Trials In Advanced Non-small Cell Lung Cancer Research Articles

Representativeness of Patients Enrolled in the Lung Cancer Master Protocol (Lung-MAP).

Lung Cancer Master Protocol (Lung-MAP), a public-private partnership, established infrastructure for conducting a biomarker-driven master protocol in molecularly targeted therapies. We compared characteristics of patients enrolled in Lung-MAP with those of patients in advanced non-small-cell lung cancer (NSCLC) trials to examine if master protocols improve trial access. We examined patients enrolled in Lung-MAP (2014-2020) according to sociodemographic characteristics. Proportions for characteristics were compared with those for a set of advanced NSCLC trials (2001-2020) and the US advanced NSCLC population using SEER registry data (2014-2018). Characteristics of patients enrolled in Lung-MAP treatment substudies were examined in subgroup analysis. Two-sided tests of proportions at an alpha of .01 were used for all comparisons. A total of 3,556 patients enrolled in Lung-MAP were compared with 2,215 patients enrolled in other NSCLC studies. Patients enrolled in Lung-MAP were more likely to be 65 years and older (57.2% v 46.3%; P < .0001), from rural areas (17.3% v 14.4%; P = .004), and from socioeconomically deprived neighborhoods (42.2% v 36.7%, P < .0001), but less likely to be female (38.6% v 47.2%; P < .0001), Asian (2.8% v 5.1%; P < .0001), or Hispanic (2.4% v 3.8%; P = .003). Among patients younger than 65 years, Lung-MAP enrolled more patients using Medicaid/no insurance (27.6% v 17.8%; P < .0001). Compared with the US advanced NSCLC population, Lung-MAP under represented patients 65 years and older (57.2% v 69.8%; P < .0001), females (38.6% v 46.0%; P < .0001), and racial or ethnic minorities (14.8% v 21.5%; P < .0001). Master protocols may improve access to trials using novel therapeutics for older patients and socioeconomically vulnerable patients compared with conventional trials, but specific patient exclusion criteria influenced demographic composition. Further research examining participation barriers for under represented racial or ethnic minorities in precision medicine clinical trials is warranted.

Peripheral myeloid cells as prognostic markers in patients (pts) with non-small cell lung cancer (NSCLC) treated with cemiplimab: Pooled analysis of EMPOWER-Lung 1 and EMPOWER-Lung 3 phase 3 trials.

9028 Background: Circulating innate and adaptive immune cells can modulate clinical responses to immune checkpoint inhibition in pts with cancer; however, there are no clear validated baseline clinical tests to guide clinicians, outside of programmed cell death-ligand 1 (PD-L1) IHC tests on limited biopsy specimens. High neutrophil/lymphocyte ratio (NLR) is associated with poor prognosis in NSCLC, but data are limited on the potential contribution of other immune cells such as monocytes and eosinophils in modulating systemic immune response. Further, previous correlative studies have not established clinically actionable immune cell cut-off values. Methods: We used multiple quantitative analytic methods including multivariable Cox regression and conditional decision trees to assess the prognostic importance of NLR and peripheral myeloid cells, including monocytes and eosinophils, in pts with NSCLC treated with cemiplimab in Phase 3 trials EMPOWER-Lung 1 (NCT03088540) and EMPOWER-Lung 3 (NCT03409614). In EMPOWER-Lung 1, pts with PD-L1 ≥50% were randomized 1:1 to cemiplimab 350 mg every 3 weeks (Q3W) or platinum-based chemotherapy (chemo). EMPOWER-Lung 3 was a 2-part study. In Part 1, pts with PD-L1 &lt; 50% were randomized 1:1:1 to chemo, cemiplimab 350 mg Q3W + chemo, or cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W + chemo. In Part 2, pts were randomized 2:1 to receive cemiplimab 350 mg or placebo Q3W + chemo. Results: Overall, 691 pts in EMPOWER-Lung 1 and 769 pts in EMPOWER-Lung 3 were included in this analysis. The results showed significant association between multiple factors including NLR and overall survival (OS) and progression-free survival (PFS). For pts with NLR &gt; 3.98 vs ≤3.98, median OS (95% CI) was 10 (9–13) vs 20 (17–24) months (HR: 2.04; 95% CI: 1.60–2.61; P&lt; 0.001) and median PFS (95% CI) was 4 (4–6) vs 6 (6–7) months (HR: 1.80; 95% CI: 1.50–2.18; P&lt; 0.001), respectively, accounting for known prognostic factors. In multivariable analyses, monocytes (OS HR: 1.72; 95% CI: 1.29–2.30; P&lt; 0.001; PFS HR: 1.37; 95% CI: 1.08–1.75; P= 0.010) and log eosinophils (OS HR: 0.90; 95% CI: 0.85–0.97; P= 0.003; PFS HR: 0.93; 95% CI: 0.88–0.98; P= 0.004) were significantly associated with OS and PFS in both studies. (Neutrophil + monocyte)/lymphocyte ratio was the top predictor of both OS and PFS in decision tree analysis. Peripheral blood cell count correlations were not affected by tumor PD-L1 levels (ρ &lt; 0.15 for all markers). Conclusions: This is a large and comprehensive prognostic analysis of data from two prospective Phase 3 clinical trials in advanced NSCLC. Clinically actionable peripheral blood cell count parameters, incorporating putative immunosuppressive myeloid cells (neutrophils and monocytes) and protective lymphocytes and eosinophils, may help predict response to anti–PD-1 therapy in advanced NSCLC. Clinical trial information: NCT03088540 , NCT03409614 .

