Beyond tobacco: genomic disparities in lung cancer between smokers and never-smokers.

BACKGROUND: Tobacco use is one of the main risk factors for Lung Cancer (LC) development. However, about 10-20% of those diagnosed with the disease are never-smokers. For Non-Small Cell Lung Cancer (NSCLC) there are clear differences in both the clinical presentation and the tumor genomic profiles between smokers and never-smokers. For example, the Lung Adenocarcinoma (LUAD) histological subtype in never-smokers is predominately found in young women of European, North American, and Asian descent. While the clinical presentation and tumor genomic profiles of smokers have been widely examined, never-smokers are usually underrepresented, especially those of a Latin American (LA) background. In this work, we characterize, for the first time, the difference in the genomic profiles between smokers and never-smokers LC patients from Chile. METHODS: We conduct a comparison by smoking status in the frequencies of genomic alterations (GAs) including somatic mutations and structural variants (fusions) in a total of 10 clinically relevant genes, including the eight most common actionable genes for LC (EGFR, KRAS, ALK, MET, BRAF, RET, ERBB2, and ROS1) and two established driver genes for malignancies other than LC (PIK3CA and MAP2K1). Study participants were grouped as either smokers (current and former, n = 473) or never-smokers (n = 200) according to self-report tobacco use at enrollment. RESULTS: Our findings indicate a higher overall GA frequency for never-smokers compared to smokers (58 vs. 45.7, p-value < 0.01) with the genes EGFR, KRAS, and PIK3CA displaying the highest prevalence while ERBB2, RET, and ROS1 the lowest. Never-smokers present higher frequencies in seven out of the 10 genes; however, smokers harbor a more complex genomic profile. The clearest differences between groups are seen for EGFR (15.6 vs. 21.5, p-value: < 0.01), PIK3CA (6.8 vs 9.5) and ALK (3.2 vs 7.5) in favor of never-smokers, and KRAS (16.3 vs. 11.5) and MAP2K1 (6.6 vs. 3.5) in favor of smokers. Alterations in these genes are comprised almost exclusively by somatic mutations in EGFR and mainly by fusions in ALK, and only by mutations in PIK3CA, KRAS and MAP2K1. CONCLUSIONS: We found clear differences in the genomic landscape by smoking status in LUAD patients from Chile, with potential implications for clinical management in these limited-resource settings.

Clinical Experience With 75-mg Dose of Erlotinib for Mutated Metastatic EGFR Non-small Cell Lung Cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer death worldwide, although important advances in target therapy have been developed in the past few years. Erlotinib is a reversible epidermal growth factor receptor (EGFR) inhibitor, which was approved at its maximum tolerated dose of 150 mg/d determined from the initial phase I study. Studies suggest that the optimal biological dose of erlotinib should be lower and dependent on different variables. STUDY QUESTION: We aimed to evaluate the response rates and toxicity with 75 mg/d dose of erlotinib in South American patients. METHOD: We performed a retrospective review of 18 patients with histologically proven (+) EGFR (+) mutation metastatic NSCLC (mNSCLC) treated with 75 mg/d erlotinib as starting dose. MEASURES AND OUTCOMES: Clinical information, including toxicity grade 1-4, drug discontinuation, clinical evolution and radiological evaluation, and overall survival (OS), was revised. RESULTS: Patients received 75 mg/d of erlotinib as starting dose. Sixteen (89%) patients were treated in first-line treatment and 2 (11%) in second-line treatment. Mean age was 62 years (range 36-89 years), and 50% patients were female. Sixteen percent of the patients had brain metastases at first diagnosis. All patients had mutation positive EGFR, 12 (66%) had Del19 and 6 (34%) exon 21 mutation. Median progression-free survival was 17 months and OS 23 months. The main grade 1-2 toxicities were rash (44%) and diarrhea (22%). No grade 3-4 toxicity and no cases of drug discontinuation were reported. CONCLUSIONS: In South American population with mutated mNSCLC, a dose of 75 mg/d of erlotinib was well tolerated. This dose resulted in comparable benefits in progression-free survival and OS when compared to those reported in the literature with the standard dose. More studies are needed to explore the use of adjusted doses of biological agents in different ethnic backgrounds.

Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial.

BACKGROUND: Docetaxel plus prednisone is standard first-line chemotherapy for men with metastatic castrate-resistant prostate cancer. Aflibercept is a recombinant human fusion protein that binds A and B isoforms of VEGF and placental growth factor, thereby inhibiting angiogenesis. We assessed whether the addition of aflibercept to docetaxel and prednisone would improve overall survival in men with metastatic castrate-resistant prostate cancer compared with the addition of placebo to docetaxel and prednisone. METHODS: VENICE was a phase 3, multicentre, randomised double-blind placebo-controlled parallel group study done in 31 countries (187 sites). Men with metastatic castrate-resistant prostate cancer, adequate organ function, and no prior chemotherapy were treated with docetaxel (75 mg/m(2) intravenously every 3 weeks) and oral prednisone (5 mg twice daily) and randomly allocated (1:1) to receive aflibercept (6 mg/kg) or placebo, intravenously, every 3 weeks. Treatment allocation was done centrally via an interactive voice response system, using a computer-generated sequence with a permuted-block size of four and stratified according Eastern Co-operative Group performance status (0-1 vs 2). Patients, investigators, and other individuals responsible for study conduct and data analysis were masked to treatment assignment. Aflibercept or placebo vials were supplied in identical boxes. The primary endpoint was overall survival using intention-to-treat analysis. This is the primary analysis of the completed trial. The study is registered with ClinicalTrials.gov, number NCT00519285 FINDINGS: Between Aug 17, 2007, and Feb 11, 2010, 1224 men were randomly allocated to treatment: 612 to each group. At final analysis, median follow-up was 35 months (IQR 29-41) and 873 men had died. Median overall survival was 22·1 months (95·6% CI 20·3-24·1) in the aflibercept group and 21·2 months (19·6-23·8) in the placebo group (stratified hazard ratio 0·94, 95·6% CI 0·82-1·08; p=0·38). We recorded a higher incidence of grade 3-4 gastrointestinal disorders (182 [30%] vs 48 [8·0%]), haemorrhagic events (32 [5·2%] vs ten [1·7%]), hypertension (81 [13%] vs 20 [3·3%]), fatigue (97 [16%] vs 46 [7·7%]), infections (123 [20%] vs 60 [10%]) and treatment-related fatal adverse events (21 [3·4%] vs nine [1·5%]) in the aflibercept group than in the placebo group. INTERPRETATION: Aflibercept in combination with docetaxel and prednisone given as first-line chemotherapy for men with metastatic castrate-resistant prostate cancer resulted in no improvement in overall survival and added toxicity compared with placebo. Docetaxel plus prednisone remains the standard treatment for such men who need first-line chemotherapy. FUNDING: Sanofi and Regeneron Pharmaceuticals Inc.

Concordance Analysis of ALK Gene Fusion Detection Methods in Patients with Non-Small-Cell Lung Cancer from Chile, Brazil, and Peru.

About 4% to 7% of the non-small-cell lung cancer patients have anaplastic lymphoma kinase (ALK) rearrangements, and specific targeted therapies improve patients' outcomes significantly. ALK gene fusions are detected by immunohistochemistry or fluorescent in situ hybridization as gold standards in South America. Next-generation sequencing-based assays are a reliable alternative, able to perform simultaneous detection of multiple events from a single sample. We analyzed 4240 non-small-cell lung cancer samples collected in 37 hospitals from Chile, Brazil, and Peru, where ALK rearrangements were determined as part of their standard of care (SofC) using either immunohistochemistry or fluorescent in situ hybridization. A subset of 1450 samples was sequenced with the Oncomine Focus Assay (OFA), and the concordance with the SofC tests was measured. An orthogonal analysis was performed using a real-time quantitative PCR echinoderm microtubule-associated protein-like 4-ALK fusion detection kit. ALK fusion prevalence is similar for Chile (3.67%; N = 2142), Brazil (4.05%; N = 1013), and Peru (4.59%; N = 675). Although a comparison between OFA and SofC assays showed similar sensitivity, OFA had significantly higher specificity and higher positive predictive value, which opens new opportunities for a more specific determination of ALK gene rearrangements.

