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Introduction Although chemoradiotherapy (CRT) is the standard of care for patients with unresectable stage III non–small-cell lung cancer (LA-NSCLC), most patients relapse. Tecemotide is a MUC1 antigen-specific cancer immunotherapy vaccine. Bevacizumab improves survival in advanced nonsquamous (NS)-NSCLC and has a role in immune modulation. This phase II trial tested the combination of tecemotide and bevacizumab following CRT in patients with LA-NSCLC. Patients and Methods Subjects with stage III NS-NSCLC suitable for CRT received carboplatin/paclitaxel weekly + 66 Gy followed by 2 cycles of consolidation carboplatin/paclitaxel ≤ 4 weeks of completion of CRT (Step 1). Patients with partial response/stable disease after consolidation therapy were registered onto step 2, which was 6 weekly tecemotide injections followed by every 6 weekly injections and bevacizumab every 3 weeks for up to 34 doses. The primary endpoint was to determine the safety of this regimen. Results Seventy patients were enrolled; 68 patients (median age, 63 years; 56% male; 57% stage IIIA) initiated therapy, but only 39 patients completed CRT and consolidation therapy per protocol, primarily owing to disease progression or toxicity. Thirty-three patients (median age, 61 years; 58% male; 61% stage IIIA) were registered to step 2 (tecemotide + bevacizumab). The median number of step 2 cycles received was 11 (range, 2-25). Step 2 worst toxicity included grade 3, N = 9; grade 4, N = 1; and grade 5, N = 1. Grade 5 toxicity in step 2 was esophageal perforation attributed to bevacizumab. Among the treated and eligible patients (n = 32) who were treated on step 2, the median overall survival was 42.7 months (95% confidence interval, 21.7-63.3 months), and the median progression-free survival was 14.9 months (95% confidence interval, 11.0-20.9 months) from step 1 registration. Conclusions This cooperative group trial met its endpoint, demonstrating tolerability of bevacizumab + tecemotide after CRT and consolidation. In this selected group of patients, the median progression-free survival and overall survival are encouraging. Given that consolidation immunotherapy is now a standard of care following CRT in patients with LA-NSCLC, these results support a role for continued investigation of antiangiogenic and immunotherapy combinations in LA-NSCLC.

Introduction The 5 year survival rate for patients with locally advanced non-small-cell lung cancer (NSCLC) not amenable for definitive resection with historical standard-of-care concurrent chemoradiotherapy (cCRT) ranges from 15% to 32%. cCRT primes anti-tumor immunity and also upregulates programmed death ligand-1 (PD-L1), providing a rationale for combining an immune checkpoint inhibitor with cCRT to improve outcomes. In the PACIFIC trial, consolidation therapy with the PD-L1 inhibitor durvalumab improved progression-free survival (PFS) and overall survival (OS) vs. placebo in patients with stage III NSCLC who did not have disease progression after cCRT. CheckMate73L (NCT04026412), a randomized phase 3 study, evaluates the efficacy of nivolumab plus cCRT followed by nivolumab with or without ipilimumab vs. cCRT followed by durvalumab for untreated, stage III NSCLC. Patients and Methods Patients with untreated, stage III NSCLC will be randomized 1:1:1 to nivolumab plus cCRT followed by nivolumab in combination with ipilimumab (Arm A) or nivolumab alone (Arm B); or cCRT followed by durvalumab (Arm C). Primary endpoints are PFS and OS (Arm A vs. Arm C). Secondary endpoints include additional analyses of PFS and OS (Arm A vs. Arm B; Arm B vs. Arm C), as well as objective response rate, complete response rate, time to response, duration of response, time to death or distant metastases, and safety and tolerability. Recruitment began on August 20, 2019, and the estimated primary completion date is October 17, 2022.

