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Summary Background We did a phase 2 trial of pembrolizumab in patients with non-small-cell lung cancer (NSCLC) or melanoma with untreated brain metastases to determine the activity of PD-1 blockade in the CNS. Interim results were previously published, and we now report an updated analysis of the full NSCLC cohort. Methods This was an open-label, phase 2 study of patients from the Yale Cancer Center (CT, USA). Eligible patients were at least 18 years of age with stage IV NSCLC with at least one brain metastasis 5–20 mm in size, not previously treated or progressing after previous radiotherapy, no neurological symptoms or corticosteroid requirement, and Eastern Cooperative Oncology Group performance status less than two. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria was used to evaluate CNS disease; systemic disease was not required for participation. Patients were treated with pembrolizumab 10 mg/kg intravenously every 2 weeks. Patients were in two cohorts: cohort 1 was for those with PD-L1 expression of at least 1% and cohort 2 was patients with PD-L1 less than 1% or unevaluable. The primary endpoint was the proportion of patients achieving a brain metastasis response (partial response or complete response, according to mRECIST). All treated patients were analysed for response and safety endpoints. This study is closed to accrual and is registered with ClinicalTrials.gov , NCT02085070 . Findings Between March 31, 2014, and May 21, 2018, 42 patients were treated. Median follow-up was 8·3 months (IQR 4·5–26·2). 11 (29·7% [95% CI 15·9–47·0]) of 37 patients in cohort 1 had a brain metastasis response. There were no responses in cohort 2. Grade 3–4 adverse events related to treatment included two patients with pneumonitis, and one each with constitutional symptoms, colitis, adrenal insufficiency, hyperglycaemia, and hypokalaemia. Treatment-related serious adverse events occurred in six (14%) of 42 patients and were pneumonitis (n=2), acute kidney injury, colitis, hypokalaemia, and adrenal insufficiency (n=1 each). There were no treatment-related deaths. Interpretation Pembrolizumab has activity in brain metastases from NSCLC with PD-L1 expression at least 1% and is safe in selected patients with untreated brain metastases. Further investigation of immunotherapy in patients with CNS disease from NSCLC is warranted. Funding Merck and the Yale Cancer Center.

This study sought to define the role of first-line platinum-based doublet chemotherapy in older patients with non-small cell lung cancer (NSCLC).We analyzed three first-line NSCLC trials: CALGB 9730, CALGB 30203, and CALGB 30801, which tested carboplatin and paclitaxel; carboplatin and gemcitabine; and carboplatin with either pemetrexed or gemcitabine, respectively. Overall survival was the primary endpoint. Age-based comparisons with a cutpoint of 65 years were performed with Cox proportional hazards models with adjustments for sex, tumor histology, cancer stage, chemotherapy, and smoking history and after stratifying by performance score. Secondary endpoints were grade 3-5 adverse events, chemotherapy cycles completed, and whether toxicity prompted chemotherapy discontinuation.730 patients were included; 337 (46%) were 65+ years of age. No statistically significant difference in survival was observed for older (≥65) versus younger patients (HR = 1.096; 95% CI = (0.94, 1.28); p = 0.25). A trend emerged with increased odds of a grade 3-5 adverse event for patients ≥65 years versus65 years (OR = 1.52; 95% CI = (0.99, 2.31); p = 0.05). The proportion of completed chemotherapy cycles was marginally lower in older patients (difference = -5%; 95% CI = (-9, 0.2); p = 0.06) for those ≥65 years versus65 years, but no statistically significant difference occurred in the rate of chemotherapy discontinuation for toxicity (OR = 1.4; 95% CI = (0.85, 2.19); p = 0.21) for patients ≥65 years versus65 years. A cutpoint of 70 years yielded similar results.These findings support carboplatin doublet-based chemotherapy in select older patients with advanced NSCLC.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the targeted therapy and immunotherapy sections in the NCCN Guidelines. For the 2018 update, a new section on biomarkers was added.

BACKGROUND: KRAS mutations are identified in approximately 25% of non-small cell lung cancer (NSCLC) cases and are associated with resistance to currently available targeted therapies. The MET oncogene may be implicated in malignant progression of KRAS-mutant tumors. In a pre-specified subset analysis of KRAS mutant cancers in an earlier phase 2 study of erlotinib plus the oral MET inhibitor tivantinib, combination therapy was associated with substantial clinical benefit compared to erlotinib alone (progression-free survival [PFS] HR 0.18; P

This selection from the NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) focuses on targeted therapies and immunotherapies for metastatic NSCLC, because therapeutic recommendations are rapidly changing for metastatic disease. For example, new recommendations were added for atezolizumab, ceritinib, osimertinib, and pembrolizumab for the 2017 updates.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 78-year-old woman with a 40-pack-year smoking history has been referred for treatment of advanced non–small-cell lung cancer. She presented with a persistent cough and worsening dyspnea on exertion. A chest x-ray followed by a chest computed tomography scan revealed a 3-cm right upper lobe mass along with a moderate-size pleural effusion. Pleural fluid cytology was positive for adenocarcinoma. A brain magnetic resonance imaging scan was negative. A reflex molecular profile, including KRAS, EGFR, ALK, BRAF, HER2, RET, MET, and ROS, did not reveal an actionable abnormality. Her past medical history includes diabetes, hypertension, and osteopenia. Her medications include a β-blocker, angiotensin-converting enzyme inhibitor, oral antidiabetic agent, calcium, and vitamin D. The laboratory evaluation is notable for a hemoglobin of 10.8 g/dL and a creatinine clearance of 36 mL/min. The other laboratories are within normal limits. She is somewhat limited by the shortness of breath but maintains an Eastern Cooperative Oncology Group performance status of 1. She is independent in all of her instrumental and basic activities of daily living and denies falls. She has been referred to discuss treatment options.

These NCCN Guidelines Insights focus on recent updates in the 2016 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC; Versions 1-4). These NCCN Guidelines Insights will discuss new immunotherapeutic agents, such as nivolumab and pembrolizumab, for patients with metastatic NSCLC. For the 2016 update, the NCCN panel recommends immune checkpoint inhibitors as preferred agents (in the absence of contraindications) for second-line and beyond (subsequent) therapy in patients with metastatic NSCLC (both squamous and nonsquamous histologies). Nivolumab and pembrolizumab are preferred based on improved overall survival rates, higher response rates, longer duration of response, and fewer adverse events when compared with docetaxel therapy.

