Survival Following Surgery with or without Adjuvant Chemotherapy for Stage I–IIIA Non‐Small Cell Lung Cancer: An East Asian Population‐Based Study

Background.

Asian ethnicity is associated with a distinct molecular etiology, treatment response, and survival outcome among patients with non-small cell lung cancer (NSCLC). This study examines the survival impact of platinum-based adjuvant chemotherapy for Asian patients with stage I–IIIA NSCLC.

Methods.

This study recruited patients aged ≥18 years with histologically proven stage IA–IIIA NSCLC registered in the Taiwan Cancer Registry database in January 2004 to December 2007. Platinum-containing adjuvant chemotherapy had to be started within 90 days of the primary surgery. Kaplan–Meier survival curves, log-rank tests, and the Cox proportional hazards regression model were used to assess the influence of various risk factors on survival time.

Results.

This study included 2,231 patients with stage IA–IIIA NSCLC who underwent primary surgery with a clear surgical margin. The percentages of all causes of death were significantly lower for the chemotherapy group for both stage II and stage IIIA patients. Multivariate analysis identified platinum-based adjuvant chemotherapy as an independent prognostic factor for the overall survival outcome of stage II (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.39–0.94; p = .024) and IIIA (HR, 0.71; 95% CI, 0.52–0.96; p = .029) patients. Among these patients, those who received adjuvant chemotherapy had a superior overall survival outcome for both genders, for the subgroup of patients aged ≥70 years, and for those with adenocarcinoma.

Conclusion.

Platinum-based adjuvant chemotherapy should be considered in the treatment plan for Asian patients with resected stage II and stage IIIA NSCLC.     

Cost‐Effectiveness of a 14‐Gene Risk Score Assay to Target Adjuvant Chemotherapy in Early Stage Non‐Squamous Non‐Small Cell Lung Cancer

Purpose.

Life Technologies has developed a 14-gene molecular assay that provides information about the risk of death in early stage non-squamous non-small cell lung cancer patients after surgery. The assay can be used to identify patients at highest risk of mortality, informing subsequent treatments. The objective of this study was to evaluate the cost-effectiveness of this novel assay.

Patients and Methods.

We developed a Markov model to estimate life expectancy, quality-adjusted life years (QALYs), and costs for testing versus standard care. Risk-group classification was based on assay-validation studies, and chemotherapy uptake was based on pre- and post-testing recommendations from a study of 58 physicians. We evaluated three chemotherapy-benefit scenarios: moderately predictive (base case), nonpredictive (i.e., the same benefit for each risk group), and strongly predictive. We calculated the incremental cost-effectiveness ratio (ICER) and performed one-way and probabilistic sensitivity analyses.

Results.

In the base case, testing and standard-care strategies resulted in 6.81 and 6.66 life years, 3.76 and 3.68 QALYs, and $122,400 and $118,800 in costs, respectively. The ICER was $23,200 per QALY (stage I: $29,200 per QALY; stage II: $12,200 per QALY). The ICER ranged from “dominant” to $92,100 per QALY in the strongly predictive and nonpredictive scenarios. The model was most sensitive to the proportion of high-risk patients receiving chemotherapy and the high-risk hazard ratio. The 14-gene risk score assay strategy was cost-effective in 68% of simulations.

Conclusion.

Our results suggest that the 14-gene risk score assay may be a cost-effective alternative to standard guideline-based adjuvant chemotherapy decision making in early stage non-small cell lung cancer.     

Approval Summary: Pemetrexed in the Initial Treatment of Advanced/Metastatic Non‐Small Cell Lung Cancer

On September 26, 2008, the U.S. Food and Drug Administration approved pemetrexed injection (Alimta® Injection; Eli Lilly and Company, Indianapolis, IN) for use in combination with cisplatin for the initial treatment of patients with stage IIIB/IV nonsquamous non‐small cell lung cancer (NSCLC). A randomized, phase III, open‐label study was conducted in 1,725 patients. Patients were randomly assigned to receive 21‐day cycles of pemetrexed plus cisplatin (AC) or gemcitabine plus cisplatin (GC). The primary objective was overall survival. The median survival time was 10.3 months in both the AC arm and the GC arm (adjusted hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.84–1.05). The median progression‐free survival times were 4.8 and 5.1 months for the AC and GC arms, respectively (adjusted HR, 1.04; 95% CI, 0.94–1.15). The overall response rates were 27.1% and 24.7% for the AC and GC arms, respectively. A prespecified analysis of the impact of NSCLC histology on overall survival was conducted. In the nonsquamous NSCLC subgroup, the median survival times were 11.0 and 10.1 months in the AC and GC groups, respectively (unadjusted HR, 0.84; 95% CI, 0.74–0.96). However, in the squamous cell histology subgroup, the median survival times were 9.4 versus 10.8 months in the AC and GC groups, respectively (unadjusted HR, 1.22; 95% CI, 0.99–1.50). This unfavorable effect of squamous histology on overall survival was also noted in a retrospective analysis of a trial that compared pemetrexed with docetaxel in NSCLC patients who received prior chemotherapy. No new pemetrexed safety signals were observed.     

