Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial.

BACKGROUND: Pleural mesothelioma usually presents at an advanced, incurable stage. Chemotherapy with platinum-pemetrexed is a standard treatment. We hypothesised that the addition of pembrolizumab to platinum-pemetrexed would improve overall survival in patients with pleural mesothelioma. METHODS: We did this open-label, international, randomised phase 3 trial at 51 hospitals in Canada, Italy, and France. Eligible participants were aged 18 years or older, with previously untreated advanced pleural mesothelioma, with an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) to intravenous chemotherapy (cisplatin [75 mg/m2] or carboplatin [area under the concentration-time curve 5-6 mg/mL per min] with pemetrexed 500 mg/m2, every 3 weeks for up to 6 cycles), with or without intravenous pembrolizumab 200 mg every 3 weeks (up to 2 years). The primary endpoint was overall survival in all randomly assigned patients; safety was assessed in all randomly assigned patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02784171, and is closed to accrual. FINDINGS: Between Jan 31, 2017, and Sept 4, 2020, 440 patients were enrolled and randomly assigned to chemotherapy alone (n=218) or chemotherapy with pembrolizumab (n=222). 333 (76 %) of patients were male, 347 (79%) were White, and median age was 71 years (IQR 66-75). At final analysis (database lock Dec 15, 2022), with a median follow-up of 16·2 months (IQR 8·3-27·8), overall survival was significantly longer with pembrolizumab (median overall survival 17·3 months [95% CI 14·4-21·3] with pembrolizumab vs 16·1 months [13·1-18·2] with chemotherapy alone, hazard ratio for death 0·79; 95% CI 0·64-0·98, two-sided p=0·0324). 3-year overall survival rate was 25% (95% CI 20-33%) with pembrolizumab and 17% (13-24%) with chemotherapy alone. Adverse events related to study treatment of grade 3 or 4 occurred in 60 (27%) of 222 patients in the pembrolizumab group and 32 (15%) of 211 patients in the chemotherapy alone group. Hospital admissions for serious adverse events related to one or more study drugs were reported in 40 (18%) of 222 patients in the pembrolizumab group and 12 (6%) of 211 patients in the chemotherapy alone group. Grade 5 adverse events related to one or more drugs occurred in two patients on the pembrolizumab group and one patient in the chemotherapy alone group. INTERPRETATION: In patients with advanced pleural mesothelioma, the addition of pembrolizumab to standard platinum-pemetrexed chemotherapy was tolerable and resulted in a significant improvement in overall survival. This regimen is a new treatment option for previously untreated advanced pleural mesothelioma. FUNDING: The Canadian Cancer Society and Merck & Co.

The Molecular Tumor Board of the Regina Elena National Cancer Institute: from accrual to treatment in real-world.