Introduction Time-to-treatment-failure (TTF) is the interval from chemotherapy initiation to premature discontinuation. We evaluated TTF based on age. Methods Pooled analyses were conducted with first-line chemotherapy trials for advanced NSCLC (CALGB 9730, 30203, and 30801). Comparisons among patients who were 65 years and older and 70 years and older were performed for TTF (primary endpoint), reasons for early chemotherapy cessation, grade 3+ adverse events, and overall survival. Results Among 1006 patients, 460 (46%) were older than 65 years of age. One hundred forty-five older patients (32% of this age cohort) completed all six planned chemotherapy cycles as did 170 (32%) younger patients. Median TTF was 2.9 months (95% confidence interval: 2.7– 3.2) in older patients and 3 months (95% confidence interval: 2.9–3.5) in younger patients; adjustment for performance status and stratification by chemotherapy by trial yielded no statistically significant age-based difference in TTF. However, reasons for early chemotherapy cessation differed between age groups (multivariate p = 0.004). Older patients were less likely to discontinue from cancer progression (41% versus 55%) and more likely from toxicity or patient choice (16% and 15%, respectively) compared to younger patients (13% and 6%, respectively). Older patients were more likely to experience grade 3+ adverse events (86% versus 79%) with no statistically significant difference in survival. An age cutpoint of 70+ years showed no difference in TTF, a lower trend of early cessation due to cancer progression, and somewhat shorter older patient survival. Conclusions TTF was comparable between older and younger patients; but different, age-based, and potentially modifiable reasons account for it.

Introduction With expanding indications for programmed death 1 (PD-1) axis inhibitors in non–small cell lung cancer (NSCLC), acquired resistance (AR) to these therapies is increasingly being encountered. We sought to characterize clinical patterns of AR to PD-1 axis inhibitors in patients with advanced NSCLC, and evaluate subsequent outcome and management strategies for such patients. Methods Patients with NSCLC who developed AR to PD-1 axis inhibitor therapy initiated between December 2009 and February 2016 at one institution were identified and examined by clinical and radiographic features. AR was defined as progressive disease after initial response by either Response Evaluation Criteria in Solid Tumors v1.1 or immune-related response criteria. Results Twenty-six patients with AR to PD-1 axis inhibitor therapy were identified and evaluated. Median time to AR was 313 days; the 2-year survival rate from AR was 70% (95% confidence interval: 0.53–0.92). Twenty patients (77%) experienced AR in lymph nodes (LNs), including 11 patients with LN-only progression. Twenty-three (88%) patients had recurrence limited to one (54%) or two (35%) sites of disease. Fourteen patients (54%) continued PD-1 axis inhibitor therapy beyond progression. Three patients were re-challenged with the same PD-1 axis inhibitor after holiday from and progression off therapy, 2 again responded. Fifteen patients (58%) received local therapy to site(s) of AR, 11 continued respective PD-1 axis inhibitor after local therapy. The 2-year survival rate from AR among these 15 patients was 92% (95% confidence interval: 0.77–1). Conclusions Acquired resistance to PD-1 axis inhibitors is often limited to one or two sites when local therapy and continuation of PD-1 axis inhibitor therapy can result in prolonged benefit. LN metastases appear to be particularly susceptible sites to AR. When progression of disease following response occurs after holiday from PD-1 axis inhibitor, re-challenge can again lead to tumor regression.

Purpose To investigate outcomes for elderly patients treated with chemotherapy (CT) alone versus chemoradiotherapy (CRT) in the modern era by using a large national database. Patients and Methods Elderly patients (age ≥ 70 years) with limited-stage small-cell lung cancer clinical stage I to III who received CT or CRT were identified in the National Cancer Data Base between 2003 and 2011. Hierarchical mixed-effects logistic regression with clustering by reporting facility was performed to identify factors associated with treatment selection. Overall survival (OS) of patients receiving CT versus CRT was compared by using the log-rank test, Cox proportional hazards regression, and propensity score matching. Results A total of 8,637 patients were identified, among whom 3,775 (43.7%) received CT and 4,862 (56.3%) received CRT. The odds of receiving CRT decreased with increasing age, clinical stage III disease, female sex, and the presence of medical comorbidities (all P < .01). Use of CRT was associated with increased OS compared with CT on univariable and multivariable analysis (median OS, 15.6 v 9.3 months; 3-year OS, 22.0% v 6.3%; log-rank P < .001; Cox P < .001). Propensity score matching identified a matched cohort of 6,856 patients and confirmed a survival benefit associated with CRT (hazard ratio, 0.52; 95% CI, 0.50 to 0.55; P < .001). Subset analysis of CRT treatment sequence showed that patients alive 4 months after diagnosis derived a survival benefit with concurrent CRT over sequential CRT (median OS, 17.0 v 15.4 months; log-rank P = .01). Conclusion In elderly patients with limited-stage small-cell lung cancer, modern CRT appears to confer an additional OS advantage beyond that achieved with CT alone in a large population-based cohort. Our findings suggest that CRT should be the preferred strategy in elderly patients who are expected to tolerate the toxicities of the combined approach.

The US lung cancer population is aging, the majority of which receive a diagnosis of incurable advanced non-small cell lung cancer (NSCLC). In US clinical oncology practice, elderly is defined as patients older than 70 years. Treatment of elderly patients with advanced NSCLC is complex. Choosing appropriate chemotherapy in this setting is complicated by multiple chronic conditions in addition to geriatric syndromes, challenging the traditional oncology practice. Although promising new options are on the horizon, the standard of care remains either platinum-based doublet or single-agent chemotherapy. Clinical trials have determined doublet therapy is appropriate for elderly patients; however, out of concern for excessive toxicity, many elderly patients do not receive appropriate treatment. Determining which patients are most likely to benefit from doublet chemotherapy versus monotherapy is a difficult challenge. Researchers have started to implement geriatric assessment and predictive chemotherapy toxicity tools in prospective clinical trials; however, knowledge gaps remain on how to appropriately select and treat elderly patients with advanced NSCLC in efforts to improve disease management and symptoms, maintain functional status, and minimize toxicity.