Novel Targets in Non‐Small Cell Lung Cancer: ROS1 and RET Fusions

The discovery of chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene in non‐small cell lung cancer (NSCLC) has stimulated renewed interest in oncogenic fusions as potential therapeutic targets. Recently, genetic alterations in ROS1 and RET were identified in patients with NSCLC. Like ALK, genetic alterations in ROS1 and RET involve chromosomal rearrangements that result in the formation of chimeric fusion kinases capable of oncogenic transformation. Notably, ROS1 and RET rearrangements are rarely found with other genetic alterations, such as EGFR, KRAS, or ALK. This finding suggests that both ROS1 and RET are independent oncogenic drivers that may be viable therapeutic targets. In initial screening studies, ROS1 and RET rearrangements were identified at similar frequencies (approximately 1%–2%), using a variety of genotyping techniques. Importantly, patients with either ROS1 or RET rearrangements appear to have unique clinical and pathologic features that may facilitate identification and enrichment strategies. These features may in turn expedite enrollment in clinical trials evaluating genotype‐directed therapies in these rare patient populations. In this review, we summarize the molecular biology, clinical features, detection, and targeting of ROS1 and RET rearrangements in NSCLC.     

Cost‐Utility of a Prognostic Test Guiding Adjuvant Chemotherapy Decisions in Early‐Stage Non‐Small Cell Lung Cancer

Background.

A prognostic test was developed to guide adjuvant chemotherapy (ACT) decisions in early-stage non-small cell lung cancer (NSCLC) adenocarcinomas. The objective of this study was to compare the cost-utility of the prognostic test to the current standard of care (SoC) in patients with early-stage NSCLC.

Materials and Methods.

Lifetime costs (2014 U.S. dollars) and effectiveness (quality-adjusted life-years [QALYs]) of ACT treatment decisions were examined using a Markov microsimulation model from a U.S. third-party payer perspective. Cancer stage distribution and probability of receiving ACT with the SoC were based on data from an academic cancer center. The probability of receiving ACT with the prognostic test was estimated from a physician survey. Risk classification was based on the 5-year predicted NSCLC-related mortality. Treatment benefit with ACT was based on the prognostic score. Discounting at a 3% annual rate was applied to costs and QALYs. Deterministic one-way and probabilistic sensitivity analyses examined parameter uncertainty.

Results.

Lifetime costs and effectiveness were $137,403 and 5.45 QALYs with the prognostic test and $127,359 and 5.17 QALYs with the SoC. The resulting incremental cost-effectiveness ratio for the prognostic test versus the SoC was $35,867/QALY gained. One-way sensitivity analyses indicated the model was most sensitive to the utility of patients without recurrence after ACT and the ACT treatment benefit. Probabilistic sensitivity analysis indicated the prognostic test was cost-effective in 65.5% of simulations at a willingness to pay of $50,000/QALY.

Conclusion.

The study suggests using a prognostic test to guide ACT decisions in early-stage NSCLC is potentially cost-effective compared with using the SoC based on globally accepted willingness-to-pay thresholds.

Implications for Practice:

Providing prognostic information to decision makers may help some patients with high-risk early stage non-small cell lung cancer receive appropriate adjuvant chemotherapy while avoiding the associated toxicities and costs in patients with low-risk disease. This study used an economic model to assess the effectiveness and costs associated with using a prognostic test to guide adjuvant chemotherapy decisions compared with the current standard of care in patients with non-small cell lung cancer. When compared with current standard care, the prognostic test was potentially cost effective at commonly accepted thresholds in the U.S. This study can be used to help inform decision makers who are considering using prognostic tests.     

A Prospective Study of Shortened Vitamin Supplementation Prior to Cisplatin–Pemetrexed Therapy for Non‐Small Cell Lung Cancer

Background.

