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In the last decade, non-small-cell lung cancer (NSCLC) treatment has improved with the approval of multiple therapies to target specific genetic alterations. Though, next generation sequencing (NGS) has traditionally been conducted from tissue biopsy samples, developing data supports the use of plasma-based circulating tumor DNA (ctDNA), also known as "liquid biopsy," to complement tissue biopsy approaches in guiding front-line therapy. This study is a retrospective analysis of 170 new NSCLC patients treated at 2 cancer centers within a 5-year period who received both tissue and liquid biopsy NGS as standard of care. Based on a treatment schema defined by testing sufficiency, biomarker detection, and turnaround time (TAT), physicians based the majority of their treatments on liquid biopsy results (73.5%) versus tissue biopsy (25.9%). Liquid biopsy NGS returned results on average 26.8 days faster than tissue and reported higher testing success. For guideline-recommended biomarkers, liquid biopsy was 94.8% to 100% concordant with tissue. In comparing testing modalities, a liquid-first approach identified guideline-recommended biomarkers in 76.5% of patients versus 54.9% in a tissue-first approach. There was no significant difference in time-to-treatment, or survival outcomes (overall survival and progression free survival) based on liquid versus tissue biopsy findings. This research demonstrates that liquid biopsy NGS is an effective tool to capture actionable genetic alterations in NSCLC. Due to its high concordance to tissue, faster TAT, and similarity in outcomes and time-to-treatment, liquid biopsy can be used either as a first-line test or concordantly with tissue biopsy to guide treatment decisions in NSCLC.

Squamous cell carcinoma (SCC) of the lung has a markedly different molecular profile to adenocarcinoma of the lung and remains difficult to treat because of the lack of targeted therapies for this type of non-small cell lung cancer (NSCLC). With immune checkpoint inhibitors moving from second-line treatment to first-line in NSCLC, effective second-line options following immunotherapy is an urgent unmet need. Appropriate treatment decisions are currently hindered by a lack of prospective clinical data. However, available real-world data suggest that ramucirumab plus docetaxel warrants prospective evaluation in this setting. Also, afatinib is approved in the second line in patients with SCC progressing on first-line platinum-based chemotherapy and may also be an option following immunochemotherapy combinations. Afatinib has the advantage of oral administration with a well-defined tolerability profile. Docetaxel, gemcitabine and platinum-based chemotherapy may be options for some patients, but overall, there are very few options for patients requiring second-line treatment after immunotherapy. This lack of options has prompted efforts to further define the molecular profile of lung SCC to match patients with relevant targeted therapies and to elucidate additional genomic targets. In order to ensure patients with SCC of the lung receive optimal treatment, genomic testing is essential to identify those patients who might benefit from existing targeted agents or clinical trials, and further prospective data are urgently required to assess potential second-line regimens following immunotherapy.

Because of the refractory nature of mutant KRAS lung adenocarcinoma (LUAD) to current therapies, identification of new molecular targets is essential. Genes with a prognostic role in mutant KRAS LUAD have proven to be potential molecular targets for therapeutic development. Here we determine the clinical, functional, and mechanistic role of inhibitor of differentiation-1 (Id1) in mutant KRAS LUAD. Analysis of LUAD cohorts from TCGA and SPORE showed that high expression of Id1 was a marker of poor survival in patients harboring mutant, but not wild-type KRAS. Abrogation of Id1 induced G2–M arrest and apoptosis in mutant KRAS LUAD cells. In vivo, loss of Id1 strongly impaired tumor growth and maintenance as well as liver metastasis, resulting in improved survival. Mechanistically, Id1 was regulated by the KRAS oncogene through JNK, and loss of Id1 resulted in downregulation of elements of the mitotic machinery via inhibition of the transcription factor FOSL1 and of several kinases within the KRAS signaling network. Our study provides clinical, functional, and mechanistic evidence underscoring Id1 as a critical gene in mutant KRAS LUAD and warrants further studies of Id1 as a therapeutic target in patients with LUAD.Significance:These findings highlight the prognostic significance of the transcriptional regulator Id1 in KRAS-mutant lung adenocarcinoma and provide mechanistic insight into how it controls tumor growth and metastasis.

An Id1 gene signature is dependent of KEAP1-related genes and a FOSL1 network.

Clinical implication of Id1 expression in LUAD patients.

Supplementary tables and figure's headings

A shRNA-resistant Id1 cDNA rescues Id1 loss.

Regulation of kinases by Id1 expression

What is this article about? This plain language summary reports the key points of a recent review article that discussed current treatment options for a type of cancer called squamous cell carcinoma (SCC) of the lung. What is SCC of the lung? SCC of the lung is a type of non-small-cell lung cancer (NSCLC for short) that is usually linked with smoking. It can be difficult to treat because it is often diagnosed after it has spread to other parts of the body. What first-line treatment options are available for people with SCC of the lung? Most patients receive a combination of chemotherapy and immunotherapy as their first-line treatment (the first treatment they receive after their diagnosis). Immunotherapy drugs have improved how long people with SCC of the lung can live for. However, for most patients, they eventually stop working. At this point, other second-line treatments are considered, meaning treatments patients receive after their first-line treatment is stopped due to side effects or because it no longer works. What second-line treatment options are available to people with SCC of the lung? Immunotherapy drugs were originally developed as second-line options after chemotherapy. However, immunotherapy drugs are now used with chemotherapies as first-line treatments. This has left a gap for second-line treatment options. There are some drugs available for second-line treatment, such as afatinib, which comes as a tablet, and docetaxel with or without ramucirumab, which is given as an infusion. Other potential treatments are being developed. What emerging treatment options are being developed? Some early clinical trials of potential treatments have shown promise, but more results are needed. Research into the genetic mutations linked with the development of SCC of the lung is also ongoing. It is hoped that this will help identify patients who might benefit from specific treatments. Who should read this article? People with SCC of the lung and their caregivers, patient advocates, and healthcare professionals, including those who are helping people learn about scientific discoveries and potential new therapeutic strategies.

