Defining aggressive or early progressing nononcogene-addicted non-small-cell lung cancer: a separate disease entity?

A substantial proportion of patients with nononcogene-addicted non-small-cell lung cancer (NSCLC) has 'aggressive disease', as reflected in short time to progression or lack of disease control with initial platinum-based chemotherapy. Recently, clinical correlates of aggressive disease behavior during first-line therapy have been shown to predict greater benefit from addition of nintedanib to second-line docetaxel in adenocarcinoma NSCLC. Positive predictive effects of aggressive disease have since been reported with other anti-angiogenic agents (ramucirumab and bevacizumab), while such features may negatively impact on outcomes with nivolumab in nonsquamous NSCLC with low PD-L1 expression. Based on a review of the clinical data, we recommend aggressive nonsquamous NSCLC should be defined by progression within <6-9 months of first-line treatment initiation.

Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial.

BACKGROUND: Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer. METHODS: We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m(2) administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m(2) administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash--a class effect of EGFR antibodies--that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov, number NCT00981058. FINDINGS: Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 11·5 months [95% CI 10·4-12·6]) vs 9·9 months [8·9-11·1]; stratified hazard ratio 0·84 [95% CI 0·74-0·96; p=0·01]). In the necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 [72%] of 538 patients) than in the gemcitabine and cisplatin group (333 [62%] of 541), as was the incidence of serious adverse events (257 [48%] of 538 patients vs 203 [38%] of 541). More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3-4 hypomagnesaemia (47 [9%] of 538 patients in the necitumumab plus gemcitabine and cisplatin group vs six [1%] of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 [4%] vs one [<1%]). Including events related to disease progression, adverse events with an outcome of death were reported for 66 (12%) of 538 patients in the necitumumab plus gemcitabine and cisplatin group and 57 (11%) of 541 patients in the gemcitabine and cisplatin group; these were deemed to be related to study drugs in 15 (3%) and ten (2%) patients, respectively. Overall, we found that the safety profile of necitumumab plus gemcitabine and cisplatin was acceptable and in line with expectations. INTERPRETATION: Our findings show that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease. FUNDING: Eli Lilly and Company.

Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study.

BACKGROUND: Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits ligand binding. We aimed to compare necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non-small-cell lung cancer (NSCLC). METHODS: We did this randomised, open-label, controlled phase 3 study at 103 sites in 20 countries. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomisation scheme (block size of four) via a telephone-based interactive voice-response system or interactive web-response system. Patients received either cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 of a 3-week cycle for a maximum of six cycles alone, or with necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects. Randomisation was stratified by smoking history, ECOG performance status, disease histology, and geographical region. Patients and study investigators were not masked to group assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00982111. FINDINGS: Between Nov 11, 2009, and Feb 2, 2011, we randomly assigned 633 patients to receive either necitumumab plus pemetrexed and cisplatin (n=315) or pemetrexed and cisplatin alone (n=318). Enrolment was stopped on Feb 2, 2011, after a recommendation from the independent data monitoring committee. There was no significant difference in overall survival between treatment groups, with a median overall survival of 11·3 months (95% CI 9·5-13·4) in the necitumumab plus pemetrexed and cisplatin group versus 11·5 months (10·1-13·1) in the pemetrexed and cisplatin group (hazard ratio 1·01 [95% CI 0·84-1·21]; p=0·96). The incidence of grade 3 or worse adverse events, including deaths, was higher in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group; in particular, deaths regarded as related to study drug were reported in 15 (5%) of 304 patients in the necitumumab group versus nine (3%) of 312 patients in the pemetrexed and cisplatin group. Serious adverse events were likewise more frequent in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group (155 [51%] of 304 vs 127 [41%] of 312 patients). Patients in the necitumumab plus pemetrexed and cisplatin group had more grade 3-4 rash (45 [15%] of 304 vs one [<1%] of 312 patients in the pemetrexed and cisplatin alone group), hypomagnesaemia (23 [8%] vs seven [2%] patients), and grade 3 or higher venous thromboembolic events (23 [8%] vs 11 [4%] patients) than did those in the pemetrexed and cisplatin alone group. INTERPRETATION: Our findings show no evidence to suggest that the addition of necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC. Unless future studies identify potentially useful predictive biomarkers, necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin. FUNDING: Eli Lilly and Company.

Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial.

BACKGROUND: Effective maintenance therapies after chemoradiotherapy for lung cancer are lacking. Our aim was to investigate whether the MUC1 antigen-specific cancer immunotherapy tecemotide improves survival in patients with stage III unresectable non-small-cell lung cancer when given as maintenance therapy after chemoradiation. METHODS: The phase 3 START trial was an international, randomised, double-blind trial that recruited patients with unresectable stage III non-small-cell lung cancer who had completed chemoradiotherapy within the 4-12 week window before randomisation and received confirmation of stable disease or objective response. Patients were stratified by stage (IIIA vs IIIB), response to chemoradiotherapy (stable disease vs objective response), delivery of chemoradiotherapy (concurrent vs sequential), and region using block randomisation, and were randomly assigned (2:1, double-blind) by a central interactive voice randomisation system to either tecemotide or placebo. Injections of tecemotide (806 µg lipopeptide) or placebo were given every week for 8 weeks, and then every 6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m(2) (before tecemotide) or saline (before placebo) was given once before the first study drug administration. The primary endpoint was overall survival in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00409188. FINDINGS: From Feb 22, 2007, to Nov 15, 2011, 1513 patients were randomly assigned (1006 to tecemotide and 507 to placebo). 274 patients were excluded from the primary analysis population as a result of a clinical hold, resulting in analysis of 829 patients in the tecemotide group and 410 in the placebo group in the modified intention-to-treat population. Median overall survival was 25.6 months (95% CI 22.5-29.2) with tecemotide versus 22.3 months (19.6-25.5) with placebo (adjusted HR 0.88, 0.75-1.03; p=0.123). In the patients who received previous concurrent chemoradiotherapy, median overall survival for the 538 (65%) of 829 patients assigned to tecemotide was 30.8 months (95% CI 25.6-36.8) compared with 20.6 months (17.4-23.9) for the 268 (65%) of 410 patients assigned to placebo (adjusted HR 0.78, 0.64-0.95; p=0.016). In patients who received previous sequential chemoradiotherapy, overall survival did not differ between the 291 (35%) patients in the tecemotide group and the 142 (35%) patients in the placebo group (19.4 months [95% CI 17.6-23.1] vs 24.6 months [18.8-33.0], respectively; adjusted HR 1.12, 0.87-1.44; p=0.38). Grade 3-4 adverse events seen with a greater than 2% frequency with tecemotide were dyspnoea (49 [5%] of 1024 patients in the tecemotide group vs 21 [4%] of 477 patients in the placebo group), metastases to central nervous system (29 [3%] vs 6 [1%]), and pneumonia (23 [2%] vs 12 [3%]). Serious adverse events with a greater than 2% frequency with tecemotide were pneumonia (30 [3%] in the tecemotide group vs 14 [3%] in the placebo group), dyspnoea (29 [3%] vs 13 [3%]), and metastases to central nervous system (32 [3%] vs 9 [2%]). Serious immune-related adverse events did not differ between groups. INTERPRETATION: We found no significant difference in overall survival with the administration of tecemotide after chemoradiotherapy compared with placebo for all patients with unresectable stage III non-small-cell lung cancer. However, tecemotide might have a role for patients who initially receive concurrent chemoradiotherapy, and further study in this population is warranted. FUNDING: Merck KGaA (Darmstadt, Germany).

Lung cancer after treatment for breast cancer.

Breast cancer is the most common cancer in women, and the second most common cause of cancer death after lung cancer. Improvements in the outcome of breast cancer mean that more patients are living longer and are, therefore, at risk of developing a second malignancy. The aim of this review is to present the current understanding of the risk of lung cancer arising in patients previously treated for early stage breast cancer. We review data on the effect of treatment factors (ie, surgery type, radiotherapy technique, and adjuvant chemotherapy) and patient factors (ie, age and smoking) on the risk of developing a subsequent lung cancer. The evidence suggests that older radiotherapy techniques were associated with a substantially increased risk of developing lung cancer in the ipsilateral lung, but there is no clear evidence of an increased risk with modern techniques. Smoking is an important risk factor, and increases the risk of lung cancer in those receiving radiotherapy. Adjuvant chemotherapy is not significantly associated with an increased risk. The risk of developing lung cancer increases with time elapsed since treatment, but any effect of age at treatment is unclear.

Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study.

BACKGROUND: Results of two phase 3 trials have shown first-line bevacizumab in combination with chemotherapy improves clinical outcomes in patients with advanced or recurrent non-squamous non-small-cell lung cancer (NSCLC). The SAiL (MO19390) study was undertaken to assess the safety and efficacy of first-line bevacizumab combined with standard chemotherapy regimens in clinical practice. METHODS: Between August, 2006, and June, 2008, patients with untreated locally advanced, metastatic, or recurrent non-squamous NSCLC were recruited to this open-label, single group, phase 4 study from centres in 40 countries. Eligible patients had histologically or cytologically documented inoperable, locally advanced, metastatic, or recurrent disease (stage IIIB-IV); an Eastern Cooperative Oncology Group performance status of 0-2; and adequate haematological, hepatic, and renal function. Patients received bevacizumab (7.5 or 15 mg/kg every 3 weeks) plus standard chemotherapy for up to six cycles, followed by single-agent bevacizumab until disease progression. The primary endpoint was safety; analysis was by intention to treat (ITT). This study is registered with ClinicalTrials.gov, number NCT00451906. FINDINGS: At the final data cutoff (July 24, 2009), an ITT population of 2212 patients was assessed. The incidence of clinically significant (grade > or = 3) adverse events of special interest was generally low; thromboembolism occurred in 172 (8%) patients, hypertension in 125 (6%), bleeding in 80 (4%), proteinuria in 67 (3%), and pulmonary haemorrhage in 15 (1%). 57 (3%) patients died because of these adverse events, with thromboembolism (26 patients, 1%) and bleeding (17, 1%) as the most common causes. The most common grade 3 or higher serious adverse events deemed by investigators to be associated with bevacizumab were pulmonary embolism (28 patients; 1%) and epistaxis, neutropenia, febrile neutropenia, and deep vein thrombosis (all of which occurred in 13 patients [1%]). Bevacizumab was temporarily interrupted after 28 (2%) of 1347 bleeding events and 72 (7%) of 1025 hypertension events, and permanently discontinued after 110 (8%) bleeding events and 40 (4%) hypertension events. No new safety signals were reported. INTERPRETATION: Our results confirm the manageable safety profile of first-line bevacizumab in combination with various standard chemotherapy regimens for treatment of advanced non-squamous NSCLC. FUNDING: F Hoffmann-La Roche Ltd.

Phase II study of weekly plitidepsin as second-line therapy for small cell lung cancer.

OBJECTIVE: To evaluate the antitumor activity and safety profile of plitidepsin administered as a 1h weekly intravenous (i.v.) infusion of 3.2mg/m(2) to patients with small cell lung cancer (SCLC) who relapsed or progressed after one line of chemotherapy. PATIENTS AND METHODS: This was a multicenter, open-label, single-arm, exploratory, phase II clinical trial. Treatment lasted until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. Objective response rate (primary efficacy endpoint) was evaluated according to response evaluation criteria in solid tumors (RECIST). The rate of stable disease (SD) lasting for at least 6 months and time-to-event variables were secondary endpoints of efficacy. Toxicity was assessed using National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0. RESULTS: Twenty pretreated SCLC patients (median age, 60 years) with extensive (n = 13) or limited-stage disease (n = 7) received a total of 24 treatment cycles (median, one cycle per patient; range, 1-2). Objective tumor responses were not observed and only one of the 17 evaluable patients had SD. With a median follow-up of 11.8 months, the progression-free survival and the median overall survival were 1.3 months and 4.8 months, respectively. The most troubling or common toxicities were fatigue, muscle weakness, lymphopenia, anemia (no patients showed neutropenia), and asymptomatic, non-cumulative increase of transaminases levels and alkaline phosphatase. CONCLUSION: This clinical trial shows that a cycle of 1h weekly i.v. infusion of plitidepsin (3.2mg/m(2)) was generally well tolerated other than fatigue and muscle weakness in patients with pretreated SCLC. One patient died due to multi-organ failure. The absence of antitumor activity found here precludes further studies of this plitidepsin schedule as second-line single-agent treatment of SCLC.

Totality of evidence in the development of ABP 215, an approved bevacizumab biosimilar.