Prior supplementation with folic acid and vitamin B₁₂ is required to reduce pemetrexed therapy toxicity; the recommended lead-in time is at least 7 days. On the basis of previous pharmacokinetic and clinical studies, we hypothesized that the lead-in time could be shortened to 24 hours, enabling earlier commencement of standard chemotherapy; thus, we planned the first prospective trial of this regimen.

Methods.

Patients with advanced nonsquamous non-small cell lung cancer who had not previously received cytotoxic chemotherapy were enrolled. After measurement of homocysteine concentrations, the patients received 1,000 μg of vitamin B₁₂ by intramuscular injection and began taking 350–500 μg of oral folic acid daily. Starting 24–48 hours after the vitamin B₁₂ injection, the patients received intravenous 500 mg/m² pemetrexed and 75 mg/m² cisplatin for 4 cycles at 3 weekly intervals. The primary endpoint was the proportion of patients who developed neutropenia grade ≥3.

Results.

Thirty patients received chemotherapy starting within 48 hours of the vitamin B₁₂ injection. No treatment-related deaths or grade 4 toxicity occurred. Neutropenia grade ≥3, other laboratory toxicities grade ≥3, and nonlaboratory toxicities grade ≥3 occurred in 6.7%, 13%, and 13% of patients, respectively. The baseline homocysteine concentrations were not higher in patients with grade ≥3 toxicities than in the remainder of the cohort (mean values, 8.6 and 10.7 μmol/L, respectively). The response rate to chemotherapy was 43%.

Conclusion.

The shortened vitamin supplementation was well tolerated and retained antitumor efficacy. Analysis of baseline homocysteine concentrations confirmed the efficacy of short-term vitamin supplementation.     

Measuring the Population Impact of Introducing Stereotactic Ablative Radiotherapy for Stage I Non‐Small Cell Lung Cancer in Canada

Background.

The Cancer Risk Management Model (CRMM) was used to estimate the health and economic impact of introducing stereotactic ablative radiotherapy (SABR) for stage I non-small cell lung cancer (NSCLC) in Canada.

Methods.

The CRMM uses Monte Carlo microsimulation representative of all Canadians. Lung cancer outputs were previously validated internally (Statistics Canada) and externally (Canadian Cancer Registry). We updated costs using the Ontario schedule of fees and benefits or the consumer price index to calculate 2013 Canadian dollars, discounted at a 3% rate. The reference model assumed that for stage I NSCLC, 75% of patients undergo surgery (lobectomy, sublobar resection, or pneumonectomy), 12.5% undergo radiotherapy (RT), and 12.5% undergo best supportive care (BSC). SABR was introduced in 2008 as an alternative to sublobar resection, RT, and BSC at rates reflective of the literature. Incremental cost effectiveness ratios (ICERs) were calculated; a willingness-to-pay threshold of $100,000 (all amounts are in Canadian dollars) per quality-adjusted life-year (QALY) was used from the health care payer perspective.

Results.

The total cost for 25,085 new cases of lung cancer in 2013 was calculated to be $608,002,599. Mean upfront costs for the 4,318 stage I cases were $7,646.98 for RT, $8,815.55 for SABR, $12,161.17 for sublobar resection, $16,266.12 for lobectomy, $22,940.59 for pneumonectomy, and $14,582.87 for BSC. SABR dominated (higher QALY, lower cost) RT, sublobar resection, and BSC. RT had lower initial costs than SABR that were offset by subsequent costs associated with recurrence. Lobectomy was cost effective when compared with SABR, with an ICER of $55,909.06.

Conclusion.

The use of SABR for NSCLC in Canada is projected to result in significant cost savings and survival gains.     

Maintenance and Consolidation Therapy in Patients with Unresectable Stage III/IV Non‐Small Cell Lung Cancer

Globally, lung cancer is the leading cause of cancer‐related mortality. Current chemotherapy combinations for the first‐line treatment of advanced disease (stage IIIB with malignant pleural effusion/stage IV) and chemoradiotherapy regimens for the treatment of unresectable locally advanced disease (stage IIIA and IIIB without malignant pleural effusion) appear to have reached an efficacy plateau. The addition of new compounds including targeted agents to standard first‐line cytotoxic doublets, administered concurrently and/or as maintenance therapy in patients who have not experienced disease progression after such treatment, has been shown to improve efficacy beyond this plateau in patients with advanced disease. However, to date, such approaches have been less successful in the treatment of patients with unresectable locally advanced stage III disease. The purpose of this review is to summarize the data from recent randomized phase III studies involving agents administered as maintenance or consolidation therapy in the treatment of unresectable stage III/IV non‐small cell lung cancer (NSCLC). A possible alternative approach to the use of cytotoxic or molecularly targeted agents in this setting is the administration of therapeutic anticancer vaccines, which are designed to stimulate a host immunological response against the tumor. Current data in relation to the potential of vaccine therapy for NSCLC are therefore also reviewed, with a particular focus on belagenpumatucel‐L and L‐BLP25 vaccines, which are currently undergoing phase III evaluation as maintenance therapies in patients with unresectable stage III/IV NSCLC who have tumor control following first‐line therapy.     