Introduction Patients with stage III non-small-cell lung cancer and poor performance status and/or weight loss do not seem to benefit from standard therapy. Based on the preclinical interaction between epidermal growth factor receptor inhibitors and radiation, we designed a trial of induction chemotherapy followed by thoracic radiotherapy and concurrent erlotinib. Methods Patients with poor-risk unresectable stage III non-small-cell lung cancer received two cycles of carboplatin at an AUC of 5 and nab-paclitaxel at 100 mg/m on days 1 and 8 every 21 days, followed by erlotinib administered concurrently with thoracic radiotherapy. Maintenance was not permitted. Molecular analysis was performed in available specimens. Seventy-two eligible patients were required to test whether the 1-year survival rate was less than 50% or greater than or equal to 65% with approximately 90% power at a significance level of 0.10. Results From March 2008 to October 2011, 78 patients were enrolled, three of whom were ineligible. The median age was 68 (range, 39-88) and 32% were aged greater than or equal to 75 years. Patients were evenly distributed between stages IIIA and IIIB and the majority had performance status 2. The overall response rate was 67% and the disease control rate was 93%. Treatment was well tolerated. The median PFS and OS were 11 and 17 months, respectively. The overall 12-month OS was 57%, which narrowly missed the prespecified target for significance. Conclusions Patients with poor-risk stage III non-small-cell lung cancer had better than expected outcomes with a regimen of induction carboplatin/nab-paclitaxel followed by thoracic radiotherapy and erlotinib. However, as per the statistical design, the 12-month OS was not sufficiently high to warrant further studies.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) focuses on the principles of radiation therapy (RT), which include the following: (1) general principles for early-stage, locally advanced, and advanced/metastatic NSCLC; (2) target volumes, prescription doses, and normal tissue dose constraints for early-stage, locally advanced, and advanced/palliative RT; and (3) RT simulation, planning, and delivery. Treatment recommendations should be made by a multidisciplinary team, including board-certified radiation oncologists who perform lung cancer RT as a prominent part of their practice.

Purpose Survival of patients with completely resected non–small-cell lung cancer (NSCLC) is unsatisfactory, and in 2002, the benefit of adjuvant chemotherapy was not established. This phase III study assessed the impact of postoperative adjuvant gefitinib on overall survival (OS). Patients and Methods Patients with completely resected (stage IB, II, or IIIA) NSCLC stratified by stage, histology, sex, postoperative radiotherapy, and chemotherapy were randomly assigned (1:1) to receive gefitinib 250 mg per day or placebo for 2 years. Study end points were OS, disease-free survival (DFS), and toxicity. Results As a result of early closure, 503 of 1,242 planned patients were randomly assigned (251 to gefitinib and 252 to placebo). Baseline factors were balanced between the arms. With a median of 4.7 years of follow-up (range, 0.1 to 6.3 years), there was no difference in OS (hazard ratio [HR], 1.24; 95% CI, 0.94 to 1.64; P = .14) or DFS (HR, 1.22; 95% CI, 0.93 to 1.61; P = .15) between the arms. Exploratory analyses demonstrated no DFS (HR, 1.28; 95% CI, 0.92 to 1.76; P = .14) or OS benefit (HR, 1.24; 95% CI, 0.90 to 1.71; P = .18) from gefitinib for 344 patients with epidermal growth factor receptor (EGFR) wild-type tumors. Similarly, there was no DFS (HR, 1.84; 95% CI, 0.44 to 7.73; P = .395) or OS benefit (HR, 3.16; 95% CI, 0.61 to 16.45; P = .15) from gefitinib for the 15 patients with EGFR mutation-positive tumors. Adverse events were those expected with an EGFR inhibitor. Serious adverse events occurred in ≤ 5% of patients, except infection, fatigue, and pain. One patient in each arm had fatal pneumonitis. Conclusion Although the trial closed prematurely and definitive statements regarding the efficacy of adjuvant gefitinib cannot be made, these results indicate that it is unlikely to be of benefit.

Purpose To compare single-agent pemetrexed (P) versus the combination of carboplatin and pemetrexed (CP) in first-line therapy for patients with advanced non–small-cell lung cancer (NSCLC) with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2. Patients and Methods In a multicenter phase III randomized trial, patients with advanced NSCLC, ECOG PS of 2, any histology at first and later amended to nonsquamous only, no prior chemotherapy, and adequate organ function were randomly assigned to P alone (500 mg/m2) or CP (area under the curve of 5 and 500 mg/m2, respectively) administered every 3 weeks for a total of four cycles. The primary end point was overall survival (OS). Results A total of 205 eligible patients were enrolled from eight centers in Brazil and one in the United States from April 2008 to July 2011. The response rates were 10.3% for P and 23.8% for CP (P = .032). In the intent-to-treat population, the median PFS was 2.8 months for P and 5.8 months for CP (hazard ratio [HR], 0.46; 95% CI, 0.35 to 0.63; P < .001), and the median OS was 5.3 months for P and 9.3 months for CP (HR, 0.62; 95% CI, 0.46 to 0.83; P = .001). One-year survival rates were 21.9% and 40.1%, respectively. Similar results were seen when patients with squamous disease were excluded from the analysis. Anemia (grade 3, 3.9%; grade 4, 11.7%) and neutropenia (grade 3, 1%; grade 4, 6.8%) were more frequent with CP. There were four treatment-related deaths in the CP arm. Conclusion Combination chemotherapy with CP significantly improves survival in patients with advanced NSCLC and ECOG PS of 2.

The use of EGF receptor inhibitors has recently been incorporated into the armamentarium of agents available to treat patients with non-small-cell lung cancer. Their use in combination with chemotherapy and radiotherapy has been investigated in Phase II and III trials. The use of EGF receptor tyrosine kinase inhibitors in combination with chemotherapy has been somewhat disappointing, whereas the use of anti-EGF receptor monoclonal cetuximab in combination with chemotherapy has provided mixed results. The use of cetuximab in combination with chemotherapy and radiotherapy in patients with locally advanced disease has generated encouraging results in Phase II trials, and Phase III trials are currently ongoing. The identification of molecular biomarkers to predict benefit is a work in progress.

Purpose IPI-504 is a novel, water-soluble, potent inhibitor of heat-shock protein 90 (Hsp90). Its potential anticancer activity has been validated in preclinical in vitro and in vivo models. We studied the activity of IPI-504 after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in patients with advanced, molecularly defined non–small-cell lung cancer (NSCLC). Patients and Methods Patients with advanced NSCLC, prior treatment with EGFR TKIs, and tumor tissue available for molecular genotyping were enrolled in this prospective, nonrandomized, multicenter, phase II study of IPI-504 monotherapy. The primary outcome was objective response rate (ORR). Secondary aims included safety, progression-free survival (PFS), and analysis of activity by molecular subtypes. Results Seventy-six patients were enrolled between December 2007 and May 2009 from 10 United States cancer centers. An ORR of 7% (five of 76) was observed in the overall study population, 10% (four of 40) in patients who were EGFR wild-type, and 4% (one of 28) in those with EGFR mutations. Although both EGFR groups were below the target ORR of 20%, among the three patients with an ALK gene rearrangement, two had partial responses and the third had prolonged stable disease (7.2 months, 24% reduction in tumor size). The most common adverse events included grades 1 and 2 fatigue, nausea, and diarrhea. Grade 3 or higher liver function abnormalities were observed in nine patients (11.8%). Conclusion IPI-504 has clinical activity in patients with NSCLC, particularly among patients with ALK rearrangements.