ABP 215 (MVASI™) is the first approved biosimilar to Avastin® (bevacizumab). It is approved in the USA and the European Union (EU) for all bevacizumab indications in these jurisdictions except for ovarian cancer in the USA due to orphan drug exclusivity. ABP 215 was shown to be structurally, functionally and clinically (pharmacokinetic, efficacy and safety) similar to the bevacizumab reference product; the pharmacokinetic study was conducted in healthy adult men (n = 202); safety and efficacy were evaluated in patients with advanced nonsquamous non-small-cell lung cancer (n = 642). Together, these results comprise the totality of evidence that provides scientific justification for extrapolation to all approved indications of the reference product and supports the clinical value of ABP 215 as an additional treatment option.

Management of unresectable stage III non-small-cell lung cancer with combined-modality therapy: a review of the current literature and recommendations for treatment.

Lung cancer remains the most common cause of cancer deaths in the United Kingdom, and long-term survival from lung cancer has hardly improved over the past 30 years. The benefit of combined-modality therapy with chemotherapy and radiation therapy in improving survival for patients with inoperable non-small-cell lung cancer (NSCLC) was discovered over 10 years ago. In this comprehensive literature review, we discuss the current status of combined-modality therapy for unresectable stage III NSCLC. The efficacy and toxicity of different chemoradiation therapy regimens are presented. The potential role of novel and targeted therapies and radiation dose escalation is also considered. Finally, recommendations are made for the treatment of unresectable stage III NSCLC.

Venous thromboembolism with EGFR monoclonal antibody necitumumab in stage IV non-small cell lung cancer: A retrospective cohort analysis.

INTRODUCTION: Metastatic non-small cell lung cancer (NSCLC) is a recognized risk factor for VTE. Some systemic treatments may increase this risk further. Here, we present the risk of VTE and its prognostic significance for patients treated with chemotherapy (chemo) and the EGFR monoclonal antibody necitumumab (neci) for metastatic NSCLC. METHODS: Four trials of 1st-line treatment for Stage IV NSCLC were analyzed: two randomized phase 3 studies of cisplatin/gemcitabine ±neci in squamous NSCLC (SQUIRE: N = 1079) and cisplatin/pemetrexed ±neci in non-squamous NSCLC (INSPIRE: N = 616); JFCL (N = 161), a randomized phase 2 trial of carboplatin/paclitaxel ±neci in squamous NSCLC; and JFCK (N = 61), a single arm phase 2 trial of cisplatin/gemcitabine +neci in squamous NSCLC. A Cox proportional hazards model with VTE as a time-dependent covariate was used for overall survival (OS) analyses. RESULTS: Neci + chemo was associated with an increased risk of VTE (Relative Risk [RR]: 1.579; 95% CI: 1.155-2.158). History of VTE (RR: 1.899; 95% CI: 1.142-3.156) and prior cardiac/cardiovascular events (RR: 1.514; 95% CI: 1.102-2.082) were associated with increased risk of VTE. Decreased VTE risk was seen with: male sex (RR: 0.696; 95% CI: 0.502-0.964), eastern European geographic region (RR: 0.387; 95% CI: 0.267-0.562) and squamous cell pathology (RR: 0.653; 95% CI: 0.483-0.883). VTE occurrence showed no association with OS (HR: 1.121; 95% CI: 0.930-1.351). CONCLUSION: Our data suggest that certain patient characteristics such as prior history of VTE and non-squamous histology might be associated with an increased risk of on-treatment VTE in NSCLC, although in this study, overall survival was not affected. Further studies to develop measures for identifying high-risk patients are needed to inform treatment decisions as well as VTE management and prophylaxis.

Efficacy and Safety of Necitumumab Continuation Therapy in the Phase III SQUIRE Study of Patients With Stage IV Squamous Non-Small-Cell Lung Cancer.