Use of Advanced Flexible Modeling Approaches for Survival Extrapolation from Early Follow-up Data in two Nivolumab Trials in Advanced NSCLC with Extended Follow-up.

Immuno-oncology (IO) therapies are often associated with delayed responses that are deep and durable, manifesting as long-term survival benefits in patients with metastatic cancer. Complex hazard functions arising from IO treatments may limit the accuracy of extrapolations from standard parametric models (SPMs). We evaluated the ability of flexible parametric models (FPMs) to improve survival extrapolations using data from 2 trials involving patients with non-small-cell lung cancer (NSCLC). Our analyses used consecutive database locks (DBLs) at 2-, 3-, and 5-y minimum follow-up from trials evaluating nivolumab versus docetaxel in patients with pretreated metastatic squamous (CheckMate-017) and nonsquamous (CheckMate-057) NSCLC. For each DBL, SPMs, as well as 3 FPMs-landmark response models (LRMs), mixture cure models (MCMs), and Bayesian multiparameter evidence synthesis (B-MPES)-were estimated on nivolumab overall survival (OS). The performance of each parametric model was assessed by comparing milestone restricted mean survival times (RMSTs) and survival probabilities with results obtained from externally validated SPMs. For the 2- and 3-y DBLs of both trials, all models tended to underestimate 5-y OS. Predictions from nonvalidated SPMs fitted to the 2-y DBLs were highly unreliable, whereas extrapolations from FPMs were much more consistent between models fitted to successive DBLs. For CheckMate-017, in which an apparent survival plateau emerges in the 3-y DBL, MCMs fitted to this DBL estimated 5-y OS most accurately (11.6% v. 12.3% observed), and long-term predictions were similar to those from the 5-y validated SPM (20-y RMST: 30.2 v. 30.5 mo). For CheckMate-057, where there is no clear evidence of a survival plateau in the early DBLs, only B-MPES was able to accurately predict 5-y OS (14.1% v. 14.0% observed [3-y DBL]). We demonstrate that the use of FPMs for modeling OS in NSCLC patients from early follow-up data can yield accurate estimates for RMST observed with longer follow-up and provide similar long-term extrapolations to externally validated SPMs based on later data cuts. B-MPES generated reasonable predictions even when fitted to the 2-y DBLs of the studies, whereas MCMs were more reliant on longer-term data to estimate a plateau and therefore performed better from 3 y. Generally, LRM extrapolations were less reliable than those from alternative FPMs and validated SPMs but remained superior to nonvalidated SPMs. Our work demonstrates the potential benefits of using advanced parametric models that incorporate external data sources, such as B-MPES and MCMs, to allow for accurate evaluation of treatment clinical and cost-effectiveness from trial data with limited follow-up. Flexible advanced parametric modeling methods can provide improved survival extrapolations for immuno-oncology cost-effectiveness in health technology assessments from early clinical trial data that better anticipate extended follow-up.Advantages include leveraging additional observable trial data, the systematic integration of external data, and more detailed modeling of underlying processes.Bayesian multiparameter evidence synthesis performed particularly well, with well-matched external data.Mixture cure models also performed well but may require relatively longer follow-up to identify an emergent plateau, depending on the specific setting.Landmark response models offered marginal benefits in this scenario and may require greater numbers in each response group and/or increased follow-up to support improved extrapolation within each subgroup.

Differences in treatment effect size between progression-free survival and overall survival in anti-PD-1/PD-L1 inhibitors-based trials in advanced NSCLC: a systematic review and meta-analysis.

