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Adding bevacizumab to erlotinib prolonged progression-free survival (PFS) of patients with EGFR-mutated advanced NSCLC in the Japanese JO25567 trial, but limited data were available in non-Asian patients. BEVERLY is an Italian, multicenter, randomized, phase 3 investigating the addition of bevacizumab to erlotinib as first-line treatment of advanced EGFR-mutated NSCLC.Eligible patients were randomized 1:1 to erlotinib plus bevacizumab or erlotinib alone. Investigator-assessed PFS and blinded independent centrally reviewed PFS were coprimary end points. With 80% power in detecting a 0.60 hazard ratio and two-sided α error of 0.05, 126 events of 160 patients were needed. The trial was registered as NCT02633189 and EudraCT 2015-002235-17.From April 11, 2016, to February 27, 2019, a total of 160 patients were randomized to erlotinib plus bevacizumab (80) or erlotinib alone (80). At a median follow-up of 36.3 months, median investigator-assessed PFS was 15.4 months (95% confidence interval [CI]: 12.2-18.6) with erlotinib plus bevacizumab and 9.6 months (95% CI: 8.2-10.6) with erlotinib alone (hazard ratio = 0.66, 95% CI: 0.47-0.92). Blinded independent centrally reviewed PFS analysis confirmed this result. A statistically significant interaction with treatment effect was found for smoking habit (p = 0.0323), with PFS prolongation being clinically significant only among current or previous smokers. Hypertension (grade ≥3: 24% versus 5%), skin rash (grade ≥ 3: 31% versus 14%), thromboembolic events (any grade: 11% versus 4%), and proteinuria (any grade: 23% versus 6%) were more frequent with the combination.The addition of bevacizumab to first-line erlotinib prolonged PFS in Italian patients with EGFR-mutated NSCLC; toxicity was increased with the combination but without unexpected safety issues.

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.

Summary Background Phase 3 clinical data has shown higher proportions of patients with objective response, longer response duration, and longer overall survival with nivolumab versus docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC). We aimed to evaluate the long-term benefit of nivolumab and the effect of response and disease control on subsequent survival. Methods We pooled data from four clinical studies of nivolumab in patients with previously treated NSCLC (CheckMate 017, 057, 063, and 003) to evaluate survival outcomes. Trials of nivolumab in the second-line or later setting with at least 4 years follow-up were included. Comparisons of nivolumab versus docetaxel included all randomised patients from the phase 3 CheckMate 017 and 057 studies. We did landmark analyses by response status at 6 months to determine post-landmark survival outcomes. We excluded patients who did not have a radiographic tumour assessment at 6 months. Safety analyses included all patients who received at least one dose of nivolumab. Findings Across all four studies, 4-year overall survival with nivolumab was 14% (95% CI 11–17) for all patients (n=664), 19% (15–24) for those with at least 1% PD-L1 expression, and 11% (7–16) for those with less than 1% PD-L1 expression. In CheckMate 017 and 057, 4-year overall survival was 14% (95% CI 11–18) in patients treated with nivolumab, compared with 5% (3–7) in patients treated with docetaxel. Survival subsequent to response at 6 months on nivolumab or docetaxel was longer than after progressive disease at 6 months, with hazard ratios for overall survival of 0·18 (95% 0·12–0·27) for nivolumab and 0·43 (0·29–0·65) for docetaxel; for stable disease versus progressive disease, hazard ratios were 0·52 (0·37–0·71) for nivolumab and 0·80 (0·61–1·04) for docetaxel. Long-term data did not show any new safety signals. Interpretation Patients with advanced NSCLC treated with nivolumab achieved a greater duration of response compared with patients treated with docetaxel, which was associated with a long-term survival advantage. Funding Bristol-Myers Squibb.