BACKGROUND: Molecular Tumor Boards (MTB) operating in real-world have generated limited consensus on good practices for accrual, actionable alteration mapping, and outcome metrics. These topics are addressed herein in 124 MTB patients, all real-world accrued at progression, and lacking approved therapy options. METHODS: Actionable genomic alterations identified by tumor DNA (tDNA) and circulating tumor DNA (ctDNA) profiling were mapped by customized OncoKB criteria to reflect diagnostic/therapeutic indications as approved in Europe. Alterations were considered non-SoC when mapped at either OncoKB level 3, regardless of tDNA/ctDNA origin, or at OncoKB levels 1/2, provided they were undetectable in matched tDNA, and had not been exploited in previous therapy lines. RESULTS: Altogether, actionable alterations were detected in 54/124 (43.5%) MTB patients, but only in 39 cases (31%) were these alterations (25 from tDNA, 14 from ctDNA) actionable/unexploited, e.g. they had not resulted in the assignment of pre-MTB treatments. Interestingly, actionable and actionable/unexploited alterations both decreased (37.5% and 22.7% respectively) in a subset of 88 MTB patients profiled by tDNA-only, but increased considerably (77.7% and 66.7%) in 18 distinct patients undergoing combined tDNA/ctDNA testing, approaching the potential treatment opportunities (76.9%) in 147 treatment-naïve patients undergoing routine tDNA profiling for the first time. Non-SoC therapy was MTB-recommended to all 39 patients with actionable/unexploited alterations, but only 22 (56%) accessed the applicable drug, mainly due to clinical deterioration, lengthy drug-gathering procedures, and geographical distance from recruiting clinical trials. Partial response and stable disease were recorded in 8 and 7 of 19 evaluable patients, respectively. The time to progression (TTP) ratio (MTB-recommended treatment vs last pre-MTB treatment) exceeded the conventional Von Hoff 1.3 cut-off in 9/19 cases, high absolute TTP and Von Hoff values coinciding in 3 cases. Retrospectively, 8 patients receiving post-MTB treatment(s) as per physician's choice were noted to have a much longer overall survival from MTB accrual than 11 patients who had received no further treatment (35.09 vs 6.67 months, p = 0.006). CONCLUSIONS: MTB-recommended/non-SoC treatments are effective, including those assigned by ctDNA-only alterations. However, real-world MTBs may inadvertently recruit patients electively susceptible to diverse and/or multiple treatments.

Real-world outcomes of Italian patients with advanced non-squamous lung cancer treated with first-line pembrolizumab plus platinum-pemetrexed.

PURPOSE: The aim of this multi-center, retrospective/prospective cohort observational study was to evaluate outcomes in routine clinical practice of first-line chemo-immunotherapy with cis/carboplatin, pemetrexed and pembrolizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC) in 33 Italian centers. METHODS: The outcome measure was to evaluate overall survival (OS) in a real-world patient population. Secondary endpoints were: progression-free survival (PFS), objective response rate (ORR), duration of response (DoR) and incidence of treatment-related adverse events (AEs). RESULTS: 1068 patients were enrolled at the time of data cut-off (January 31st, 2023), and 812 (76.0%) belonged to the retrospective cohort. Median age was 66 years (27-85), ECOG PS was ≥ 2 in 91 (8.6%) patients; 254 (23.8%) patients had brain metastases at baseline; 38 (3.6%) patients had tumor with PD-L1 expression ≥ 50%. After a median follow-up of 17.0 months (95% CI, 16.1-17.9), median OS was 16.1 months (95% CI, 14.4-18.8) and PFS was 9.9 months (95% CI, 8.8-11.2). Median DoR (n = 493) was 14.7 months (95% CI, 13.6-17.1). ORR was 43.4% (95% CI, 40.4-46.4). Any-grade AEs occurred in 636 (59.6%) patients and grade ≥ 3 in 253 (23.7%) patients. Most common grade ≥ 3 AEs were neutropenia (6.3%) and anemia (6.3%). CONCLUSIONS: First-line chemo-immunotherapy was effective and tolerable in this large, real-world Italian study of patients with advanced non-squamous NSCLC. Our results were in line with the KEYNOTE-189 registration study, also considering the low number of PD-L1 ≥ 50% patients included in our study.

Analysis of predictive factors of unforeseen nodal metastases in resected clinical stage I NSCLC.

Background: Despite notable advances made in preoperative staging, unexpected nodal metastases after surgery are still significantly detected. In this study we aim to analyze the upstaging rate in patients with clinical stage I NSCLC without evidence of nodal disease in the preoperative staging who underwent lobectomy and radical lymphadenectomy. Methods: Patients who underwent lobectomy and systematic lymphadenectomy for clinical stage I NSCLC were evaluated. Exclusion criteria included the neoadjuvant treatment, incomplete resection and no adherence to preoperative guidelines. Results: A total of 297 patients were included in the study. 159 patients were female, and the median age was 68 (61 - 73). The variables that showed a significant correlation with the upstaging rate at the univariate analysis were the number of resected lymph nodes and micropapillar/solid adenocar-cinoma subtype. This result was confirmed in the multivariate analysis with a OR= 2.545 (95%CI 1.136-5.701; p=0.02) for the number of resected lymph nodes and a OR=2.717 (95%CI 1.256-5.875; p=0.01) for the high-grade pattern of adenocarcinoma. Conclusion: Our results showed that in a homogeneous cohort of patients with clinical stage I NSCLC, the number of resected lymph nodes and the histological subtype of adenocarcinoma can significantly be associated with nodal metastasis.