INTRODUCTION: In a retrospective analysis of the SQUamous NSCLC treatment with the Inhibitor of EGF REceptor (SQUIRE) study, we investigated the efficacy and safety of single-agent necitumumab continuation therapy in patients with stage IV squamous non-small-cell lung cancer and in a subpopulation of patients with epidermal growth factor receptor (EGFR)-expressing tumors. PATIENTS AND METHODS: Patients were randomized 1:1 for ≤ 6 cycles of gemcitabine and cisplatin either with or without necitumumab. Patients who received necitumumab continued receiving single-agent necitumumab until progressive disease (necitumumab continuation). Tissue collection was mandatory in SQUIRE. EGFR protein expression was assessed using immunohistochemistry in a central lab. In this subgroup analysis we compared patients treated with necitumumab monotherapy after completion of ≥ 4 cycles of chemotherapy with those in the chemotherapy arm who were progression-free and did not discontinue because of adverse events (AEs) after completion of ≥ 4 cycles of chemotherapy (gemcitabine-cisplatin nonprogressors). The same analysis was done for the subgroup of EGFR-expressing patients (EGFR > 0). RESULTS: Baseline characteristics and chemotherapy exposure were well balanced between the necitumumab continuation (n = 261) and gemcitabine-cisplatin nonprogressor (n = 215) arms and in the EGFR-expressing population. Median overall survival (OS) from randomization in the necitumumab with gemcitabine-cisplatin versus gemcitabine-cisplatin nonprogressor arm was 15.9 versus 15.0 months (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.69-1.05) and median progression-free survival (PFS) from randomization was 7.4 versus 6.9 months (HR, 0.86; 95% CI, 0.70-1.06). OS and PFS benefits were similar when assessed from the postinduction period and in EGFR-expressing patients. No new safety findings emerged. CONCLUSION: There was a consistent treatment effect in favor of necitumumab continuation versus that in gemcitabine-cisplatin nonprogressors, with no unexpected increases in AEs in intention-to-treat as well as EGFR-expressing populations.

EGFR Gene Copy Number by FISH May Predict Outcome of Necitumumab in Squamous Lung Carcinomas: Analysis from the SQUIRE Study.

INTRODUCTION: Necitumumab is a monoclonal antibody targeting EGFR. In the SQUIRE trial, the addition of necitumumab to chemotherapy for squamous cell lung cancer significantly improved overall survival (OS) (hazard ratio [HR] = 0.84); in a post hoc analysis, EGFR copy number gain determined by fluorescence in situ hybridization (FISH) showed a trend toward improved OS (HR = 0.70) and progression-free survival (PFS) (HR = 0.71) with the addition of necitumumab. We present the analysis of granular EGFR FISH data from SQUIRE to examine the potential predictive role of high polysomy and gene amplification, as both were included in the FISH-positive category. METHODS: Available specimens from SQUIRE underwent FISH analysis in a central laboratory, and each sample was evaluated by using the Colorado EGFR scoring criteria. The correlation of granular FISH parameters with clinical outcomes was assessed. RESULTS: Samples were available for 557 of 1093 patients; 208 patients (37.3%) were FISH-positive, including 167 (30.0%) with high polysomy and 41 (7.4%) with gene amplification. In patients with high polysomy, the addition of necitumumab resulted in a statistically significant increase in PFS (6.08 versus 5.13 months [p = 0.044]) and nonstatistically significant increase in OS (12.6 versus 9.5 months [p = 0.133]); among patients with gene amplification, the addition of necitumumab did not significantly improve PFS (7.4 versus 5.6 months; [p = 0.334]) but did improve OS (14.8 versus 7.6 months; [p = 0.033]). CONCLUSIONS: EGFR copy number gain by FISH might have a role as a predictive biomarker for necitumumab in squamous cell lung cancer. In our opinion, these data encourage further studies to prospectively evaluate this potential biomarker.

Safety and Efficacy of Bevacizumab Plus Standard-of-Care Treatment Beyond Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer: The AvaALL Randomized Clinical Trial.

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

Current and Emergent Therapy Options for Advanced Squamous Cell Lung Cancer.

Squamous cell lung cancer (SqCLC) is a distinct histologic subtype of NSCLC that is challenging to treat because of specific clinicopathologic characteristics, which include older age, advanced disease at diagnosis, comorbid diseases, and the central location of tumors. These characteristics have a bearing on treatment outcomes in advanced SqCLC, resulting in a median survival approximately 30% shorter than for patients with other NSCLC subtypes. In the context of the specific features of SqCLC, we review challenges of treating SqCLC and the current guideline-recommended treatments for advanced (metastatic) SqCLC in different patient subpopulations. We also evaluate recently approved treatment options, including necitumumab, afatinib, nivolumab, pembrolizumab, and atezolizumab; discuss the survival benefits associated with each agent in the advanced SqCLC population; and propose a treatment algorithm incorporating these agents for this challenging-to-treat disease. Lastly, we review the preliminary clinical evidence for immunotherapy agents in development for advanced NSCLC.