Background: Lung cancer is a complex disease with many subtypes. However, histochemical characteristics, and genetic mutation determinations are contributing to better define therapeutic targets and new drugs. Although this guarantees patients the possibility of obtaining tailored treatment, it makes it more difficult for clinicians patient management more difficult for clinicians who have to define the most suitable therapeutic strategy and to deal with new treatment-related adverse events (TRAEs). It has been seen that the administration of a tyrosine kinase inhibitor (TKI) sequential to an immune checkpoint inhibitor (ICI) can lead to a higher rate of severe and life-threatening TRAEs. We report the case of a patient with advanced non-small cell lung cancer (NSCLC) who experienced severe hepatotoxicity and Stevens-Johnson syndrome (SJS) induced by osimertinib sequential to pembrolizumab.Case presentation: A 54-year-old woman with advanced NSCLC received one cycle of chemotherapy plus pembrolizumab after diagnosis. Ten days later she began osimertinib 80 mg daily because epidermal growth factor receptor (EGFR) analysis had revealed an exon 19 deletion. On day 23 of osimertinib the patient experienced an episode of grade (G) 3 hepatotoxicity resolved by discontinuing osimertinib and corticosteroid therapy. The patient restarted osimertinib 80 mg daily after the remission of symptoms but was hospitalized 14 days later following a second episode of severe G3 hepatotoxicity and the onset of SJS, successfully treated with high-dose corticosteroids. Despite the short exposure to osimertinib, the patient obtained a good pathological response.Conclusion: It is important to alert clinicians to carefully evaluate the sequential therapeutic strategy in patients with NSCLC who are candidates for TKI- or ICI-based treatment. Our experience suggests that the use of tyrosine kinase inhibitors (TKIs) as front-line treatment is a more reasonable and safe option for EGFR-mutated lung adenocarcinoma, with ICIs considered as a possible further treatment in sequential approaches.

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...

Background Concurrent chemotherapy and radiation using conventional fractionation is the standard treatment for inoperable, locally advanced non-small-cell lung cancer (NSCLC). We tested accelerated hypofractionated radiotherapy (AHR) and chemotherapy for the treatment of locally advanced NSCLC. Methods Eligible patients with locally advanced NSCLC were treated with induction chemotherapy (cisplatin and docetaxel), followed by AHR using tomotherapy and consolidation chemotherapy. The prescribed doses were 30 Gy/5 daily fractions at the reference isodose (60–70%) to the tumor, and 25 Gy/5 daily fractions to the clinically involved lymph nodes. The primary end-point was response rate (RR); the secondary end-points were acute and late side-effects, local progression-free survival (PFS), metastasis-free survival (MFS) and overall survival (OS). This trial closed before the first planned interim analysis due to poor accrual. Results From January 2009 to January 2012, 17 of the 23 enrolled patients were evaluable. Treatment yielded an overall RR of 82%. Median follow-up was 87 months (range: 6–87), local PFS was 19.8 months (95% CI 9.7 - not reached), MFS was 9.7 months (95% CI 5.8–46.0) and OS was 23 months (95% CI 8.4–48.4). 70% of patients experienced acute G4 neutropenia, 24% G4 leukopenia, 24% G3 paresthesia, 4% G3 cardiac arrythmia, 4% underwent death after chemotherapy. Late toxicity was represented by 24% dyspnea G3. Conclusions AHR combined with chemotherapy is feasible with no severe side-effects, and it appears highly acceptable by patients. Trial registration This study is registered with the EudractCT registration 2008-006525-14. Registered on 9 December 2008.

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.

Anaplastic lymphoma kinase (ALK) gene translocations are pro-tumoral driver alterations that encompass 3–7% of non-squamous non-small cell lung cancer (NSCLC) with specific, clinic and histologic features. The therapeutic strategy depends on anti-ALK tyrosine kinase inhibitors (TKIs) of which crizotinib was the first approved for clinical use. Despite its use improved significantly progression-free survival, overall response rate and duration of response of this illness, after a median period of 10.9 months all patients progress due to the development of acquired resistance mutations in the ALK tyrosine kinase domain in approximately one third of patients. Moreover, 60–90% of patients treated with crizotinib has a progression in the central nervous system (CNS) in absence of extracranial worsening of the disease. This is primarily attributed to poor CNS penetration by crizotinib as many pre-clinical and clinical models suggest. For instance, in order to overtake acquired resistance to crizotinib, prolong the control of the disease and manage CNS localizations, several II and III generation TKIs have been developed. Some of them were approved after the failure of crizotinib (ceritinib, alectinib, brigatinib and lorlatinib) and in first line setting (ceritinib, alectinib and brigatinib) while others are still under evaluation for TKI-naive patients such as lorlatinib, ensartinib and entrectinib. In this review we will discuss the most recent results of new TKIs in order to describe a fast growing therapeutic landscape in this setting.

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.