Purpose This signal finding study (S1400G) was designed to evaluate the efficacy of talazoparib in advanced stage squamous cell lung cancer harboring homologous recombination repair deficiency. Patients and Methods The full eligible population (FEP) had tumors with a deleterious mutation in any of the study-defined homologous recombination repair genes and without prior exposure to a PARP inhibitor. The primary analysis population (PAP) is a subset of FEP with alteration in ATM, ATR, BRCA1, BRCA2, or PALB2. Treatment consisted of talazoparib 1 mg daily continuously in 21-day cycles. A 2-stage design with exact 93% power and 1-sided 0.07 type I error required enrollment of 40 patients in the PAP in order to rule out an overall response rate (ORR) of 15% or less if the true ORR is ≥ 35%. Results The study enrolled 47 patients in the FEP, of whom 24 were in the PAP. The median age for the FEP was 66.7 years; 83% were male and 85% white. ORR in the PAP was 4% (95% confidence interval [CI], 0, 21) with disease control rate of 54% (95% CI, 33, 74). Median progression-free survival and overall survival were 2.4 months (95% CI, 1.5-2.8) and 5.2 months (95% CI, 4.0-10), respectively. In the FEP, ORR was 11% (95% CI, 3.6, 23), the disease control rate was 51% (95% CI, 36, 66), and the median duration of response was 1.8 months (95% CI, 1.3, 4.2). Median progression-free and overall survival were 2.5 months and 5.7 months, respectively. Conclusions S1400G failed to show sufficient level of efficacy for single agent talazoparib in a biomarker defined subset of squamous lung cancer with homologous recombination repair deficiency.

The LAURA trial (NCT03521154) will evaluate the efficacy and safety of osimertinib as maintenance therapy in patients with locally advanced, unresectable, epidermal growth factor receptor mutation-positive (EGFRm), stage III non-small-cell lung cancer (NSCLC) without disease progression during/following definitive platinum-based chemoradiation therapy (CRT). Eligible patients include adults aged ≥ 18 years (≥ 20 years in Japan) with locally advanced, unresectable, stage III NSCLC with local/central confirmation of an EGFR exon 19 deletion/L858R mutation. Patients must have received ≥ 2 cycles of concurrent/sequential platinum-based CRT, have no investigator-assessed progression, and have creatinine 1.5 × upper limit of normal and creatinine clearance ≥ 30 mL/min. In this phase III trial, patients will be randomized 2:1 to once-daily osimertinib 80 mg or placebo, until objective radiological disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, confirmed by blinded independent central review (BICR). The primary objective is to assess the efficacy of osimertinib per BICR-confirmed progression-free survival (PFS). Secondary objectives include central nervous system PFS, overall survival, PFS by mutation status and safety. Patients with BICR-confirmed disease progression (or investigator-confirmed progression if after primary PFS analysis) may be unblinded and receive open-label osimertinib; all will have post-progression follow-up. Serious adverse events and adverse events of special interest will be collected throughout the trial and survival follow-up. The first patient was enrolled in July 2018, with results expected in late 2022.

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. ispartof: CLINICAL LUNG CANCER vol:19 issue:4 pages:331-339 ispartof: location:United States status: published

Current evidence-based guideline-concordant care (GCC) for locally advanced non-small-cell lung cancer (NSCLC) patients with good performance status is concurrent chemoradiation. In this study we evaluated factors associated with lack of GCC and its effects on overall survival (OS).Unresectable stage III NSCLC patients, diagnosed from 2005 to 2013 with a Charlson-Deyo score of 0, were identified from the National Cancer Database. Primary outcomes were receipt of GCC, defined as concurrent chemoradiation (thoracic radiotherapy, starting within 2 weeks of chemotherapy, to at least 60 Gy), and OS. Multivariable logistic regression modeling identified variables associated with non-GCC. Cox proportional hazard modeling was used to examine OS.Twenty-three percent of patients (n = 10,476) received GCC. Uninsured patients were more likely to receive non-GCC (odds ratio [OR], 1.54; P .001) compared with privately insured patients. Other groups with greater odds of receiving non-GCC included: patients treated in the western, southern, or northeastern United States (ORs, 1.39, 1.37, and 1.19, respectively; all Ps .001) compared with the Midwest; adenocarcinoma histology (OR, 1.48; P .001) compared with squamous cell carcinoma; and women (OR, 1.08; P = .002). Those who received non-GCC had higher death rates compared with those who received GCC (hazard ratio [HR], 1.42; P .001). The uninsured (HR, 1.53; P .001), patients treated in the western, southern, or northeastern United States (HRs, 1.56, 1.41, and 1.34, respectively; P .001), adenocarcinomas (HR, 1.39; P .001), and women (HR, 1.44; P .001) also all had lower OS for non-GCC versus GCC.Socioeconomic factors, including lack of insurance and geography, are associated with non-GCC. Patient- and disease-specific factors, including increasing adenocarcinoma histology and sex, are also associated with non-GCC. Non-GCC diminishes OS.