9099Background: We report final Phase I results of a Phase I/II prospective trial assessing safety and tolerability of SBRT and concurrent pembrolizumab. Methods: Eligible patients had metastatic N...

2009Background: Pembrolizumab can have significant and durable activity in patients (pts) with advanced NSCLC, however the activity in the central nervous system (CNS) and the long-term benefit in ...

Purpose:Data from two randomized phase III trials were analyzed to evaluate prognostic factors and treatment selection in the first-line management of advanced non-small cell lung cancer patients with performance status (PS) 2.Patients and Methods:Patients randomized to combination chemotherapy (carboplatin and paclitaxel) in one trial and single-agent therapy (gemcitabine or vinorelbine) in the second were included in these analyses. Both studies had identical eligibility criteria and were conducted simultaneously. Comparison of efficacy and safety was performed between the two cohorts. A regression analysis identified prognostic factors and subgroups of patients that may benefit from combination or single-agent therapy.Results:Two hundred one patients were treated with combination and 190 with single-agent therapy. Objective responses were 37 and 15%, respectively. Median time to progression was 4.6 months in the combination arm and 3.5 months in the single-agent arm (p < 0.001). Median survival times were 8.0 and 6.6 months, and 1-year survival rates were 31 and 26%, respectively. Albumin

Patients with performance status (PS) 2 represent approximately 30%-40% of all patients with advanced non-small-cell lung cancer (NSCLC) seen in clinical practice. Although these patients have been historically excluded from randomized clinical trials, recent studies have suggested a benefit from systemic chemotherapy. The development of biologic agents offers a new promise for the treatment of PS 2 patients as a result of the perceived improved therapeutic index of these agents. However, many of the recent advances in NSCLC have been limited to good PS patients and have not translated into an improvement in the management of the PS 2 population because the studies have excluded this patient population or have failed to demonstrate a survival benefit.

The treatment of advanced non-small cell lung cancer has evolved substantially during the last decade. Chemotherapy with a platinum-based doublet prolongs survival and improves quality of life in patients with good performance status. Recently, the addition of bevacizumab and the use of epidermal growth factor receptor inhibitors in appropriately selected patients have further improved the outcome of patients with advanced non-small cell lung cancer. Newer targeted agents are being developed and tested in the clinical arena at a rapid pace. In addition, the identification by clinical or molecular criteria of patient populations that benefit the most from these agents is under active investigation. In contrast, the development of newer cytotoxic agents, with innovative mechanisms of action, has been comparatively disappointing. Whether standard cytotoxic drugs are required as newer biologic agents are more frequently used or whether a more active and safer chemotherapy can be used as a template for combinations with biologic agents remains an important research topic.

Introduction We conducted a multicenter phase II study to evaluate the efficacy and safety of oxaliplatin and gemcitabine with bevacizumab in patients with advanced non-small cell lung cancer (NSCLC). Methods Patients with chemotherapy-naive, nonsquamous, stage IIIB or IV NSCLC received gemcitabine 1000 mg/m 2 on days 1 and 8, oxaliplatin 130 mg/m 2 on day 1, and bevacizumab 15 mg/kg on day 1 every 21 days for 4 cycles. Patients with stable disease or response received maintenance bevacizumab every 3 weeks until progression. Primary end point was median time to progression (TTP). Results Nineteen of 44 eligible patients had partial response in the intent-to-treat analysis for an objective response rate of 43% (95% confidence interval [CI], 26.3–60.1%); 16 patients had stable disease for a disease control rate of 80% (95% CI, 72.0–87.0%). Median TTP was 5.5 months (95% CI, 3.8–6.9 months), which approached that seen in phase III studies. Median survival was 13.7 months (95% CI, 7.3–21.8 months). The most common grade 3 or 4 adverse events were hypertension (11%), neutropenia (9%), diarrhea (7%), dyspnea (7%), and thromboembolic events (7%). Pulmonary hemorrhage was not observed. Conclusions The results of this phase II study suggest that oxaliplatin and gemcitabine with bevacizumab was active and reasonably well tolerated. Median TTP approached that in phase III studies. This combination represents another treatment option for advanced NSCLC.

Background: Because the elderly are underrepresented on clinical trials, physicians have few sources of information to estimate the risks (ie, toxicities) and benefits of chemotherapy administration to the elderly. Objective: Our goal was to determine whether the standard measures of toxicity used in clinical trials could be captured from observational Medicare claims data. Methods: We identified 175 elderly clinical trial patients treated on 2 Cancer and Leukemia Group B (CALGB) trials (9344, adjuvant breast study and 9730, advanced lung cancer study) and merged participants’ CALGB data with their Medicare data. From CALGB data, we identified the most frequent Extended Clinical Toxicity Critieria grade III/IV toxicities. We reviewed diagnostic and procedure codes from Medicare manuals, developed algorithms to measure the toxicities, and then finalized the algorithms after empiric review of patients’ codes. We compared results of Medicare algorithms to gold standard CALGB toxicity information to calculate test characteristics. Results: CALGB data documented that 15 grade III/IV chemotherapy-related toxicities occurred in 3% of the 175 patients: white blood cell, hemoglobin, platelets, anorexia, nausea, vomiting, diarrhea, stomatitis, sensory neuropathy, motor neuropathy, motor or sensory neuropathy, dyspnea, hyperglycemia, infection, and malaise. Vomiting was the only toxicity identified by the Medicarebased algorithm with a sensitivity, specificity, and area under the receiver operator curve of 80%. Conclusions: The results of this preliminary study suggest that Medicare diagnostic and procedure codes may be of only limited value in measuring clinically significant chemotherapy-related toxicities in elderly Medicare beneficiaries. Future research includes confirming these findings in a larger and more diverse sample.

