Maintenance Chemotherapy in Non–Small Cell Lung Cancer

Recent trials have shown a benefit with maintenance therapy after 4 to 6 cycles of chemotherapy. These trials have shown improvement in progression-free survival using agents approved as second-line therapy in non-small cell lung cancer. Trials using erlotinib and pemetrexed showed improvement in overall survival. Consideration of trial design is critical for the interpretation of these results. Data on quality of life and cost have not been presented, but will ultimately be important in evaluating the usefulness of these approaches.

Abstract

Recent trials have shown a benefit with maintenance therapy after 4 to 6 cycles of chemotherapy. These trials have shown improvement in progression-free survival using agents approved as second-line therapy in non-small cell lung cancer. Trials using erlotinib and pemetrexed showed improvement in overall survival. Consideration of trial design is critical for the interpretation of these results. Data on quality of life and cost have not been presented, but will ultimately be important in evaluating the usefulness of these approaches.

Medscape: Continuing Medical Education Online

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Learning Objectives

Upon completion of this activity, participants will be able to:

  • Identify medications that have demonstrated efficacy as maintenance chemotherapy for NSCLC

  • Describe clinical trials of maintenance therapy for NSCLC

  • Describe survival data from trials of maintenance chemotherapy for NSCLC

  • Counsel patients effectively regarding the known benefits and harms of maintenance chemotherapy for NSCLC

Two thousand and eight marked the 20th anniversary of the publication of a landmark trial conducted by the National Cancer Institute of Canada (NCIC).1 This was the first randomized study conducted in North America that showed a clear survival benefit in patients with advanced non–small cell lung cancer (NSCLC) treated with palliative chemotherapy compared with best supportive care alone. Over the past 20 years, therapy for advanced NSCLC has improved through the development of better-tolerated chemotherapy agents and improvements in supportive care, particularly through improved antiemetics. Despite the development of several new chemotherapy agents with activity in NSCLC over this period, the survival for patients with advanced disease remains poor. In fact, the best chemotherapy arm of the NCIC trial had a median survival of 7.4 months, although it was 7.9 months for patients enrolled on ECOG 1594, a trial comparing 3 third-generation doublets with cisplatin and paclitaxel published 14 years later.2

Several strategies have built on these initial results to improve the therapeutic efficacy of conventional chemotherapy. Second-line chemotherapy with docetaxel,3 pemetrexed,4 or erlotinib5 improves survival and quality of life (QOL) for patients with NSCLC. In first-line treatment, until recently, most strategies to improve on the established platin doublets failed. Incorporation of a third conventional chemotherapy agent to standard doublets,6 the addition of oral inhibitors of the epidermal growth factor receptor (EGFR) to chemotherapy,7 and the incorporation of other non-chemotherapy agents8 all failed to improve survival and QOL. Recently, the addition of the anti–vascular endothelial growth factor (VEGF) antibody bevacizumab9 and the anti-EGFR antibody cetuximab10 have improved survival when combined with first-line chemotherapy.

In an effort to improve the results of first-line chemotherapy, the concept of maintenance therapy has been tested in NSCLC (Table 1). Multiple clinical trial designs are testing maintenance therapy, and various nomenclatures have been adopted to describe these approaches. This article uses the nomenclature described in the recent NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Non–Small Cell Lung Cancer: “Continuation maintenance refers to the use of at least one of the agents in first-line, beyond 4 to 6 cycles in the absence of disease progression. Switch maintenance refers to the initiation of a different agent, not included as part of the first-line regimen, in the absence of disease progression, after 4 to 6 cycles of initial therapy” (in this issue, on page 740; to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org).11

Table 1

Summary of Recent Clinical Trials of Maintenance Chemotherapy in NSCLC

Table 1

Trials of Maintenance Therapy

Two biologic agents have shown improved survival when combined with first-line chemotherapy: bevacizumab9 and cetuximab.10 However, 2 other randomized phase III trials12,13 failed to confirm the improvement in survival of these agents in the first-line setting. Both of these negative trials had progression-free survival as their primary objective and, although the bevacizumab trial showed an improvement in this end point, the cetuximab trial failed to show a benefit. The designs of these 4 studies included continuation maintenance of the biologic agent after 6 cycles of chemotherapy. No trial has examined whether the benefit of these agents is derived from the phase that is concurrent with cytotoxic chemotherapy, the maintenance phase, or both. The consensus of the NCCN NSCLC panel is to continue these agents until evidence is seen of disease progression after their use with first-line chemotherapy, in accord with the design of the studies showing benefit.11 This recommendation is based on historical precedent in clinical trials rather than definitive data for the continuation maintenance phase.