Background Lung adenocarcinoma accounts for almost 60% of non–small-cell lung cancer. According to the 2011 International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) classification and 2015 World Health Organization classification of tumors of the lung, lepidic-predominant adenocarcinomas ≤ 3 cm in size can be classified as adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma, lepidic predominant. AIS lesions, which are noninvasive, and MIA lesions, which show ≤ 0.5 cm of invasion, have been recommended to be considered stage pTis (adenocarcinoma) and pT1(mi), respectively. We conducted a systematic analysis of the published data to evaluate the prognostic differences between AIS and MIA. Materials and Methods A comprehensive search of published studies was conducted from the electronic databases using relevant search criteria. Studies that reported outcomes for ≥ 8 cases classified as AIS or MIA using the 2011 IASLC/ATS/ERS criteria were selected for the present analysis. A systematic analysis of the extracted data were performed using Comprehensive Meta-Analysis software, version 2.2. Results Nineteen studies published from 2011 to 2015 were eligible. A total of 972 patients were included (429 with AIS and 294 with MIA; 2 studies reported AIS and MIA together, n = 249). The median age was 65.5 years, 63% were female, and 40% were smokers. The 5-year disease-free survival rate for the whole population was 97.9%. The 5-year disease-free survival rate was 100% for AIS and MIA pooled from the studies that reported the 2 groups separately. The 5-year overall survival rate for the entire group was 97.5%, and the 5-year overall survival rate was 100% for AIS and 98.5% for MIA. Conclusion No significant differences were found in the survival rates between patients with lung adenocarcinoma categorized as MIA or AIS. This finding raises questions regarding the evidence for TNM staging of AIS and MIA as recommended by the 2011 IASLC/ATS/ERS and 2015 World Health Organization classification of tumors of the lung and should be reevaluated with further studies.

Introduction Reports have suggested improvements in dosimetry, toxicity, and quality of life with intensity-modulated radiation therapy (IMRT) in locally advanced non–small-cell lung cancer (NSCLC). The selection criteria for those patients who may benefit is unclear. This study sought to identify subgroups of patients who may derive survival benefit from intensity modulated radiation therapy (IMRT) compared with 3D conformal radiation therapy (3DCRT). Methods and Materials The National Cancer Data Base was queried for stage III NSCLC treated with radiation and chemotherapy alone with curative intent. All received ≥ 58 Gy. Kaplan-Meier and log-rank test were performed to compare overall survival (OS) by treatment modality. A multivariable Cox proportional hazards model was used to assess association with OS. Propensity score matching was also implemented. Results A total of 2543 patients treated between 2003 and 2006 were eligible; 422 (16.6%) received IMRT, 2121 (83.4%) received 3DCRT. In patients with T3 and T4 disease, IMRT was associated with an improvement in median OS and 5-year survival rate (17.2 vs. 14.6 months; 19.9% vs. 13.4%, P = .021.) In multivariable analysis, there was an interaction between treatment type and T stage that was found to be significant ( P = .03). In the propensity matched cohort of T3 and T4 patients, the use of IMRT remained associated with improved OS (hazard ratio, 0.80; 95% confidence interval, 0.64-1.00; P = .048). Conclusions Use of IMRT in patients with T3 and T4 tumors was associated with improved overall survival in this large population-based analysis. This is a novel finding that is in concordance with the well-described dosimetric benefits of IMRT in NSCLC.

Introduction Ramucirumab, a recombinant human immunoglobulin G1 monoclonal antibody receptor antagonist designed to block the ligand-binding site of vascular endothelial growth factor receptor-2 (VEGFR-2), was evaluated as second-line treatment in combination with docetaxel in patients with non–small-cell lung cancer in the REVEL trial ( NCT01168973 ). Ramucirumab significantly improved overall survival (OS) and progression-free survival (PFS). We report age subgroup analysis results primarily on the basis of a 65-year cutoff. Patients and Methods Patients were randomized 1:1 to ramucirumab with docetaxel or placebo with docetaxel (n = 1253). Of these, 798 were younger than 65 years (ramucirumab, n = 391; control, n = 407) and 455 were 65 years or older (ramucirumab, n = 237; control, n = 218). Treatment comprised 21-day cycles of 75 mg/m2 docetaxel with 10 mg/kg ramucirumab or placebo. Prespecified age subgroup analyses were performed, including OS, PFS, and objective response rate. Quintiles age analysis was conducted to establish a relationship between efficacy and age. The Lung Cancer Symptom Scale (LCSS) measured quality of life outcomes. Safety was assessed according to adverse events (AEs). Results Patients younger than 65 years showed favorable OS outcomes with ramucirumab treatment (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.62-0.87; P Conclusion In this subgroup analysis, true treatment effect differences on the basis of age have not been established, and treatment should not be deterred solely because of age.