Surgical and survival outcomes with perioperative or neoadjuvant immune-checkpoint inhibitors combined with platinum-based chemotherapy in resectable NSCLC: A systematic review and meta-analysis of randomised clinical trials.

The use of neoadjuvant or perioperative anti-PD(L)1 was recently tested in multiple clinical trials. We performed a systematic review and meta-analysis of randomised trials comparing neoadjuvant or perioperative chemoimmunotherapy to neoadjuvant chemotherapy in resectable NSCLC. Nine reports from 6 studies were included. Receipt of surgery was more frequent in the experimental arm (odds ratio, OR 1.39) as was pCR (OR 7.60). EFS was improved in the experimental arm (hazard ratio, HR 0.55) regardless of stage, histology, PD-L1 expression (PD-L1 negative, HR 0.74) and smoking exposure (never smokers, HR 0.67), as was OS (HR 0.67). Grade > = 3 treatment-related adverse events were more frequent in the experimental arm (OR 1.22). The experimental treatment improved surgical outcomes, pCR rates, EFS and OS in stage II-IIIB, EGFR/ALK negative resectable NSCLC; confirmatory evidence is warranted for stage IIIB tumours and with higher maturity of the OS endpoint.

Brief Report: Canadian Cancer Trials Group IND.227: A Phase 2 Randomized Study of Pembrolizumab in Patients With Advanced Malignant Pleural Mesothelioma (NCT02784171).

Immune checkpoint inhibitors have activity in mesothelioma. IND.227 was a phase 2 trial (120 patients planned) comparing progression-free survival of standard platinum and pemetrexed (CP) versus CP + pembrolizumab (pembro) versus pembro. Accrual to the pembro arm was discontinued on the basis of interim analysis (IA-16 wk disease control rate). CP + pembro was tolerable, with progression-free survival similar between arms and median survival and overall response rate higher than those of CP alone (19.8 mo [95% confidence interval or CI: 8.4-41.36] versus 8.9 mo [95% CI: 5.3-12.8] and 47% [95% CI: 24%-71%] versus 19% [95% CI: 5%-42%], respectively). The subsequent phase 3 trial has completed accrual; results are expected in 2023.

Oncological Outcomes of Robotic Lobectomy and Radical Lymphadenectomy for Early-Stage Non-Small Cell Lung Cancer.

Background: While the thoracotomy approach was considered the gold standard until two decades ago, robotic surgery has increasingly strengthened its role in lung cancer treatment, improving patients' peri-operative outcomes. In this study, we report our experience in robotic lobectomy for early-stage non-small cell lung cancer, with particular attention to oncological outcomes and nodal upstaging rate. Methods: We retrospectively reviewed patients who underwent lobectomy and radical lymphadenectomy at our Institute between 2016 and 2020. We selected 299 patients who met the inclusion criteria of the study. We analyzed the demographic features of the groups as well as their nodal upstaging rate after pathological examination. Then, we analyzed disease-free and overall survival of the entire enrolled patient population and we compared the same oncological outcomes in the upstaging and the non-upstaging group. Results: A total of 299 patients who underwent robotic lobectomy were enrolled. After surgery, 55 patients reported nodal hilar or mediastinal upstaging. The 3-year overall survival of the entire population was 82.8%. The upstaging group and the non-upstaging group were homogeneous for age, gender, smoking habits, clinical stage, tumor site, tumor histology. The non-upstaging group had better OS (p = 0.004) and DFS (p < 0.0001). Conclusion: Our results show that robotic surgery is a safe and feasible approach for the treatment of early-stage NSCLC, especially for its accuracy in mediastinal lymphadenectomy. The oncological outcomes were encouraging and consistent with previous findings.