BackgroundTo investigate the differences in treatment effect sizes between progression-free survival (PFS) and overall survival (OS) in advanced non-small cell lung cancer (NSCLC) treated with programmed cell death 1 (PD-1) and its ligand (PD-L1) blockade-based treatments.MethodsThe differences in treatment effect sizes between PFS and OS were assessed by using a ratio of hazard ratio (rHR): the HR for PFS to that for OS. A random effects meta-analysis across trials was conducted to generate the combined rHR. We also evaluated the feasibility of adopting PFS as the surrogate of OS by using Spearman correlation coefficient (R) between logHRPFS and logHROS.ResultsA total of 27 randomized controlled trials (RCTs) with 15,590 patients were included. Treatment effect sizes were comparable, on average, for OS than for PFS (pooled rHR, 0.98; 95% CI, 0.91 to 1.08). Subgroup analysis revealed that treatment effect sizes were greater for OS than for PFS for trials with immunotherapy as second or above line treatment (rHR, 1.17; 95% CI, 1.06 to 1.29), while the differences were greater for PFS than for OS for trials with immunotherapy as first-line setting (rHR, 0.91; 95% CI, 0.84 to 0.99; Pinteraction<0.01). The coefficient of determination was 40% and R was 0.63 between logHRPFS and logHROS. Subgroup analysis showed that coefficient of determination and R were 62% and 0.79 in trials with immunotherapy as first-line setting, 22% and 0.47 in trials with immunotherapy as second or above line treatment, respectively.DiscussionTreatment effect sizes between PFS and OS were roughly consistent in trials with different anti-PD-(L)1 inhibitor-based therapies. PFS could be a potential alternative endpoint for OS in trials with immunotherapy as first-line setting, but PFS should be cautiously interpreted without OS data for trials with immunotherapy as second or above line treatment.

Patient-Centered Approach to Benefit-Risk Characterization Using Number Needed to Benefit and Number Needed to Harm: Advanced Non-Small-Cell Lung Cancer.

This work summarizes the benefit and risk of the results of clinical trials submitted to the US Food and Drug Administration of therapies for the treatment of non-small cell lung cancer (NSCLC) using number needed to benefit (NNB) and number needed to harm (NNH) metrics. NNB and NNH metrics have been reported as potentially being more patient centric and more intuitive to medical practitioners than more common metrics, such as the hazard ratio, and valuable to medical practitioners in complementing other metrics, such as the median time to event. This approach involved the characterization of efficacy and safety results in terms of NNB and NNH of 30 clinical trials in advanced NSCLC supporting US Food and Drug Administration approval decisions from 2003 to 2017. We assessed trends of NNB over time of treatment (eg, for programmed death 1 inhibitors) and variation of NNB across subpopulations (eg, characterized by epidermal growth factor receptor mutation, programmed death ligand 1 expression, Eastern Cooperative Oncology Group performance status, age, and extent of disease progression). Furthermore, the evolution of NNB of treatments for advanced NSCLC was charted from 2003 to 2017. Across subpopulations, NNB, on average, was 4 patients for approved targeted therapies in molecularly enriched populations, 11 patients for approved therapies in nonmolecularly enriched populations, and 23 patients for withdrawn or unapproved therapies. Furthermore, the NNB analysis showed variation for attributes of epidermal growth factor receptor mutations, level of programmed death 1 expression, Eastern Cooperative Oncology Group performance status, etc. When considering the best-case subpopulations and available drugs, the NNB frontier reduced from an estimated value of 7.7 in 2003 to an estimated value of 2.5 in 2017 at the estimated median overall survival-equal to 6 months-of an untreated patient.

Tislelizumab: an investigational anti-PD-1 antibody for the treatment of advanced non-small cell lung cancer (NSCLC)

ABSTRACT Introduction Non-small cell lung cancer (NSCLC) accounts for most lung cancers worldwide and has a poor prognosis at later stages; programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have provided promising new treatment approaches for these patients. Tislelizumab, an anti-PD-1 monoclonal antibody, was engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Tislelizumab has demonstrated clinical activity and is approved in China for treatment of previously treated classical Hodgkin lymphoma and previously treated metastatic PD-L1–high urothelial carcinoma. Areas covered This review summarizes the clinical efficacy, safety, and tolerability of tislelizumab in patients with NSCLC and examines the mechanism of action, pharmacokinetic, and pharmacodynamic profiles of tislelizumab. Expert opinion Tislelizumab has higher affinity to PD-1 than pembrolizumab and nivolumab, potentially due to its differential PD‑1 binding orientation. Tislelizumab demonstrated encouraging efficacy results, long duration of response, and a manageable safety profile across multiple clinical trials in advanced NSCLC. Ongoing trials of drug combinations (e.g. tislelizumab plus angiogenesis inhibitors, immune checkpoint inhibitors, or immune agonists) and examining efficacy across the severity of disease will provide opportunities to understand and feature tislelizumab in clinical practice.