The prognosis of patients with extensive-stage small-cell lung carcinoma (ES-SCLC) is poor. The benefit of consolidative thoracic radiation therapy (TRT) in ES-SCLC has been inconclusive, and its use inconsistent. The objective of this study was to evaluate overall survival (OS) of ES-SCLC patients treated with chemotherapy (CT) with or without TRT using an administrative database approach.The National Cancer Database was queried to identify patients with ES-SCLC diagnosed between 2010 and 2014. Those with brain metastases, those who received radiotherapy before CT, or radiotherapy outside the thorax, were excluded. Propensity score-matching (PSM) was used to compare OS of patients treated with CT and TRT with those who received CT alone. Patients who received10 radiotherapy fractions were also compared with those who received 10 or fewer.We included 14,367 patients in the primary analysis; 12,019 received CT alone, and 2348 received CT with TRT. In multivariate analysis, CT was associated with an increased risk of death relative to CT with TRT (hazard ratio [HR], 1.74 [95% confidence interval (CI), 1.64-1.84]; log-rank P .001), which remained significant with PSM. Median OS was 12.1 versus 8.2 months (CT with TRT vs. CT); 12-month OS was 50.5% versus 28.5%, and 5-year OS 7.6% versus 2.0% (HR, 1.80 [95% CI, 1.67-1.95], HR P .001). Of 3099 patients who received TRT,10 radiotherapy fractions was associated with superior OS (HR, 1.70 [95% CI, 1.49-1.95], log-rank P .001); this finding remained significant with PSM.Use of TRT after CT in ES-SCLC patients was associated with long-term survival; its use should be considered in addition to standard of care CT.

Background Lung cancer is the leading cause of cancer-related mortality. Understanding patient attributes that enhance survival and predict recurrence is necessary to individualize treatment options. Methods Patients (N = 162) were dichotomized into favorable (n = 101) and unfavorable (n = 61) groups based on survival characteristics. Ku86 and poly(ADP-ribose) polymerase (PARP) expression measures were incorporated into the analyses. LR, Kaplan-Meier analysis, and Cox regression were used to investigate intervariable relationships and survival. Odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were used to assess associations. Results Sex (OR, 0.32; CI-0.14, 0.76), squamous cell carcinoma (SCC) (OR, 0.41; CI-0.17, 0.98), and recurrence (OR, 0.04; CI-0.01, 0.20) confer an unfavorable outcome with area under the receiver operating characteristic curve (Az) = 0.788. Patients with increased tumor grade (OR = 1.84; CI-1.06, 3.19) or increased Ku86 intensity (OR, 2.03; CI-1.08, 3.82) were more likely to be male individuals, and older patients (OR, 1.70; CI-(1.14, 2.52) were more likely to have SCC. Patients older than the median age (HR, 1.86; CI-1.11, 3.12), patients with SCC (HR, 1.78; CI-1.05, 3.01), patients with recurrence (HR, 4.16; CI-2.37, 7.31), and male patients (HR, 2.03; CI-1.20, 3.43) have a higher hazard. None of the DNA repair measures were associated with significant HRs. Conclusion Clinical and pathologic factors that enhance and limit survival for patients with stage I NSCLC were quantified. The DNA repair measures showed little association. These findings are important given that certain clinical and pathologic features are related to better long-term survival outcome than others.

