana Medical Systems) on Benchmark XT Platform (Ventana Medical Systems). Biomarker expression was detected and semiquantitatively quantified as the percentage of immunopositive tumor cells on the total of tumor cells. We correlated PD-L1 and Vimentin expression through linear regression. We compared survival of patients with both PD-L1 and Vimentin 0% and all the others via Kaplan-Meier method by using MedCalc software version 18.11.3. Results: Ninety-nine samples underwent PD-L1 and Vimentin IHC analysis. A weak positive statistically significant correlation was found between the 2 biomarkers (r = 0.41; p < 0.001). For 40 patients survival data (from first NSCLC diagnosis) were available. Survival analysis showed that PD-L1 and Vimentin negative patients (n = 12) experienced not statistically significant longer survival (HR = 0.35; 95%CI: 0.08-1.51; p = 0.16). Conclusions: These preliminary findings suggest that an interplay can exist between PD-L1 and vimentin in NSCLC, but analysis in a wider population is necessary. Studies on the significance of this interplay for immunotherapy efficacy should be designed.

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.

Background - Circulating tumor cells (CTCs) are the liquid phase of a solid tumor. An advanced CTC phenotyping and genotyping procedure could allow a superior understanding of tumor heterogeneity aimed at improving personalized treatment selection. However, these investigations are hampered by the difficulty to catch and analyze CTCs. EML4-ALK chromosomal rearrangement is a fundamental marker of sensitivity in metastatic non-small cell lung cancer (mNSCLC), but conventional tissue-based ALK scrutiny is not always possible. A CTC-based ALK evaluation may be an easy and not invasive method for identifying rearrangements and hence patients eligible for specific treatments. Methods - Analyses were performed via the Gilupi CellCollector CANCER01 (DC01), a device that allows the in vivo isolation of CTCs from a high volume of peripheral blood. The DC01 is a CE-approved functionalized 16 cm long medical wire that includes a functionalized 2 cm long gold-coated tip covalently coupled with antibodies against EpCAM. The DC01 can be inserted through a standard venous cannula into the cubital vein of cancer patients for 30 minutes where it captures CTCs directly from the bloodstream of cancer patients. CTC presence was investigated in 18 mNSCLC patients and CTC-ALK-chromosomal status was studied by an innovative method, the 3D-immuno-FISH, that combined immuno-fluorescence and FISH approaches on a 3D structure (the DC01). Two DC01 per patients were utilized. After removal, on one wire, CTCs were identified and counted by nuclei, EpCAM and cytokeratins staining. On the second wire, CTCs were recognized by EpCAM staining and analyzed for ALK alterations by FISH. Formalin-fixed paraffin-embedded primary tumor tissues from the same patients were analyzed for comparison. Immortalized cell lines attached to DC01 devices were exploited as positive controls. Results - Using the DC01 it was feasible to isolate and detect CTCs. Among the 18 enrolled patients, 7 presented tumor-tissue ALK-translocation, whereas 11 were wild type. Overall, 61.1% patients were CTC positive (median CTC number, 3.0 per patient). Amid those that owned ALK-translocation, 28.6% were CTC-positive, whereas 81.8 % patient without ALK-translocation were CTC positive. ALK rearrangements were detectable directly on cells attached to the wires. However, the 3D-immuno-FISH analysis in patients was hampered by the low median number of detected CTCs. Conclusions - The detection of ALK-chromosomal rearrangements with the 3D-immuno-FISH analysis in cells recovered by DC01 was feasible. This method is valid for tracking positive CTC patients, but the few cells retrieved per patients still limit CTC full exploitation. Although further studies are needed to validate our data and to improve DC01 capture efficiency, our results pave the way to CTC-based chromosomal rearrangement identification and therapy personalization. Citation Format: Giulia Gallerani, Angelo Delmonte, Claudia Cocchi, Martine Bocchini, Filippo Piccinini, Marco Angelo Burgio, Carla Casadei, Andrea Rocca, Francesco Fabbri. Feasibility investigation of EML4-ALK rearrangements in mNSCLC CTCs using a new in vivo procedure [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 5196.

