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Despite the positive results obtained by first-line chemoimmunotherapy in patients with metastatic non-small-cell lung cancer (NSCLC), only a few second-line options are available after disease progression. Combi-TED is a phase II international study that will assess the efficacy of Tedopi®, a cancer vaccine, combined with either docetaxel or nivolumab and compared with docetaxel monotherapy in patients with metastatic NSCLC after chemoimmunotherapy. The study, currently in the recruitment phase, will assess 1-year overall survival (primary end point), patient's progression-free survival and overall response rate, as well as the correlation of efficacy with several tumor or blood biomarkers. The results will hopefully provide more information on Tedopi combinational treatment compared with current standard of care in NSCLC patients who fail first-line chemoimmunotherapy. Clinical Trial Registration: NCT04884282 ( ClinicalTrials.gov )

Background Immune checkpoint inhibitors (ICIs) have revolutionised treatment of advanced non-small cell lung cancer (aNSCLC), but a proportion of patients had no clinical benefit and even experienced detrimental effects. This study aims to characterise patients experiencing hyperprogression (HPD) and early death (ED) by longitudinal liquid biopsy. Methods aNSCLC receiving ICIs were prospectively enrolled. Plasma was collected at baseline (T1) and after 3/4 weeks of treatment, according to the treatment schedule (T2). Cell-free DNA (cfDNA) was quantified and analysed by NGS. cfDNA quantification and variant allele fraction (VAF) of tumour-associated genetic alterations were evaluated for their potential impact on outcome. The genetic alteration with the highest VAF (maxVAF) at baseline was considered as a reference. Results From March 2017 to August 2019, 171 patients were enrolled. Five cases matched criteria for HPD and 31 ED were recorded; one overlapped. Quantification of cfDNA at T2 and its absolute and relative variation (T2–T1) were significantly associated with the risk of ED (P = 0.012, P = 0.005, P = 0.009). MaxVAF relative change (T2–T1/T1) was significantly associated with the risk of HPD (P = 0.02). After identifying optimal cut-off values, a two-step risk assessment model was proposed. Discussion Liquid biopsy performed early during treatment has the potential to identify patients at high risk of ED and HPD.

The majority of epidermal growth factor receptor (EGFR) mutations (85–90%) are exon 19 deletions and L858R point mutations of exon 21, characterized by high sensitivity to EGFR-tyrosine kinase inhibitors (TKIs). Less is known about uncommon mutations (10–15% of EGFR mutations). The predominant mutation types in this category include exon 18 point mutations, exon 21 L861X, exon 20 insertions, and exon 20 S768I. This group shows a heterogeneous prevalence, partly due to different testing methods and to the presence of compound mutations, which in some cases can lead to shorter overall survival and different sensitivity to different TKIs compared to simple mutations. Additionally, EGFR-TKI sensitivity may also vary depending on the specific mutation and the tertiary structure of the protein. The best strategy remains uncertain, and the data of EGFR-TKIs efficacy are based on few prospective and some retrospective series. Newer investigational agents are still under study, and there are no other approved specific treatments targeting uncommon EGFR mutations. Defining the best treatment option for this patient population remains an unmet medical need. The objective of this review is to evaluate existing data on the outcomes, epidemiology, and clinical characteristics of lung cancer patients with rare EGFR mutations, with a focus on intracranial activity and response to immunotherapy.

Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer of the pleural surface, associated with asbestos exposure, whose incidence is still growing in some areas of the world. MPM is still considered a rare and an orphan disease with an unchanged median overall survival (OS) ranging from 8 to 14 months and no treatment advances in the last 15 years both in local and advanced disease. In the recent years, chronic inflammation of the mesothelium together with local tumor suppression plays a major role in the malignant transformation. Also, significant heterogeneity in both tumor and the microenvironment is at the basis of MPM biology. Preclinical data have demonstrated the immunogenicity and the lack of an effective antitumor response by the immune system in MPM thus paving the way to the development of immune therapeutics in this disease. Still there is no clear evidence of any predictive biomarker so that, given the close interaction between the immune infiltrate and mesothelial cells, a number of trials are ongoing to investigate the role and prognostic value of the immune microenvironment. In this review we summarize the rationale for immune therapeutics development in MPM, as well as, the relevant literature and ongoing trials of immune checkpoint inhibitors (ICIs) and vaccines used as both first-line treatment and beyond.