Maintenance chemotherapy trials using conventional chemotherapy alone were reviewed by Soon et al.14 in a recent meta-analysis of 13 randomized clinical trials including 3027 patients. When compared with the control arm, extending chemotherapy improved progression-free survival (hazard ratio [HR], 0.75; P < .00001), and overall survival was modestly improved (HR, 0.92; P = .03). They also found that extending chemotherapy with third-generation agents (gemcitabine, vinorelbine, paclitaxel, docetaxel, or pemetrexed) resulted in greater improvements in progression-free survival compared with older regimens. The addition of maintenance chemotherapy was associated with more frequent adverse events and found to be detrimental to QOL in 2 of 7 trials.

Several positive trials of maintenance therapy for advanced NSCLC have recently been reported. All of these trials use FDA-approved agents for the treatment of NSCLC in the second-line setting, including docetaxel,3 pemetrexed,4 and erlotinib.5

Docetaxel Maintenance

Docetaxel was the first agent approved for the second-line treatment of NSCLC. Fidias et al.15 investigated whether immediate treatment with docetaxel after first-line therapy resulted in improved patient outcomes. In a phase III trial, chemotherapy-naïve patients were treated with carboplatin and gemcitabine (CG). Patients who did not progress after 4 cycles of treatment were randomized to immediate docetaxel or treatment with docetaxel at disease progression. The primary end point was overall survival and secondary end points included progression-free survival and QOL. Of the 566 enrolled patients, 398 completed first-line CG therapy and 309 were randomly assigned to immediate or delayed treatment with docetaxel. Immediate treatment with docetaxel improved progression-free survival (5.7 vs. 2.7 months; P = .0001). Median survival was greater in the immediate treatment group (12.3 vs. 9.7 months); however, this finding failed to meet statistical significance (P = .0853).

A potential shortcoming of this trial is the sampling bias from the different intervals between CT response assessments performed every 3 months for the delayed treatment group and every 6 weeks in the immediate treatment group. Only 98 of 156 (63%) of the patients randomized to delayed therapy actually received docetaxel. Among the patients in the delayed arm who received docetaxel, median overall survival was 12.5 months, identical to the overall survival in the immediate treatment arm. The authors concluded that the overall benefit seen in the immediate treatment arm was apparently from more patients receiving docetaxel treatment. QOL was not statistically different between the immediate and delayed treatment arms.

Pemetrexed Maintenance

Ciuleanu et al.16 recently published the most compelling data for maintenance therapy in NSCLC. In this multinational, randomized, double-blinded study, 663 patients with stage IIIB/IV disease that had not progressed after 4 cycles of platinum doublet chemotherapy (cisplatin or CG, paclitaxel, or docetaxel) were randomly assigned in a 2:1 fashion to receive pemetrexed, 500 mg/m2, or an infusion of placebo every 21 days plus best supportive care until disease progression. The primary end point, progression-free survival, was significantly improved in the pemetrexed maintenance arm (4.3 vs. 2.6 months; P < .0001). Overall survival was also improved (13.4 vs. 10.6 months; P < .012). Toxicities were greater in the pemetrexed arm, with grade 3 and 4 toxicities seen in 16% of patients versus 4% of placebo-treated patients. When the nonsquamous subset was analyzed, the results were even more significant. Improvement in investigator-assessed median progression-free survival was similar (4.5 vs. 2.6 months), but the median overall survival increased by approximately 5 months compared with placebo (15.5 vs. 10.3 months; P < .0001). No benefit was seen in the subset of patients with squamous histology.

Subsequent anticancer systemic therapies were used in 51% of patients randomized to pemetrexed (constituting third-line treatment) and 67% of patients randomized to placebo (constituting second-line treatment). Agents used included docetaxel, erlotinib, gefitinib, and others. However, only 18% of patients treated in the placebo arm received subsequent pemetrexed. Based on these data, the FDA approved pemetrexed as maintenance treatment for nonsquamous NSCLC.

Erlotinib Maintenance

Erlotinib has been shown to improve overall survival in patients receiving second- or third-line treatment for stage IIIB/IV NSCLC5 and is FDA-approved for this indication. Side effects of treatment include rash and diarrhea and are generally believed to be less severe than with conventional cytotoxic chemotherapy. Furthermore, toxicity generally decreases over time and is not cumulative; this was the rationale for bringing erlotinib into the maintenance setting.