Despite the significant progress in the treatment of unresectable or metastatic BRAF V600-mutant melanoma, there remains two primary treatment options: targeted therapy and immunotherapy. Targeted therapy or immunotherapy alone is associated with efficacy limitations including efficacy limited to select patient subsets. With separate mechanisms of action and different response patterns, the combination of targeted agents and immunotherapy to treat patients with BRAF V600-mutant melanoma may further improve patient outcomes. Current treatment guidelines recommend treatment with targeted agents alone, immunotherapy, or the combination of targeted agents and immunotherapy. The randomized, double-blind STARBOARD trial aims to evaluate efficacy and safety of encorafenib, binimetinib and pembrolizumab in treatment-naive patients with metastatic or unresectable locally advanced BRAF V600-mutant melanoma in comparison to pembrolizumab.

Background BRAF V600 mutations are frequently found in metastatic melanoma. This mutation constitutively activates the MAPK pathway, which leads to melanoma progression. Patients with BRAF V600-mutant metastatic melanoma typically receive BRAF inhibitors (BRAFi) + MEK inhibitors (MEKi), such as enco + bini, or immune checkpoint inhibitors (CPIs; eg, pembro). However, these have limitations. BRAFi and MEKi may increase BRAF V600-mutant tumor sensitivity to CPIs. Previous studies reported improved progression-free survival (PFS) in patients with advanced BRAF V600-mutant melanoma receiving BRAFi + MEKi + CPI compared with targeted therapy alone. This phase 3 trial will evaluate the efficacy and safety of enco + bini + pembro vs placebo + pembro for unresectable locally advanced or metastatic BRAF V600-mutant melanoma. A safety lead-in (SLI) was built in to determine the recommended phase 3 dose (RP3D) prior to starting phase 3. Trial design STARBOARD (NCT04657991) is a randomized, double-blind, placebo-controlled, phase 3 study evaluating approximately 600 patients with BRAF V600 advanced melanoma. Patients will be stratified by prior systemic adjuvant treatment (CPI, BRAFi/MEKi, or none) and by disease stage (per AJCC 8th edition; IIIB, IIIC, IIID, IV M1a[0], and IV M1b[0] vs IV M1a[1], IV M1b[1], IV M1c[0], IV M1c[1], IV M1d[0], and IV M1d[1]). Patients must have measurable disease (per RECIST 1.1); ECOG performance status of 0 or 1; and adequate bone marrow, hepatic, and renal function. Patients must not have received prior systemic therapy for unresectable or metastatic melanoma; adjuvant treatment with BRAFi/MEKi, anti-PD-1, or anti-CTLA-4 is permitted. Patients cannot have symptomatic brain metastases. Study treatments and end points are shown in Table 1. RP3D was established in May 2022; phase 3 enrollment began in June 2022. Table 1. Study treatments and end points Phase 3 Treatment (21-day cycle) RP3D from SLI: enco + bini + pembro Control: placebo + pembro Primary PFS (RP3D vs control; by BICR) Secondary Key: OS (RP3D vs control) Other: PFS by investigator assessment, objective response rate, duration of response, disease control rate, and time to response, all by BICR and investigator assessment, PFS2, quality of life, safety, pharmacokinetics BICR, blinded independent central review; OS, overall survival. Citation Format: Dirk Schadendorf, Reinhard Dummer, Caroline Robert, Antoni Ribas, Ryan J. Sullivan, Timothy Panella, Meredith McKean, Edgardo S. Santos, Jill Clancy, Anna Polli, Alessandra di Pietro, Paolo A. Ascierto. Randomized phase 3 study (STARBOARD) evaluating encorafenib (enco) + binimetinib (bini) + pembrolizumab (pembro) for first-line treatment of unresectable locally advanced or metastatic BRAF V600-mutant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT069.

Despite the significant progress in the treatment of unresectable or metastaticTargeted therapy, including BRAF- and MEK-inhibitors, and immunotherapies have greatly contributed to advances in the treatment of

Introduction: The recent approvals of checkpoint inhibitors as single agents or in combination with chemotherapy with programmed death ligand 1 expression of < or ≥1% have challenged clinicians when it is time to begin a metastatic lung cancer patient in second-line therapy. The advantages given by immunotherapy over conventional chemotherapy such as improved overall survival and a better toxicity profile make the second-line clinical scenario more difficult for a patient who faces a likely inferior regimen as well as toxicity which may significantly impact the quality of life.Areas covered: Options given today by the National Comprehensive Cancer Network are very limited, and essentially, we go back to conventional cytotoxic agents alone or in combination with biological agents if possible. In this article, we discuss the actual treatment available for this difficult scenario and some of the ongoing trials which aim to address this dilemma.Expert commentary: This is an unmet need in lung cancer management; we need a better understanding of the mechanism of resistance to immunotherapy so we can target them once the patient moves to second-line treatment.