Purpose A multicenter randomized phase II trial to evaluate two treatment strategies in the first-line management of advanced non–small-cell lung cancer (NSCLC) patients with a performance status (PS) of 2. Patients and Methods Patients were assigned to erlotinib 150 mg orally daily until progression or to carboplatin (area under the curve [AUC] 6) and paclitaxel (200 mg/m2 day 1 every 3 weeks) for up to four cycles. Patients who experienced progression or did not tolerate or refused further chemotherapy were allowed to cross over to erlotinib. The primary end point was progression-free survival (PFS). Secondary end points were response, survival, quality of life (QOL), and a retrospective molecular correlation. Results Fifty-two patients were randomly assigned to erlotinib and 51 to chemotherapy. Partial responses were 2% and 12%, respectively. Median PFS was 1.9 months in the erlotinib arm and 3.5 months in the chemotherapy arm (hazard ratio [HR] = 1.45; 95% CI, 0.98 to 2.15; P = .06). Median survival times were 6.5 and 9.7 months, respectively (HR = 1.73; 95% CI, 1.09 to 2.73; P = .018). Patients who crossed over to erlotinib had a median survival of 14.9 months. Sex, histology, skin rash, and smoking history predicted outcome with erlotinib. Rash and diarrhea were more common with erlotinib; emesis, alopecia, peripheral neuropathy, and fatigue were more common with chemotherapy. QOL was similar between the two arms. Molecular correlation was limited by available samples. Conclusion Unselected patients with advanced NSCLC and PS 2 are best treated with combination chemotherapy as first-line therapy. Erlotinib may be considered in patients selected by clinical or molecular markers.

Background Stage IV non-small cell lung cancer (NSCLC) remains a treatable but incurable disease. Methods A MEDLINE search was performed to identify pertinent peer-reviewed articles that addressed the questions posed for this section. The writing committee developed and graded recommendations, which were subsequently approved by the American College of Chest Physicians. Results Platinum-based doublets remain the standard of care in patients with good performance status (PS); there is no evidence that the addition of a third cytotoxic agent improves survival. Likewise, with only one exception, the addition of a new targeted or biological agent to platinum-based doublets does not improve survival. The one exception is the addition of bevacizumab, an antiangiogenic agent, to carboplatin/paclitaxel in patients with stage IV disease and good PS. Patients for whom bevacizumab is recommended must also be selected on the basis of histology (nonsquamous), absence of brain metastases and hemoptysis, and no indication for therapeutic anticoagulation. In patients with stage IV NSCLC and PS of 2, chemotherapy is recommended, but the optimal approach has not been defined. Elderly patients, defined as ≥ 70 years old, also derive benefit from chemotherapy. Most elderly patients should receive single-agent chemotherapy, but elderly patients with good PS and without significant comorbidities seem to derive a similar benefit from platinum-based doublets compared with their younger counterparts without a prohibitive difference in treatment toxicities. Because stage IV NSCLC is incurable, quality-of-life issues are important, and tools exist to monitor a patient's quality of life during therapy. Last, patients need to be informed of the implication of the diagnosis of stage IV NSCLC and be educated about treatment options that are available to them. Conclusions Advances have been made in stage IV NSCLC, and the appropriate use of chemotherapy continues to evolve on the basis of well-designed clinical trials that address critical issues in this population.

Background:We conducted a multicenter randomized phase II trial to evaluate two schedules of single-agent docetaxel in the first-line treatment of elderly and performance status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC).Methods:Patients 70 years of age and older with a PS 0–1 or patients of any age and PS 2 were randomly assigned to docetaxel 75 mg/m2 on day 1 every 3 weeks or 30 mg/m2 on days 1, 8, and 15 every 28 days. The primary end point was frequency of grade 3/4 toxicities. Health-related quality of life, response, and survival were secondary end points.Results:Fifty-five patients were randomized to received docetaxel every 3 weeks and 56 to receive docetaxel weekly. Hematologic toxicity, primarily grade 3/4 neutropenia, was significantly lower in the weekly schedule (0% versus 44%; p < 0.001). Health-related quality of life was similar between the two arms. Efficacy parameters were not significantly different, with a trend toward better survival in the weekly schedule group (6.7 versus 3.5 months). Patients with PS 0–1 had a significantly longer survival compared with PS 2 patients (7.8 versus 2.9 months; p < 0.001). A subset analysis of 30 octogenarian patients revealed similar outcomes as in 70- to 79-year-old patients.Conclusion:Weekly docetaxel is associated with less neutropenia and a trend toward improved survival in elderly or PS 2 patients. PS rather than age is the primary determinant of outcome in this population. Octogenarians benefited from weekly docetaxel. Future studies should separate elderly patients from PS 2 patients.

One of the main challenges oncologists face in the care of patients with lung cancer is the decision to incorporate new clinical trial data into routine clinical practice. Beyond the question of statistical significance, which is a more objective metric, are the results meaningful and applicable to a broader population? Furthermore, in an era of value care, do the results justify a potential increase in costs? This article discusses the main points that clinicians consider in their decision-making process and illustrates the arguments with real-life examples.

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC). Appropriate targeted therapy is very effective in patients with advanced NSCLC who have specific genetic alterations. Therefore, it is important to test tumor tissue from patients with advanced NSCLC to determine whether they have genetic alterations that make them candidates for specific targeted therapies. These NCCN Guidelines Insights describe the different testing methods currently available for determining whether patients have genetic alterations in the 2 most commonly actionable genetic alterations, notably anaplastic lymphoma kinase (ALK) gene rearrangements and sensitizing epidermal growth factor receptor (EGFR) mutations.

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has been shown to benefit patients with a variety of cancers.Between July 2001 and April 2004, the Eastern Cooperative Oncology Group (ECOG) conducted a randomized study in which 878 patients with recurrent or advanced non-small-cell lung cancer (stage IIIB or IV) were assigned to chemotherapy with paclitaxel and carboplatin alone (444) or paclitaxel and carboplatin plus bevacizumab (434). Chemotherapy was administered every 3 weeks for six cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous-cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or performance status (ECOG performance status,1) were excluded. The primary end point was overall survival.The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (hazard ratio for death, 0.79; P=0.003). The median progression-free survival in the two groups was 6.2 and 4.5 months, respectively (hazard ratio for disease progression, 0.66; P0.001), with corresponding response rates of 35% and 15% (P0.001). Rates of clinically significant bleeding were 4.4% and 0.7%, respectively (P0.001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including 5 from pulmonary hemorrhage.The addition of bevacizumab to paclitaxel plus carboplatin in the treatment of selected patients with non-small-cell lung cancer has a significant survival benefit with the risk of increased treatment-related deaths. (ClinicalTrials.gov number, NCT00021060.)