Non-small cell lung cancer (NSCLC) is still one of the leading causes of death worldwide. This is mostly because the majority of lung cancers are discovered in advanced stages. In the era of conventional chemotherapy, the prognosis of advanced NSCLC was grim. Important results have been reported in thoracic oncology since the discovery of new molecular alterations and of the role of the immune system. The advent of new therapies has radically changed the approach to lung cancer for a subset of patients with advanced NSCLC, and the concept of incurable disease is still changing. In this setting, surgery seems to have developed a role of rescue therapy for some patients. In precision surgery, the decision to perform surgical procedures is tailored to the individual patient; taking into consideration not only clinical stage, but also clinical and molecular features. Multimodality treatments incorporating surgery, immune checkpoint inhibitors, or targeted agents are feasible in high volume centers with good results in terms of pathologic response and patient morbidity. Thanks to a better understanding of tumor biology, precision thoracic surgery will facilitate optimal and individualized patient selection and treatment, with the goal of improving the outcomes of patients affected by NSCLC.

Patients with non-small cell lung cancer, especially adenocarcinomas, harbour at least one oncogenic driver mutation that can potentially be a target for therapy. Treatments of these oncogene-addicted tumours, such as the use of tyrosine kinase inhibitors (TKIs) of mutated epidermal growth factor receptor, have dramatically improved the outcome of patients. However, some patients may acquire resistance to treatment early on after starting a targeted therapy. Transformations to other histotypes—small cell lung carcinoma, large cell neuroendocrine carcinoma, squamous cell carcinoma, and sarcomatoid carcinoma—have been increasingly recognised as important mechanisms of resistance and are increasingly becoming a topic of interest for all specialists involved in the diagnosis, management, and care of these patients. This article, after examining the most used TKI agents and their main biological activities, discusses histological and molecular transformations with an up-to-date review of all previous cases published in the field. Liquid biopsy and future research directions are also briefly discussed to offer the reader a complete and up-to-date overview of the topic.

Background: The role of MET alterations in non-small cell lung cancer (NSCLC) is increasing and several targeted agents are under evaluation. MET exon 14 skipping mutations and MET amplifications are associated with potential sensitivity to MET inhibition, though resistance mechanisms are emerging. In MET addicted cells, MET inhibition leads to activation of proviral integration site for Moloney murine leukemia virus-1 (PIM1). PIM1 and proto-oncogene tyrosine-protein kinase Src (SRC) can regulate the expression of receptor tyrosine kinases (RTKs), potentially inducing resistance to MET inhibition through cross-activation. Methods: We evaluated the activity of class I-II MET inhibitors, the SRC inhibitor dasatinib, and panPIM inhibitors in four MET addicted cell lines. We assessed the effect of the dual MET/PIM and MET/ SRC inhibition on cell viability and at the protein level. We evaluated RNA expression profiles of the cell lines. Advanced NSCLCs were also screened for MET alterations. Results: All cell lines were sensitive to class I-II MET inhibitors. All cell lines were resistant to single PIM and SRC inhibition. Dual MET/PIM inhibition was synergistic or additive in MET amplified cell lines and dual MET/SRC inhibition was highly synergistic in all MET addicted cell lines. The addition of an SRC inhibitor partially prevents the RTKs cross-activation. MET alterations were found in 9 out of 97 evaluable samples (9.3%); median overall survival in MET altered patients was 5 months (95% CI, 3 m-NA). Conclusions: We identified a potential role of PIM inhibition in MET amplified tumors and of SRC inhibition in MET addicted tumors. Potential applications of this new treatment strategy warrant further evaluation.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive tumor but approximately 12% of patients survive more than 3 years. The biological differences underlying better outcomes are not known. Several targeted agents and immunotherapy have been ineffective. Hedgehog (Hh) is one emerging pathway. We compared the biological profiles of patients with different survival, investigating the most frequently altered genes, including the Hh pathway. METHODS: We analyzed 56 MPM. A 36-month overall survival (OS) cut-off divided patients into 32 normo (NS) and 24 long (LS) survivors. We used next generation sequencing to test 21 genes, immunohistochemistry to evaluate SMO expression. Mutation differences between NS and LS and their associations with clinical features were analysed by Fisher’s test, OS with the Kaplan-Meier method and its association with mutations by univariate and multivariate Cox proportional hazard models. RESULTS: Clinical features were similar in both groups. Eighteen out of 56 patients (32%) were wild-type for the genes analysed. At least five had mutations in BAP1, NF2, TP53, SMO and PTCH1 with no significant differences between the groups except for SMO. SMO, a member of the Hh pathway, was mutated only in NS (15.6%) and only SMO mutations were significantly associated with poor prognosis at univariate (HR =4.36, 95% CI: 2.32–8.18, P