PURPOSE To provide evidence-based recommendations to practicing clinicians on radiographic imaging and biomarker surveillance strategies after definitive curative-intent therapy in patients with stage I-III non–small-cell lung cancer (NSCLC) and SCLC. METHODS ASCO convened an Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary, radiology, primary care, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2000 through 2019. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS The literature search identified 14 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS Patients should undergo surveillance imaging for recurrence every 6 months for 2 years and then annually for detection of new primary lung cancers. Chest computed tomography imaging is the optimal imaging modality for surveillance. Fluorodeoxyglucose positron emission tomography/computed tomography imaging should not be used as a surveillance tool. Surveillance imaging may not be offered to patients who are clinically unsuitable for or unwilling to accept further treatment. Age should not preclude surveillance imaging. Circulating biomarkers should not be used as a surveillance strategy for detection of recurrence. Brain magnetic resonance imaging should not be used for routine surveillance in stage I-III NSCLC but may be used every 3 months for the first year and every 6 months for the second year in patients with stage I-III small-cell lung cancer who have undergone curative-intent treatment.

Because of the refractory nature of mutant KRAS lung adenocarcinoma (LUAD) to current therapies, identification of new molecular targets is essential. Genes with a prognostic role in mutant KRAS LUAD have proven to be potential molecular targets for therapeutic development. Here we determine the clinical, functional, and mechanistic role of inhibitor of differentiation-1 (Id1) in mutant KRAS LUAD. Analysis of LUAD cohorts from TCGA and SPORE showed that high expression of Id1 was a marker of poor survival in patients harboring mutant, but not wild-type KRAS. Abrogation of Id1 induced G2–M arrest and apoptosis in mutant KRAS LUAD cells. In vivo, loss of Id1 strongly impaired tumor growth and maintenance as well as liver metastasis, resulting in improved survival. Mechanistically, Id1 was regulated by the KRAS oncogene through JNK, and loss of Id1 resulted in downregulation of elements of the mitotic machinery via inhibition of the transcription factor FOSL1 and of several kinases within the KRAS signaling network. Our study provides clinical, functional, and mechanistic evidence underscoring Id1 as a critical gene in mutant KRAS LUAD and warrants further studies of Id1 as a therapeutic target in patients with LUAD. Significance: These findings highlight the prognostic significance of the transcriptional regulator Id1 in KRAS-mutant lung adenocarcinoma and provide mechanistic insight into how it controls tumor growth and metastasis.

Objective Big Data is widely seen as a major opportunity for progress in the practice of personalized medicine, attracting the attention from medical societies and presidential teams alike as it offers a unique opportunity to enlarge the base of evidence, especially for older patients underrepresented in clinical trials. This study prospectively assessed the real-time availability of clinical cases in the Health & Research Informatics Total Cancer Care™ (TCC) database matching community patients with cancer, and the impact of such a consultation on treatment. Materials and Methods Patients aged 70 and older seen at the Lynn Cancer Institute (LCI) with a documented malignancy were eligible. Geriatric screening information and the oncologist's pre-consultation treatment plan were sent to Moffitt. A search for similar patients was done in TCC and additional information retrieved from Electronic Medical Records. A report summarizing the data was sent and the utility of such a consultation was assessed per email after the treatment decision. Results Thirty one patients were included. The geriatric screening was positive in 87.1% (27) of them. The oncogeriatric consultation took on average 2.2 working days. It influenced treatment in 38.7% (12), and modified it in 19.4% (6). The consultation was perceived as “somewhat” to “very useful” in 83.9% (26). Conclusion This study establishes a proof of concept of the feasibility of real time use of Big Data for clinical practice. The geriatric screening and the consultation report influenced treatment in 38.7% of cases and modified it in 19.4%, which compares very well with oncogeriatric literature. Additional steps are needed to render it financially and clinically viable.

Introduction The osimertinib (AZD9291) US Expanded Access Program (EAP) provided compassionate access to osimertinib prior to US Food and Drug Administration (FDA) approval for patients with advanced/metastatic epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC) following progression on tyrosine kinase inhibitors (TKIs) targeting EGFR. Here, we report the patient demographics, safety and tolerability, and diagnostic methods used for T790M testing in the EAP. Methods Adult patients with EGFR T790M-positive NSCLC following progression on prior EGFR-TKI therapy (irrespective of line of therapy) were enrolled in the EAP and treated with 80 mg osimertinib once daily until dose reduction, discontinuation, or completion of the EAP following FDA approval (November 2015). Various testing methods were allowed for the required T790M testing. Results In total, 248 patients from 25 centers throughout the USA were enrolled in the EAP. The starting dose of 80 mg osimertinib once daily was maintained for 96% (n = 238) of patients over the duration of the EAP (median duration of exposure 84 days). Most patients (overall 83% [n = 205/238]; patients aged ≥ 75 years 83% [n = 48/58]) completed the EAP and transitioned to commercially available osimertinib following FDA approval. Serious adverse events considered to be treatment related by investigators were reported in five patients (2%), all aged ≥ 65 years, and were dyspnea, deep vein thrombosis, femur fracture, alanine aminotransferase increase, and pneumonitis, respectively. A variety of biospecimen types were collected: solid tumor tissue (73%), blood (20%), cytology (6%), and urine (2%). PCR-based methods were most commonly used for determining EGFR mutation status (47%) followed by next-generation sequencing (33%). Conclusion In a real-world setting, osimertinib was well tolerated, and most patients, including patients aged ≥ 75 years, transitioned to commercially available osimertinib following FDA approval. The EAP suggests there has been an uptake of minimally invasive T790M testing methods at some centers. Funding AstraZeneca (Wilmington, DE, USA).