Stereotactic body radiotherapy (SBRT) is the standard of care for medically inoperable early-stage non-small-cell lung cancer. Despite the limited number of octogenarians and nonagenarians on trials of SBRT, its use is increasingly being offered in these patients, given the aging cancer population, medical fragility, or patient preference. Our purpose was to investigate the efficacy, safety, and survival of patients ≥ 80 years old treated with definitive lung SBRT.Patients who underwent SBRT were reviewed from 2009 to 2015 at 4 academic centers. Patients diagnosed at ≥ 80 years old were included. Kaplan-Meier and multivariate logistic regression and Cox proportional hazard regression analyses were performed. Recursive partitioning analysis was done to determine a subgroup of patients most likely to benefit from therapy.A total of 58 patients were included, with a median age of 84.9 years (range, 80.1-95.2 years), a median follow-up time of 19.9 months (range, 6.9-64.9 months), a median fraction size of 10.0 Gy (range, 7.0-20.0 Gy), and a median number of fractions of 5.0 (range, 3.0-8.0 fractions). On multivariate analysis, higher Karnofsky performance status (KPS) was associated with higher local recurrence-free survival (hazard ratio [HR], 0.92; P .01), regional recurrence-free survival (HR, 0.94; P .01), and overall survival (HR, 0.91; P .01). On recursive partitioning analysis, patients with KPS ≥ 75 had improved 3-year cancer-specific and overall survival (99.4% and 91.9%, respectively) compared with patients with KPS 75 (47.8% and 23.6%, respectively; P .01).Definitive lung SBRT for early-stage non-small-cell lung cancer was efficacious and safe in patients ≥ 80 years old. Patients with a KPS of ≥ 75 derived the most benefit from therapy.

Pulmonary sarcomatoid carcinoma (PSC) is a grouping of 5 rare non-small-cell lung cancer (NSCLC) subtypes. We studied the clinical characteristics and outcomes of PSC utilizing the National Cancer Data Base (NCDB), an oncology outcomes database.The NCDB lung cancer database was queried from 1998 to 2011 for PSC using ICD-O-3 codes. Data were extracted for patient demographics, tumor pathology, treatment, and outcomes. Overall survival (OS) data were available for patients diagnosed from 1998 to 2006 and comorbidity data from 2003 to 2011. Univariate association with covariates between PSC and other forms of NSCLC was assessed by the chi-square test or ANOVA, as appropriate.Of the 1,547,531 NSCLC patients in the NCDB from 1998 to 2011, 7965 were identified with PSC (0.5%). PSC patients had a median age of 70 years, 59% were men, and 89% were white. At presentation, 18% had American Joint Committee on Cancer stage I disease, 10% stage II, 24% stage III, and 48% stage IV. The median OS for stage I-II PSC was 16.9 months, 5.8 months for stage III, and 5.4 months for stage IV. There was a higher risk of death on multivariate analysis for PSC patients compared to other histologic subtypes of NSCLC in all patients (hazard ratio = 1.34 (95% confidence interval, 1.20-1.48) P .001) and in propensity score-matched subsets (hazard ratio = 1.34; 95% confidence interval, 1.15-1.56; P .001).PSC is a rare histologic subtype of NSCLC, accounting for 0.5% of all lung cancers. The disease of patients with PSC has aggressive clinical characteristics and an inferior survival outcome relative to other histologic subtypes of NSCLC.

Background The proteasome inhibitor bortezomib sensitizes tumor cells to chemotherapy-induced apoptosis. In preclinical non–small-cell lung cancer (NSCLC) models, p53-dependent growth arrest after bortezomib treatment resulted in reduced cytotoxicity if bortezomib preceded docetaxel. The reverse sequence of docetaxel before bortezomib was associated with increased apoptosis, cleavage of caspase-3 and PARP (poly [ADP-ribose] polymerase), and reduction in Bcl-2. A prospective randomized phase II trial of concurrent versus sequential docetaxel and bortezomib was conducted to assess whether administration sequence resulted in measurable clinical differences. Patients and Methods Previously treated patients with advanced NSCLC were randomized to concurrent (CON) or sequential (SEQ) docetaxel (75 mg/m2 intravenous [I.V.]) followed by bortezomib, every 3 weeks. In the CON arm, bortezomib (1.6 mg/m2 I.V.) was given on days 1 and 8, and in the SEQ arm, it was given on days 2 and 8. Previous erlotinib as well as treated or controlled brain metastases were allowed. The primary endpoint was objective response rate (RR); progression-free (PFS) and overall survival (OS) were secondary endpoints. Results Eighty-one patients were randomized (40 CON and 41 SEQ). Grade 3+ toxicities were mostly due to myelosuppression. One patient each had grade 4 hyponatremia and syncope. Toxicities were similar between the arms. There was 1 treatment-related death in the SEQ arm. There were 8 partial responders, 4 in each arm, for an overall RR of 10%. Disease control rate was similar in both arms (50% vs. 49%). Median PFS was 12 weeks in the CON arm and 11 weeks in the SEQ arm. Median OS times in the CON and SEQ arms were 13.3 and 10.5 months, respectively. Conclusion Docetaxel plus bortezomib given sequentially or concurrently has similar RR and PFS. Median survival in the SEQ arm exceeds published survival estimates for either agent alone or in combination. Any further studies in this population would require molecular characterization of a phenotype most likely to benefit from proteasome inhibitor therapy.