Background Liquid biopsy has the potential to monitor biological effects of treatment. KRAS represents the most commonly mutated oncogene in Caucasian non-small-cell lung cancer (NSCLC). The aim of this study was to explore association of dynamic plasma KRAS genotyping with outcome in advanced NSCLC patients. Methods Advanced NSCLC patients were prospectively enrolled. Plasma samples were collected at baseline (T1), after 3 or 4 weeks, according to treatment schedule (T2) and at first radiological restaging (T3). Patients carrying KRAS mutation in tissue were analysed in plasma with droplet digital PCR. Semi-quantitative index of fractional abundance of mutated allele (MAFA) was used. Results KRAS-mutated cohort included 58 patients, and overall 73 treatments (N = 39 chemotherapy and N = 34 immune checkpoint inhibitors) were followed with longitudinal liquid biopsy. Sensitivity of KRAS detection in plasma at baseline was 48.3% (95% confidence interval (CI): 35.0–61.8). KRAS mutation at T2 was associated with increased probability of experiencing progressive disease as best radiological response (adjusted odds ratio: 7.3; 95% CI: 2.1–25.0, p = 0.0016). Increased MAFA (T1–T2) predicted shorter progression-free survival (adjusted hazard ratio (HR): 2.1; 95% CI: 1.2–3.8, p = 0.0142) and overall survival (adjusted HR: 3.2; 95% CI: 1.2–8.4, p = 0.0168). Conclusions Longitudinal analysis of plasma KRAS mutations correlated with outcome: its early assessment during treatment has great potentialities for monitoring treatment outcome in NSCLC patients.

Lay abstract Extended-stage small-cell lung cancer (ES-SCLC) is a highly aggressive lung cancer subtype, accounting for 13-15% of all lung cancers. For several years, the standard treatment for this disease was based on polychemotherapy, with a rapid disease response but with an equally rapid disease progression. The new standard treatment has recently been changed, based on the results of two large clinical trials, which showed the efficacy and safety of the combination of chemotherapy with immunotherapy compared to chemotherapy alone. Nevertheless, prognosis of ES-SCLC remains poor, and new treatment strategies are urgently needed. Therefore, we designed the CeLEBrATE trial to investigate whether the combination of chemotherapy with antiangiogenetic therapy and immunotherapy is safe and could improve survival in patients with ES-SCLC.Based on improved survival from the addition of PD-L1 inhibitors in phase III trials, the combination of immunotherapy and platinum-doublet chemotherapy has become the new standard treatment for extended-stage small-cell lung cancer (ES-SCLC). Furthermore, the antiangiogenetic agent bevacizumab showed a longer progression-free survival by targeting VEGF that has pleiotropic effects, including immunosuppressive ones. We, therefore, hypothesized that targeting angiogenesis would improve the efficacy of chemoimmunotherapy. The CeLEBrATE trial is an open-label, multicenter, phase II study designed to assess the efficacy and safety of the combination of carboplatin and etoposide plus bevacizumab and atezolizumab in treatment-naive patients with ES-SCLC. The primary end point is overall survival rate at 1 year, while secondary end points include overall response rate, progression-free survival and toxicity.

Data on tumor immune-milieu after chemo-radiation (CT-RT) are scarce. Noninvasive tools are needed to improve the treatment of non-small cell lung cancer (NSCLC), especially in the locally advanced (LA) setting.We collected a series of superior-sulcus (SS)- patients with NSCLC referred to our Institute (2015-2019), eligible for a preoperative CT-RT. We characterized tumor-infiltrating immune cells (TIICs), determined PD-L1-TPS and the residual viable tumor cells (RVTC). Radiological and metabolic responses were reviewed. We calculated pre-surgery neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR).Eight patients were included. Radiological responses were 6 disease stabilities (SD) and 2 partial responses (PR). Metabolic responses were 4 SD and 4 PR. CD68+-TIICs were correlated with metabolic response and lower RVTC. CD68+-TIICs were associated with higher PLR. Higher PLR values seemed linked with lower RVTC.These preliminary results could be useful for consolidation treatment selection for patients with LA-NSCLC without evaluable baseline PD-L1 and higher PLR values.