PurposeTrials combining irinotecan/docetaxel and irinotecan/gemcitabine in second-line treatment of non–small-cell lung cancer (NSCLC) have yielded promising results. Preliminary data suggested that the selective cyclooxygenase -2 inhibitor celecoxib (CBX) might enhance efficacy of chemotherapeutic regimens. This multicenter, phase II, randomized trial investigated efficacy and safety of irinotecan and docetaxel and irinotecan and gemcitabine, with or without CBX, in second-line treatment of NSCLC.Patients and MethodsPatients 18 years or older were randomly assigned to receive irinotecan 60 mg/m2and docetaxel 35 mg/m2, or irinotecan 100 mg/m2and gemcitabine 1,000 mg/m2, with or without CBX 400 mg twice daily, for four cycles. Primary efficacy end points were median and 1-year survival probabilities. Patient-reported symptoms were assessed by the Lung Cancer Symptoms Scale (LCSS).ResultsA total of 133 patients were assessable for efficacy and safety. Median survival time was 6.31 months for patients treated with CBX and 8.99 months for those treated with chemotherapy alone. One-year survival rates were 24% and 36% respectively. The overall toxicity rates and LCSS scores were similar between patients treated or not treated with CBX. Four deaths were considered possibly treatment related.ConclusionSurvival results for the second-line regimens in this study were similar to results reported for single-agent therapy in this setting. CBX did not appear to enhance efficacy or improve patient-reported symptoms. The addition of high-dose CBX to second-line chemotherapy in NSCLC cannot be recommended.

The treatment of patients with advanced non-small cell lung cancer has changed considerably in the past decade. This paper reviews the most significant changes seen in chemotherapy and the most promising new agents in development for this disease.Chemotherapy prolongs survival and improves quality of life in patients with a good performance status and appears to alleviate disease-related symptoms in patients with a lower performance status. Platinum-based regimens became standard; none of the third-generation drug combinations seemed to be superior to the others. Nonplatinum combinations are reasonable alternatives now and offer a better toxicity profile in certain populations. Attempts to add molecular-targeted therapy to combination chemotherapy have failed except for bevacizumab. New compounds such as pemetrexed, bortezomib, TLK286, bevacizumab, and the epothilones are currently being evaluated in non-small cell lung cancer.Management of non-small cell lung cancer has improved considerably in the past decade. The overall benefit of chemotherapy over supportive care has been shown, platinum-based doublets have been established, nonplatinum regimens have been developed, chemotherapy has been used more broadly in subgroups of patients who have been previously neglected, and a shorter chemotherapy duration has been shown to be equally effective. After hitting a plateau in the benefit of chemotherapy, new drugs with novel action mechanisms such as the ones described here offer hope to improve therapy for this disease.

The antisense oligonucleotide aprinocarsen specifically inhibits the transcription of protein kinase C-alpha. This study evaluated the response rate of the combination therapy of aprinocarsen, gemcitabine, and carboplatin in previously untreated patients with advanced non-small cell lung cancer (NSCLC). Secondary objectives included the measurement of time-to-event efficacy parameters and toxicity. Patients with stage IV or stage IIIB disease (N(3) and/or pleural/pericardial effusion) were treated with gemcitabine 1,250 mg/m(2) on days 1 and 8 and carboplatin AUC 5 on day 1 every 21 days. Aprinocarsen was administered as 2mg/kg/day continuous iv infusion on the first 14 days of each cycle, following the carboplatin treatment. A total of 36 patients received a median of 3 treatment cycles, with 10 patients completing 6 cycles. No complete response was observed, while partial response was seen in 25% of patients. Stable disease and progressive disease was observed in 36.1% and 22.2% of patients. The median overall survival was 8.3 months, and the median duration of progression-free survival was 5.7 months (95% CI, 3.2-7.1 months). Thrombocytopenia (78%) and neutropenia (50%) were the major grade 3/4 toxicities. Enrollment for this study was stopped and the study was terminated in March 2003 due to the results of a large phase III study, which suggested that aprinocarsen did not improve response or add survival benefit to chemotherapy in advanced NSCLC. The addition of aprinocarsen to gemcitabine+carboplatin therapy in patients with NSCLC showed moderate activity. However, this combination resulted in severe thrombocytopenia in the majority of patients.

Background The purpose of this study was to compare quality of life and overall toxicity in patients with advanced non-small-cell lung cancer (NSCLC) treated with vinorelbine–gemcitabine (VG) or carboplatin–paclitaxel (Taxol) (CP). Patients and methods A total of 165 previously untreated patients were randomized to the two regimens. Quality of life was assessed by the Lung Cancer Symptom Scale (LCSS). Overall toxicity and secondary efficacy end points were evaluated by standard WHO criteria. Results There was no significant difference in overall quality of life between the two treatments. Neutropenia, thrombocytopenia, peripheral neuropathy, and alopecia, were more common in the CP arm, whereas constipation was more frequent in the VG arm. Response rates were 14.6% in the VG arm and 16.9% in the CP arm. Median survival times were 7.8 and 8.6 months, and 1 year survival rates were 38.4% and 31.9%, respectively. Conclusions Patients treated with VG experienced lower toxicity, but overall quality of life was similar in both arms. Efficacy seemed comparable between VG and CP. Our study shows that VG is a viable alternative to platinum-based chemotherapy in patients with advanced NSCLC.

Most patients with non-small-cell lung cancer (NSCLC) are elderly, and age has important implications for their management and treatment. In May 2014, the Italian Association of Thoracic Oncology organized an International Experts Panel Meeting with the intent to review the available evidence regarding the treatment of elderly patients with NSCLC and to discuss the implications for clinical practice and future research in this field; this article summarizes the panelists' conclusions. All patients aged more than 70 years should receive an assessment of physiologic age, including mortality and toxicity prediction. Age itself does not contraindicate adjuvant chemotherapy after resection. Elderly patients with locally advanced NSCLC should be considered for combined chemo-radiotherapy. In the advanced setting, the combination of carboplatin/paclitaxel results in prolonged survival compared with single-agent gemcitabine or vinorelbine, albeit with increased toxicity. In fit selected patients, other carboplatin-based or cisplatin-based regimens are feasible, but randomized trials specifically showing survival prolongation in elderly patients are lacking. The survival benefit for bevacizumab added to chemotherapy seems limited to patients aged less than 75 years. In unfit elderly patients, single agents are recommended. Regardless of age, patients with advanced nonsquamous NSCLC, and those who have never smoked independently of their histologic subtype, should be tested for epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement. In patients with NSCLC harboring EGFR mutation or ALK rearrangement, targeted drugs are feasible and well tolerated.