Background: Small-cell lung cancer (SCLC) is known to express antigens of both the neural crest and epithelium, and to secrete polypeptide hormones and enzymes. Anecdotal reports correlate lung cancer with marked hyperamylasemia, and a review of the literature reveals only one case of metastatic SCLC linked to high paraneoplastic lipase production. Case presentation: We present the case of a patient with metastatic SCLC who showed both lipase and pancreatic isoamylase elevation in the absence of acute pancreatitis. Chemotherapy resulted in a rapid reduction in serum lipase and in pancreatic isoamylase which was correlated with the radiological response of the tumor to therapy. Lipase and pancreatic isoamylase expression in tumor cells from the lung biopsy was confirmed by immunohistochemical staining. Conclusions: This is a very rare case of paraneoplastic syndrome linked to metastatic SCLC. The enzymes secreted could be used as markers of response to treatment until clonal selection mechanisms and intratumor heterogeneity induce changes in biochemical characteristics and consequently in tumor behavior.

Objectives Anaplastic lymphoma kinase ( ALK )-positive non-small cell lung cancer (NSCLC) is sensitive to treatment with an ALK-tyrosine kinase inhibitor (-TKI). However, the benefit of sequential treatment with a 2nd ALK-TKI in patients who fail a 1st ALK-TKI has been poorly addressed. Materials and methods We collected the data of 69 advanced ALK -positive NSCLCs who were treated with one or more ALK-TKIs at three Italian institutions. The clinical outcome of treatment with an ALK-TKI and the patterns of treatment upon failing a 1st ALK-TKI were recorded. Results Objective response rate (ORR) and median progression-free survival (PFS) on a 1st ALK-TKI (mostly crizotinib) were 60.9% and 12 months, respectively. Of the 50 patients who progressed on a 1st ALK-TKI, 22 were further treated with a 2nd ALK-TKI (either ceritinib or alectinib), for whom an ORR of 86.4% and median PFS of 7 months, respectively, were reported. Conversely, 13 patients underwent rapid clinical/radiographic disease progression leading to death shortly after discontinuation of the 1st ALK-TKI, 7 patients were managed with a 1st ALK-TKI beyond progression, and 8 patients transitioned to other systemic treatments (mostly chemotherapy). Post-progression survival (PPS) significantly favored the 22 patients who were sequentially treated with a 2nd ALK-TKI over those who transitioned to other systemic treatments ( P =0.03), but not versus those who were treated with a 1st ALK-TKI beyond progression ( P =0.89). Conclusion Sequential treatment with a 2nd ALK-TKI is effective in patients who fail a 1st ALK-TKI. Continuous ALK-inhibition upon failing a 1st ALK-TKI may be associated with improved clinical outcome.

Tyrosine kinase inhibitors (TKIs) are very efficacious in non-small-cell lung cancer (NSCLC) patients harboring activating Epidermal Growth Factor Receptor (EGFR) mutations. However, about 10% of EGFR wild type (wt) patients respond to TKI, with unknown molecular mechanisms of sensitivity. We considered a case series of 34 EGFR wt NSCLC patients responsive to erlotinib after at least one line of therapy. Responsive patients were matched with an equal number of non-responsive EGFR wt patients. A panel of 26 genes, for a total of 214 somatic mutations, was analyzed by MassARRAY® System (Sequenom, San Diego, CA, USA). A 15% KRAS mutation was observed in both groups, with a prevalence of G12C in non-responders (80% vs. 40% in responders). NOTCH1, p53 and EGFR-resistance-related mutations were found more frequently in non-responders, whereas EGFR-sensitizing mutations and alterations in genes involved in proliferation pathways were more frequent in responders. In conclusion, our findings indicate that p53, NOTCH1 and exon 20 EGFR mutations seem to be related to TKI resistance. KRAS mutations do not appear to influence the TKI response, although G12C mutation is more frequent in non-responders. Finally, the use of highly sensitive methodologies could lead to the identification of under-represented EGFR mutations potentially associated with TKI sensitivity.