About 30% of new non-small cell lung cancer (NSCLC) cases are diagnosed at a locally advanced stage, which includes a highly heterogeneous group of patients with a wide spectrum of treatment options. The management of stage III NSCLC involves a multidisciplinary team, adequate staging, and a careful patient selection for surgery or radiation therapy integrated with systemic treatment.This is a single-center observational retrospective and prospective study including a consecutive series of stage III NSCLC patients who were referred to the Veneto Institute of Oncology and University Hospital of Padova (Italy) between 2012 and 2021. We described clinico-pathological characteristics, therapeutic pathways, and treatment responses in terms of radiological response in the entire study population and in terms of pathological response in patients who underwent surgery after induction therapy. Furthermore, we analysed survival outcomes in terms of relapse-free survival (RFS) and overall survival (OS).A total of 301 patients were included. The majority of patients received surgical multimodality treatment (Our work provides insights into the management and the survival outcomes of stage III NSCLC over about 10 years. We found that the choice of radical treatment impacts on outcome, thus suggesting the importance of appropriate staging at diagnosis, patient selection, and of the multidisciplinary approach in the decision-making process. Our results confirmed that the PACIFIC trial and the following introduction of durvalumab as consolidation treatment may be considered as a turning point for several improvements in the diagnostic-therapeutic pathway of stage III NSCLC patients.

The monoclonal antibody durvalumab, an immune-checkpoint inhibitor (ICI) antiprogrammed death ligand 1 (PD-L1), is available for unresectable stage III NSCLC patients as consolidation therapy following induction chemoradiotherapy, with very promising overall survival (OS) and progression-free survial (PFS) results in registration trials. The purpose of this study was to provide policymakers with an estimate of the cost-effectiveness of durvalumab in the treatment of non-small cell lung cancer (NSCLC).The study developed a Markov model covering a 5-year period to compare costs and outcomes of treating PD-L1 positive patients with or without durvalumab. We conducted a series of sensitivity analyses (Tornado analysis and Monte Carlo simulation) by varying some parameters to assess the robustness of our model and identify the parameters with the greatest impact on cost-effectiveness.Prior to the release of durvalumab, the management of NSCLC over a 5-year period cost €33 317 per patient, with an average life expectancy of 2.01 years. After the introduction of the drug, this increased to €37 317 per patient, with an average life expectancy of 2.13 years. Treatment with durvalumab led to an incremental cost-effectiveness ratio (ICER) of €35 526 per year. OS is the variable that contributes the most to the variability of the ICER.The study observed that durvalumab is a cost-effective treatment option for patients with unresectable stage III NSCLC.

Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC.This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up.Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were enrolled and randomly assigned to treatment with ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months (IQR 15·8-27·2). At the time of primary analysis, progression-free survival was significantly longer in the ramucirumab plus erlotinib group (19·4 months [95% CI 15·4-21·6]) than in the placebo plus erlotinib group (12·4 months [11·0-13·5]), with a stratified hazard ratio of 0·59 (95% CI 0·46-0·76; p0·0001). Grade 3-4 treatment-emergent adverse events were reported in 159 (72%) of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225 in the placebo plus erlotinib group. The most common grade 3-4 treatment-emergent adverse events in the ramucirumab plus erlotinib group were hypertension (52 [24%]; grade 3 only) and dermatitis acneiform (33 [15%]), and in the placebo plus erlotinib group were dermatitis acneiform (20 [9%]) and increased alanine aminotransferase (17 [8%]). Treatment-emergent serious adverse events were reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and 47 (21%) of 225 in the placebo plus erlotinib group. The most common serious adverse events of any grade in the ramucirumab plus erlotinib group were pneumonia (seven [3%]) and cellulitis and pneumothorax (four [2%], each); the most common in the placebo plus erlotinib group were pyrexia (four [2%]) and pneumothorax (three [1%]). One on-study treatment-related death due to an adverse event occurred (haemothorax after a thoracic drainage procedure for a pleural empyema) in the ramucirumab plus erlotinib group.Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC.Eli Lilly.

