Special Report: Maintenance Therapy in Advanced Non-Small-Cell Lung Cancer
Executive Summary
Background
Lung cancer is the most frequently diagnosed major cancer in the world and the leading cause of worldwide cancer mortality. In 2010, in the U.S. alone, there were an estimated 221,000 cases and more than 157,000 deaths. More than 85% of cases are classified as non-small-cell lung cancer (NSCLC), a subgroup with unique biological, therapeutic, and prognostic features and that is identified most commonly (70% of cases) as advanced disease (i.e., stage III or IV).
The mainstay of treatment of advanced-stage NSCLC has been platinum-based, 2-drug regimens, so-called “platinum doublet” therapy. In multiple studies, this therapy has been shown to produce modest results with a median survival of 8 to 11 months and a 1-year survival of 30 to 45%. Numerous efforts have been made to improve the efficacy of treatment of advanced NSCLC, and there is a growing menu of doublet chemotherapeutic choices.
While maintenance therapy has been widely studied and discussed as a technique for improving outcomes, the term itself has been variably defined in the literature. In some studies or reviews, it is considered equivalent to consolidation therapy and the two categories combined to identify all patients receiving extended drug treatments, regardless of duration. In other studies or reviews, maintenance therapy is used to refer specifically to patients receiving therapy for an indefinite period of time and is clearly distinguished from consolidation therapy, which is specifically used to refer to patients receiving therapy for a defined and usually short-term (i.e., 6 cycles or less) time beyond the initial course of treatment. This Special Report does recognize a distinction between maintenance therapy (i.e., treatment that is given continuously until there is evidence of disease progression or drug toxicity) and consolidation therapy (i.e., short-term interventions of 6 cycles or less).
The National Comprehensive Cancer Network makes a further distinction between maintenance therapy using one or more drugs carried over from first-line therapy (so-called continuous maintenance therapy) and using non-cross-reacting new drugs not part of first-line therapy (so-called switch maintenance therapy). Ideally in both cases, reduced tumor burden would enhance the effect of continued therapy.
Objective
The purpose of this Special Report is to survey the literature on the use of maintenance therapy to improve outcomes in patients being treated with first-line platinum doublet therapy for advanced NSCLC. Special attention will be directed to the recent introduction of new molecularly targeted treatments. Endpoints evaluated will include progression-free survival, overall survival, toxicity and, when available, information on quality of life.
Search Strategy
A MEDLINE® search (via Pub Med) for relevant articles was completed for all articles on “maintenance therapy” or “consolidation therapy” and lung cancer through February 2011. A targeted search was also performed on 3 drugs: Tarceva® (erlotinib), Avastin® (bevacizumab), and Erbitux® (cetuximab) combined with the term “lung cancer.” The bibliographies of review articles were also examined for relevant articles, and abstracts were obtained from several recent meetings for information on unpublished, but completed, clinical trials.
Selection Criteria
All clinical trials providing information on “maintenance therapy” for treatment of NSCLC were reviewed. In addition, relevant abstracts, the transcript for the recent U.S. Food and Drug Administration (FDA) Advisory Panel meeting for the Office of New Oncology Drugs on use of erlotinib for maintenance therapy (December 12, 2009; www.fda.gov/downloads/ AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/ UCM197771.pdf) and multiple review articles were also reviewed.
Articles were selected if they described randomized clinical trials evaluating first-line standard chemotherapy followed in responders by augmented treatment using either standard chemotherapy or molecularly targeted therapy. Studies were included only if results of progression-free survival/time to progression and/or overall survival were reported. Toxicity and quality-of-life data from these reports were analyzed when available. A broad definition for advanced cancers was used for this Report. Most commonly, studies used the term to refer to patients with either stage IIIB or IV disease.
Main Results
This Special Report evaluates 5 studies of maintenance therapy including use of both continuous and switch therapies using chemotherapeutic agents and use of switch therapy with a molecularly targeted agent, erlotinib (Tarceva®). None of the studies specifically compares results of maintenance therapy to use of standard second line therapy. Data in the text and tables have been aligned to answer key questions about the use of maintenance in 4 categories: continuous maintenance chemotherapy, switch maintenance chemotherapy, continuous maintenance molecularly targeted therapy, and switch maintenance molecularly targeted therapy.