Radical consolidative treatment provides a clinical benefit and long-term survival in patients with synchronous oligometastatic non-small cell lung cancer: A phase II study.

OBJECTIVES: Evidence is rapidly accumulating for the use of radical consolidative treatment (RCT) for patients with oligometastatic non-small cell lung cancer (NSCLC). Nonetheless, published studies have several limitations, including a selection of patients whose favorable characteristics might dictate therapeutic success, as well as scarce prospective data regarding overall survival (OS). The objective of this study was to determine whether RCT increases OS in patients with oligometastatic NSCLC. MATERIALS AND METHODS: In this prospective, single-arm phase II study, we sought to evaluate the efficacy of RCT in patients with oligometastatic NSCLC in terms of OS. Patients with pathologically confirmed stage IV NSCLC who presented ≤5 synchronous, any-site metastases (including central nervous system [CNS] metastases), as assessed by PET-CT, were included. All patients received four initial cycles of systemic treatment. Following, those with stable disease/partial response received RCT to the primary site and metastases. The response to RCT was evaluated with PET-CT. The primary end-point was OS. Secondary end-points included progression-free survival (PFS) and best response by PET-CT. The study is registered in clinicaltrials.gov (NCT02805530). RESULTS: Thirty-seven patients were included in the analysis. The mean age was 55.8 years (range: 33-75 years). At diagnosis, 43.2% of patients presented with CNS metastases. Following RCT, 19 (51.4%) patients achieved a complete-response (CR) by PET-CT, while 18 (48.6%) had a non-complete response (NON-CR). The median OS was nonreached (NR) and was positively affected by CR on PET-CT (NR vs. 27.4 [95% CI: 16.4-38.3]; p = 0.011). The median PFS was 23.5 months (95% CI: 13.6-33.3) and was positively affected by CR on PET-CT (NR vs. 14.3 [95% CI: 11.7-16.9]; p < 0.001; HR: 0.19 [0.07-0.52]; p=0.001). CONCLUSION: Patients with oligometastatic NSCLC who undergo RCT have a high response rate and favorable OS. Patients with a CR by PET-CT have significantly longer OS, rendering this an important potential prognostic marker.

Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial.

OBJECTIVES: LUME-Lung 2 investigated the efficacy/safety of nintedanib plus pemetrexed in patients with pretreated non-squamous non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients with stage IIIB/IV or recurrent non-squamous NSCLC who had received one prior chemotherapy regimen were randomized (1:1 stratified by histology [adenocarcinoma/non-adenocarcinoma], prior bevacizumab, Eastern Cooperative Oncology Group performance status and presence of brain metastases) to receive intravenous pemetrexed 500mg/m2 on Day 1 plus nintedanib 200mg orally twice daily or matching placebo on Days 2-21, every 3 weeks until progression/unacceptable toxicity. Progression-free survival (PFS) by independent central review was the primary endpoint. Overall survival (OS) was the key secondary endpoint. RESULTS: Based on the pre-planned futility analysis of investigator-assessed PFS, conducted by an independent data monitoring committee, recruitment was halted on 18 June 2011 after 713 (n=353 nintedanib/pemetrexed; n=360 placebo/pemetrexed)/1300 planned patients had enrolled. There were no safety concerns. Subsequent analysis demonstrated a significant improvement in PFS favoring nintedanib/pemetrexed over placebo/pemetrexed (median 4.4 months vs 3.6 months; hazard ratio [HR]=0.83, 95% confidence interval [CI] 0.70-0.99, p=0.0435). There was no significant difference in OS (median 12.0 months vs 12.7 months; HR=1.01, 95% CI 0.85-1.21, p=0.8940) after 514 deaths. Nintedanib/pemetrexed resulted in a higher incidence of grade ≥3 elevated alanine aminotransferase (23.3% vs 7.3%), elevated aspartate aminotransferase (12.1% vs 1.7%) and diarrhea (3.5% vs 1.1%) compared with placebo/pemetrexed, but no difference in hypertension, bleeding or thrombosis. CONCLUSION: Although recruitment stopped prematurely, combining nintedanib with pemetrexed significantly prolonged PFS in patients with advanced non-squamous NSCLC after first-line chemotherapy, with a manageable safety profile.