Preoperative identification of unresectable pleural mesothelioma could spare unnecessary surgical intervention and accelerate the initiation of medical treatments. The aim of this study is to determine predictors of unresectability, testing our impression that the contraction of the ipsilateral hemithorax is often associated with exploratory thoracotomy. Between 1994 and 2020, 291 patients undergoing intended macroscopic complete resection for mesothelioma after chemotherapy were retrospectively investigated. Eligible patients (n = 58) presented a preoperative 3 mm slice-thickness chest computed tomography without pleural effusion or hydropneumothorax. Lung volumes (segmented using a semi-automated method), modified-Response Evaluation Criteria in Solid Tumors (RECIST) measurements, and spirometries were collected after chemotherapy. Multivariable analysis was performed to determine the predictors of unresectability. An unresectable disease was found at the time of operation in 25.9% cases. By multivariable analysis, the total lung capacity (p = 0.03) and the disease burden (p = 0.02) were found to be predictors of unresectability, cut-off values were &lt, 77.5% and &gt, 120.5 mm, respectively. Lung volumes were not confirmed to be associated with unresectability at multivariable analysis, probably due to the correlation with the disease burden (p &lt, 0.001, r = −0.4). Our study suggests that disease burden and total lung capacity could predict MPM unresectability, helping surgeons in recommending surgery or not in a multimodality setting.

Background Osimertinib became the standard treatment for patients with untreated EGFR-mutant advanced non-small cell lung cancer (aNSCLC) following results reported in the phase III randomized FLAURA trial. Because of strict exclusion criteria, patient populations included in pivotal trials are only partially representative of real-world patients. Methods We designed an observational, prospective, multicenter study enrolling patients with EGFR-mutant aNSCLC receiving first-line osimertinib to evaluate effectiveness, safety, and progression patterns in the real-world. Results At data cutoff, 126 White patients from nine oncology centers were included. At diagnosis, 16 patients (12.7%) had a performance status (PS) ≥2 and 38 (30.2%) had brain metastases. Overall response rate (ORR) was 73%, disease control rate (DCR) 96.0%. After a median follow-up of 12.3 months, median time to treatment discontinuation (mTTD) was 25.3 months, median progression-free-survival (mPFS) was 18.9 months and median overall survival (mOS) was not reached (NR). One hundred and ten patients (87%) experienced adverse events (AEs), 42 (33%) of grade 3–4, with venous thromboembolism (VTE) as the most common (n = 10, 7.9%). No difference in rates of VTE was reported according to age, PS, comorbidity, and tumor load. We observed longer mTTD in patients without symptoms (NR vs. 18.8 months) and with fewer than three metastatic sites at diagnosis (NR vs. 21.4 months). Patients without brain metastases experienced longer mPFS (NR vs. 13.3 months). No difference in survival outcome was observed according to age, comorbidity, and type of EGFR mutation. Isolated progression and progression in fewer than three sites were associated with longer time to treatment discontinuation (TTD). Conclusion Osimertinib confirmed effectiveness and safety in the real world, although thromboembolism was more frequent than previously reported.

IMPORTANCE: Bevacizumab treatment beyond progression has been investigated in breast and metastatic colorectal cancers. Avastin in All Lines Lung (AvaALL) is the first randomized phase 3 study of bevacizumab across multiple lines of treatment beyond progression in non–small cell lung cancer (NSCLC). OBJECTIVE: To assess the efficacy and safety of continuous bevacizumab treatment beyond first progression in NSCLC. DESIGN, SETTING, AND PARTICIPANTS: AvaALL was a randomized, open-label, phase 3b trial, conducted from 2011 to 2015 in 123 centers worldwide. Patients with nonsquamous NSCLC previously treated with first-line bevacizumab plus platinum-doublet chemotherapy and at least 2 cycles of bevacizumab maintenance were randomized (1:1) at first progression to receive bevacizumab plus standard of care (SOC) or SOC alone. INTERVENTIONS: Patients received bevacizumab (7.5 or 15 mg/kg intravenously every 21 days) and/or investigator’s choice of SOC. For subsequent lines, patients treated with bevacizumab received SOC with or without bevacizumab; the SOC arm received SOC only. MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival from first to second (PFS2) and third progression (PFS3), time to second (TTP2) and third progression (TTP3), and safety. RESULTS: Between June 2011 and January 2015, 485 patients (median age, 63.0 years [range, 26-84 years]; 293 [60.4%] male) were randomized. Median OS was not significantly longer with bevacizumab plus SOC vs SOC alone: 11.9 (90% CI, 10.2-13.7) vs 10.2 (90% CI, 8.6-11.9) months (hazard ratio [HR], 0.84; 90% CI, 0.71-1.00; P = .104). Median PFS2 was numerically longer with bevacizumab plus SOC vs SOC alone: 5.5 (90% CI, 4.2-5.7) vs 4.0 (90% CI, 3.4-4.3) months (HR, 0.83; 90% CI, 0.70-0.98; P = .06). Median PFS3 appeared longer with bevacizumab plus SOC vs SOC alone: 4.0 (90% CI, 2.9-4.5) vs 2.6 (90% CI, 2.3-2.9) months (HR, 0.63; 90% CI, 0.49-0.83), as did TTP2 and TTP3. Grade 3/4 adverse events were more frequent with bevacizumab plus SOC (186 [76.5%]) vs SOC alone (140 [60.3%]). No new safety signals were observed. CONCLUSIONS AND RELEVANCE: The primary end point was not met; however, OS was underpowered according to initial statistical assumptions. Continued therapy beyond first progression led to improved PFS3 (but not PFS2), TTP2, and TTP3. Although a result with P = .06 for PFS2 would conventionally be considered significant at a specified 2-sided α of .10, in the absence of adjustments for multiplicity, this result could be a chance finding. No new safety signals were identified with bevacizumab treatment beyond progression. TRIAL REGISTRATION: clinicaltrialsregister.eu Identifier: 2010-022645-14; ClinicalTrials.gov identifier: NCT01351415