Background Long-term data with immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are limited. Two phase III trials demonstrated improved overall survival (OS) and a favorable safety profile with the anti-programmed death-1 antibody nivolumab versus docetaxel in patients with previously treated advanced squamous (CheckMate 017) and nonsquamous (CheckMate 057) NSCLC. We report results from ≥3 years’ follow-up, including subgroup analyses of patients with liver metastases, who historically have poorer prognosis among patients with NSCLC. Patients and methods Patients were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks) until progression or discontinuation. The primary end point of each study was OS. Patients with baseline liver metastases were pooled across studies by treatment for subgroup analyses. Results After 40.3 months’ minimum follow-up in CheckMate 017 and 057, nivolumab continued to show an OS benefit versus docetaxel: estimated 3-year OS rates were 17% [95% confidence interval (CI), 14% to 21%] versus 8% (95% CI, 6% to 11%) in the pooled population with squamous or nonsquamous NSCLC. Nivolumab was generally well tolerated, with no new safety concerns identified. Of 854 randomized patients across both studies, 193 had baseline liver metastases. Nivolumab resulted in improved OS compared with docetaxel in patients with liver metastases (hazard ratio, 0.68; 95% CI, 0.50–0.91), consistent with findings from the overall pooled study population (hazard ratio, 0.70; 95% CI, 0.61–0.81). Rates of treatment-related hepatic adverse events (primarily grade 1–2 liver enzyme elevations) were slightly higher in nivolumab-treated patients with liver metastases (10%) than in the overall pooled population (6%). Conclusions After 3 years’ minimum follow-up, nivolumab continued to demonstrate an OS benefit versus docetaxel in patients with advanced NSCLC. Similarly, nivolumab demonstrated an OS benefit versus docetaxel in patients with liver metastases, and remained well tolerated. Clinical trial registration CheckMate 017: NCT01642004; CheckMate 057: NCT01673867.

Purpose The role played by radiation therapy after pleurectomy/decortication or surgical biopsy in malignant pleural mesothelioma is uncertain. We treated patients with accelerated hypofractionated radiotherapy using helical tomotherapy and intensity-modulated arc therapy in an attempt to keep lung toxicity to a minimum. The present study reports the feasibility and toxicity of this approach. Material and Methods Between 2008 and 2012, 36 patients with malignant pleural mesothelioma underwent accelerated hypofractionated radiotherapy to the hemithorax after pleurectomy/decortication (19 patients) or biopsy (17 patients). The prescription dose was 25 Gy in five fractions over 5 consecutive days. Results We observed three patients with G3 pneumonitis, five cases of grade 2 dyspnea and six cases of grade 2 cough. The median follow-up was 37 months (range: 3–54 months). The median overall survival for patients who underwent pleurectomy/decortication followed by radiotherapy was 21.6 months [95% confidence interval (95% CI): 15.5–24.1] compared to 19.4 months for patients not submitted to surgery. Conclusion Treatment of intact lung with pleural intensity-modulated arc irradiation in malignant pleural mesothelioma patients with malignant pleural mesothelioma proved safe and feasible, with an acceptable rate of pneumonitis. Survival rates were encouraging for both biopsy-only and pleurectomy/decortication groups. We are currently conducting a phase II dose escalation trial in a similar patient setting to prospectively evaluate the impact of radiotherapy on toxicity, disease-free survival and overall survival.

// Lucia Kim 1,12,* , Mauro Saieg 1,13,* , Massimo Di Maio 2,14,* , Ciro Gallo 3,* , Charles Butts 4 , Fortunato Ciardiello 5 , Ronald Feld 6 , Dengxiao Cheng 6 , Vittorio Gebbia 7 , Marco Angelo Burgio 8 , Yasmin Alam 9 , Simona Signoriello 3 , Antonio Rossi 10 , Natasha Leighl 6 , Paolo Maione 10 , Alessandro Morabito 2 , Geoffrey Liu 6,** , Ming-Sound Tsao 1,** , Francesco Perrone 2,** and Cesare Gridelli 10,11,** 1 Department of Pathology, University Health Network, Princess Margaret Cancer Center and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada 2 National Cancer Institute, G. Pascale Foundation, IRCCS, Naples, Italy 3 Department of Mental Health and Preventive Medicine, Chair of Statistics, Second University of Naples, Naples, Italy 4 Medical Oncology, Cross Cancer Institute, Edmonton, Canada 5 Medical Oncology, Second University, Naples, Italy 6 Division of Hematology and Oncology, Princess Margaret Cancer Centre and Department of Medicine, University of Toronto, Toronto, Canada 7 Medical Oncology, Casa di Cura La Maddalena, Palermo, Italy 8 Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola, Italy 9 Medical Oncology, Windsor Regional Cancer Centre, Windsor, Canada 10 Department of Oncology/Hematology, Division of Medical Oncology, “S.G. Moscati” Hospital, Avellino, Italy 11 On behalf of the TORCH Investigators 12 Department of Pathology, Inha University School of Medicine, Incheon, South Korea 13 Santa Casa Medical School, Sao Paulo, SP, Brazil 14 University of Turin, Turin, Italy * Co-first author ** Co-last author Correspondence to: Cesare Gridelli, email: // Keywords : NSCLC, EGFR TKI, biomarker analysis, predictive factors, prognostic factors Received : November 09, 2016 Accepted : February 01, 2017 Published : February 25, 2017 Abstract Background: The TORCH phase III trial compared the efficacy of first-line erlotinib followed by chemotherapy at progression (experimental arm) with the reverse sequence (standard arm) in unselected advanced non-small cell lung cancer (NSCLC) patients. Here we report biomarker analyses. Methods: EGFR and KRAS mutation, expression of EGFR family members and of cMET and PTEN and EGFR and ABCG2 germline polymorphisms were tested on tumor tissue or blood samples to either confirm previously proposed predictive role or describe it in an explorative setting. Progression-free survival (PFS) was the primary end-point, overall survival, response rate and side effects (diarrhoea and skin toxicity) were secondary end-points. Interactions between biomarkers and treatment were studied with multivariable models (either Cox model or logistic regression). Statistical analyses accounted for multiple comparisons. Results: At least one biomarker was assessed in 324 out of 760 patients in the TORCH study. EGFR mutation was more common in female ( P = 0.0001), East Asians ( P < 0.0001) and never smoker ( P < 0.0001) patients; low MET protein expression by IHC (H-score