Programmed Cell Death Ligand 1 Expression in Resected Non–Small Cell Lung Cancer

BackgroundRecently, anti–programmed cell death 1 (PD-1) and anti–programmed cell death ligand 1 (PD-L1) immunotherapies have yielded promising outcomes for patients with advanced non–small cell lung cancer (NSCLC) and led to great interest in applying these agents to treat resectable early-stage NSCLC. The objective of our study was to evaluate PD-L1 protein expression in resectable early-stage NSCLC specimens from a large Northern European cohort, examine the relationship to clinical characteristics, and demonstrate the prognostic role in resected NSCLC. Materials and MethodsA large cohort of 875 NSCLC tumors consisted of 337 patients from Sweden and 538 patients from Norway was studied. All the patients had undergone pulmonary resection, and most patients had had early-stage NSCLC. PD-L1 protein expression was assessed by immunohistochemistry using the Dako PD-L1 22C3 pharmDx kit. The tumor proportion score for PD-L1 protein expression was compared with comprehensive demographic and clinicopathologic data. ResultsThe overall prevalence of PD-L1 protein expression in the resectable NSCLC cohort was 9.5% at a tumor proportion score cutoff of ≥ 50%. Stage I NSCLC had lower PD-L1 expression compared with that of the other stages (P = .0012). PD-L1 expression correlated with wild-type EGFR gene expression (P = .0156) and mutated KRAS gene expression (P = .0004). No significant association was found between PD-L1 expression and mortality after multivariable adjustment for clinical characteristics, although the survival curves showed PD-L1 expression significantly correlated with a poor prognosis in the total NSCLC cohort and in the adenocarcinoma subgroup. ConclusionPD-L1 expression in the present large cohort of resectable NSCLC was relatively low compared with data from clinical trials of advanced NSCLC. PD-L1 expression correlated positively with tumor stage, wild-type EGFR, and KRAS mutation. PD-L1 expression was not found as an independent prognostic factor in the present study. These findings could be important in the future when evaluating the role of anti–PD-1/PD-L1 immunotherapy in the setting of neoadjuvant or adjuvant trials for early-stage resectable NSCLC.

Trends in endpoint selection and result interpretation in advanced non-small cell lung cancer clinical trials published between 2000 and 2012: A retrospective cohort study.

BackgroundThe objective of this review was to investigate trends in clinical trial design, specifically, the primary outcomes used, interpretation of results, and the magnitude of the benefits described in phase III controlled clinical trials in the first‐line treatment of patients with advanced non‐small cell lung cancer (NSCLC).MethodsSeventy‐six trials published between 2000 and 2012 were selected from a total of 122 identified in a structured search.ResultsOverall survival (OS) was evaluated as the primary study endpoint in 50 (65.8%) trials, followed by progression‐free survival (PFS) in 15 (19.7%), and other variables, such as toxicity, quality of life (QoL), and response rate in 11 (14.5%). Ten (66.7%) out of 15 clinical trials using PFS as the primary endpoint were published between 2010 and 2012. Median overall survival (mOS) was 9.90 months (interquartile range: 3.5) with an increase of 0.384 months per year of publication (P < 0.001). A statistically significant improvement in mOS was obtained in only 13 (18.8%) trials. A total of 41 (53.9%) studies concluded that the result was positive. Of these, only 16 (39.1%) showed a statistically significant benefit in OS. QoL was assessed in 46 trials (60.5%) and of these, 10 (21.7%) reported significant improvements.ConclusionsThese findings raise important questions about how clinical benefits are measured in clinical trials in advanced NSCLC. Appropriate clinically relevant outcome variables should be established and validated, and post‐marketing studies should be requested by regulatory authorities to ensure meaningful clinical benefits in OS and QoL.

Clinical prognostic model for older patients with advanced non-small cell lung cancer.

Older patients with non-small cell lung cancer (NSCLC) are often not prescribed standard therapy. It is important to know which older patients would be candidates for aggressive therapy based on their prognosis, and to develop a model that can help determine prognosis. Data on older patients (≥70 years) enrolled on 38 NCI cooperative group trials of advanced NSCLC from 1991 to 2011 were analyzed. Multivariable Cox PH model was built with a stepwise selection. We derived a prognostic score using the estimated Cox PH regression coefficient. We then calculated the area under receiver operating characteristic (ROC) curve of survival in the testing set. The final analysis included 1467 patients, who were randomly divided into a training (n = 963) and a testing set (n = 504). The prognostic risk score was calculated as: 3 (if male) + 3 (if PS = 1) + 8 (if PS = 2) + 11 (if initial stage = IV) + 4 (if weight loss). Patients were classified into two prognostic groups: good (0-8) and poor (≥9). The median survival in the two groups in the testing set were 13.15 (95% CI, 10.82-15.91) and 8.52 months (95% CI, 7.5-9.63), respectively. The model had area under the 1-year and 2-year ROCs (0.6 and 0.65, respectively) that were higher than existing models. Male gender, poor performance status, distant metastases and recent weight loss predict for poor overall survival (OS) in older patients with advanced NSCLC. This study proposes a simple prognostic model for older adults with advanced NSCLC.