Molecular and Immune Biomarker Testing in Squamous-Cell Lung Cancer: Effect of Current and Future Therapies and Technologies.

Patients with non-small-cell lung cancer, including squamous-cell lung cancer (SqCLC), typically present at an advanced stage. The current treatment landscape, which includes chemotherapy, radiotherapy, surgery, immunotherapy, and targeted agents, is rapidly evolving, including for patients with SqCLC. Prompt molecular and immune biomarker testing can serve to guide optimal treatment choices, and immune biomarker testing is becoming more important for this patient population. In this review we provide an overview of current and emerging practices and technologies for molecular and immune biomarker testing in advanced non-small-cell lung cancer, with a focus on SqCLC.

Role of colony stimulating factors (CSFs) in solid tumours: results of an expert panel.

Febrile neutropenia is a relatively frequent event in cancer patients treated with chemotherapy. A relevant body of scientific evidence has been produced in the last 2 decades, through clinical trials addressing the efficacy of colony stimulating factors (CSFs) in the prevention and treatment of febrile neutropenia. The correct use of CSFs needs to be optimized, and several guidelines have been produced and periodically updated, in order to uniform and guide clinical practice. The aim of this review is to synthesize the most relevant clinical trials and the most important existing guidelines about the role of CSFs in solid tumours. Role of CSFs as primary prophylaxis, secondary prophylaxis and treatment of afebrile and febrile neutropenia is discussed. A special focus is dedicated to neutropenia and the use of CSFs in the treatment of the three "big killers" among the solid tumours: breast cancer, lung cancer and colorectal cancer.

Modern management of small-cell lung cancer.

In this article, we review best standard practice for the management of small-cell lung cancer (SCLC) and indicate the likely areas of development over the next 5-10 years. A number of prognostic scores have been developed and these allow more rational decisions on treatment. Treatment with cisplatin plus etoposide with early, concurrent radiotherapy is the standard of care for patients with limited-stage disease (LD) suitable for this approach. A 5-year survival rate of 25% has been reported for concurrent hyperfractionated radiotherapy; however, the applicability of this in most busy hospitals is uncertain and this treatment is currently being compared with a high-dose, once-daily regimen. Patients unsuitable for concurrent chemo-radiotherapy are treated with a sequential approach. Patients with LD responding to treatment should be offered prophylactic cranial irradiation (PCI). A variety of strategies for improving survival have been investigated. Intensification of chemotherapy has not shown any clear survival advantage, but maintenance of dose intensity in patients with good prognosis is important. The evidence around maintenance therapy is conflicting and this is not routinely used. Patients with extensive-stage disease but few other adverse prognostic factors should be treated with a platinum compound plus etoposide, and carboplatin is a reasonable choice. Responding patients should be offered PCI as this is associated with a survival benefit. The initial positive results for irinotecan have not been repeated in a larger study. Age is not a prognostic factor, but caution needs to be exercised as prognostic scores do not reflect co-morbidity. Patients with relapsed disease have a poor prognosis, but there is evidence of a survival benefit for salvage chemotherapy in those fit for treatment. The choice of treatment will depend on a number of factors, including the disease-free interval. Topotecan is the only drug licensed in this indication, but myelosuppression is considerable. A number of new drugs are under evaluation and showing promise in SCLC. One of the most promising of these is amrubicin. A large randomised study has failed to show any benefit from the addition of thalidomide to chemotherapy with carboplatin and etoposide in extensive-stage disease patients responding to chemotherapy. Studies of a number of targeted treatments are also ongoing. The challenge for the future is to identify new targets, overcome drug-resistance mechanisms and redundancy in biological systems, and incorporate these new treatments into concurrent chemo-radiotherapy schedules.

Erlotinib for frontline treatment of advanced non-small cell lung cancer: a phase II study.

