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Malignant pleural mesothelioma (MPM) is a tumour associated with asbestos exposure. Approximately, 10% of patients with MPM carry a germline pathogenic variant (PV), mostly in DNA repair genes, suggesting the occurrence of inherited predispositions.This article aimed to 1) search for new predisposing genes and assess the prevalence of PVs in DNA repair genes, by next-generation sequencing (NGS) analysis of germline DNA from 113 unselected patients with MPM and 2) evaluate whether these patients could be sensitive to tailored treatments.NGS was performed using a custom panel of 107 cancer-predisposing genes. To investigate the response to selected drugs in conditions of DNA repair insufficiency, we created a three-dimensional-MPM cell model that had a defect in ataxia telangiectasia mutated (ATM), the master regulator of DNA repair.We identified PVs in approximately 7% of patients with MPM (8/113) and a new PV in BAP1 in a further patient with familial MPM. Most of these PVs were in genes involved or supposedly involved in DNA repair (BRCA1, BRIP1, CHEK2, SLX4, FLCN and BAP1). In vitro studies showed apoptosis induction in ATM-silenced/inhibited MPM spheroids treated with an enhancer of zeste homologue 2 inhibitor (tazemetostat).Overall these data suggest that patients with MPM and DNA repair insufficiency may benefit from this treatment, which induces synthetic lethality.

The outcomes of patients with SCLC have not yet been substantially impacted by the revolution in precision oncology, primarily owing to a paucity of genetic alterations in actionable driver oncogenes. Nevertheless, systemic therapies that include immunotherapy are beginning to show promise in the clinic. Although, these results are encouraging, many patients do not respond to, or rapidly recur after, current regimens, necessitating alternative or complementary therapeutic strategies. In this review, we discuss ongoing investigations into the pathobiology of this recalcitrant cancer and the therapeutic vulnerabilities that are exposed by the disease state. Included within this discussion, is a snapshot of the current biomarker and clinical trial landscapes for SCLC. Finally, we identify key knowledge gaps that should be addressed to advance the field in pursuit of reduced SCLC mortality. This review largely summarizes work presented at the Third Biennial International Association for the Study of Lung Cancer SCLC Meeting.

Background Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonistplus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial.Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m 2 (60 mg/m 2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues.Findings Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7.4 months (IQR 3.5-13.9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4.1 months [95% CI 3.3-4.8] vs 2.8 months [2.6-2.9]; HR 0.696 [95% CI 0.573-0.845]; p=0.0002). Median overall survival was 9.4 months (95% CI 7.9-11.4) in the ramucirumab group versus 7.9 months (7.0-9.3) in the placebo group (stratified HR 0.887 [95% CI 0.724-1.086]; p=0.25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group.Interpretation Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Introduction The hepatocyte growth factor receptor mesenchymal-epithelial transition (MET) is reported to be a negative prognostic marker in EGFR-mutant NSCLC and involved in resistance to EGFR inhibitors. Emibetuzumab, a humanized immunoglobulin G4 monoclonal bivalent MET antibody, blocks ligand-dependent and ligand-independent hepatocyte growth factor/MET signaling. This phase 2 study compared erlotinib with and without emibetuzumab in first-line treatment of EGFR-mutant metastatic NSCLC. Methods Patients with stage IV EGFR-mutant NSCLC and disease control after an 8-week lead-in with erlotinib (150 mg daily) were randomized to continue taking erlotinib with or without emibetuzumab (750 mg every 2 weeks). The primary end point was progression-free survival (PFS). Additional end points included overall survival, overall response rate, safety, pharmacokinetics, and exploratory analysis of MET expression. Results No significant difference in median PFS was observed in the intent-to-treat population (9.3 months with emibetuzumab + erlotinib versus 9.5 months with erlotinib monotherapy [hazard ratio (HR) = 0.89, 90% confidence interval (CI): 0.64–1.23]). The median overall survival was 34.3 months with emibetuzumab plus erlotinib versus 25.4 months with erlotinib (HR = 0.74, 90% CI: 0.49–1.11). Emibetuzumab plus erlotinib was well tolerated, with peripheral edema and mucositis as the only adverse events occurring 10% or more frequently relative to erlotinib. Exploratory post hoc analysis showed an improvement of 15.3 months in median PFS for the 24 patients with the highest MET expression (MET expression level of 3+ in ≥90% of tumor cells) (20.7 with emibetuzumab + erlotinib versus 5.4 months with erlotinib [HR = 0.39, 90% CI: 0.17–0.91]). Conclusions No statistically significant difference in PFS was noted in the intent-to-treat population. Exploratory analysis confirmed that high MET expression is a negative prognostic marker for patients treated with erlotinib, indicating that emibetuzumab plus erlotinib may provide clinically meaningful benefit.