Development of a patient-reported outcome (PRO) measure for assessing non-small cell lung cancer (NSCLC) symptoms in clinical trials: Interim report from the PRO Consortium’s NSCLC Working Group (WG).

e17620 Background: In collaboration with the FDA, the Critical Path Institute - PRO Consortium NSCLC WG is developing a new PRO measure to assess treatment (tx) benefit in advanced NSCLC trials and...

Shifting Patterns in the Interpretation of Phase III Clinical Trial Outcomes in Advanced Non–Small-Cell Lung Cancer: The Bar Is Dropping

Despite multiple trials of new agents in advanced non-small-cell lung cancer (NSCLC), outcomes remain poor. This study explores how the design and interpretation of randomized trials in advanced NSCLC has changed over time. Phase III randomized controlled trials of systemic therapy for advanced NSCLC between 1980 and 2010 were identified, and their primary end point, outcome, statistical significance, and conclusions were recorded. Of 245 trials identified, 203 were eligible for study inclusion. Although overall survival remains the most common primary end point of phase III trials, more trials from the last decade have used progression-free survival instead (none in 1980 to 1990, 13% in 2001 to 2010; P = .002). The percentage of trials meeting their primary statistical end points remained stable over time; however, the percentage of trials reporting a positive outcome without meeting that end point increased (30% in 1980 to 1990, 53% in 2001 to 2010; P < .001). A trend toward decreasing magnitude of survival gain in positive trials was seen over time (3.9 months in 1980 to 1990, 2.5 months in 2001 to 2010; P = .11), with a concomitant increase in the sample size of clinical trials over the same time period (median: 152 patients in 1980 to 1990, 413 in 2001 to 2010; P < .001). Only studies predating 1990 reported negative results as a result of insufficient magnitude of survival benefit despite statistical significance. A significant shift has occurred over the past three decades in the design and interpretation of phase III trials in advanced NSCLC. The use of survival as the primary measure of benefit is declining, as is the magnitude of benefit deemed clinically relevant.

The impact of both platinum-based chemotherapy and EGFR-TKIs on overall survival of patients with advanced non-small cell lung cancer

Both platinum-based doublet chemotherapy (PBC) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) prolong the survival of patients with advanced non-small cell lung cancer (NSCLC). In early studies, most patients underwent PBC as first-line treatment, but not all patients could afford EGFR-TKIs as second-line treatment. To understand the impact of PBC and EGFR-TKIs on NSCLC prognosis, we evaluated the association between the receipt of both regimens and overall survival (OS). Using MEDLINE and EMBASE, we identified prospective, randomized, controlled phase III clinical trials in advanced NSCLC that met the inclusion criteria: in general population with advanced NSCLC, the percentage of patients treated with both PBC and EGFR-TKIs was available in the trial and OS was reported. After collecting data from the selected trials, we correlated the percentage of patients treated with both PBC and EGFR-TKIs with the reported OS, using a weighted analysis. Fifteen phase III clinical trials—involving 11,456 adult patients in 32 arms—were included in the analysis, including 6 trials in Asian populations and 9 in non-Asian (predominantly Caucasian) populations. The OS was positively correlated with the percentage of patients treated with both PBC and EGFR-TKIs (r = 0.797, P < 0.001). The correlation was obvious in the trials in Asian populations (r = 0.936, P < 0.001) but was not statistically significant in the trials in predominantly Caucasian populations (r = 0.116, P = 0.588). These results suggest that treatment with PBC and EGFR-TKIs may provide a survival benefit to patients with advanced NSCLC, highlighting the importance of having both modalities available for therapy.