Options for the treatment of squamous cell lung carcinoma expanded in recent years with the introduction of the immune checkpoint inhibitors into routine clinical practice in both the first- and second-line settings but are still limited. As a result, pembrolizumab, given either alone or in combination with platinum-based chemotherapy, is now a standard first-line treatment for squamous cell lung cancer. However, few options exist once patients have progressed on immune checkpoint inhibitors and chemotherapy. In this setting, the irreversible ErbB family blocker, afatinib, has a potential role as second or subsequent therapy for some patients. The Phase III LUX-Lung 8 study demonstrated that afatinib significantly prolonged progression-free and overall survival compared with erlotinib in patients with squamous cell lung carcinoma. Notably, retrospective, ad-hoc biomarker analyses of a subset of patients from LUX-Lung 8 suggested that patients with ErbB family mutations derived particular benefit from afatinib, especially those with ErbB2 (HER2) mutations. Afatinib has a manageable and predictable safety profile, and adverse events can be managed with the use of a tolerability-guided dose modification protocol. Until more data are available, afatinib could be considered as a potential second-line treatment option for patients who have progressed on combined pembrolizumab and platinum-based chemotherapy and are ineligible for more established second-line options, or as a third-line option in patients who have received first-line immunotherapy, and second-line chemotherapy or chemotherapy and antiangiogenesis therapy. However, further data are required to support the use of afatinib following immunotherapy. Given that treatment options are limited in both of these settings, investigating an agent with an entirely new mechanism of action is warranted. If available, molecular analysis to identify ErbB family mutations or the use of proteomic profiling could help to further isolate patients who are likely to derive the most benefit from afatinib.

INTRODUCTION: We assessed the Aurora A kinase inhibitor, alisertib, plus paclitaxel (henceforth referred to as alisertib/paclitaxel) as second-line treatment for SCLC. METHODS: In this double-blind study, patients with relapsed or refractory SCLC were stratified by relapse type (sensitive versus resistant or refractory) and brain metastases and randomized 1:1 to alisertib/paclitaxel or placebo plus paclitaxel (henceforth referred to as placebo/paclitaxel) in 28-day cycles. The primary end point was progression-free survival (PFS). Associations of c-Myc expression in tumor tissue (prespecified) and genetic alterations in circulating tumor DNA (retrospective) with clinical outcome were evaluated. RESULTS: A total of 178 patients were enrolled (89 in each arm). The median PFS was 3.32 months with alisertib/paclitaxel versus 2.17 months with placebo/paclitaxel (hazard ratio [HR] = 0.77, 95% confidence limit [CI]: 0.557-1.067, p = 0.113 in the intent-to-treat population versus HR = 0.71, 95% CI: 0.509-0.985, p = 0.038 with corrected analysis applied). Among 140 patients with genetic alternations, patients with cell cycle regulator mutations (cyclin-dependent kinase 6 gene [CDK6], retinoblastoma-like 1 gene [RBL1], retinoblastoma-like 2 gene [RBL2], and retinoblastoma 1 gene [RB1]) had significantly improved PFS with alisertib/paclitaxel versus with placebo/paclitaxel (3.68 versus 1.80 months, respectively [HR = 0.395, 95% CI: 0.239-0.654, p = 0.0003]), and overall survival (7.20 versus 4.47 months, respectively [HR = 0.427, 95% CI: 0.259-0.704, p = 0.00085]). A subset of patients with c-Myc expression showed significantly improved PFS with alisertib/paclitaxel. The incidence of grade 3 or higher drug-related adverse events was 67% (58 patients) with alisertib/paclitaxel versus 22% (25 patients) with placebo/paclitaxel. Twelve patients (14%) versus 11 (12%) died on study, including four versus zero treatment-related deaths. CONCLUSIONS: Efficacy signals were seen with alisertib/paclitaxel in relapsed or refractory SCLC. c-Myc expression and mutations in cell cycle regulators may be potential predictive biomarkers of alisertib efficacy; further prospective validations are warranted. ispartof: JOURNAL OF THORACIC ONCOLOGY vol:15 issue:2 pages:274-287 ispartof: location:AUSTRIA, Vienna status: published

Lung cancer, the deadliest cancer worldwide, is of particular concern in Latin America. The rising incidence poses a myriad of challenges for the region, which struggles with limited resources to meet the health care needs of its low- and middle-income populations. In this environment, we are concerned that governments are relatively unaware of the pressing need to implement effective strategies for screening, diagnosis, and treatment of lung cancer. The region has also been slow in adopting molecularly-based therapies in the treatment of advanced disease: testing for epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangements are not routine, and access to targeted agents such as monoclonal antibodies and tyrosine kinase inhibitors is problematic. In this paper, we review the current situation in the management of lung cancer in Latin America, hoping that this initiative will help physicians, patient associations, industry, governments, and other stakeholders better face this epidemic in the near future.