Introduction Historiquement, la survie des patients atteints de CBNPC avance etait mediocre, avec des taux a 5 ans Methodes Les patients (n = 854 ; CM 017/057 regroupes) atteints d’un CBNPC avance, avec un ECOG PS ≤ 1 et dont la maladie avait progresse pendant ou apres une premiere ligne de chimiotherapie ont ete randomises 1 :1 pour recevoir nivolumab 3 mg/kg toutes les 2 semaines ou docetaxel 75 mg/m2 toutes les 3 semaines jusqu’a progression ou toxicite inacceptable. La SG etait le critere principal d’evaluation pour les deux etudes. Resultats A 5 ans de suivi, 50 patients dans le bras nivolumab et 9 patients dans le bras docetaxel etaient en vie. Les caracteristiques initiales des survivants a 5 ans dans les deux bras etaient similaires a celles de la population globale et a celles des patients ayant survecu Conclusion Les CM 017 et CM 057 sont les premiers essais de phase III a rapporter les resultats a 5 ans d’un anti-PD1 dans le CBNPC avance prealablement traite et font etat d’une augmentation de plus de 4 fois des taux de SG a 5 ans avec nivolumab (13 %) par rapport au docetaxel (3 %). Le traitement par nivolumab reste bien tolere, sans nouveau signal de toxicite.

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.

Background Small-cell lung cancer (SCLC) may express somatostatin transmembrane receptors (SSTRs) in 50-75% of cases. We evaluated the accuracy and prognostic significance of somatostatin receptor scintigraphy (SSRS) in staging compared with conventional radiological procedures. Patients and methods Newly diagnosed SCLC patients underwent scintigraphy with the radiolabeled somatostatin analog indium-111 (In)-pentetreotide (OctreoScan). Histological data were available for 20 (38%) patients for immunohistochemical analysis of SSTR-2 expression. Results From May 2007 to December 2011 we analyzed 52 SCLC patients. In comparison with standard radiologic staging, the sensitivity and specificity of SSRS were 63 and 100% for primary pulmonary tumor (T), 51 and 100% for mediastinal lymph node (N), and 23 and 91% for metastatic disease (M), respectively. The overall SSRS accuracy was 65% for T, 62% for N, and 52% for M. Patients with positive SSRS achieved a disease control rate of 97 versus 84% in those with negative exam results; median progression-free survival was 9.5 months versus 11.0 and median overall survival was 15.3 versus 14.5 months for patients with positive SSRS versus those with a negative result. Notably, seven (78%) patients with a positive quantitative analysis for SSTR-2 had a positive SSRS; at semiquantitative analysis this correlation was found in eight (73%) patients. Conclusion SSRS has a lower accuracy in comparison with standard radiological staging in SCLC. However, patients with a positive SSRS given standard treatments showed better disease control compared with those with a negative SSRS, but similar progression-free survival and overall survival.