The SATURN trial tested the role of maintenance erlotinib in patients not experiencing progression after 4 cycles of platinum doublet therapy in a phase III, randomized, placebo-controlled trial.17 This trial enrolled 1949 patients with chemotherapy-naïve stage IIIB/IV NSCLC and underwent 4 cycles of chemotherapy. Of these patients, 889 had nonprogressive disease and were randomized in a 1:1 fashion to erlotinib or placebo. The results presented at the 2009 ASCO annual meeting showed a statistically significant prolongation of progression-free survival in the intent-to-treat population (12.3 vs. 11.1 weeks; HR, 0.71; P < .0001). Subgroup analysis showed a progression-free survival benefit in EGFR immunohistochemistry–positive, EGFR mutation–positive, wild-type EGFR, adenocarcinoma, and squamous cell carcinoma. Not unexpectedly, this benefit in the EGFR mutation–positive subgroup was significant, with an HR of 0.1.

Subsequent to the presentation at ASCO, a press release indicated that overall survival improved from 11.0 to 12.0 months in the erlotinib arm (HR, 0.81; P = .0088).18 Rash was seen in 49% of patients and diarrhea in 20%, with 6% grade 3 rash and 2% grade 3 diarrhea. No grade 4 rash or diarrhea was seen. In April 2010, the FDA approved erlotinib “for maintenance treatment of patients with locally advanced or metastatic NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.”19 An important caveat to the survival data is the low rate of subsequent EGFR tyrosine kinase inhibitor (TKI) use in the placebo arm (16%). Because EFGR TKIs have known therapeutic benefit, the lack of crossover in this trial reinforces the data showing that erlotinib is an effective agent in NSCLC, but does not definitively prove that the modest improvements in overall and progression-free survival are from the switch maintenance strategy.

In advanced nonsquamous NSCLC, the addition of bevacizumab to carboplatin/paclitaxel chemotherapy has been shown to improve overall survival compared with carboplatin/paclitaxel chemotherapy alone.9 Trials testing the role of bevacizumab continued it as continuation maintenance after a set duration of the conventional cytotoxic chemotherapy. Continued treatment with bevacizumab after cytotoxic therapy until disease progression has become standard care, but this is based on how the treatments were delivered in clinical trials. No trial has addressed whether this bevacizumab maintenance confers a survival benefit over the combination of chemotherapy and bevacizumab without maintenance bevacizumab.

The ATLAS trial studied the role of adding erlotinib to bevacizumab in the maintenance setting.20 When the study was designed, phase II data suggested the addition of bevacizumab to erlotinib prolonged progression-free survival.21 A subsequent phase III trial confirmed the prolongation of progression-free survival (3.4 months for the combination vs. 1.7 months for erlotinib monotherapy; P < .0001), but the primary end point of the study, overall survival, was not met, with similar survival in both arms.22 The ATLAS trial enrolled 1160 patients who underwent first-line therapy with bevacizumab, of which 743 with non-progressive disease were continued on bevacizumab and randomized to receive erlotinib or placebo. Progression-free survival was improved in the erlotinib arm (4.8 vs. 3.7 months; P = .0012). Overall survival has not yet been reported. Grade 3/4 toxicities were more common in the erlotinib/bevacizumab group (44.1% vs. 30.4% in the bevacizumab-alone group).

Discussion

Maintenance chemotherapy after first-line chemotherapy for advanced NSCLC is associated with increased costs for chemotherapy and will likely increase overall costs. However, maintenance therapies may decrease costs in areas of palliative radiotherapy and hospital admissions caused by performance status deterioration. For example, in the previously cited NCIC study published more than 20 years ago, the administration of one of the first-line chemotherapy regimens was associated with absolute savings.23 It would be very important to have a cost-effectiveness analysis incorporated into these studies investigating maintenance chemotherapy.

The role of continuation maintenance has not been clarified by the recently reported trials on switch maintenance strategies. For example, the role of maintenance pemetrexed has not been established in patients receiving a first-line platinum and pemetrexed combination, and is currently being tested in a clinical trial (NCT00789373).

Trial design considerations may also influence interpretation of these studies.

Progression-Free Survival as the Primary End Point

Four recent randomized trials have investigated the immediate use of agents approved for second-line chemotherapy1517,20 (docetaxel, pemetrexed, and erlotinib) after the use of a predetermined number of first-line chemotherapy cycles. In these 4 studies, the agent investigated was not part of the first-line regimen. All studies were positive in achieving their primary objective of improving progression-free survival. These agents are approved for the second-line therapy of NSCLC based on demonstrated improved survival compared with best supportive care. Use of one of these agents immediately after first-line chemotherapy would certainly be expected to alter the natural history of the disease (by improving progression-free and overall survival), as it does when it is used after documentation of disease progression. Progression-free survival would be a valid primary end point only if combined with detailed data on cost-effectiveness and QOL. Unfortunately, data on QOL have not been consistently included in the reporting of these trials

Use of Placebo When Progression-Free Survival is the Primary Objective

When progression-free survival is the primary objective of a clinical trial, the use of placebo is very important. Trials have a predetermined schedule of radiologic follow-up. However, investigators may order additional tests based on their suspicion of disease progression. More frequent evaluation for progression may lead to earlier detection of progression, and consequently alter progression-free survival. Patients and physicians who are aware that the patient is not undergoing therapy may be more likely to suspect that symptoms may be secondary to disease progression rather than from toxicities of therapy, prompting earlier radiographic evaluation.