Surgery for malignant pleural mesothelioma (MPM) should be reserved only for patients who have a good performance status. Sarcopenia, a well-known predictor of poor outcomes after surgery, is still underinvestigated in MPM. The aim of this study is to evaluate the role of sarcopenia as a predictor of short-and long-term outcomes in patients surgically treated for MPM. In our analysis, we included patients treated with a cytoreductive intent in a multimodality setting, with both pre- and post-operative CT scans without contrast available. We excluded those in whom a complete macroscopic resection was not achieved. Overall, 86 patients were enrolled. Sarcopenia was assessed by measuring the mean muscular density of the bilateral paravertebral muscles (T12 level) on pre-and post-operative CTs; a threshold value of 30 Hounsfield Units (HU) was identified. Sarcopenia was found pre-operatively in 57 (66%) patients and post-operatively in 61 (74%). Post-operative sarcopenic patients had a lower 3-year overall survival (OS) than those who were non-sarcopenic (34.9% vs. 57.6% p = 0.03). Pre-operative sarcopenia was significantly associated with a higher frequency of post-operative complications (65% vs. 41%, p = 0.04). The evaluation of sarcopenia, through a non-invasive method, would help to better select patients submitted to surgery for MPM in a multimodality setting.

2549 Background: ICIs lead to durable response and a significant survival improvement in a limited number of advanced stage Mel and NSCLC pts. The identification of predictive circulating biomarkers could be a promising tool to optimize pts’ selection and outcome for ICIs treatment. Methods: This is a prospective real-world study enrolling advanced stage Mel and NSCLC pts referred to four Italian Centers and treated with ICIs. The primary endpoint is to verify the presence of an association between circulating cytokines (IL-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNFα, GM-CSF) and disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Pts undergo a blood collection, before every cycle for 6 cycles (T1-T6) and at tumor assessment till disease progression (PD) or for 2 years. Biomarker levels were assessed by Luminex xMAP based technology using R&D High Sensitivity kits. Each marker was categorized according to high and low levels by maximizing its discriminative ability, and the association with the outcome was tested in univariate and multiple analyses. Results: We report preliminary results on the T1-T2 blood samples from the first 78 enrolled pts (32 females/46 males; 43 Mel/35 NSCLC; median age 69 years). Serum IL-6, IL-8 and IL-10 were significantly higher at T1 and T2 in pts with PD (Kruskal-Wallis test). The median relative increase (RI) of IL-8 was 32% and 2% in pts with PD and disease control (DC), respectively (p = 0.0001). At multiple logistic analysis, IL-6 and IL-8 at T2 and the RI of IL-8 were independent factors predicting the probability of DC, with an overall accuracy of 83.8%. High levels of IL-6 and IL-8 at T2 were significantly associated with a low probability of DC (OR = 0.13, 95%CI: 0.03-0.52 and OR = 0.09, 95%CI: 0.02-0.37, respectively), and the RI showed a significantly lower probability of DC (OR = 0.14, 95%CI: 0.02-0.58). With a median follow-up of 10.6 months (m), mPFS and mOS were 5.8 m, 95%CI: 2.3-7.4 and 8.3 m, 95%CI: 4.0-13.8 for NSCLC; 6.9 m, 95%CI: 2.8-15.9 and 12.6 m, 95%CI: 4.7-NE for Mel pts, respectively. In the multiple Cox model, elevated IL-6 and IL-8 at T1 (HR = 3.03, 95%CI: 1.55-6.37, HR = 2.86, 95%CI: 1.46-5.63), elevated IL-10 at T2 (HR = 2.86, 95%CI: 1.39-5.94), and a RI of IL-8 (HR = 4.22, 95%CI: 1.85-11.21) remained significantly associated with a worse PFS. Higher levels of IL-6 (HR = 3.85, 95%CI: 1.13-20.0) and IL-8 (HR = 4.29, 95%CI: 1.98-9.83) at T2 and a RI of IL-8 (HR = 3.06, 95%CI: 1.43-6.72) remained significantly associated with a worse OS. Conclusions: High serum levels of IL-8 and IL-6 at T2 of ICI, combined with an increase of IL-8 from baseline, are strong predictors of PD, PFS, OS, in pts with advanced Mel and NSCLC. The role of the other cytokines tested, their time fluctuations and associations with clinical prognostic factors, gender, and immuno-related adverse events will be presented at the meeting.