Targeting Angiogenesis with Multitargeted Tyrosine Kinase Inhibitors in the Treatment of Non‐Small Cell Lung Cancer

It has been >35 years since the link between angiogenesis and the growth of tumors was first reported. Targeting angiogenesis became feasible with the availability of bevacizumab, an anti–vascular endothelial growth factor monoclonal antibody. Initial studies revealed that the combination of bevacizumab and chemotherapy led to longer overall survival times than with chemotherapy alone in patients with advanced colorectal cancer. Since then, drug development strategies have added small molecule tyrosine kinase inhibitors to the panel of antiangiogenic agents under evaluation; data from numerous trials are now available. The challenge now is to identify the optimal antiangiogenic agent for specific patient groups and to understand not only the mechanistic differences between agents, but also the variability in their antitumor activity across different tumor types and their differing side‐effect profiles. As in other solid tumors, angiogenesis contributes to the development of non‐small cell lung cancer (NSCLC), and this review summarizes the role of angiogenesis in this disease. We review the current developmental status of antiangiogenic tyrosine kinase inhibitors (including vandetanib, sunitinib, axitinib, sorafenib, vatalanib, and pazopanib) in NSCLC and conclude by briefly discussing the need for optimal patient selection and potential future directions.     

非小细胞肺癌术后辅助化疗和靶向治疗的临床疗效对比分析

目的 比较观察术后辅助化疗和易瑞沙用于Ⅲa期非小细胞肺癌(NSCLC)的术后辅助治疗的疗效.方法 入组76例Ⅲa期行完全性切除术的NSCLC,选择口服易瑞沙治疗33例,选择术后辅助化疗43例.治疗结束后分别观察两组的生存情况.结果 易瑞沙组1、2年生存率分别为93.9%和51.5%,化疗组分别为88.4%和48.8%,...     

Randomized Phase II Trial of Erlotinib Beyond Progression in Advanced Erlotinib‐Responsive Non‐Small Cell Lung Cancer

Background.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy is clearly beneficial in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). However, acquired resistance develops uniformly and the benefit of continuation of EGFR TKI therapy beyond progression remains unclear.

Materials and Methods.

This was a randomized phase II study of chemotherapy (arm A: pemetrexed or docetaxel) versus chemotherapy plus erlotinib (ERL) (arm B) in patients with progressive NSCLC following clinical benefit from erlotinib. In arm B, chemotherapy was given with erlotinib at an oral daily dose of 150 mg on days 2–19 of each cycle to minimize negative pharmacodynamic interactions. The primary endpoint was that continuation of erlotinib in this patient population could extend progression-free survival (PFS) by 50%.

Results.

A total of 46 patients were randomized (arm A: 24; arm B: 22). Patient characteristics were well balanced except there were more female patients in arm A (p = .075). The median PFS of patients in arm A was 5.5 months and for those in arm B, 4.4 months (p = .699). The response rates were 13% and 16% in arms A and B, respectively (p = .79). EGFR status data were available for 39 of the 46 patients and no significant difference in PFS was seen for continuing ERL beyond progression in mutation-positive patients. Substantially more toxicity was seen in arm B than arm A.

Conclusion.

There was added toxicity but no benefit with the continuation of ERL beyond progression along with chemotherapy as compared with chemotherapy alone.

Implications for Practice:

The benefits of continuing erlotinib upon progression alongside conventional chemotherapy are unclear. This randomized phase II study, initiated prior to the establishment of routine epidermal growth factor receptor (EGFR) mutation testing, addressed this clinically relevant issue through randomizing patients with prior clinical benefit from erlotinib (thereby enriching for EGFR-mutated tumors) upon progression in the second- or third-line setting to conventional chemotherapy (single-agent pemetrexed or docetaxel) with or without continued erlotinib. The results showed no benefit to continuing erlotinib beyond progression, while significantly more side effects were noted in the combination arm. Along with other recently presented study findings, these results argue against the routine practice of continuing erlotinib in this setting.