9002 Background: The role of platinum in first line treatment of elderly patients with advanced NSCLC is still debated. We tested its efficacy in two parallel phase 3 trials. Methods: Advanced NSCLC patients, > 70 years, ECOG performance status 0-1, were eligible. In MILES-3 (started in 2011) patients with any tumor histology were randomly assigned 1:1 to cisplatin/gemcitabine (C 60 mg/m² d1, G 1000mg/m² dd1,8) or gemcitabine (G 1200 mg/m² dd1,8). In MILES-4 (started in 2013 with a factorial design) patients with non-squamous histology were randomly assigned 1:1:1:1 to CG, G, cisplatin/pemetrexed (C 60 mg/m² d1, P 500 mg/m² d1) or pemetrexed (P 500 mg/m² d1). Six cycles were planned. In each trial, to have 80% power in detecting a HR of death 0.75 (corresponding to 3-month prolongation of median survival), with 0.05 two-tailed α, 382 events were required. The two trials were closed prematurely because of slow accrual but a joint analysis allowed to properly perform the final analysis, according to IDMC advice. Analysis was based on intention-to treat and adjusted by possible confounding factors. Results: From Mar 2011 to Aug 2016, 531 patients (MILES-3: 299, MILES-4: 232) were assigned to cisplatin-doublet (n = 263) or single-agent chemotherapy (n = 268). Median age was 75, 79% were male, 70% had non-squamous histology. Median number of cycles was 4 and 3 with and without cisplatin, respectively. With a median follow-up of 2 years, 384 deaths and 448 progression-free survival (PFS) events were reported. With and without cisplatin, median OS was 9.6 vs 7.5 months (HR 0.86, 95% CI: 0.70-1.04, p = 0.14); median PFS was 4.6 vs 3.0 months (HR 0.76, 95% CI: 0.63-0.92, p = 0.005); response rate was 15.5% vs 8.5% (p = 0.02). Significantly more severe hematologic toxicity and fatigue were reported with cisplatin. Conclusions: Although improving PFS and response rate, addition of cisplatin to single-agent chemotherapy does not significantly prolong overall survival of elderly patients with advanced NSCLC. QOL data will be reported separately. Partially supported by AIFA (grant FARM8KAJZK) and Eli Lilly. Clinical trial information: NCT01405586 and NCT01656551.

Chemo-radiotherapy is standard treatment of stage IIIA-N2 bulky or IIIB non-small cell lung cancer (NSCLC). Surgical resection of residual disease in downstaged patients may improve overall survival. In this setting, restaging disease is still a challenge. 18F-FDG PET/CT represents the gold standard although accuracy results are disappointing. Endoscopic bronchial/ esophageal ultrasound (EBUS/EUS)-guided fine needle aspiration (FNA) may confirm lymph node (LN) involvement. We analyzed 16 patients with stage IIIA-N2 bulky or IIIB NSCLC treated with chemo-radiotherapy. At restaging, all patients performed EBUS/EUS with FNA and PET/CT scan and results were compared. Patients underwent PET/CT scan 43 days (range: 24-89) and EBUS/EUS 42 days (range: 14-71) after therapy. Overall, 7 EBUS and 9 EUS procedures were performed: no complications resulting from the procedure occurred. In 6 patients EBUS/EUS did not reveal any suspicious lesions; in 2 the exam showed enlarged mediastinal LN that were biopsied, but with no evidence of tumor cells; in 2 the sample was not considered diagnostic; 6 had persistent mediastinal LN involvement. PET/CT scan showed 4 cases of complete metabolic response, 9 partial metabolic response, 2 stable metabolic disease and one progressive metabolic disease. Notably, all 7 patients with .80% decrease in SUV with respect to basal value showed a pathological complete response or negative EBUS/EUS. EBUS/EUS could be used to complement PET/CT scanning to verify mediastinal LN clearance. Further prospective trials are warranted to confirm the utility of EBUS/EUS together with PET/CT in restaging locally advanced NSCLC.