9545 Background: Immune checkpoint inhibition (ICI) has improved outcomes for many treatment-naïve advanced non-small cell lung cancer (NSCLC) patients. However, better biomarkers are needed to predict patient response and guide treatment decisions considering added toxicity and higher cost of combination treatments. A prospectively designed, observational study assessed the ability of a clinically validated, blood-based, host immune classifier (HIC) to predict ICI therapy outcomes. Methods: The study (NCT03289780) includes 33 US sites having enrolled over 3,000 NSCLC patients at any stage and line of therapy. All enrolled patients are tested and designated HIC-Hot (HIC-H) or HIC-Cold (HIC-C) prior to therapy initiation. An interim analysis of secondary and exploratory endpoints was performed after 12- 18 months (mo) follow-up with the first 2,000 enrolled patients. We report the overall survival (OS) of HIC-defined subgroups comprising advanced stage (IIIB and higher) NSCLC patients treated with first-line regimens (284 ICI containing treatments, 877 total first-line patients). Results: In a real-world clinical setting, OS of advanced stage NSCLC treatment-naïve patients receiving platinum-based chemotherapy (n = 392) did not differ significantly from patients receiving any type of ICI containing regimen (n = 284); 11.7 mo vs. 14.4 mo; hazard ratio (HR) = 0.94 [95% confidence interval (CI): 0.76–1.17], p = 0.59. HIC-H patients experienced longer survival than HIC-C across multiple regimens, including ICI. For all ICI, median OS (mOS) was not reached for HIC-H (n = 196, CI: 15.4 mo–undefined) vs. 5.0 mo (n = 88, CI: 2.9 mo–6.4 mo) for HIC-C patients (HR = 0.38 [CI: 0.27–0.53], p < 0.0001). Similar results were seen in the ICI only (16.8 mo vs. 2.8 mo; n = 117, HR = 0.36 [CI: 0.22–0.58], p < 0.0001) and ICI/chemotherapy combination subgroups (unreached vs. 6.4 mo; n = 161, HR = 0.41 [CI: 0.26–0.67], p = 0.0003). In the PD-L1 high cohort (PD-L1 ≥50%), mOS for HIC-H was not reached (n = 81, CI: 13.9 mo–undefined) vs. 3.9 mo (n = 41, CI: 2.1 mo–7.8 mo) for HIC-C (HR: 0.39 [CI: 0.24-0.66], p = 0.0003). HIC results were independent of PD-L1 score (p = 0.81) and remained predictive of OS in first-line ICI-treated patients when adjusted for PD-L1 and other covariates by multivariate analysis (HR = 0.40 [CI: 0.28-0.58], p < 0.0001). Conclusions: Blood-based host immune profiling may provide clinically meaningful information for selecting NSCLC patients for two common ICI containing regimens independent of and complementary to PD-L1 score.

Pembrolizumab is a humanized monoclonal antibody that blocks the programmed cell death 1 (PD-1) pathway, thereby enhancing antitumor immunity. As the use of immune checkpoint inhibitors becomes more prevalent, so do immune-related adverse events associated with their use. The immune-related adverse events linked with this class of drugs are commonly seen and most of the time are classified as mild adverse events. These are easily treated with steroids if recognition of symptomatology and treatment are promptly established. However, neurologic immune-related adverse events are less understood and have been infrequently cited in the medical literature, thus representing a challenge for clinicians.

Introduction The phase II ABOUND.PS2 study (NCT02289456) assessed safety/tolerability of a first-line modified nab-paclitaxel/carboplatin regimen for patients with advanced non-small cell lung cancer (NSCLC) and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2. Methods Chemotherapy-naive patients with stage IIIB/IV NSCLC and ECOG PS 2 received four cycles of nab-paclitaxel 100 mg/m2 days 1 and 8 plus carboplatin area under the curve 5 day 1 q3w (induction). Patients without progression received nab-paclitaxel monotherapy (100 mg/m2 days 1 and 8 q3w) until progression/unacceptable toxicity. Primary endpoint: percentage of patients discontinuing induction due to treatment-emergent adverse events (TEAEs). Results 11/40 treated patients (27.5%; 95% CI, 14.60–43.89) discontinued chemotherapy induction due to TEAEs; 16/40 (40.0%) continued nab-paclitaxel monotherapy. Median progression-free and overall survival were 4.4 (95% CI, 2.99–7.00) and 7.7 (95% CI, 4.93–13.17) months. Grade 3/4 TEAEs during induction included neutropenia (22.5%), anemia (17.5%), thrombocytopenia (5.0%), and peripheral neuropathy (2.5%). Conclusion This nab-paclitaxel–based regimen was tolerable in patients with advanced NSCLC and ECOG PS 2, with efficacy comparable to historical chemotherapy data.