Malignant pleural mesothelioma (MPM) is a global health issue, the principal cause of which is exposure to asbestos. The prevalence is anticipated to rise over the next 2 decades, particularly in developing countries, due to the 30-50-year latency period between exposure to asbestos and carcinogenic development. Unresectable MPM has a poor prognosis and limited treatment options and, as such, there is a broad range of therapeutic targets of interest, including angiogenesis, immune checkpoints, mesothelin, as well as chemotherapeutic agents. Recently, the results of several randomized trials in the first-line setting combining antiangiogenic agents with chemotherapy have been reported. This review examines the scientific rationale for targeting angiogenesis in the treatment of unresectable MPM and analyzes recent clinical results with antiangiogenic agents in development (bevacizumab, nintedanib, and cediranib) for the management of MPM.

The global coronavirus disease 2019 pandemic continues to escalate at a rapid pace inundating medical facilities and creating substantial challenges globally. The risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with cancer seems to be higher, espe- cially as they are more likely to present with an immuno- compromised condition, either from cancer itself or from the treatments they receive. A major consideration in the delivery of cancer care during the pandemic is to balance the risk of patient exposure and infection with the need to provide effective cancer treatment. Many aspects of the SARS-CoV-2 infection currently remain poorly characterized and even less is known about the course of infection in the context of a patient with cancer. As SARS-CoV-2 is highly contagious, the risk of infection directly affects the cancer patient being treated, other cancer patients in close prox- imity, and health care providers. Infection at any level for patients or providers can cause considerable disruption to even the most effective treatment plans. Lung cancer pa- tients, especially those with reduced lung function and cardiopulmonary comorbidities are more likely to have increased risk and mortality from coronavirus disease 2019 as one of its common manifestations is as an acute respi- ratory illness. The purpose of this manuscript is to present a practical multidisciplinary and international overview to assist in treatment for lung cancer patients during this pandemic, with the caveat that evidence is lacking in many areas. It is expected that firmer recommendations can be developed as more evidence becomes available. (C) 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Introduction This exploratory subgroup analysis of the MARQUEE study evaluated the efficacy and safety of erlotinib plus tivantinib in patients with EGFR -mutant NSCLC. Methods Patients with advanced, nonsquamous, EGFR and mesenchymal-epithelial transition inhibitor–naive NSCLC previously treated with one or two lines of systemic therapy were randomized to oral erlotinib (150 mg once daily) plus tivantinib (360 mg twice daily) or to erlotinib plus placebo. The primary end point was overall survival. Results Among 1048 patients enrolled, 109 (10.4%) had EGFR -mutant disease. Erlotinib plus tivantinib improved progression-free survival in this subpopulation; median progression-free survival was 13.0 months for erlotinib plus tivantinib (n = 56) and 7.5 months for erlotinib plus placebo (n = 53) (hazard ratio = 0.49, 95% confidence interval: 0.31–0.77). Deaths occurred in 73 patients (67%), and median overall survival was 25.5 months in the erlotinib plus tivantinib arm versus 20.3 months in the erlotinib plus placebo arm (hazard ratio = 0.68, 95% confidence interval: 0.43–1.08). Common adverse events included diarrhea, rash, and asthenia. Neutropenia and febrile neutropenia were more common with erlotinib plus tivantinib. Conclusions Erlotinib plus tivantinib was tolerable and showed improved efficacy over erlotinib monotherapy in previously treated EGFR -mutant NSCLC.