Systemic effect of radiotherapy before or after nivolumab in lung cancer: an observational, retrospective, multicenter study.

BACKGROUND: The combination of radiotherapy (RT) and programmed death 1 inhibitors seems to increase antitumor immune responses. OBJECTIVE: To assess the outcome and the role of the best combination sequence, i.e. immunotherapy given before, during, and/or after RT, in patients with non-small cell lung cancer (NSCLC). METHODS: We conducted an observational, retrospective analysis of 95 consecutive patients with advanced NSCLC who received any radiotherapy treatment and nivolumab, as clinically indicated. Median overall survival (OS) and the 95% confidence interval (CI) were estimated with the Kaplan-Meier method. Cox model was used to obtain hazard ratio (HR) and associated 95% CI with statistical inference by log-rank statistic. RESULTS: Median OS was 11.9 months (95% CI, 6.6-17.2). Patients who received radiotherapy during an immune checkpoint inhibitor treatment started more than 60 days before showed a better outcome than patients who started immunotherapy over 60 days after RT ending (HR, 2.90 [1.37-6.12], p = 0.005; median OS, 22.4 months vs 8.6 months, p = 0.005). Median progression-free survival was 6.3 months (95% CI, 4.6-8.0). CONCLUSIONS: This study shows that combining irradiation with nivolumab for the treatment of advanced NSCLC leads to improved OS. The optimal time window for the combination of RT and immunotherapy seems to play a critical role for therapeutic antitumor response derived by abscopal effect.

Not enough can be enough: feasibility of the Idylla EGFR mutation test when reuse of stained tissue slides is the only option available.

AIMS: The minimally invasive procedures used in the diagnostic workup of patients with advanced non-small cell lung cancer (NSCLC) often provide poor yields of pathological material suitable for molecular analyses. Not infrequently, the DNA yield from small biopsies/cytological samples is insufficient for the assessment of genomic biomarkers that inform personalised therapies. The Idylla EGFR mutation test (IEMT) has been specifically designed to process formalin-fixed paraffin-embedded sections without requiring preliminary DNA extraction.This study aims to evaluate the diagnostic accuracy of IEMT when used to analyse archival histopathology material. More specifically, our objective was to establish whether or not different staining procedures could affect assay performance. METHODS: Twenty NSCLC samples were selected accordingly to EGFR mutational status. To mimic archived stained material, sections were subjected to H&E staining, fluorescent in situ hybridisation analyses or immunodetection by immunohistochemistry before being processed for IEMT. RESULTS: Parallel assessment of EGFR mutational status by IEMT on stained sections and next-generation sequencing on DNA yielded a concordant result in 50 out of 60 tests (83.3%). The discoloration of H&E of the archived sample was found to be the optimal procedure to highlight all the actionable alterations of EGFR. CONCLUSIONS: IEMT can provide remarkable diagnostic accuracy for the assessment of EGFR mutational status also when the only source of pathological material available for molecular analyses is represented by H&E stained sections. Ad hoc supervision by a qualified molecular biologist is in any case recommended.

A Real-World Systematic Analysis of Driver Mutations' Prevalence in Early- and Advanced-Stage NSCLC: Implications for Targeted Therapies in the Adjuvant Setting.