Because of the refractory nature of mutant

Lung cancer is the deadliest cancer worldwide and is of particular concern for Latin America. Its rising incidence in this area of the world poses myriad challenges for the region’s economies, which are already struggling with limited resources to meet the health care needs of low- and middle-income populations. In this environment, we are concerned that regional governments are relatively unaware of the pressing need to implement effective strategies for the near future. Low-dose chest computed tomography (LDCT) for screening, and routine use of minimally invasive techniques for diagnosis and staging remain uncommon. According to results of the National Lung Screening Trial, LDCT lung cancer screening provided a 20% relative reduction in mortality rates among at-risk individuals. Nevertheless, this issue is still a matter of debate, particularly in developing countries, and it is not fully embraced in developing countries. The aim of this article is to provide an overview of what the standard of care is for lung cancer computed tomography screening around the world and to aid understanding of the challenges and potential solutions that can help with the implementation of LDCT in Latin America.

Lung cancer is a public health problem worldwide and Latin America (LATAM) cannot escape this reality. This malignant disease has not only a high prevalence in the region, but is also the main cause of cancer related deaths, and in other emerging countries, the incidence rates are still on the rise. Interestingly in most LATAM countries, lung cancer mortality has been decreasing in men but not in women, reflecting smoking patterns in countries such as Chile, Bolivia, and Brazil. Despite the fact that these issues are well known to government agencies, physicians and patients in the region, current efforts still fall behind those needed in order to face this problem of epidemic proportions. Tobacco control and smoking cessation are the most important interventions against lung cancer, but even with their optimal implementation (which is far from reality at this time) the number of cases in the foreseeable future would still be significant. Beyond tobacco control, advances in our understanding of the molecular component of lung cancer have resulted in new targeted therapies and immune check point inhibitors, which have improved clinical outcomes but at a considerably higher financial cost. LATAM has not widely and speedily adopted these strategies, including new technology and approved novel drugs, due to a number of facts, and therefore only a dismal proportion of LATAMs patient population have benefited from these new advances. A keen focus on a heterogeneous education system for caregivers in lung cancer treatment would likely help standardize care and improve future potential gains from domestic research. In this review we discuss the challenges of treatment implementation, focusing on new technologies.

Purpose of Review The landscape of lung cancer therapy has completely shifted in the last decade. From the surge of targeted therapy to the resurrection of immunotherapy, the need for adequate lung tissue specimen is critical to evaluate tumor specimens for predictive biomarkers for both types of therapies, hence, the importance of obtaining several samples via endoscopic bronchial ultrasound performed by pulmonologists or thoracic surgeons. Moreover, these novel therapies have also been associated with respiratory side effects which will require prompt evaluation and aggressive management by pulmonologists, oncologists, and intensive care unit personnel. Recent Findings Pneumonitis is commonly coined to refer to interstitial lung disease. It is a side effect from checkpoint inhibitors, a type of immunotherapy, which has proved overall survival advantage in lung cancer patients in different clinical settings: first- and second-line therapy for metastatic non-small cell lung cancers as well as for locally advanced disease after being treated with concurrent chemoradiation. Thus, the number of patients who will be exposed to these agents is considerable, and we should expect to see an increased management of this autoimmune phenomenon as well as others. Summary The mechanism of checkpoint inhibitor-induced pneumonitis is not well understood yet, but its management is like that of other autoimmune complications that affect the lung parenchyma. Prompt recognition is critical to avoid a fatal outcome.

Pulmonary blastoma (PB) is a rare biphasic neoplasm. Surgery is the preferred treatment with no consensus on the role of other therapies. We report the clinicopathologic features of PB in three patients. We reviewed the medical records of patients diagnosed with PB at Jackson Memorial Hospital, Miami, FL, since 2009–2012. The mean age at diagnosis was 53 years; two were male and both were heavy smokers. At diagnosis, all cases were symptomatic; two were stage IV with metastatic disease. Two out of three patients were treated with absolute curative surgical resection and both patients had no evidence of disease. Patient with stage IV and resection relapsed in 28 months, received chemotherapy and then radiation without response and died after 33 months. The other surgical patient has no evidence of disease at the end of this study. The patient with unresectable disease received chemotherapy alone attaining partial response. Pathologically, all cases showed biphasic morphology composed of epithelial and spindle cell stroma with mesenchymal differentiation. Immunohistochemical analysis revealed positivity in all cases for thyroid transcription factor, keratin, and epithelial membrane antigen in the epithelial component and negative in the mesenchymal component. In conclusion, surgery was the most beneficial intervention. Chemotherapy has shown mixed responses which is consistent with the literature. Targeted therapies should be explored as additional treatment options in PB.

The large knowledge learned in molecular biology specifically in the oncology field during the last ten years has resulted in fruitful results for the treatment of non-small cell lung cancer. The first pathway to be effectively targeted in lung cancer was the epidermal growth factor receptor. The acceptance of epidermal growth factor receptor mutation as a strong predictive biomarker in non-small cell lung carcinoma has encouraged the search for more targets. In 2011, regulatory entities granted conditional approval to an anaplastic lymphoma kinase inhibitor (crizotinib) based on an impressive overall response rate in previously treated non-small cell lung cancer patients whose tumors harbored EML4/ALK translocations. The landmark approval of crizotinib based on early promising clinical data highlights the remarkable success of molecular medicine in lung cancer therapeutics. The cumulative data developed after that approval has confirmed the appropriateness of this decision as recently reported phase III has now demonstrated. Unfortunately, resistance to this agent invariably develops and we now face the challenge of understanding several resistance pathways and overcoming them with new and more potent compounds. New agents in clinical development such as alectinib, LDK378, AP26113, and AUY922 have not only demonstrated promising activity in crizotinib resistant patients, but also crossing new pharmacokinetic boundaries in ALK inhibition as potent CNS penetration.