Three of the recent trials have used placebo. Although erlotinib and pemetrexed are well tolerated,16,17,20 treating investigators were probably aware of treatment assignment. This was likely the case secondary to skin changes in the case of erlotinib and hematologic/liver function tests in the case of pemetrexed. The effect of early radiologic assessment on progression-free survival could be evaluated if data regarding unscheduled radiologic evaluations were available.

Use of Second-Line Therapy at Disease Progression

Second-line chemotherapy and erlotinib improve survival in NSCLC.35 However, no improvement can occur if therapy is not delivered. Among the recent trials resulting in prolonged progression-free survival, only the trial investigating the role of docetaxel had a design in which patients in the observation arm crossed over at disease progression.15 Only 63% of the patients randomized to delayed docetaxel after evidence of disease progression underwent this therapy. However, in the trials with pemetrexed and erlotinib, in which subsequent crossover to the investigational drug was not part of the design, the rate of use of the investigated agent was less than 20%.16,17

When trials with this design are conducted in health care systems in which access to the drugs is not possible, either because of lack of coverage for second-line therapy or because the drugs are not approved, the trial becomes a randomized study between receiving and not receiving the agent, rather than immediate vs. delayed therapy. The benefit of switch maintenance therapy may derive from the fact that effective second-line therapies are always delivered before decline in performance status occurs. This must be balanced against the cumulative toxicities incurred from continuous treatment. Current clinical trials data do not preclude the equivalence or superiority of the paradigm of watchful waiting between first- and second-line treatments. To avoid an unexpected decline in performance status that would preclude further treatment, regular office visits and frequent radiographic assessment at a comparable frequency to patients under active treatment (i.e., every 6–8 weeks) are advised.4

Conclusions

The trials reviewed in this article all suggest that a switch maintenance strategy using approved second-line therapies for NSCLC (pemetrexed, docetaxel, and erlotinib) prolongs progression-free survival. The benefit of continuation maintenance, when these agents were part of the first-line regimen and continued after 4 to 6 cycles, remains unanswered. Two of these trials that used pemetrexed or erlotinib also showed a superior survival. However, interpretation of these results is complicated by access to therapy in the control arm. The trial of switch maintenance to docetaxel versus docetaxel at disease progression is the trial that most directly tests the value of the maintenance strategy. This trial showed improved progression-free survival, which was expected based on the known activity of docetaxel in the second-line setting. Although the trial did not meet statistical significance for the end point of overall survival, the P value of .0853 suggests a clear trend for improved survival. This difference in overall survival between arms disappeared when the patients in the delayed arm who underwent therapy alone were compared with those who underwent immediate treatment. However, the benefit may have been secondary to the fact that more patients underwent therapy in the immediate treatment group.

Close follow-up may be a reasonable alternative to immediate therapy after first-line chemotherapy. It is important that patients are followed closely to avoid deterioration of their performance status, which would make them ineligible to undergo further therapy.

EDITOR

Kerrin G. Robinson, MA, Assistant Managing Editor, JNCCN–Journal of the National Comprehensive Cancer Network

Disclosure: Kerrin G. Robinson, MA, has disclosed no relevant financial relationships.

CME AUTHOR

Charles P. Vega, MD, Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine

Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

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Correspondence: Renato G. Martins, MD, MPH, Thoracic/Head and Neck Medical Oncology, Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance/University of Washington, 825 Eastlake Avenue East, Seattle, WA 98109. E-mail: rgmart@u.washington.edu

Disclosure: Keith D. Eaton, MD, PhD, has disclosed that he has participated in funded research on technology, process, or product development for OSI, Genentech, NovaRx, Merck, Novartis, Pfizer, and Boehringer Ingelheim.

Disclosure: Renato G. Martins, MD, MPH, has disclosed that he has participated in funded or unfunded research on a technology, process, or product development for Lilly (PI), OSI (Sub-I), and Genentech (Sub-I), and that he has received compensation as a speaker from Lilly and Genentech.

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