The available fluoropyrimidines and oxaliplatin combinations for colorectal cancer patients have different safety profiles. The aim of this systematic review was to compare their toxicities. The eligible studies were classified as: no bolus; 5-FU single bolus; 5-FU double bolus; capecitabine. We calculated the incidence of "any-grade" and "severe" toxicity for haematological and non-haematological adverse events of each group. We identified 184 treatment groups; compared to 5-FU double bolus, except for high-grade anaemia, all the groups showed reduced risk of haematological toxicities, with the most relevant advantages for single bolus regimens. Concerning non-haematological toxicities, compared to double bolus, the single bolus group showed a statistically significant reduced risk for many gastrointestinal toxicities and for pheripheral neuropathy. This is the first systematic review of the toxicity profile of different 5-FU or capecitabine and oxaliplatin regimens. Single 5-FU bolus is associated with a definitely favourable toxicity profile, both for haematological and non-haematological toxicity.

Introduction Malignant pleural mesothelioma (MPM) is a rare, highly aggressive, and relatively chemoresistant and radioresistant malignancy with limited therapeutic options. Our objective was to investigate the prevalence of programmed death ligand 1 (PD-L1) and the characteristics of the immune environment in this disease. Methods A total of 99 archival tumors from advanced-stage MPM were immunohistochemically tested in parallel for PD-L1 in two different laboratories, and 87 of them were profiled for immune gene expression by NanoString analysis for 800 genes. A prior study on the same samples indicated a low mutational load with a complex mutational landscape of genetic variations more frequently associated with the p53/DNA repair and phosphoinisitide-3-kinase pathways. Results PD-L1 expression was found in 16% of the MPM tumor samples, either in the tumor cells or the infiltrating immune cells. Gene expression analysis suggested that MPM is an inflamed tumor type and can be classified into three different subgroups on the basis of the different expression profiles of immune-related genes, of which two groups showed varying degrees of expression of immune-related genes. Overall, these molecular findings suggest that these subgroups of MPM associated with PD-L1 positivity and expression of immune-related genes accounting for 60% of MPMs represent a candidate subtype that may respond to cancer immunotherapy. Conclusions These data suggest that 60% of patients with MPM characterized by either PD-L1 expression or an inflamed status are attractive candidates for cancer immunotherapeutic options.

Objectives Non-small-cell-lung-cancer (NSCLC) in young adults (≤45 years-old) accounts for a very small proportion, as this disease usually occurs in people at older age. The youthful NSCLC may constitute an entity with different clinical-pathologic characteristics, having predominance of adenocarcinoma histology and affecting mostly non-smoker subjects. However, without specific guidelines, it is currently considered, both clinically and biologically, as the same disease of the older counterpart, although differences have been documented. Materials and methods Using formalin-fixed paraffin embedded diagnostic tissues (FFPE), targeted next-generation sequencing (NGS) technology allowed to provide insight the mutational pattern of 46 oncogenes and tumor-suppressor genes in 26 young patients (Y). Two additional populations, including a FFPE series of aged counterpart (A: 29 patients) and a group of healthy young controls (C: 21, blood provided), were also investigated to compare NGS profiles. Results Clinical features of enrolled young patients harmonized with literature data, being most of patients women (58%), never-smokers (38%) and with adenocarcinoma histology (96%). C group was adopted to filter all the non-synonymous genetic variations (NS-GVs) not-associated with malignant overt disease. This skimmed selection mostly highlighted three genes: TP53, EGFR and KRAS. TP53 NS-GVs were numerically more numerous in younger, many involving specific annotated hotspot (R248, R273, G245, R249 and R282); the majority of EGFR NS-GVs was detected in young patients, with higher allelic frequency and mostly represented by exon 19 deletions. On the contrary, KRAS NS-GVs were mainly detected in aged population, with a prevalent compact pattern involving p.G12 position and associated with adenocarcinoma histology. Conclusion This retrospective study confirmed the feasibility of NGS approach for genetic characterization of NSCLC young adult patients, supporting the involvement of TP53, EGFR, and KRAS alterations in the early onset of NSCLC. Some of these GVs, or their pattern, may potentially contribute to customized targeted therapies.