Key Question 1. In patients who have responded to first-line chemotherapy, does using continuous chemotherapy as maintenance therapy until disease progression or drug intolerability improve outcomes compared to observation alone?
Neither median overall survival nor progression-free survival showed a statistically significant improvement in any of the studies of continuous maintenance chemotherapy. In one study, quality of life was reported to be the same for patients receiving maintenance therapy versus controls. All studies observed increases in toxicity, with a broad range of findings including increases in nausea and vomiting, in neuropathy, asthenia, and neutropenia, and in grade 3 neutropenia.
Key Question 2. In patients who have responded to first-line chemotherapy, does using switch chemotherapy as maintenance therapy until disease progression or drug intolerability improve outcomes compared to observation alone?
A single study using pemetrexed (Alimta®) demonstrated a statistically significant increase in overall survival (4.9 months) and in progression-free survival (1.7 months) in patients with nonsquamous NSCLC. Quality-of-life assessment showed that patients receiving maintenance treatment using pemetrexed (Alimta®) reported a statistically significant decrease in pain with other parameters being not statistically different.
Key Question 3. In patients who have responded to first-line chemotherapy supplemented by molecularly targeted therapy (MTT), does using continuous MTT as maintenance therapy until disease progression or drug intolerability improve outcomes compared to observation alone?
No studies were identified to answer this question. As noted in the Appendix, there is considerable interest in the use of MTT. However, studies to date have not specifically looked at the contribution of maintenance therapy in affecting treatment outcomes. Results of use as first-line therapy followed by maintenance therapy have been inconsistent, but several observations of modest improvements in overall survival have been made.
Key Question 4. In patients who have responded to first-line chemotherapy, does using switch molecularly targeted therapy as maintenance therapy until disease progression or drug intolerability improve outcomes compared to observation alone?
A single study of erlotinib (Tarceva®) has shown a statistically significant increase in overall survival – from 11 to 12 months in placebo versus erlotinib, respectively. Progression-free survival was also reported in this study to be statistically significantly increased from 11.1 to 12.3 weeks. Quality of life between the 2 arms of the study was reported to be the same, but few details about the study were provided. Toxicities were mild to moderate and typical for erlotinib (Tarceva®), including diarrhea and skin rash.
Maintenance Therapy versus Second-Line Therapy
Although second-line therapy is now a standard treatment option for NSCLC, no studies using maintenance therapy directly compared results of this approach versus the use of second-line therapy.
Author’s Comments and Conclusions
The concept of maintenance therapy in lung cancer is not new; reports on use of this treatment approach date back to 1958. The goal is to increase overall survival with good or at least satisfactory quality of life. Evaluation of maintenance therapy is complicated by the fact that there are a growing number of potentially effective treatment agents (both new generation chemotherapeutic drugs and molecularly targeted agents) to consider. Many of these have more favorable toxicity profiles than first-generation drugs, and some of the molecularly targeted agents can be taken orally, which provides for ease of administration. The drugs selected for extended use can be derived from the first-line of therapy (continuous therapy) or can make use of a new non-cross-reacting drug (switch therapy).
After analysis of the data reviewed in studies of maintenance therapy, it appears that at least 2 approaches (switch chemotherapy and switch molecularly targeted therapy) can provide statistically significant improvements in both progression-free and median overall survival. The largest change in overall survival observed in this Report was obtained with pemetrexed (Alimta®) with a 1.7-month increase in progression-free and a 4.9-month increase in overall survival in patients with nonsquamous cell subtypes of NSCLC. The importance of these results is reflected in a recommendation by the National Institute for Health and Clinical Excellence (NICE) in the U.K. to consider pemetrexed (Alimta®) therapy in patients who are candidates for maintenance therapy. Pemetrexed (Alimta®) is also recognized as both a potential continuous and switch maintenance therapy choice by the National Comprehensive Cancer Network.
Because of the complexity of choices, study of new treatments including maintenance treatment regimens for NSCLC would ideally be performed using a multi-arm study. Multi-arm study designs clearly add complexity and cost to clinical studies. To contain study costs and improve study efficiency, it has been suggested Phase II studies be conducted using adaptive statistical designs to optimize selection of drugs and drug regimens for further Phase III studies. While these techniques are relatively new, they offer important potential benefits––containing study costs while optimizing the quality and usefulness of data generated from drug studies.
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Maintenance Therapy Advanced Non-Small-Cell Lung Cancer