Time trends in overall survival (OS) gain in advanced non-small-cell lung cancer (NSCLC).

e19144 Background: There is an ongoing debate about the adequacy of OS as primary endpoint (PEP) in phase III trials in various tumor types, including NSCLC (Soria Ann Oncol 2010). Moreover, median OS and post-progression survival are increasing in NSCLC (Hotta PLoS One 2011 and Hayashi Ann Oncol 2012). We assessed the frequency and time trends in OS gain in recent trials. Methods: We searched PubMed for phase III trials in advanced NSCLC published between January 1998 and December 2011 in 13 leading journals. The PEP was the endpoint stated explicitly, used for N calculation, or listed first. Gain in OS was ascertained when there were significant differences in any pairwise comparison on OS following the original authors’ definitions. Results: We retrieved 148 trials that enrolled a total of 70,716 patients in 325 trial arms. The median number of patients per arm was larger for the 2005-2011 period than for the 1998-2004 period (207 vs 150; P&lt;0.01). OS was used as PEP alone in 99 trials, and as one of the co-primary endpoints in 3 trials (the PEP could not be ascertained for one trial). There was no trend regarding the use of OS as PEP in the two periods compared, either overall (P=0.44) or in first line (P=0.41). Gain in OS according to trial features is shown in the Table. Conclusions: Significant gains in OS appear to decrease along the years, despite the growth in size of NSCLC trials and the continued use of OS as PEP. [Table: see text]

Review of end points of phase III clinical trials with combination chemotherapy regimens for non-small cell lung cancer evaluating importance of quality of life.

e19119 Background: Systemic combination chemotherapy is accepted as a standard of care for patients with advanced non-small cell lung cancer (NSCLC). Substantial similarities in terms of treatment efficacy and survival have emerged over the years between the different systemic chemotherapy regimens used. Quality of life (QOL) analysis will help to customize chemotherapy to improve outcome in NSCLC patients. Methods: Using PUBMED database, a review of randomized controlled phase III trials of advanced NSCLC published in last 5 years reporting comparative safety and efficacy between chemotherapeutic regimens as end points was conducted. An evaluation of end points, difference in efficacy endpoints, QOL analysis, and final conclusion was conducted. Results: The search criteria identified 51 trials (33,481 patients). Out of these 51 clinical trials, 16 trials showed difference in efficacy (13 survival endpoint, 1 ORR (objective response rate), 2 survival without grade 3/4 toxicity) and 11 trials used validated QOL instruments and were included for review. Two trials; one comparing pemetrexed/cisplatin with gemcitabine/cisplatin, and other comparing cisplatin/weekly vinoralbine with cisplatin/vinoralbine on day 1 and 8; showed difference with QOL; though not statistically significant. The QOL reporting/analysis techniques were heterogeneous. Two trials used QOL as primary endpoint. Safety reporting included percentage adverse events with treatment arms. Conclusions: Based on our review, it seems critical to have QOL as an endpoint while evaluating newer combination chemotherapeutic regimens for NSCLC. Secondly, it is unlikely that a major difference exists in the global QOL associated with standard chemotherapy regimens for NSCLC. An effort to have uniform QOL assessment across trials evaluating newer combination regimens for NSCLC will help to customize treatment.

Elderly Patients with Advanced NSCLC in Phase III Clinical Trials: Are the Elderly Excluded from Practice-Changing Trials in Advanced NSCLC?

Elderly patients constitute the majority of patients with advanced non-small-cell lung cancer (NSCLC). The median age of newly diagnosed patients with lung cancer in the United States is approximately 70 years. Despite this, the elderly are significantly underrepresented in clinical trials. This has led to increasing uncertainty as to their optimal treatment. Here, we seek to determine the proportion of elderly patients in key phase III clinical trials in advanced NSCLC. A literature search for all phase III trials of systemic therapy for advanced NSCLC between 1980 and 2010 was performed using PubMed. The 100 most highly cited trials were then determined using the "Web of Science" application. The inclusion criteria and results of each of these studies were examined for the exclusion of elderly patients, median patient age, and age range. A total of 248 trials were reviewed. Among the 100 most cited trials, 33% specifically excluded elderly patients in their trial design (age exclusion ranged from >65 to >75 years of age). The average-reported patient median age in these trials was 60.9 years. The average age for trials that did not exclude elderly patients was not significantly different at 61.0 (p = 0.97). The average median age of patients was 61 years (95% confidence interval (CI): 60.4-61.6) in all trials. Elderly patients are significantly underrepresented in these recent key practice-defining trials. Greater representation of elderly patients in phase III trials is required to better define evidence-based treatment paradigms in the increasingly elderly NSCLC population.

The impact of tumor size change after target therapy on survival: analysis of patients enrolled onto three clinical trials of advanced NSCLC from one institution