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 The TORCH phase III trial compared the efficacy of first-line erlotinib followed by chemotherapy at progression (experimental arm) with the reverse sequence (standard arm) in unselected advanced non-small cell lung cancer (NSCLC) patients. Here we report biomarker analyses. Methods EGFR and KRAS mutation, expression of EGFR family members and of cMET and PTEN and EGFR and ABCG2 germline polymorphisms were tested on tumor tissue or blood samples to either confirm previously proposed predictive role or describe it in an explorative setting. Progression-free survival (PFS) was the primary end-point, overall survival, response rate and side effects (diarrhoea and skin toxicity) were secondary end-points. Interactions between biomarkers and treatment were studied with multivariable models (either Cox model or logistic regression). Statistical analyses accounted for multiple comparisons. Results At least one biomarker was assessed in 324 out of 760 patients in the TORCH study. EGFR mutation was more common in female (P = 0.0001), East Asians (P < 0.0001) and never smoker (P < 0.0001) patients; low MET protein expression by IHC (H-score

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.

Purpose: Talc pleurodesis (TP) is employed worldwide for the management of persistent pneumothorax or pleural effusion, particularly of malignant origin. However, there are very little available data on 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (18F FDG PET/CT) response evaluation in malignant pleural mesothelioma (MPM) patients treated with TP and chemotherapy.Methods: Patients with histologically confirmed MPM underwent TP and FDG PET/CT staging and restaging after 3-4 courses of chemotherapy. All patients fasted and received a dose of 5.18 MBq 18F-FDG per kilogram of body weight. Whole-body emission scans were acquired with and without Ordered Subset Expectation Maximization (OSEM) iterative reconstruction algorithm.Results: From January 2004 to March 2010, 8 patients with biopsy confirmed MPM (7 epithelial, 1 biphasic), with a median age of 65 years (range: 54-77), were evaluated. Median follow-up was 31 months (range: 4-44). After TP treatment, there was a mean interval of 14 days (range: 9-22) and 125 days (range: 76-162) between FDG PET/CT staging and restaging. According to modified RECIST and EORTC criteria, there was a concordance between the radiologic and metabolic SUVmean and SUVmax responses in 6 (75%) and 3 (37.5%) patients, respectively.Conclusion: TP produces an increased FDG PET uptake which may interfere with the post-chemotherapy disease evaluation. In our case series, the metabolic response measured by SUVmean seems to be in better agreement with the radiologic response compared to the SUVmax.

Purpose: Talc pleurodesis (TP) is employed worldwide for the management of persistent pneumothorax or pleural effusion, particularly of malignant origin. However, there are very little available data on 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (18F FDG PET/CT) response evaluation in malignant pleural mesothelioma (MPM) patients treated with TP and chemotherapy. Methods: Patients with histologically confirmed MPM underwent TP and FDG PET/CT staging and restaging after 3-4 courses of chemotherapy. All patients fasted and received a dose of 5.18 MBq 18F-FDG per kilogram of body weight. Whole-body emission scans were acquired with and without Ordered Subset Expectation Maximization (OSEM) iterative reconstruction algorithm. Results: From January 2004 to March 2010, 8 patients with biopsy confirmed MPM (7 epithelial, 1 biphasic), with a median age of 65 years (range: 54-77), were evaluated. Median follow-up was 31 months (range: 4-44). After TP treatment, there was a mean interval of 14 days (range: 9-22) and 125 days (range: 76-162) between FDG PET/CT staging and restaging. According to modified RECIST and EORTC criteria, there was a concordance between the radiologic and metabolic SUVmean and SUVmax responses in 6 (75%) and 3 (37.5%) patients, respectively. Conclusion: TP produces an increased FDG PET uptake which may interfere with the post-chemotherapy disease evaluation. In our case series, the metabolic response measured by SUVmean seems to be in better agreement with the radiologic response compared to the SUVmax.

Despite state-of-the-art therapeutic strategies for pain, some types of chronic pain remain difficult to treat. We evaluated the effectiveness of an innovative neuromodulative approach to the treatment of chronic pain using electrical stimulus integrated with pharmacological support. The MC5-A Calmare© is a new device for patient-specific cutaneous electrostimulation which, by “scrambling” pain information with “no pain” information, aims to reduce the perception of pain intensity. We prospectively treated 73 patients with cancer- (40) and non-cancer-related (33) pain whose pain management was unsatisfactory. The primary objective of the study was to assess efficacy and tolerability of the device. Pain intensity was assessed daily with a Numerical Rating Scale (NRS) for the duration of treatment (2 weeks) and then on a weekly basis for the 2 weeks of follow-up. Mean pain value at T0 (pre-treatment value) was 6.2 [±2.5 SD (standard deviation)], 1.6 (±2.0) (p