Inhibition of the epidermal growth factor receptor (EGFR) pathway has emerged as a proven strategy for the treatment of advanced-stage non-small-cell lung cancer (NSCLC). Cetuximab is a chimeric monoclonal antibody that inhibits EGFR by binding to the extracellular domain of the receptor. The relatively modest anticancer activity as monotherapy in NSCLC has prompted the evaluation of cetuximab as part of novel combination regimens. The safety of cetuximab in combination with the commonly used platinum-based 2-drug regimens in NSCLC has been established in several phase II studies. Recently, the addition of cetuximab to the regimen of cisplatin and vinorelbine resulted in improved overall survival in patients with advanced NSCLC with EGFR-expressing tumors. In contrast, a study in unselected advanced NSCLC patients failed to demonstrate a statistically significant improvement in overall survival with cetuximab in combination with a carboplatin and taxane regimen. It is hoped that identification of predictive biomarkers would lead to the optimal utilization of cetuximab in combination with chemotherapy. The combination of cetuximab with radiotherapy for patients with locally advanced NSCLC has demonstrated promising results in a phase II study and is now being evaluated in a confirmatory trial. This article reviews the clinical data with cetuximab in NSCLC.

Background Access to specialty care is critical for patients with advanced stage lung cancer. This study assessed access to cancer specialists and cancer treatment in a broad population of patients with advanced stage lung cancer. Materials and Methods Two study samples were extracted from 2 claims databases and analyzed independently: patients aged ≥ 18 years with de novo diagnosis of metastatic lung cancer in the MarketScan database between 2008 and 2014 (commercially insured adult patients; n = 22,268); and patients aged ≥ 65 years in the Surveillance, Epidemiology, and End Results–Medicare database with a diagnosis of advanced non–small-cell lung cancer between 2007 and 2011 (Medicare-insured elderly patients; n = 9651). The study period spanned from 6 weeks before the first lung biopsy tied to the initial lung cancer diagnosis until the end of continuous health insurance enrollment, or data availability, or death. Results Among the commercially insured adults (MarketScan), most patients were seen by a cancer specialist within a month of first lung biopsy (80%), 12% were never seen by a cancer specialist, and 6% did not receive cancer-directed therapy. Among the Medicare-insured elderly patients (SEER–Medicare), the proportions were 79%, 4%, and 10%, respectively. Patients seen by a cancer specialist were more likely to receive cancer-directed therapy (95% vs. 92%, P P Conclusion Between 4% and 12% of patients with advanced stage lung cancer do not have appropriate access to cancer specialist, which appears to negatively affect access to optimal and timely treatment.