PurposeTo explore whether changes in tumor size impact survival in advanced non-small-cell lung cancer (NSCLC) after target therapy, especially in patients with evaluation of stable disease (SD), and to review the applicability of the Response Evaluation Criteria in Solid Tumors (RECIST) criteria in target therapy.Patients and methodsData from 88 NSCLC patients receiving gefitinib (250 mg, daily [qd]), erlotinib (150 mg, qd), and ZD6474 (100 mg, qd) in three clinical trials (IRESSA registration clinical trial, TRUST study, ZD6474 study) during November 2003 to June 2005 were retrospectively analyzed. The treatment effect (complete response, partial response, stable disease [SD], or progressive disease) was evaluated with radiologic assessment according to the RECIST criteria. SD patients were divided into two groups: SD−/0, in which the sum of the longest diameter of target lesions decreased by less than 30% or did not change; and SD+, in which the sum of the longest diameter of target lesions increased by less than 20%. The differences of progression-free survival (PFS) and overall survival (OS) between these groups were analyzed.ResultsIn the whole group, 27 patients achieved complete response or partial response as best response, 40 achieved SD, and 22 had progressive disease. The median PFS and OS were 4 months and 11.1 months, respectively. In SD patients, 27 were SD−/0 and 13 patients were SD+. The PFS and OS of SD+ patients was shorter than that of SD−/0 patients (5.65 months vs 2.03 days, P < 0.001 and 12.2 months vs 7.1 months, P < 0.001).ConclusionThe applicability of RECIST criteria was called into question in the evaluation of target therapy. Change in tumor size might predict survival in advanced NSCLC patients with target therapy and may be a surrogate endpoint for efficacy in target therapy.

1263P - Impact of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Treatment in Advanced Non-Small Cell Lung Cancer: A Meta-Analysis

ABSTRACT Background Previous meta-analyses have reported that epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) improves progression-free survival (PFS) in patients with advanced non-small cell lung cancer (NSCLC) harbouring EGFR mutation. We examined the influence of EGFR-TKI on PFS and overall survival (OS) in those with (EGFR+) and without mutation (EGFR-). Methods We included published and unpublished randomised trials of advanced NSCLC that compared EGFR-TKI monotherapy or combination EGFR-TKI chemotherapy with chemotherapy or placebo. We used published hazard ratios (HR) if available, or derived treatment estimates from other survival data. We investigated treatment effects in different treatment settings and trial regimens. Results We identified 20 eligible trials investigating EGFR-TKI in front-line (n = 12), second or subsequent (n = 5), and maintenance (n = 3) treatment, with EGFR status known in 3198 (23%) patients. Overall, HR for EGFR-TKI over control for PFS were (EGFR+) 0.37 (95% CI, 0.32 to 0.42; p Conclusions In this meta-analysis, treatment with EGFR-TKI was found to significantly delay disease progression in EGFR+ patients; however, no impact on OS was identified. EGFR mutation is a predictive biomarker of PFS benefit with EGFR-TKI treatment in all settings. These findings support assessment for EGFR mutation before initiation of EGFR-TKI treatment and that EGFR-TKI should be considered as front-line therapy in EGFR+ patients with advanced NSCLC. Disclosure R. Gralla: Consultant or advisory role for Boehringer Ingelheim. V. Hirsh: Advisory role for Boehringer Ingelheim. A. Inoue: Received lecture fees and research grants from AstraZeneca. C.J. Yang: Advisory roles for Boehringer Ingelheim, AstraZeneca, Roche and OSI, and have received honoraria from AstraZeneca, Roche and OSI. All other authors have declared no conflicts of interest.

Statistical considerations and endpoints for clinical lung cancer studies: Can progression free survival (PFS) substitute overall survival (OS) as a valid endpoint in clinical trials for advanced non-small-cell lung cancer?

In the last decades significant progress has been achieved in the biological understanding of non-small-cell lung cancer (NSCLC) and its tumor heterogeneity has become more evident. The identification of novel tumor targets with different pathways has stimulated the search for anti-tumor agents with a specific target directed mode of action, stipulating the need of testing these agents in clinical trials with an appropriate choice of the study endpoint. Gold standard as an endpoint has been so far overall survival (OS). By definition there are 3 categories of classical endpoints applied generally in clinical lung cancer studies: survival time endpoints, symptom endpoints, and endpoints relying on patients' reporting. Beside classical endpoints like OS which are tending to show the direct clinical effect of treatment, efforts have been taken to substitute these classical endpoints by surrogates. As a surrogate candidate for OS progression-free survival (PFS) should have the inherent considerable advantage, that it can detect subpopulations with longer PFS intervals early. Based on the (sub-) population treated and having in mind the risk-benefit profile of the drug under consideration, PFS can be considered for regulatory decision making. If accompanied by some independent measures like quality of life or treatment toxicity, PFS should be able to cover the clinical benefit achieved by treatment. Selecting PFS as primary endpoint in Phase III trials of advanced NSCLC may be based on a number of questions such as: Does the definition of PFS fit into the setting used by other trials? Are there accepted consensus standards? Are there consistent surveillance intervals? Is validation for each agent group planned? Is the incremental improvement of PFS big enough (≥30%)? And are there some additional measures to confine clinical benefit? OS is still accepted as the gold standard in trials investigating advanced NSCLC. OS is easy to measure and precise but it may be difficult to interpret if treatment action takes place only in a small subinterval of overall survival. PFS with some additional measures has become attractive when it seems advisable to make study results available earlier. Candidates for supporting PFS as "additional measures" may be treatment toxicity and quality of life measures. PFS allows a more precise detection and attribution to effects of the investigational treatment without being compromised by subsequent treatments. Therefore "enriched PFS" can be considered as an alternative primary endpoint replacing OS in studies investigating advanced NSCLC. The endpoint selection process should always be performed carefully considering all true and surrogate endpoint options in respect to the hypotheses to be proven.