Although there has been a significant progress in the recognition and management of the most common chemotherapy side effects, there is limited data on CNS toxicities. Since CNS toxicities can cause significant morbidity and delay or interruption of potentially effective therapies, there is a need for better understanding, early detection, prompt discontinuation of the offending drug, and use of antidotes when available. This review describes neurological toxicities from some of the commonly used chemotherapy agents.

Cyclooxygenase-2 (COX-2) overexpression is associated with a poor prognosis in non-small-cell lung cancer (NSCLC) and may promote resistance to epidermal growth factor receptor inhibitors. This randomized phase 2 trial evaluated apricoxib, a novel COX-2 inhibitor, in combination with erlotinib in biomarker-selected patients. Patients with stage IIIB/IV NSCLC previously treated with platinum-based chemotherapy were randomized (2:1) to 400 mg/day apricoxib plus 150 mg/day erlotinib (AP/E) or placebo plus erlotinib (P/E) in 21-day cycles until disease progression or unacceptable toxicity. The primary endpoint was time to progression (TTP). A decrease of 50% or more from baseline urinary prostaglandin E2 metabolite after a 5-day, open-label, run-in period was used to select eligible patients. One hundred twenty patients (median age 64 years) were randomized (78 to AP/E and 42 to P/E). Overall median TTP was 1.8 months in the AP/E group and 2.1 months in the P/E group, with a 12% objective response rate in both groups (intent-to-treat analysis). A subgroup analysis in patients aged 65 years or younger demonstrated a statistically significant TTP benefit for AP/E (hazard ratio 0.5 [95% confidence interval: not applicable-0.9]; p=0.018) and overall survival advantage at minimum 1-year follow-up (median 12.2 versus 4.0 months; hazard ratio=0.5; p=0.021). The most common adverse events were rash, diarrhea, fatigue, and nausea. Toxicity contributed to early discontinuations in patients aged more than 65 years treated with AP/E. This is the first randomized placebo-controlled study of a COX-2 inhibitor in NSCLC to use a prospective patient-selection strategy. Although AP/E seemed to improve TTP and overall survival in a subset of patients aged 65 years or younger, the primary endpoint of the trial was not met.

Angiogenesis is a crucial mechanism for growth, proliferation and metastasis in many tumor types including lung cancer [1]. The VEGF ligand plays a key role in regulation, both in normal and cancer cells, promoting endothelial cell migration and proliferation necessary for angiogenesis. VEGF is overexpressed in a majority of malignant tumors, including non-small-cell lung cancer (NSCLC), and elevated blood levels of VEGF are associated with tumor aggressiveness and a poor prognosis [2]. Thus, it was logical that inhibiting abnormal blood vessel formation we can induce an antitumor effect [3]. There are many agents that demonstrate anti angiogenic properties but unfortunately, for many years, only bevacizumab (a monoclonal antibody against VEGF ligand) has shown consistent efficacy in several cancer types; however, cancer cells inhibited by bevacizumab escape from its effect by upregulating other proangiogenic molecules such as PDGF and FGF. Hence, ongoing research has focused on developing novel agents that inhibit multiple signaling pathways for angiogenesis [4–7]. The concept of developing multi targeted tyrosine kinase inhibitors (TKIs) is significantly important because it allows us to block several key receptors in the tumor cells, decrease their chance of resistance and, at the same time, keep a selected and tolerable toxicity profile. Unfortunately, in lung cancer, all these multitargeted TKIs have shown controversial results. As an example, sorafenib which was approved for the treatment of renal cell carcinoma and hepatocellular carcinoma [8,9] was studied in lung cancer. Two Phase III trials of first-line chemotherapy for NSCLC (paclitaxel/carboplatin in ESCAPE and gemcitabine/cisplatin in NExUS) alone or in combination with sorafenib failed to demonstrate overall survival (OS) benefit in the sorafenib arms [10,11]. Sunitinib, another oral small molecule inhibitor of VEGF receptor (VEGFR), PDGF receptor (PDGFR), c-Kit and Flt-3, has approval indications for renal cell carcinoma and gastrointestinal stromal tumor [12,13]. Phase II data suggested that sunitinib has single-agent activity in previously treated advanced NSCLC patients with response

SUMMARY Adjuvant cisplatin-based chemotherapy for early-stage non-small-cell lung cancer has become standard of care, after three recent meta-analyses validated survival benefit of approximately 5% at 5 years. Subgroup analyses, however, demonstrated that the benefit appears largely confined to patients with stage II disease; however, 25–30% of patients with stage I disease are at high risk of relapse and death within 5 years. Therefore, there is a need to predict more accurately which patients are likely to relapse after surgery and thus benefit from adjuvant therapy. Recent studies indicate that molecular biomarkers, gene-expression profiling and gene-mutation analysis may not only identify those tumors that are more likely to respond to adjuvant chemotherapy, but also to specific cytotoxic agents. These novel bioanalyses will allow physicians to deliver personalized medicine that utilizes cancer therapeutic drugs more cost effectively, thereby improving response rates and, hopefully, conferring survival advantage.