The approval of osimertinib for adjuvant treatment of stage I-II-III EGFR-mutated NSCLC (early stage) represents a paradigm shift, raising the question of whether other genotype-matched therapeutics approved for advanced-stage NSCLC can also provide clinical benefit in the adjuvant setting. However, there is a paucity of real-world data on the prevalence of actionable genomic alterations (GAs) in early-stage NSCLC. We used next-generation sequencing, complemented by immunohistochemistry and fluorescence in situ hybridization, to screen our single-institution cohort of 1961 NSCLC consecutive cases for actionable molecular targets. The prevalence of actionable GAs was comparable in early versus advanced-stage NSCLC, the only exception being KRAS mutations (more frequent in early-stage cases). Consistent with advanced-stage tumors being more aggressive, co-occurrence of TP53 and EGFR GAs as well as copy number gains were less frequent in early-stage tumors. EGFR mutations and high expression of PD-L1 were inversely associated, whereas KRAS mutations and high PD-L1 reactivity showed positive association. Recapitulating advanced-stage tumors, early-stage NSCLC had the highest share of EGFR mutations in lepidic and acinar subtypes. Resected lepidic tumors contained the highest proportion of the KRAS G12C actionable variant. These results, obtained with routine diagnostic technologies in an unselected clinical setting, provide a significant addition of real-world data in early-stage NSCLC.

Nodal Upstaging Evaluation After Robotic-Assisted Lobectomy for Early-Stage Non-small Cell Lung Cancer Compared to Video-Assisted Thoracic Surgery and Thoracotomy: A Retrospective Single Center Analysis.

Introduction: The standard surgical procedures for patients with early-stage NSCLC is lobectomy-associated radical lymphadenectomy performed by using the thoracotomy approach. In the last few years, minimally invasive techniques have increasingly strengthened their role in lung cancer treatment, especially in the early stage of the disease. Although the lobectomy technique has been accepted, controversy still surrounds lymph node dissection. In our study, we analyze the rate of upstaging early non-small cell lung cancer patients who underwent radical surgical treatment using the robotic and the VATS techniques compared to the standard thoracotomy approach. Methods and Materials: We retrospectively reviewed patients who underwent a lobectomy and radical lymphadenectomy at our Institute between 2010 and 2019. We selected 505 patients who met the inclusion criteria of the study: 237 patients underwent robotic surgery, 158 patients had thoracotomy, and 110 patients were treated with VATS. We analyzed the demographic features between the groups as well as the nodal upstaging rate after pathological examination, the number of dissected lymph nodes and the ratio of dissected lymph nodes to metastatic lymph nodes of the three groups. Results: The patients of the three groups were homogenous with respect to age, sex, and histology. The postoperative major morbidity rate was significantly higher in the thoracotomy group, and hospital stay was significantly longer. The percentage of the mediastinal nodal upstaging rate and the number of dissected lymph nodes was significantly higher in the robotic group compared with the VATS group. The ratio of dissected lymph nodes to metastatic lymph nodes was significantly lower compared with the VATS group and the thoracotomy group. Discussion: The prognostic impact of the R(un) status is still highly debated. A surgical approach that allows better results in terms of resection has still not been defined. Our results show that robotic surgery is a safe and feasible approach especially regarding the accuracy of mediastinal lymphadenectomy. These findings can lead to defining a more precise pathological stage of the disease and, if necessary, to more accurate postoperative treatment.

Ovarian metastasis from malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and aggressive disease of the pleura with a dismal prognosis. Distant metastases most commonly occur in the liver, spleen, and thyroid gland. To our knowledge, ovarian metastases have never been described. CASE DESCRIPTION: We describe a case of a woman with recurrent malignant pleural mesothelioma presenting a single ovarian metastasis, surgically resected. CONCLUSIONS: This case report highlights the importance of using a complete staging protocol in patients with MPM to improve patient management. A whole-body computed tomography (CT) scan with contrast enhancement and possibly positron emission tomography-CT should be performed to identify any distant metastases before deciding on treatment strategy.

Predicting the Role of DNA Polymerase ß Alone or with KRAS Mutations in Advanced NSCLC Patients Receiving Platinum-Based Chemotherapy.