Pretreatment Quality of Life Is an Independent Prognostic Factor for Overall Survival in Patients with Advanced Stage Non-small Cell Lung Cancer

We conducted this pooled analysis to assess the prognostic value of pretreatment Quality of Life (QOL) assessments on overall survival (OS) in advanced non-small cell lung cancer (NSCLC). Four hundred twenty patients with advanced NSCLC (stages IIIB with pleural effusion and IV) from six North Central Cancer Treatment Group trials were included in this study. QOL assessments included the single-item Uniscale (355 patients), Lung Cancer Symptom Scale (217 patients), and Functional Assessment of Cancer Therapy-Lung (197 patients). QOL scores were transformed to a 0 to 100 scale with higher scores representing better status and categorized using the sample median or clinically deficient score (CDS, <or=50 versus >50). Cox proportional hazards models stratified by study were used to evaluate the prognostic importance of QOL on OS alone and in the presence of other prognostic factors such as performance status, age, gender, body mass index, and laboratory parameters. Pretreatment QOL accessed by Uniscale was significantly associated with OS univariately (p < 0.0001). Uniscale (p < 0.0001; hazard ratio = 1.6 for the sample median and 2.0 for the CDS categorization) and body mass index were the only significant predictors of OS multivariately. The median survival of patients who had a Uniscale score less than or equal to the CDS (<or=50) was 5.7 versus 11.1 months for the >50 group; and 7.8 versus 13 months for the less than or equal to sample median (<or=83) group and >83 group, respectively. The Lung Cancer Symptom Scale and the Functional Assessment of Cancer Therapy-Lung total scores were not significant predictors of OS. Pretreatment QOL measured by Uniscale is a significant and an independent prognostic factor for OS, and QOL should be routinely integrated as a stratification factor in advanced NSCLC trials.

KRAS mutation analysis in cetuximab-treated advanced stage non-small cell lung cancer (NSCLC): SWOG experience with S0342 and S0536

8022 Background: KRAS mutations occur in NSCLC with a frequency of 15–25% and have been associated with a poor response to EGFR tyrosine kinase inhibitors. In colorectal cancer, benefit from the EGFR-targeted monoclonal antibody cetuximab is largely limited to patients (pts) whose tumors are KRAS wild-type (WT). However, in cetuximab-treated NSCLC, a predictive role for KRAS mutations has not been established. We evaluated KRAS status in specimens from two cetuximab-based front-line multicenter SWOG phase II trials in advanced NSCLC. Methods: DNA extracted from archival tumor and plasma specimens from S0342 (carboplatin-paclitaxel plus sequential vs. concurrent cetuximab) and S0536 (carboplatin-paclitaxel-cetuximab-bevacizumab) was analyzed for KRAS mutations by micro-dissection/sequencing and/or Scorpion-ARMS (DxS LTD). Results: For S0342, 45 archival tissues and 90 plasma specimens were analyzed. Combined, KRAS mutations were detected in 24% of pts. No differences between mutant and WT tumors were observed for response rate (p=0.62) or progression-free survival (PFS; p=0.65). Overall survival (OS) was non-significantly higher for pts with WT vs. mutant KRAS [median OS: 11 vs. 8 mo.; p=0.39]. When evaluated with EGFR copy number analysis conducted previously (JCO 10:3351, 2008), pts with both low EGFR copy number and mutant KRAS trended towards a worse OS [7 mo. vs. 17 mo. for all others, p=0.08, n=31]. For S0536, 6/26 pt specimens (23%) harbored KRAS mutations. In the limited sample set available from S0536, no associations were observed between KRAS status and clinical outcome [response rate: p=0.83; PFS: p=0.93; OS p=0.89]. Conclusions: These data suggest that KRAS mutations may not play a significant predictive role for cetuximab-based therapy in NSCLC, contrary to colorectal cancer. KRAS analysis in recently completed phase III trials of chemotherapy ± cetuximab will be of interest to confirm these observations. Trends in favorable OS in pts with WT KRAS may reflect prognostic effects of KRAS mutations. [Table: see text]