Introduction: Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) yields tumour responses in non-small cell lung cancer (NSCLC) patients harbouring activating EGFR mutations. However, even in long-lasting responses, resistance to EGFR TKIs invariably occurs. Areas covered: This review examines resistance mechanisms to EGFR TKI treatment, which mainly arise from secondary EGFR mutations. Other resistance-inducing processes include mesenchymal-epithelial transition factor (MET) amplification, epithelial-mesenchymal transformation, phenotypic change from NSCLC to small-cell lung carcinoma, and modifications in parallel signalling pathways. Current therapeutic strategies to overcome these EGFR TKI resistance mechanisms focus on the inhibition or blocking of multiple members of the ErbB family. Several molecules which target multiple ErbB receptors are being investigated in NSCLC and other indications including afatinib, an ErbB Family Blocker, as well as dacomitinib and lapatinib. Novel, non-quinazoline, EGFR inhibitors, that also target EGFR activating and resistance (T790M) mutations, are currently under clinical development. Other therapeutic strategies include inhibition of parallel and downstream pathways, using agents which target heat shock protein (HSP)90 or poly (ADP-ribose) polymerase in addition to mammalian target of rapamycin (mTOR), monoclonal antibodies against the insulin-like growth factor-1 receptor, and fulvestrant-mediated oestrogen receptor regulation. Conclusion: Improved understanding of mechanisms underlying resistance to EGFR TKIs emphasises the importance of a genotype-guided approach to therapy. Elucidation of resistance mechanisms is indeed crucial to target innovative therapeutic approaches and to improve the efficacy of anticancer regimes in NSCLC. (C) 2014 Elsevier Ltd. All rights reserved.

Platinum-based doublets are standard of care for advanced non-small-cell lung cancer (NSCLC). The combination of docetaxel and oxaliplatin has shown acceptable toxicity and encouraging activity. This phase II study aimed to determine the safety and efficacy of this doublet with bevacizumab as first-line treatment for stage IIIB/IV NSCLC.Newly diagnosed patients ≥18 years with histologically proven non-squamous NSCLC and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2 received six 21-day cycles of docetaxel, oxaliplatin, and bevacizumab followed by single-agent bevacizumab for a total of 1 year. Primary efficacy end point was radiographically documented progression-free survival (PFS); secondary end points included objective response rate (ORR), overall survival (OS), time to treatment failure, and safety.Fifty-three patients were enrolled. Median age was 62.0 years, 71.7 % male, 79.2 % Caucasian. A total of 88.7 % had stage IV or recurrent disease; 94.3 % adenocarcinoma; and 94.3 % ECOG PS 0 or 1. Efficacy results are as follows: median PFS 5.6 months, ORR 30.2 % (complete response 1.9 %, partial response 28.3 %); 37.7 % stable disease; and OS 14.0 months. At least one adverse event (AE) was reported in all patients (n = 52); 98.1 % of AEs were treatment related. The most common treatment-emergent grade ≥3 AEs were neutropenia (15.4 %), diarrhea (13.5 %), and fatigue (11.5 %). A serious AE was present in 32.7 %; the most common were pneumonia (7.7 %) and abdominal pain (5.8 %). Dehydration, diarrhea, febrile neutropenia, sepsis, and supraventricular tachycardia each occurred in 3.8 %.The addition of bevacizumab to docetaxel/oxaliplatin is effective with an acceptable safety profile in patients with chemotherapy-naïve advanced NSCLC.

Concurrent chemoradiation is considered the standard-of-care for locally advanced head and neck cancer of the hypopharynx, oropharynx and larynx, as well as unresectable disease. This paradigm was challenged by the introduction of induction chemotherapy (IC), which demonstrated non-inferiority in regards of overall survival (OS), along with increased organ preservation, when compared to the surgery and radiotherapy. More recently, IC followed by concurrent chemoradiation, the so-called sequential approach was developed in an attempt to decrease metastatic spread and improve locoregional control (LRC) rates, with much controversy amongst experts. A careful evaluation by a multidisciplinary team is necessary to recognize which patients should be offered this therapeutic approach due to a significantly greater rate of toxicity. Herein, we analyze the most current available evidence regarding the use of sequential therapy versus concurrent chemoradiation. Different factors including toxicity profile, adherence and patient characteristics play a major role in choosing the most appropriate treatment regimen.

SUMMARY We know how important antiangiogenesis therapy can be in cancer treatment. However, it took some time before the first compound became approved. Currently, several agents are approved and used against cancer. Moreover, the possible number of clinical indications and agents that are in development is extraordinary. A lot of questions regarding angiogenesis in cancer still remain unanswered. One of the major weaknesses is the fact that most of the approved agents do not have a predictive or prognostic biomarker that can be used to tailor these novel agents in terms of inducing the best possible antitumor effect. Many of these new targeted agents inhibit several tumorigenesis pathways, but most of the time only one of these pathways is the main driver for cancer proliferation. In this article, we present the most current clinical information available in antiangiogenic therapy and the potential development in non-small-cell lung cancer.