Clinical data suggest that only a subgroup of non-small cell lung cancer (NSCLC) patients has long-term benefits after front-line platinum-based therapy. We prospectively investigate whether KRAS status and DNA polymerase ß expression could help identify patients responding to platinum compounds. Prospectively enrolled, advanced NSCLC patients treated with a first-line regimen containing platinum were genotyped for KRAS and centrally evaluated for DNA polymerase ß expression. Overall survival (OS), progression-free survival (PFS), and the objective response rate (ORR) were recorded. Patients with KRAS mutations had worse OS (hazard ratio (HR): 1.37, 95% confidence interval (95% CI): 0.70-2.27). Negative DNA polymerase ß staining identified a subgroup with worse OS than patients expressing the protein (HR: 1.43, 95% CI: 0.57-3.57). The addition of KRAS to the analyses further worsened the prognosis of patients with negative DNA polymerase ß staining (HR: 1.67, 95% CI: 0.52-5.56). DNA polymerase ß did not influence PFS and ORR. KRAS may have a negative role in platinum-based therapy responses in NSCLC, but its impact is limited. DNA polymerase ß, when not expressed, might indicate a group of patients with poor outcomes. KRAS mutations in tumors not expressing DNA polymerase ß further worsens survival. Therefore, these two biomarkers together might well identify patients for whom alternatives to platinum-based chemotherapy should be used.

Atezolizumab in a CoHort of pretreated, advanced, non-small cell lung cancer patients with rare HistologiCal SubtypEs (CHANCE trial).

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

Clinical Features and Progression Pattern of Acquired T790M-positive Compared With T790M-negative EGFR Mutant Non-small-cell Lung Cancer: Catching Tumor and Clinical Heterogeneity Over Time Through Liquid Biopsy.

BACKGROUND: Clinical-pathologic predictors of acquired T790M epidermal growth factor receptor (EGFR) mutation in Caucasian patients with non-small-cell lung cancer (NSCLC) progressing after first-/second-generation tyrosine kinase inhibitors (TKIs) is an open field for research. Similarly, the best time point for T790M detection by liquid or tissue biopsy after disease progression is currently matter of debate. PATIENTS AND METHODS: This is an observational study at 7 Italian centers enrolling patients with EGFR-mutant NSCLC progressing after first-/second-generation EGFR TKIs, between 2014 and 2018, aiming at comparing baseline clinical-pathologic features and progression patterns in acquired T790M-positive compared with T790M-negative cases. RESULTS: A total of 235 patients received first-line treatment with gefitinib (N = 126; 53%), erlotinib (N = 51; 22%), or afatinib (N = 58; 25%). In 120 (51%) cases, T790M was detected in liquid biopsy, tissue biopsy, or both. Age younger than 65 years (P = .037), the presence of common mutations (P = .004), and better response to first-line TKI (P = .023) were correlated with T790M positivity. T790M detection was associated with higher number of new progressing sites (P = .04), liver progression (P = .002), and a lower frequency of lung metastases (P = .027). When serial liquid biopsies were performed (N = 15), an oligoprogressive disease was correlated with a negative test outcome, whereas systemic progression was observed at the time of T790M positivity. CONCLUSION: This study on a Caucasian population showed that age, type of EGFR mutation at diagnosis, response to first-line treatment, and peculiar progression pattern are associated with T790M status. Serial liquid biopsy might be useful for treatment selection, especially when tissue rebiopsy is not feasible.

Thymic Epithelial Tumors as a Model of Networking: Development of a Synergistic Strategy for Clinical and Translational Research Purposes.