Background: Systemic capillary leak syndrome is a rare disease with a high mortality rate. This syndrome is characterised by generalised edema, hypotension, hemoconcentration, and hypoproteinemia. The cause is the sudden onset of capillary hyperpermeability with extravasations of plasma from the intravascular to the extravascular compartment. We present the case of a patient who experienced two episodes of systemic capillary leak syndrome and pulmonary hypertension; the first after gemcitabine in an adjuvant setting and the second three years later after treatment with nab-paclitaxel for metastatic disease.Case presentation: A 65-year-old patient underwent a pancreatectomy in January 2010 for ductal carcinoma (pT3 N0 M0, stage IIa), followed by adjuvant chemotherapy. Seven days after the last cycle, she developed dyspnea associated with orthopnea and cough. A transthoracic cardiac ecocolordoppler was performed, with evidence of pulmonary hypertension (58 mmHg). Blood tests showed an increase in creatinine, pro-BNP and D-Dimer. She began high-dose diuretic therapy combined with cortisone. After a month, the patient was eupneic and the anasarca had resolved. We decided gradually to reduce the steroid and diuretic therapy. After ten days of the reduction, the patient began to re-present the same symptoms after treatment with gemcitabine. Corticosteroid therapy was restored with rapid clinical benefit and decreased pro-BNP after a week of treatment. After two years, the disease returned. As a first line treatment, it was decided to use nab-paclitaxel 100 mg/m2 weekly. After two doses, followed by approximately 14 days of treatment, the patient developed acute respiratory distress syndrome. The clinical suspicion was a relapse of capillary leak syndrome and treatment with a high-dose diuretic (furosemide 250 mg daily) was started combined with cortisone (40 mg methylprednisolone). The patient showed a progressive clinical benefit.Conclusions: In patients treated with gemcitabine and nab-paclitaxel who experience a sudden onset of diffuse edema with respiratory distress, capillary leak syndrome should be suspected. Immediate treatment with corticosteroids may be life-saving. © 2013 Casadei Gardini et al.; licensee BioMed Central Ltd.

9052Background: Patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations are usually responsive to tyrosine kinase inhibitors (TKIs). However, ab...

e20513Background: Epidermal growth factor receptor (EGFR) mutations are associated with response to tyrosine kinase inhibitors (TKIs). However, different EGFR mutations appear to have different pre...

e19149 Background: the association of venous thromboembolic events (VTE) and lung cancer has a high prevalence. Limited data are available in the adenocarcinoma subtype population especially in rel...

LBA109 Background: Options for advanced non-SQ NSCLC patients (pts) who progress after platinum-based doublet chemotherapy (PT-DC) are limited, with minimal improvement in overall survival (OS). We report results from a randomized, global phase III study of NIVO, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, vs DOC in pts with advanced non-SQ NSCLC after failure of PT-DC and tyrosine kinase inhibitor, if eligible. Methods: Pts were randomized to NIVO 3 mg/kg Q2W (n=292) or DOC 75 mg/m2 Q3W (n=290) until progression or discontinuation due to toxicity/other reasons. Primary objective was OS; Secondary objectives were investigator-assessed objective response rate (ORR; per RECIST v1.1), progression-free survival (PFS), efficacy by PD-L1 expression, quality of life, and safety. Results: NIVO demonstrated superior OS (HR=0.73; 96% CI: 0.59, 0.89; P=0.00155) and improved ORR (19.2% vs 12.4%; P=0.0235). HR for PFS was 0.92 (95% CI: 0.77, 1.11; P=0.393). PD-L1 expression was associated with benefit from NIVO (Table). In PD-L1+ pts, NIVO showed improved efficacy across all endpoints at predefined 1%, 5%, and 10% cut- points. Grade 3–5 drug-related AEs occurred in 10.5% (30/287) of NIVO and 53.7% (144/268) of DOC pts. No deaths were related to NIVO vs 1 DOC-related death. After discontinuation, 42.1% of NIVO and 49.7% of DOC pts received subsequent systemic therapy. Conclusions: NIVO demonstrated superior OS vs DOC in pts with advanced non-SQ NSCLC after failure of PT-DC. The safety profile of NIVO 3 mg/kg Q2W was favorable vs DOC. NIVO demonstrated survival benefit across histologies in two randomized phase III trials. Clinical trial information: NCT01673867. [Table: see text]

e19086 Background: Tyrosine kinase inhibitors (TKIs) are the first choice of treatment in a subset of patients with non- small cell lung cancer (NSCLC) harboring specific epidermal growth factor re...