TPS9140 Background: First line combination of chemotherapy and immune checkpoint inhibitors (ICIs) improves overall survival (OS) compared with chemotherapy alone in non-small cell lung cancer (NSCLC) patients. However, only few options are available at chemoimmunotherapy failure, with docetaxel representing the standard of care. Tedopi is a cancer vaccine which stimulates killer T cells, currently under development for the therapy of HLA-A2+ lung cancer. In the ATALANTE-1 Phase III trial (EudraCT no. 2015-003183-36), Tedopi provided clinical benefits in patients with advanced NSCLC who failed to respond to checkpoint inhibitors. Given the need for new therapeutic options in patients failing first-line chemo-immunotherapy and the encouraging preliminary data with Tedopi, there is a strong rationale for investigating the activity of Tedopi plus nivolumab or Tedopi plus docetaxel in patients with metastatic NSCLC failing standard first-line therapy. Methods: This is a phase II, non-comparative, randomized multicenter study assessing the combination of Tedopi with docetaxel or nivolumab in NSCLC patients failing after first-line chemoimmunotherapy (EudraCT no. 2020-005170-10). All NSCLC patient candidates for second-line therapy are considered eligible for the study if they are HLA-A2+, with no evidence of EGFR mutations or ALK/ROS1 rearrangement and if they progressed after at least 4 cycles of previous first-line chemo-immunotherapy. Patients are randomly assigned to Tedopi plus docetaxel, Tedopi plus nivolumab (treatment arms) or docetaxel monotherapy (standard arm). The primary endpoint is 1-year OS rate. Secondary endpoints include OS, 2-year OS rate, progression-free survival (PFS), objective response rate (ORR), and safety. An explorative analysis of the correlation of efficacy with several tumor or blood biomarkers (PD-L1 expression, tumor mutational burden, Tedopi neoantigen expression, T cell infiltration), is also performed. Sample size was calculated assuming a 1-year OS rate in the standard arm of 20%. According to the single-stage design, in both treatment arms a 1-year OS rate of 20% would imply that treatment does not warrant further investigation and a 1-year OS rate of 40%, would imply that treatment has a sufficient activity. With a one-sided significance level of 5% and a power of 80%, a total number of 105 patients (35 per treatment arm) need to be enrolled. At the drafting of this abstract, 7 patients have already been enrolled. Total follow-up will be 24 months from last enrolment, for an approximate duration of 48 months. Clinical trial information: NCT04884282.