In clinical practice, elderly patients are often undertreated relative to younger patients. This meta-analysis was designed to determine whether older patients with non-squamous non-small cell lung cancer (NSCLC) could derive an overall survival (OS) benefit from pemetrexed treatment comparable to that experienced by younger patients in the first-line, second-line, or maintenance settings.Data from 2671 patients with non-squamous NSCLC participating in four pemetrexed phase III studies were included in a meta-analysis using a random-effects model. Studies included were: JMEI (second-line pemetrexed, N=399); JMDB (first-line pemetrexed/cisplatin, N=1252); JMEN (pemetrexed maintenance after non-pemetrexed/platinum doublet, N=481); and PARAMOUNT (pemetrexed maintenance after first-line pemetrexed/cisplatin, N=539). Patients were predominantly Eastern Cooperative Oncology Group performance status (PS) 0/1. The ratio of OS hazard ratio (HR) (pemetrexed versus control) for younger patients over that for older patients within each study was used as the measure of the differential effect of pemetrexed. Data were examined using age cutoffs of 65 and 70 years.Among the four studies, 32% of patients were aged ≥65 years and 14% were aged ≥70 years. The test of heterogeneity among studies was non-significant for subgroups defined by age 65 (P=0.083) and age 70 (P=0.848). The pooled ratio of the OS HR (pemetrexed versus control) in patients65years to that in patients ≥65 years was 0.92 (95% confidence intervals [CI] 0.67-1.25). Similar results were seen for the analysis using the age 70 years cut-off (0.80 [95% CI 0.62-1.04]).In patients with non-squamous NSCLC with good PS, the effect of pemetrexed on OS was not found to be different in younger and older patients undergoing treatment in the first-line, second-line, or maintenance settings.

Introduction Mucin-rich lung adenocarcinomas (ADCs), namely mucinous and colloid ADCs, are classified as ADC variants according to the World Health Organization 2015 classification. A correlation between morphological patterns and mutational status of these rare entities is not well established. Methods We investigated the mutational profile of mucin-rich lung ADCs in correlation with histopathological and morphological features with the goal of identifying biological tumor characteristics of potential prognostic and therapeutic interest. A series of 54 surgically resected primary mucinous lung ADC samples were retrospectively analyzed for clinicopathological characteristics and by targeted next-generation sequencing. Results Fifty cases were invasive mucinous ADCs (32 pure and 18 mixed) and four were colloid-predominant ADCs. Invasive mucinous ADC cases with a pure mucinous pattern were associated with a lower risk of vascular invasion ( p = 0.01), absence of signet ring cells ( p = 0.03), negative nodal status ( p = 0.006), and early clinical stage ( p = 0.02). The most prevalent mutations involved the Kirsten rat sarcoma viral oncogene homolog gene ( KRAS ) and tumor protein p53 gene ( TP53 ). Most mutations clustered in the mitogen-activated protein/protein kinase B pathway and in the p53/DNA repair pathway. A few uncommon epidermal growth factor receptor gene ( EGFR ) mutations were found. A correlation between a higher number of mutations and favorable clinical outcome was seen ( p Conclusions Our data showed that mucinous ADCs have peculiar pathological and molecular features that might suggest the need for a differentially tailored therapeutic approach compared with that to conventional lung ADC.

Immunotherapy-based options for patients with advanced non-small cell lung cancer (NSCLC) are increasing at an unprecedented pace, carrying the promise to prolong survival of this deadly disease. To maximize responses and extend benefit to a larger portion of patients, immunotherapy combination strategies are currently under investigation, with chemo-immunotherapy already in use. Combinations of programmed death-1/ligand-1 (PD-1/L1) and cytotoxic T lymphocytes antigen-4 (CTLA-4) were developed with the rationale of targeting complementary pathways involved in T cell activation, and already showed to be highly active in other malignancies. Recently, the phase III Checkmate 227 trial showed that combination of nivolumab and ipilimumab provided survival benefit in untreated advanced NSCLC patients. However, accurate patients' selection and appropriate sequencing of different immunotherapy-based approaches remain unsolved. In this review, we provide an overview of the currently available evidence on double immune checkpoint inhibition (ICI) for NSCLC treatment and discuss current issues and future perspectives.