Purpose/Objective(s): To analyze retrospectively 47 cases of malignant pleural mesothelioma (MPM) treated during the period 2008-2012 using helical tomotherapy (HT) either to confirm the role of adjuvant radiation therapy after extra-pleural pneumonectomy (EPP) or to define the role of radiation therapy after pleurectomy/decortication (P/D) or medical/surgical biopsy (B). Materials/Methods: In the Radiotherapy Department of our institute (IRCCS IRST), 47 consecutive patients with MPM (I-IV stage) were treated by HT. Thirty-six patients had previously received chemotherapy (platins and pemetrexed), 9 had undergone adjuvant radiation therapy after EPP and 38 had received definitive radiation therapy after P/D or B. Two different radiation therapy strategies and schedules were planned: (1) Adjuvant treatment after EPP: conventional fractionation schedule and 50 Gy/25 daily fractions to the hemithorax. (2) Definitive treatment after P/D or B: accelerated hypofractionation schedule and 25 Gy/5 daily fractions dose prescription at the reference isodose (60%-70% isodose) with an increasing dose of up to 37.5-40 Gy inside the gross tumor mass/masses) to the PTV (pleura) whilst maintaining the dose to the organs at risk (BED 2 Gy) below conventional fractionation values. Feasibility and toxicity were evaluated. Results: We obtained satisfactory dose distributions while also sparing organs at risk in both treatment schedules: (1) at least 95% of the dose prescription was delivered to 95% of the target volume. The median dose to the target was 51.39 Gy (range, 50.5-52.2 Gy) for conventional fractionation and 29 Gy (range, 26.7-30 Gy) for the hypofractionated schedule; (2) at least 5 Gy covered less than 5% of the controlateral lung volume with an average dose lower than 4 Gy in both treatment schedules; and (3) one-third intact lung volume of the homolateral pleural tumor received 10 Gy/5 daily fractions with the accelerated hypofractionation schedule. We closely adhered to normal tissue constraints relative to the IMRT treatment in order to compare DVHs. Conclusions: Our results indicate the usefulness/efficacy of helical tomotherapy for patients who have already undergone extrapleural/pneumonectomy and also for those submitted to P/D or biopsy using an accelerated hypofractionated schedule. No heavy functional injuries were recorded for either treatment schedule. A study is ongoing to treat patients with accelerated hypofractionated radiation therapy after P/D using tomotherapy. Author Disclosure: E. Parisi: None. A. Romeo: None. G. Ghigi: None. M. Burgio: None. E. Neri: None. M. Taurchini: None. M. Romagnoli: None. A. Sarnelli: None. C. Arienti: None. R. Polico: None.

e18052 Background: Non Small Cell Lung Cancer (NSCLC) accounts for almost 80% of all lung malignancies, and 40% of these patients go on to develop brain metastases (BM). Furthermore, there are no g...

e19591 Background: Chronic cancer pain (CCP) is present in 50% of cancer patients at any stage of disease and in 70% of those in an advanced setting. Preliminary results have shown the effectivenes...