e20574 Background: Recent evidences have suggested potential applications of radiomics in early diagnosis, prognostic stratification and treatment outcome prediction of Non-Small Cell Lung Cancer (NSCLC) patients. The purpose of this study is to evaluate the ability of radiomic analysis to discriminate between different clinical-pathological conditions in patients with stage III NSCLC. Methods: Baseline CT studies from 59 patients with stage III NSCLC referred to our Institution from 2010 and 2020 were retrospectively reviewed, and the segmentation of the main lung lesion and the extraction of 517 radiomic features performed using a commercial software. The number of features was reduced to 46 by means of principal component analysis applied using the R package “RadAR” (Radiomics Analysis with R). The Kruskal-Wallis test was applied to all the radiomic features in order to evaluate which of them can discriminate between 7 clinical dichotomous characteristics: tumor stage, type, presence of mutation, treatment response, relapse free survival (RFS), smoking habit, patient outcome. P < 0.05 means that there is a statistically significant difference between the two subgroups. Results: The median age at diagnosis was 69 years (range 43-83). Most patients were males (40/59 = 67.8%) and heavy smokers (36/59 = 61.0%). Adenocarcinoma was the most common histology (41/59 = 70.7%), while cases were almost equally splitted between stage IIIA (45.8%) and stage IIIB or IIIC (54.2%). Most selected radiomic features (29/46 = 63.0%) showed a statistically significant difference between patients with and without mutations. Ten (10/46 = 21.7%) radiomic features were associated with patient sex. Seven features (7/45 = 15.2%) were “sensitive” to the tumor clinical stage (stage IIIA vs. stage IIIB+IIIC), 4 (4/46 = 8.7%) to the histological type, and 2 (2/46 = 4.3%) to the patient outcome. None of the selected radiomic features was able to discriminate between responder and non-responder patients, current/previous smokers and never smokers, and patients with RFS lower than 12 months versus RFS equal or higher than 12 months. Conclusions: This preliminary analysis showed that radiomics has the potential of identifying mathematical features associated with clinical and histopathological characteristics in stage III NSCLC patients, which might feed multiparametric predictive models. Larger datasets and further analysis are necessary in order to confirm initial results.

Lay abstract Osimertinib is an oral drug that inhibits the growth of non-small-cell lung cancer (NSCLC) tumors with a specific mutation in

PURPOSE: The present work aimed at conducting a real-world data analysis on the management costs and survival analysis comparing data from non–small-cell lung cancer (NSCLC) cases diagnosed in the Veneto region before (2015) and after (2017) the implementation of a regional diagnostic and therapeutic pathway including all new diagnostic and therapeutic strategies. METHOD: This study considered 254 incidental cases of NSCLC in 2015 and 228 in 2017 within the territory of the Padua province (Italy), as recorded by the Veneto Cancer Registry. Tobit regression analysis was performed to verify if total and each item costs (2 years after NSCLC diagnosis) are associated with index year, adjusting by year of diagnosis, sex, age, and stage at diagnosis. Logistic regression models were run to study overall mortality at 2 years, adjusting by the same covariates. RESULTS: The 2017 cohort had a lower mortality odd (odds ratio, 0.93; P = .02) and a significant increase in the average overall costs ( P = .009) than the 2015 cohort. The Tobit regression analysis by cost item showed a very significant increase in the average cost of drugs (coefficient = 5,953, P = .008) for the 2017 cohort, as well as a decrease in the average cost of hospice care (coefficient = –1,822.6, P = .022). CONCLUSION: Our study showed a survival improvement for patients with NSCLC as well as an economic burden growth. Physicians should therefore be encouraged to follow new clinical care pathways, while the steadily rising related costs underscore the need for policymakers and health professionals to pursue.

To date, there have been no established therapies for recurrent malignant pleural mesothelioma (MPM) after multimodality treatment. Aims of this retrospective study are to analyze the recurrence pattern, its treatment and to identify the predictors of best oncological outcomes for relapsed MPM, comparing extrapleural pneumonectomy (EPP) vs. pleurectomy/decortication (PD). Study population: 94 patients with recurrence of MPM after multimodality treatment underwent macroscopic complete resection (52.1% with EPP and 47.9% with PD) between July 1994 and February 2020. Distant spread was the most frequent pattern of recurrence (71.3%), mostly in the EPP group, while the PD group showed a higher local-only failure rate. Post-recurrence treatment was administered in 86.2%, whereas best supportive care was administered in 13.8%. Median post-recurrence survival (PRS) was 12 months (EPP 14 vs. PD 8 months, p = 0.4338). At multivariate analysis, predictors of best PRS were epithelial histology (p = 0.026, HR0.491, IC95%0.263–0.916), local failure (p = 0.027, HR0.707, IC95%0.521–0.961), DFS ≥ 12 months (p = 0.006, HR0.298, IC95%0.137–0.812) and post-recurrence medical treatment (p = 0.046, HR0.101, IC95%0.897–0.936). The type of surgical intervention seems not to influence the PRS if patients are fit enough to face post-recurrence treatments. In patients with a prolonged disease-free interval, in the case of recurrence the most appropriate treatment seems to be the systemic medical therapy, even in the case of local-only relapse.