Testosterone suppression by androgen deprivation therapy is the cornerstone of prostate cancer treatment. New-generation hormone therapies improved overall survival in castration-resistant prostate cancer. More recent trials showed a further increase in overall survival when enzalutamide or abiraterone are associated with androgen deprivation therapy in hormone-sensitive disease. However, a higher clonal pressure may lead to the upregulation of alternative pathways for cancer progression and to dedifferentiated diseases that would probably respond poorly to subsequent treatments. In this contest, new strategies that could be able to delay or even revert resistance are needed. The bipolar androgen therapy is an under-investigation treatment that consists in periodical oscillation between castration levels and supraphysiological levels of testosterone in order to prevent the adaptation of prostate cancer cells to a low-androgen environment. This review aims to underline the biological rationale of bipolar androgen therapy and gather evidences from the most recent clinical trials.

Incidence of bone metastases is very high in advanced prostate cancer patients. Bone metastases likely have a significant impact on functional status and quality of life, not only related to pain, but also to the relevant risk of skeletal-related events. A better understanding of mechanisms associated with bone metastatic disease secondary to prostate cancer and more specifically to the cross-talk between tumor cells and bone microenvironment in metastatic progression represented the background for the development of new effective bone-targeted therapies. Furthermore, a better knowledge of biological mechanisms driving disease progression led to significant advances in the treatment of castration-resistant prostate cancer, with the development and approval of new effective drugs. Aim of this review is to outline the physiopathology of bone metastases in prostate cancer and summarize the main results of clinical trials conducted with different drugs to control morbidity induced by skeletal metastases and bone disease progression. For each agent, therapeutic effect on bone metastases has been measured in terms of pain control and/or incidence of skeletal-related events, usually defined as a composite endpoint, including the need for local treatment (radiation therapy or surgery), spinal cord compression, pathological bone fractures. In details, data obtained with chemotherapy (mitoxantrone, docetaxel, cabazitaxel), new generation hormonal agents (abiraterone, enzalutamide), radium-223, bone-targeted agents (zoledronic acid, denosumab) and with several experimental agents (cabozantinib, dasatinib, anti-endothelin and other agents) in patients with castration-resistant prostate cancer are reviewed.

The correct pathologic classification of adrenocortical carcinoma (ACC) is relevant to establish an early therapeutic strategy of this rare malignancy. The aim of the study was to assess the most frequent pitfalls in ACC diagnosis reviewing a large consecutive series of 300 cases with an original diagnosis or a clinical suspect of ACC, which were sent in consultation to our institution between 2004 and 2014. A major disagreement that significantly modified the clinical management of patients was recorded in 26 cases (9%). The most common pitfall (10 cases) was to distinguish ACC from pheochromocytoma and vice versa. Seven other cases diagnosed as ACC were reclassified as metastases from other primaries and primary adrenal soft tissue tumors (including 3 angiosarcomas). Finally, 5 adrenocortical adenomas were reclassified into carcinomas, and 4 ACCs were converted into adenomas. Minor disagreements were mostly related to the identification of ACC variants (up to 32% of cases of adrenocortical tumors in the present series). Moreover, more than 50% of ACC cases lacked Ki-67. In conclusion, our results indicate that, in the presence of a histologically suspected ACC, a special attention should be devoted to exclude metastatic and soft tissue tumors and pheochromocytoma (in this latter case with special reference to the oncocytic variant of adrenocortical tumors). Moreover, pathologists should be aware of the major role of Ki-67 in determining prognosis and in selecting patients to the most appropriate treatment.