e17546 Background: Thymic epithelial tumors (TETs) consist of a series of neoplasm arising from the anterior mediastinum. Due to its rarity, large-scale prospective trials have been lacking. This retrospective multicenter analysis aimed to evaluate clinical outcome and clinico-pathological features of TETs after surgery resection and adjuvant treatments as chemotherapy and/or radiotherapy. Methods: All medical records about TETs surgically resected between 2000 and 2007 and eventually treated with adjuvant therapies (chemotherapy and/or radiotherapy) were reported. Surgical procedures included complete removal of thymic, mediastinal fat tissue and any suspicious lesions. Histological classification has been made in according to WHO criteria and Masaoka staging system was adopted. Adjuvant chemotherapy was represented by anthracycline and platin-based regimen whereas adjuvant radiotherapy was delivered on irradiation field covered primary tumor bed. Overall survival was calculated from the date of diagnosis until patient death or last follow-up visit. Disease free-survival was defined the interval from operation until date of recurrence. Results: Overall 32 patients were analyzed of whom 12 (37%) male and 20 (63%) female. Median age was 61 years (range: 33 - 86). At the beginning of their oncologic history 14 (42%) patients had miastenia. Overall at clinical staging there were 19 (60%) stage I, 4 (12%) stage II, 4 (12%) stage III, and 5 (16%) stage IVb at radiological staging. The histological exam reported: 5 (16%) A tumor type, 11 (34%) AB type, 3 (10%) B1 type, 3 (10%) B2 type, 8 (24%) B3 type, 2 (6%) C type. At pathological staging there were: 18 (56%) stage I, 7 (22%) stage II, 2 (6%) stage III and 5 (16%) stage IVb. Post-surgical therapies were represented by chemotherapy in 2 (6%) patients and radiotherapy in 13 (41%) patients. Disease relapse was recorded in 1 (3%) patient after 27 months from diagnosis. Overall survival rate at 78 months is 86% (CI: 66-100). Conclusions: TETs are rare and indolent cancer. Surgery offers the good perspectives eventually improved with adjuvant therapies like chemotherapy and/or radiotherapy. Supported by GIPO.

(50% drop, 75% drop, @ 3 cutoffs) was the same in the 2 dose groups. Median survival was 50 months for the entire cohort, with a 2& 5year survival of 88%, 65%. DE-RT pts have not yet achieved median survival. The 2-year DFS was 70% (37 mo median DFS). None of the factors including RT dose, T down staging, MNC, different cut off points for SUV drop were significant for outcomes on DFS, OS. At last follow-up, 17 pts (46%) were free of disease and 14 alive (38%). Conclusions: RT dose escalation resulted in improvement in MNC and correlated with the PET response in our series. Long-term follow-up and larger pt numbers are needed for the DE-RT pts to prove the concept. PET response can be utilized as predictor of outcomes in operable NSCLC pts. Author Disclosure: A. Turaka: None. S. Hasan: None. T. Li: None. R. Mehra: None. W.J. Scott: None. J.Q. Yu: None.

e18561 Background: Response and duration to initial chemotherapy are important factors used to classify SCLC patients into two groups. The first group comprises sensitive disease that responds to initial chemotherapy and relapses after more than 3 months and for which disease control could be obtained by re-challenging with first-line chemotherapy. The second group comprises refractory disease that progresses at the end or within 3 months of finishing first-line chemotherapy and for whom second-line chemotherapy represents the gold-standard. Methods: We reviewed clinical data from 4 Oncology Departments on sensitive SCLC treated with a first-line chemotherapy re-challenge in order to evaluate its activity and efficacy. Results: Of 211 SCLC patients diagnosed from January 2007 to December 2011, 25 (12%; 20 males, 5 females) had sensitive disease of whom 13 (52%) limited disease (LD) and 12 (48%) extended disease (ED). Median interval between the last day of chemotherapy and the onset of disease progression was 205 days (95% CI 169 – 279; range: 90 – 665). Chemotherapy consisted of etoposide + carboplatin in 15 (60%) patients or cisplatin in 10 (40%). On average 3-4 (range: 1-6) chemotherapy courses were administered, producing 8 (32%) partial responses, 3 (12%) stable disease, 10 (40%) progressive disease and 4 (16%) non evaluable disease. Further-line chemotherapy, mainly topotecan, was administered in 13 (52%) patients. Median overall survival produced by all treatments was 19.6 months (95% CI 16.5 – 27.6). Conclusions: In our experience, sensitive SCLC treated with first-line platinum/etoposide re-challenge produced interesting results in terms of activity and efficacy. Prospective randomized trials are warranted to investigate whether this strategy produces better results than standard second-line chemotherapy.

7600 Background: Rechallenge might be used as rescue therapy in progressing platinum-sensitiveSmall Cell Lung Cancer (SCLC). This international multicenter retrospective analysis evaluates the clin...