Among the group of thymic epithelial tumors (TET), thymomas often show either uncertain or explicit malignant biological behavior, local invasiveness, and intrathoracic relapse and are often difficult to manage. From the initial stages, thymic carcinomas tend to show aggressive behavior and extrathoracic spread. Moreover, the interplay of epithelial cells and thymocytes in thymomas causes complex immune derangement and related systemic autoimmune diseases. Due to their rare occurrence and to the limited funding opportunities available for rare tumors, it is challenging to make advances in clinical and translational research in TET. The authors of this paper are all members of a multidisciplinary clinical and research thoracic tumor team. Strong input was given to the team by long-standing expertise in TET in the Pathology Department. In addition, thanks to the collaboration between research units at our Institute as well as to national collaborations, over the last 10 years we were able to perform several tissue-based research studies. The most recent studies focused on microRNA and on functional studies on the thymic carcinoma cell line 1889c. The recent implementation of our biobank now provides us with a new tool for networking collaborative research activities. Moreover, the participation in a worldwide community such as ITMIG (International Thymic Malignancy Interest Group) has allowed us to significantly contribute toward fundamental projects/research both in tissue-based studies (The Cancer Genome Atlas) and in clinical studies (TNM staging of TET). Our achievements derive from constant commitment and long-standing experience in diagnosis and research in TET. New perspectives opened up due to the establishment of national [the Italian Collaborative Group for ThYmic MalignanciEs (TYME)] and European reference networks such as EURACAN, for an empowered joint clinical action in adult solid rare tumors. The challenge we face still lies in the advancement of clinical and basic science in thymic epithelial malignancies.

BRAF as a positive predictive biomarker: Focus on lung cancer and melanoma patients.

In the era of personalized medicine, BRAF mutational assessment is mandatory in advanced-stage melanoma and non-small cell lung cancer (NSCLC) patients. The identification of actionable mutations is crucial for the adequate management of these patients. To date various drugs have been implemented in clinical practice. Similarly, various methods may be adopted for the identification of BRAF mutations. Here, we briefly review the current literature on BRAF in melanoma and NSCLC, focusing attention in particular on the different methods and drugs adopted in these patients. In addition, an overview of the real-world practice in different Italian laboratories with high expertise in molecular predictive pathology testing is provided.

First-line pembrolizumab in advanced non-small cell lung cancer patients with poor performance status.

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

Is recurrent venous thromboembolism after therapy reduced by low-molecular-weight heparin compared with oral anticoagulants?

PURPOSES: To evaluate whether the incidence of recurrent venous thromboembolism (VTE) events after therapy differs for patients treated with long-term low-molecular-weight heparin (LMWH) or oral anticoagulant therapy (OAT). METHODS: All randomized studies were searched through computerized queries of MEDLINE, the Cochrane Controlled Trials Register, the American Society of Hematology abstract database, and the American Society of Clinical Oncology abstract database. RESULTS: Eleven studies including 2,907 patients were identified. Seven studies evaluated a period of 3 to 9 months after cessation of the allocated treatment: 5.4% of patients in the LMWH group vs 4% in the arm allocated to OAT had an episode of recurrent symptomatic VTE. Combined analysis showed a nonsignificant trend in lowering recurrent symptomatic VTE in favor of OAT (relative risk [RR], 1.29; 95% confidence interval [CI], 0.82 to 2.02; p = 0.27). By contrast, during active treatment, a statistically significant reduction of the risk of recurrent symptomatic VTE in favor of LMWH over OAT was registered (RR, 0.63; 95% CI, 0.47 to 0.83; p = 0.001). Regarding cancer patients only, 37 of 569 patients (6.5%) in the LMWH group had recurrent symptomatic VTE vs 69 of 546 patients (12.6%) in the OAT group, with a statistically significant reduction of the risk of recurrent symptomatic VTE in favor of LMWH (RR, 0.52; 95% CI, 0.35 to 0.76; p = 0.001). CONCLUSIONS: Despite the significant reduction of the risk of recurrent symptomatic VTE in favor of LMWH over OAT during treatment, patients treated with long-term LMWH do not seem to have more frequently recurrent VTE events compared with OAT after cessation of therapy. The significant difference favoring LMWH over OAT among all patients receiving treatment comes mostly from studies enrolling cancer patients.