Background In the United States, patients who enroll in chemotherapy trials seldom reflect the attributes of the general population with cancer, as they are often younger, more functional, and have less comorbidity. We compared survival following three chemotherapy regimens according to the setting in which care was delivered (ie, clinical trial vs usual care) to determine the generalizability of clinical trial results to unselected elderly Medicare patients. Methods Using SEER-Medicare data, we estimated survival for elderly patients (ie, age 65 years or older, n = 14097) with advanced pancreatic or lung cancer following receipt of one of three guideline-recommended first-line chemotherapy regimens. We compared their survival to that of similarly treated clinical trial enrollees, without age restrictions, with the same diagnosis and stage (n = 937). All statistical tests were two-sided. Results Trial patients were 9.5 years younger than elderly Medicare patients. Medicare patients were more often white and tended to live in areas of greater educational attainment than trial enrollees. For each tumor type, Medicare patients who were 75 years or older had median survivals that were six to eight weeks shorter than those of trial patients (4.3 vs 5.8 months following treatment with single agent gemcitabine for advanced pancreatic cancer, P = .03; 7.3 vs 8.9 months following treatment with carboplatin and paclitaxel for stage IV non-small cell lung cancer, P = .91; 8.2 vs 10.2 months following treatment with CDDP/ VP16 for extensive stage small cell lung cancer, P ≤ .01), whereas younger Medicare patients had survival times that were similar to those of trial patients. Conclusions Results of clinical trials for advanced pancreatic cancer and lung cancers tended to correctly estimate survival for Medicare patients aged 65 to 74 years, but to overestimate survival for older Medicare patients by six to eight weeks. These estimates of Medicare patients' survival may aid subsequent patients and their oncologists in treatment decision-making.

Although platinum-containing regimens prolong survival in advanced non-small cell lung cancer (NSCLC), toxicity remains substantial. There is a clear need for a nonplatinum-based regimen which is active, well tolerated, and suitable for outpatient administration. Vinorelbine and gemcitabine have different mechanisms of action and are both active in NSCLC. A phase II trial was undertaken to evaluate activity and tolerability when the two drugs were administered as a first-line combination regimen in 32 patients with stage IIIB/IV disease. Gemcitabine was administered at a dose of 1,000-1,250 mg/m2 together with vinorelbine 25 mg/m2 on days 1 and 8 of a 21-day cycle. The overall response rate was 25%, median survival 8.3 months and one-year survival rate 38% (48% in patients of performance status 0-1). Grade 3/4 neutropenia was observed in 38% of 148 treatment cycles, however, thrombocytopenia was infrequent and there was no grade 3/4 anemia. Nonhematological toxicity was minimal. The response and survival rates experienced were comparable with standard platinum-based combinations. Ongoing randomized trials will further define the role of the vinorelbine/gemcitabine combination in advanced NSCLC.

BACKGROUND The authors conducted a Phase II study to evaluate the activity and toxicity of weekly docetaxel in second-line therapy for nonsmall cell lung carcinoma (NSCLC). METHODS Patients with documented recurrent or refractory NSCLC, previously treated with no more than one chemotherapy regimen, were eligible if they had a performance status (PS) of 0–2, measurable or evaluable disease, and adequate organ function. Patients were treated with docetaxel 36 mg/m2/week for 6 consecutive weeks, administered intravenously with dexamethasone premedication. Cycles were repeated every 8 weeks. RESULTS Thirty-one patients were enrolled. One patient was ineligible because of uncontrolled brain metastases. Hematologic toxicity was minimal. Nonhematologic toxicities were modest except for diarrhea and cumulative fatigue. There were no treatment-related deaths. The overall response rate was 10% (95% confidence interval [CI], 1.6–29%). The median survival time (MST) was 8.0 months. and the 1-year survival rate was 31% (95% CI, 17– 58%). Patients with PS 0–1 had a MST of 11.9 months with 1-year survival of 42%. CONCLUSIONS Weekly docetaxel is very well tolerated as second-line therapy for NSCLC. The activity of this regimen appears to be comparable to the standard 3-week schedule. This regimen offers new opportunities for combination regimens, both as first- and second-line therapy for NSCLC. Cancer 2001;92:2158–63. © 2001 American Cancer Society.

BACKGROUND The authors conducted a Phase II study to evaluate the activity of the combination of gemcitabine and vinorelbine in patients with advanced nonsmall cell lung carcinoma (NSCLC). METHODS Patients were eligible if they had Stage IIIB (malignant pleural effusion) or Stage IV NSCLC, no prior chemotherapy, and Cancer and Leukemia Group B performance status (PS) 0–2. Patients with brain metastases were eligible if they were neurologically stable after brain irradiation. Thirty-three patients from participating institutions were enrolled. One patient was ineligible due to untreated brain metastases. Patients were treated with gemcitabine 1250 mg/m2 over 30 minutes (1000 mg/m2 for the first 6 patients) and vinorelbine 25 mg/m2 over 6 minutes, both administered intravenously on Days 1 and 8 every 21 days. Treatment was planned for a total of six cycles or more if the patient had persistent benefit. Growth factors were not allowed. RESULTS Among all 32 eligible patients, there were 8 partial responses, for an overall response rate of 25% (95% confidence interval [CI], 11.5–43.4%). The median survival time was 8.3 months and the 1-year survival rate was 38% (95% CI, 24–59%). Patients with PS 0–1 had a median survival of 11.7 months and a 1-year survival rate of 48%. Grade 3 and 4 neutropenia was observed in 13% and 25% of the 148 treatment cycles, respectively. One patient died of neutropenic sepsis. Only 2 episodes of Grade 3 and 4 thrombocytopenia were observed. Nonhematologic toxicity was minimal. CONCLUSIONS Gemcitabine and vinorelbine is an active and well-tolerated regimen in patients with advanced NSCLC, with response and survival rates at least comparable to those achieved with standard platinum-based regimens. This combination may be particularly suitable for the elderly or for patients who cannot tolerate more toxic platinum-based regimens. Cancer 2000;88:557–62. © 2000 American Cancer Society.