Monotherapy Administration of Sorafenib in Patients With Non-Small Cell Lung Cancer (MISSION) Trial: A Phase III, Multicenter, Placebo-Controlled Trial of Sorafenib in Patients with Relapsed or Refractory Predominantly Nonsquamous Non-Small-Cell Lung Cancer after 2 or 3 Previous Treatment Regimens.

INTRODUCTION: Sorafenib monotherapy has shown benefits in phase II trials as third-/fourth-line treatment in patients with non-small-cell lung cancer (NSCLC). METHODS: The phase III, multinational, double-blind, placebo-controlled Monotherapy admInistration of Sorafenib in patientS wIth nOn-small-cell luNg cancer (MISSION) trial randomized patients with advanced relapsed/refractory NSCLC, following two or three prior treatment regimens, to sorafenib 400 mg twice a day (n = 350) or matching placebo (n = 353) plus best supportive care. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS) and time to progression. Epidermal growth factor receptor and KRAS mutation status was analyzed in archival tumor and/or circulating tumor DNA from blood samples obtained during screening. RESULTS: Median OS was similar in the sorafenib and placebo groups (8.2 versus 8.3 mo; hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.84-1.17; p = 0.47). Median PFS (2.8 versus 1.4 mo; HR, 0.61; 95% CI, 0.51-0.72; p < 0.0001), and time to progression (2.9 versus 1.4 mo; HR, 0.54; 95% CI, 0.45-0.65; p < 0.0001) were significantly greater with sorafenib than with placebo. Among the 89 patients with epidermal growth factor receptor mutations, OS (13.9 versus 6.5 mo; HR, 0.48; 95% CI, 0.30-0.76; p = 0.002) and PFS (2.7 versus 1.4 mo; HR, 0.27; 95% CI, 0.16-0.46; p < 0.001) were significantly higher with sorafenib than placebo. PFS was significantly longer with sorafenib than placebo in patients with either wild-type or mutated KRAS, but OS was similar. Common drug-related adverse events were rash/desquamation, diarrhea, and fatigue, consistent with the safety profile of sorafenib. CONCLUSIONS: Third-/fourth-line sorafenib therapy did not significantly increase OS in patients with relapsed/refractory NSCLC, despite significantly increasing PFS.

Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer.

PURPOSE This phase III, multicenter, randomized, placebo-controlled trial assessed the efficacy and safety of sorafenib, an oral multikinase inhibitor, in combination with carboplatin and paclitaxel in chemotherapy-naïve patients with unresectable stage IIIB or IV non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Nine hundred twenty-six patients were randomly assigned to receive up to six 21-day cycles of carboplatin area under the curve 6 and paclitaxel 200 mg/m(2) (CP) on day 1, followed by either sorafenib 400 mg twice a day (n = 464, arm A) or placebo (n = 462, arm B) on days 2 to 19. The maintenance phase after CP consisted of sorafenib 400 mg or placebo twice a day. The primary end point was overall survival (OS); secondary end points included progression-free survival and tumor response. RESULTS Overall demographics were balanced between arms; 223 patients (24%) had squamous cell histology. On the basis of a planned interim analysis, median OS was 10.7 months in arm A and 10.6 months in arm B (hazard ratio [HR] = 1.15; 95% CI, 0.94 to 1.41; P = .915). The study was terminated after the interim analysis concluded that the study was highly unlikely to meet its primary end point. A prespecified exploratory analysis revealed that patients with squamous cell histology had greater mortality in arm A than in arm B (HR = 1.85; 95% CI, 1.22 to 2.81). Main grade 3 or 4 sorafenib-related toxicities included rash (8.4%), hand-foot skin reaction (7.8%), and diarrhea (3.5%). CONCLUSION No clinical benefit was observed from adding sorafenib to CP chemotherapy as first-line treatment for NSCLC.