On February 18, 2008, a press release from Bayer and Onyx Pharmaceuticals reported that their large, randomized phase III trial evaluating the multitargeted tyrosine kinase inhibitor (TKI) sorafenib in patients with advanced non–small-cell lung cancer (NSCLC) was stopped. This was after the independent Data Monitoring Committee (DMC) concluded that the study would not meet its primary endpoint of improved overall survival (OS).1 This trial, widely known as ESCAPE (Evaluation of Sorafenib, Carboplatin, and Paclitaxel Efficacy in NSCLC), tested the standard first-line doublet of carboplatin plus paclitaxel with or without sorafenib. Interestingly, the same report stated that higher mortality was seen in the subset of patients with squamous cell carcinoma treated in the sorafenib arm. These trial results are summarized in the Meeting Highlights of this issue. Shortly thereafter, AstraZeneca issued a press release announcing the early closure of its own phase II/III trial in patients with advanced NSCLC combining the vascular endothelial growth factor receptor (VEGFR)–targeted TKI cediranib with carboplatin and paclitaxel.2 According to the release, following a planned efficacy and tolerability analysis by the study’s DMC at the end of the phase II stage, “there appeared to be an imbalance in toxicity...therefore the study was considered not to have met the predefined criteria for automatic continuation into phase III.” These results highlight a series of failed randomized trials of chemotherapy with or without TKIs, directed either toward the epidermal growth factor receptor (EGFR) or VEGFR, in the first-line therapy of advanced NSCLC. Early this century, the entire research community was disappointed by the results of the 4 large, randomized trials of the EGFR TKIs gefitinib or erlotinib in combination with platinum-based doublets. In sum, these 4 trials (INTACT I, INTACT II, TRIBUTE, and TALENT) collectively accrued > 4000 patients with chemotherapy-naive NSCLC and found no benefit for the concurrent use of either EGFR-targeted TKI with platinum-based therapy.3-6 In contrast, phase III trials combining chemotherapy with monoclonal antibodies (MoAbs) have demonstrated modest improvements in efficacy. The first positive result was from the Eastern Cooperative Oncology Group (ECOG) 4599 study, a trial of carboplatin/paclitaxel with or without the VEGF-targeted antibody bevacizumab, which showed significant improvements in tumor response, progression-free survival (PFS), and OS.7 Subsequently, a phase III study of cisplatin/gemcitabine with or without 2 different doses of bevacizumab showed a modest improvement in the primary endpoint of PFS in the bevacizumab arms, although there was no improvement in OS.8,9 As expected, both trials also showed enhanced toxicity with the addition of bevacizumab. More recently, Merck KGaA issued a press release (September 11, 2007) announcing the positive survival results of its large, randomized, multinational trial, known as FLEX (First-Line Treatment for Patients with EGFR-Expressing Advanced NSCLC). This study treated patients with EGFR-overexpressing tumors with cisplatin/vinorelbine alone or in combination with cetuximab, a MoAb against the EGFR.10 The definition of EGFR positivity was very lenient, as patients with ≥ 1 EGFR-expressing cell in their tumor by immunohistochemistry (IHC) were deemed eligible. Although this trial had not yet been formally presented as of this writing, the press release noted that FLEX met its primary endpoint of a 25% increase in survival in favor of the cetuximab arm. Indeed, with the exception of lapatinib in combination with capecitabine in advanced breast cancer (and arguably, erlotinib plus gemcitabine in pancreatic cancer, which was only marginally positive), there have been few chemotherapy-plus-TKI trials that have yielded any substantial changes in oncologic community practice. On the other hand, chemotherapy-plus-MoAb (eg, rituximab, trastuzumab, and bevacizumab) combinations are now established as standard of care in hematologic malignancies and/or solid tumors such as colorectal, breast, and lung cancer. Why is there an apparent divergence in the results of trials of concurrent chemotherapy plus TKIs or MoAbs? Although editorial

Elucidation of molecular pathways that promote malignancies has led to the identification of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) as key components involved in regulation of tumor proliferation and angiogenesis, respectively. Biologic agents that target these individual pathways have proven effective in treating patients with advanced non-small-cell lung cancer (NSCLC), adding to previously available therapies and often with fewer side effects. However, inhibition of a single molecular pathway does not account for alternate pathways or biologic adaptations that eventually lead to resistance. Therefore, combining EGFR and VEGF inhibition is currently under investigation as a means to overcome resistance and promote synergy. Erlotinib, an anti-EGFR agent, and bevacizumab, an anti-VEGF agent, are both approved in NSCLC, demonstrating single-agent activity. The phase II trials evaluating the combination of erlotinib and bevacizumab have shown efficacy as first-line therapy or in patients with previously treated NSCLC either alone or with chemotherapy. Dual inhibition of EGFR and VEGF pathways has also been accomplished by the novel agents vandetanib and XL647, which are able to target both pathways. Vandetanib has also demonstrated activity in patients with advanced NSCLC either alone or with chemotherapy in phase I/II studies. Another novel agent, XL647, has demonstrated promising single-agent activity in patients who have been resistant to previous anti-EGFR therapy. Further evaluation of combined EGFR and VEGF inhibition is under investigation.