Small cell lung cancer (SCLC) accounts for about 10% to 15% of all lung cancers. It is characterized by its rapid doubling time, high rate of dissemination, and increased sensitivity to chemotherapy and radiation. Although the incidence of SCLC has been steadily decreasing over time, it remains a serious public health problem given its aggressive clinical behavior and the lack of effective therapies. This review looks at the evolution of SCLC treatment and the standard treatments that are currently available, including platinum-based combination chemotherapy, hyperfractionated thoracic radiation, and prophylactic cranial irradiation. The development of novel therapies for SCLC has been lagging behind, but completed clinical trials and ongoing investigations are helping us define what will be the best therapeutic targets for this disease.

Introduction Performance status (PS) is a standard functional classification in oncology research and practice. However, despite its widespread use, little is known about the prevalence of poor PS in lung cancer patients, in relation to other cancers, based on the assessments of health care providers and patients. Methods Data from two quality of life studies were pooled for analysis. Analyses were performed on the subset of patients with lung cancer (n = 503) from the entire population of cancer patients (n = 2885). The prevalence of poor PS (defined as PS=2–4 on a 0–4 scale) was determined for lung cancer patients. Results Prevalence of poor PS among lung cancer patients was 34% when estimated by providers and 48% when estimated by patients themselves. Agreement between providers and patients was only fair (weighted [ kappa ] = 0.41). For both advanced and early stage disease, lung cancer patients were at the highest risk for poor PS compared with other common cancers. Conclusions The prevalence of poor PS is quite high in lung cancer patients. Providers tend to underestimate poor PS. Specific clinical trials and treatment guidelines for this patient population are urgently needed.

Introduction We report outcomes for the combined cohort of patients ages 80 or older from two chemotherapy trials in advanced non-small cell lung cancer (NSCLC) conducted by the Southwest Oncology Group (S0027) and an investigator-initiated trial (LUN 6). Methods Patients with chemotherapy-naive, stage IIIB/IV NSCLC, ages 70 years or older with a performance status (PS) of 0 or 1, or patients of any age with PS 2, were eligible. Treatment in the S0027 study was 25 mg/m2 of vinorelbine on days 1 and 8, every 21 days for three cycles, and then 35 mg/m2 of docetaxel on days 1, 8, and 15, every 28 days for three cycles. Treatment in the LUN 6 study was 30 mg/m2 of docetaxel on days 1, 8, and 15, every 28 days, or 75 mg/m2 every 21 days. Of the 228 patients treated, 49 (21.5%; 26 in LUN 6 and 23 in S0027) were ages 80 years or older. Analysis of outcome was conducted in the 80-and-older group and was compared with the under-80 cohort from S0027. Results Among patients with measurable disease, disease-control rates (partial response + stable disease) were 54% (n = 48) and 46% (n = 89) in the 80-and-older and under-80 groups, respectively. Median survival was 7 and 11 months in PS 0/1 patients in the 80-and-older and under-80 groups, respectively. Median survival was 4 and 5 months in PS 2 patients in the 80-and-older and under-80 groups, respectively. Treatment was well tolerated. Five treatment-related deaths were noted: two (4%) and three (3.4%) in the 80-or-younger and the under-80 groups, respectively. Conclusions These chemotherapy regimens were associated with an encouraging disease-control rate (54%) in patients 80 years or older with advanced NSCLC, with good tolerance. Selected octogenarians with advanced NSCLC may benefit from single-agent chemotherapy.

PurposeTo determine the efficacy of cetuximab in patients with recurrent or progressive non–small-cell lung cancer (NSCLC) after receiving at least one prior chemotherapy regimen.Patients and MethodsThis was an open-label, phase II study of patients with epidermal growth factor receptor (EGFR) –positive and EGFR-negative advanced NSCLC with Eastern Cooperative Oncology Group performance status 0 to 1. Patients received cetuximab 400 mg/m2intravenously (IV) during 120 minutes on week 1 followed by weekly doses of cetuximab 250 mg/m2IV during 60 minutes. A cycle was considered as 4 weeks of treatment and therapy was continued until disease progression or intolerable toxicities. The primary end point was to assess response rate. Secondary end points included an estimation of time to progression and survival.ResultsPatient and disease characteristics (n = 66) included EGFR-positive status (n = 60); EGFR-negative status (n = 6); number of prior regimens (one, n = 28; two, n = 27; ≥ three, n = 11); male (n = 41); female (n = 25); adenocarcinoma (n = 36); and smoking status (never, n = 13; former, n = 45; current, n = 8). Grade 3/4 toxicities included acne-like rash (6.1%), anaphylactic reactions (1.5%), and diarrhea (1.5%). The response rate for all patients (n = 66) was 4.5% (95% CI, 0.9% to 12.7%) and the stable disease rate was 30.3% (95% CI, 19.6% to 42.9%). The response rate for patients with EGFR-positive tumors (n = 60) was 5% (95% CI, 1.0% to 13.9%). The median time to progression for all patients was 2.3 months (95% CI, 2.1 to 2.6 months) and median survival time was 8.9 months (95% CI, 6.2 to 12.6 months).ConclusionAlthough the response rate with single-agent cetuximab in this heavily pretreated patient population with advanced NSCLC was only 4.5%, the disease control rates and overall survival seem comparable to that of pemetrexed, docetaxel, and erlotinib in similar groups of patients.

Cetuximab is a monoclonal antibody directed against the ligand binding site in the extracellular domain of the epidermal growth factor receptor (EGFR). Cetuximab is currently approved for the treatment of patients with refractory colorectal cancer. In locally advanced head and neck carcinoma, cetuximab in combination with radiotherapy significantly improved survival compared with radiotherapy alone, and this treatment awaits Food and Drug Administration approval. In previously treated non–small cell lung cancer, single-agent cetuximab produced an objective response in 3 of 66 eligible patients and a median survival of 8.1 months. Treatment was well tolerated, with skin rash as the principal toxicity. The vast majority of patients (60 of 66) expressed EGFR by immunohistochemistry but no correlation existed between response and EGFR mutations. Two single-arm phase II trials testing cetuximab in combination with a platinum-based doublet in previously untreated patients showed responses in the range of 26% to 29%, with median survival times of 10 to 11 months. A European phase II randomized trial tested cisplatin/vinorelbine with or without cetuximab as first-line therapy in 86 patients with advanced non–small-cell lung cancer. Overall efficacy was slightly superior in the cetuximab arm and a phase III trial is currently ongoing to definitively determine the role of cetuximab in this setting.