PURPOSE: Erlotinib has proven activity in pretreated patients with advanced non-small cell lung cancer (NSCLC). We evaluated erlotinib in the frontline treatment of advanced NSCLC and assessed biological predictors of outcome. EXPERIMENTAL DESIGN: In this phase II study, chemotherapy-naive patients with stage IIIB/IV NSCLC received oral erlotinib (150 mg/d) until disease progression or unacceptable toxicity occurred. Tumor response was assessed every 6 weeks, and samples were analyzed for potential molecular markers of treatment response and survival. The primary end point was the proportion of patients without disease progression after 6 weeks of treatment. RESULTS: Fifty-three patients were eligible. The overall rate of nonprogression at 6 weeks was 52.8% (28 of 53 patients). Tumor response rate was 22.7%, with 1 complete response, 11 partial responses, and 16 cases of stable disease. Responses were seen across most patient clinical characteristics. The median duration of tumor response was 333 days; median overall survival was 391 days; and median time to disease progression was 84 days. Erlotinib was well tolerated, the main treatment-related adverse events being mild-to-moderate rash and diarrhea. Histologic material for biological studies was available in 29 cases. Four of five responders and one patient with stable disease had a classic epidermal growth factor receptor tyrosine kinase mutation. Two progressing patients exhibited epidermal growth factor receptor point mutations (one with T790M mutation), and K-ras mutations were detected in 10 nonresponders. CONCLUSIONS: Erlotinib shows significant antitumor activity in the first-line treatment of advanced NSCLC and may be a viable alternative to chemotherapy. Patient selection cannot easily be based on clinical or biological variables.

Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer).

BACKGROUND: This placebo-controlled phase III study investigated the effect on survival of gefitinib as second-line or third-line treatment for patients with locally advanced or metastatic non-small-cell lung cancer. METHODS: 1692 patients who were refractory to or intolerant of their latest chemotherapy regimen were randomly assigned in a ratio of two to one either gefitinib (250 mg/day) or placebo, plus best supportive care. The primary endpoint was survival in the overall population of patients and those with adenocarcinoma. The primary analysis of the population for survival was by intention to treat. This study has been submitted for registration with ClinicalTrials.gov, number 1839IL/709. FINDINGS: 1129 patients were assigned gefitinib and 563 placebo. At median follow-up of 7.2 months, median survival did not differ significantly between the groups in the overall population (5.6 months for gefitinib and 5.1 months for placebo; hazard ratio 0.89 [95% CI 0.77-1.02], p=0.087) or among the 812 patients with adenocarcinoma (6.3 months vs 5.4 months; 0.84 [0.68-1.03], p=0.089). Preplanned subgroup analyses showed significantly longer survival in the gefitinib group than the placebo group for never-smokers (n=375; 0.67 [0.49-0.92], p=0.012; median survival 8.9 vs 6.1 months) and patients of Asian origin (n=342; 0.66 [0.48-0.91], p=0.01; median survival 9.5 vs 5.5 months). Gefitinib was well tolerated, as in previous studies. INTERPRETATION: Treatment with gefitinib was not associated with significant improvement in survival in either coprimary population. There was pronounced heterogeneity in survival outcomes between groups of patients, with some evidence of benefit among never-smokers and patients of Asian origin.

Novel therapies for the treatment of small-cell lung cancer: a time for cautious optimism?

Small-cell lung cancer accounts for up to one-fifth of all lung cancers diagnosed. While the response rates to chemotherapy are high, ultimately the majority of patients will relapse and die from their disease. Long-term outcomes are poor. A number of new agents and novel strategies for the treatment of small-cell lung cancer are under evaluation, and this review outlines the current most promising agents and pivotal trials. Oblimersen, an antisense oligonuclide to the oncogene bcl-2, has been safely combined with chemotherapy. The proteosome inhibitor bortezomib has not demonstrated single-agent activity in phase II trials but is now being evaluated with proapoptotic triggers. A number of anti-angiogenic strategies have been evaluated in small-cell lung cancer. The vascular endothelial growth factor (VEGF) antibody bevacizumab and a number of VEGF receptor tyrosine kinase inhibitors are in the early phases of clinical trials. Results from trials have not demonstrated any survival advantage with the addition of matrix metalloproteinase inhibitors. A phase III trial has reported improvements in median survival with the addition of thalidomide to chemotherapy, but toxicity has been problematic. Immunotherapy with p53 vaccines and BEC2 antibodies have shown some promise and require further evaluation to determine whether humoral responses can predict for response. Trials with the immunoconjugate BB-10901 and temirolimus are ongoing.