Background In this study, our aim was to describe quality of life (QoL) prevalence and heterogeneity in QoL reporting in colorectal cancer phase III trials. Methods We included all phase III trials evaluating anticancer drugs in colorectal cancer patients published between 2012 and 2018 by 11 major journals. Results Out of the 67 publications identified, in 41 (61.2 %) QoL was not listed among endpoints. Out of 26 primary publications of trials including QoL among endpoints, QoL results were not reported in 10 (38.5 %). Overall, no QoL data were available in 51/67 (76.1 %) primary publications. In particular, in the metastatic setting, QoL data were not available in 12/18 (66.7 %) trials with primary endpoint overall survival, and in 20/29 (69.0 %) trials with other primary endpoints. Conclusions QoL was absent in a high proportion of recently published phase III trials in colorectal cancer, even in trials of second or further lines, where attention to QoL should be particularly high.

Introduction The vast majority of non–small-cell lung cancers (NSCLCs) presents as advanced disease, and histological diagnosis is widely based on small samples. The differential activity and toxicity profile of new cytotoxic and molecular-targeted therapies according to histotypes requires a precise subtyping of NSCLC. Immunohistochemistry (IHC) contributes to define the most probable histotype; however, the real impact of IHC characterization of NSCLC-not otherwise specified (NOS) in terms of outcome is not well established. Methods A large series of 224 advanced "nonsquamous" NSCLC diagnosed on small biopsy or cytological samples and homogeneously treated was retrospectively selected, all having adequate follow-up data available. Reviewed diagnoses resulted into two groups: adenocarcinoma (ADC) and NSCLC-NOS. The latter was further characterized by IHC (TTF-1, Napsin-A, p40, and Desmocollin-3) –identify a possible, most probable differentiation lineage. Results Sixty-seven percentage of cases were classified as ADC based on morphological examination only ("morphological ADC") and 33% as NSCLC-NOS. IHC profiling of NSCLC-NOS identified 43.2% of cases with an ADC immunophenotype ("NSCLC favor ADC"), 10.8% with a phenotype favoring squamous lineage, and 46% lacking differentiation features. Survival curves confirmed no difference in terms of outcome between the morphological ADC and the NSCLC favor ADC groups, while a significantly poorer outcome was found in the "null" group in terms of best response, progression-free survival or overall survival (OS). Conclusion Tumors with an IHC profile ADC-like had an OS comparable with that of morphological ADCs. These findings support the use of IHC to optimize lung cancer histological typing and therapy.

Introduction The phase 3 MONET1 study evaluated motesanib (a small-molecule inhibitor of vascular endothelial growth factor receptors) plus carboplatin/paclitaxel versus placebo plus carboplatin/paclitaxel as first-line therapy for advanced non–small-cell lung cancer (NSCLC). Treatment and enrollment of patients with squamous histology were permanently discontinued following higher early mortality and gross hemoptysis in those with squamous NSCLC who received motesanib. Enrollment of patients with nonsquamous histology was temporarily halted, but resumed following a protocol amendment (Scagliotti et al. J Clin Oncol . 2012;30:2829–2836). Herein, we report data from the squamous cohort. Methods Patients with stage IIIB/IV or recurrent squamous NSCLC (without prior systemic therapy for advanced disease) received up to six 3-week cycles of chemotherapy (carboplatin, area under the curve 6 mg/mL•min/paclitaxel, 200 mg/m 2 ) and were randomized 1:1 to receive motesanib 125 mg (Arm A) or placebo (Arm B) once daily. The primary end point was overall survival. Results Three-hundred and sixty patients with squamous NSCLC were randomized (Arm A, n = 182; Arm B, n = 178) between July 2007 and November 2008. Twenty-three patients (13%) in Arm A and 10 (6%) in Arm B had fatal adverse events within the first 60 days of treatment. Among these, six patients in Arm A, but none in Arm B, had fatal bleeding events. At final analysis, serious adverse events had occurred in 47% of patients in Arm A and 29% of patients in Arm B. Median overall survival was similar in Arms A and B (11.1 versus 10.7 months). Conclusions Motesanib plus carboplatin/paclitaxel had unacceptable toxicity compared with carboplatin/paclitaxel alone in patients with advanced squamous NSCLC.