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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 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.

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.

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.

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.

Purpose thymic epithelial tumors (TETs) are a rare neoplasms. Due to their rarity, large-scale prospective trials are lacking. The present retrospective multicenter analysis aimed to evaluate clinical outcome and clinical-pathological features of TETs after complete surgical resection and adjuvant treatments (Adj) such as chemotherapy (CHT) or radiotherapy (RT). Patients and methods Patients who underwent a complete surgical resections for TETs between 2000 and 2007 were reviewed. WHO histological classification criteria and Masaoka staging system were used. Adj were: anthracycline- and platin-based CHT, RT on irradiation fields covering the primary tumor bed. Overall survival (OS) was calculated from the date of diagnosis until patient death or last follow-up visit. Disease free-survival (DFS) was defined as the interval between surgery and date of first documentation of recurrence. OS, DFS and 95% Confidence Interval (95% CI) were estimated by Kaplan-Meier method. Results 62 patients were analyzed: 30 patients (48%) male and 32 (52%) female. Median age was 60 years (range: 33 - 86). At the beginning of their cancer history 20 (32%) patients had myasthenia. Clinical staging showed: 31 (50%) stage I disease, 19 (30%) stage II, 5 (8%) stage III, 2 (4%) stage IVa, 5 (8%) stage IVb. Histologies were: 11 (19%) A tumor type, 18 (29%) AB type, 7 (12%) B1 type, 11 (17%) B2 type, 11 (17%) B3 type and 3 (6%) C type. Pathological staging were: 30 (48%) stage I, 22 (35%) stage II, 3 (6%) stage III, 2 (3%) stage IVa, 5 (8%) stage IVb. 3 (5%) patients received Adj-CHT and 16 (26%) Adj-RT. Median follow-up was 71 months (range 1-145), DFS and OS are the following: % DFS (95% CI) % OS (95% CI) Events 48 mo 60 o0 72 mo Events 48 mo 60 mo 72 mo 9 89 (80-97) 89 (80-97) 86 (76-96) 7 97 (92-100) 95 (88-100) 92 (85-100) mo, months. Conclusions TETs are rare and indolent tumors. Surgery offers good results which can be further improved by Adj such as CHT and/or RT. Supported by GIPO. Disclosure All authors have declared no conflicts of interest.

Aim: In the TORCH trial, molecularly unselected pts with advanced NSCLC were randomized to erlotinib (E) or cisplatin + gemcitabine (CG) as first line within planned treatment sequences. Several biomarkers were studied with exploratory aim. Here we report cMET and PTEN data. Methods: cMET and PTEN immunohistochemistry (IHC) was performed using standard method and SP44 (Ventana) and 138G6 (Cell Signaling) antibodies, respectively. H-score (intensity x % stained tumor cells) was used to classify cMET IHC ( Results: PTEN was positive in 118 pts (80%). PTEN showed no significant interaction with treatment and did not vary between EGFR mut+ and wildtype (wt). cMET was high in 92 pts (59%). As for PFS, HR (E vs CG) was 1.22 (95% CI 0.71-2.07) in cMET low and 2.81 (95% CI 1.79 – 4.41) in cMET high (interaction p = 0.013); in the E arm, HR for cMET low vs cMET high pts was 0.45 (95% CI 0.27-0.74). Response rate (RR) to E/CG was 21%/17% in cMET low vs 0%/24% in cMET high (interaction p = 0.005). The RR difference within the E arm was statistically significant (p = 0.002). cMET was high in 76% (16/21) of EGFR mut+ pts and 58% (76/132) of EGFR wildtype (wt) pts (p = 0.11). Among EGFR wt pts, PFS HR (E vs CG) was 1.65 (95% CI 0.95-2.89) in cMET low and 3.25 (95% CI 1.95 – 5.42) in cMET high (interaction p = 0.07). In the E arm, HR for cMET low vs cMET high was 0.49 (95% CI 0.29-0.83). RR to E/CG was 14%/19% in cMET low vs 0%/21% in cMET high (interaction 0.07). The RR difference within the E arm was statistically significant (p = 0.03). Numbers were too small to test interaction in EGFR mut+ pts. Conclusions: In pts unselected for EGFR mutation and in those with EGFR wt, the relative effect on PFS of E vs CG is less worse among low cMET cases. Objective responses to first line E were only reported among low cMET cases, even if EGFR wt. Disclosure: M. Tsao: received honoraria on this subject matter from: Roche, AstraZeneca, and received a research grant from Roche; M. Di Maio: acted as consultant or advisory role for Eli Lilly and received honoraria from Eli Lilly and Roche; A. Rossi, P. Maione and C. Gridelli: acted as consultant for Eli Lilli, Roche and received honoraria from Eli Lilli, Roche; C.A. Butts: acted as consultant for Roche and received honoraria from Roche; R. Feld: acted as consultant for Roche, received honoraria from Roche and received a research grant from Roche; F. Perrone: received honoraria from Roche and received a research funding from Roche. All other authors have declared no conflicts of interest.

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.