February 2011 VOL 2, NO 1

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Review

Maintenance Therapy For Non–Small Cell Lung Cancer

Contributions By Loretta Fala 

Lung cancer is the most common type of cancer in the United States.1,2 An estimated 221,520 people (115,750 men and 105,770 women) will be diagnosed with cancer of the lung and bronchus in 2010, and only 15.8% of patients with lung cancer survive 5 years or more after diagnosis. 3 Lung cancer accounts for more cancer deaths in the United States than any other type of cancer.4Advances in surgical techniques and combined therapies have helped increase the 1-year relative survival for patients with lung cancer to 42% in 2002-2005, from 35% 2 decades earlier in 1975-1979.2 Although the 5-year survival rate is greater than 50% for early-stage disease, unfortunately only 15% of lung cancers are detected when the disease is still localized.2

According to the National Cancer Institute, lung cancer costs the American public an estimated $10.3 billion a year and is the third costliest cancer after breast cancer and colorectal cancer.5 Furthermore, lung cancer tops the list in terms of lost productivity, accounting for $36.1 billion in lost lifetime earnings—lost productivity costs 3 times greater than those associated with breast cancer or colorectal cancer.5 The financial burden of cancer may continue to expand with the aging of the US population, improved survival, and the increasing cost of cancer treatments.5

The median age at diagnosis of lung cancer is 71 years.3 As the baby boom generation (people born between 1946 and 1964) reaches age 65 and older over the next 2 decades,6 the number of Americans in this age-group is expected to increase by 36% from 2010 to 2020.7 Because lung cancer is widespread and carries a dire prognosis, urgency prevails in the search for better therapies and improved outcomes for patients. Efforts are particularly robust in non–small cell lung cancer (NSCLC), which accounts for 85% of all cases.4

For patients with advanced NSCLC, maintenance therapy may help control the disease and extend a patient’s life.8 Administered after induction chemo therapy and generally in lower doses than initial chemotherapy, maintenance therapy often involves standard chemotherapy (an agent used in the initial treatment plan therapy or another drug), or it may include a combination of therapies, including vaccines, hormones, or other drugs.8 Decisions about maintenance therapy include consideration of the associated benefits, risks, and costs, as well as patient-specific factors and preferences. Two chemotherapy agents have recently received US Food and Drug Admin - istration (FDA) approval for the maintenance therapy of patients with advanced NSCLC.

Recent advances have also yielded a number of novel agents that target specific molecular pathways in tumor cells, and research on these discoveries is ongoing. The molecular/genetic profiling of NSCLC can now be used to characterize tumors by their expression of specific markers. These molecular profiles hold promise for their potential in predicting a response, or resistance, to specific standard or novel therapies and in identifying a benefit from a new or standard agent, based on clinical trial evidence.9

MAINTENANCE THERAPY BRINGS A NEW TREATMENT APPROACH FOR ADVANCED NSCLC

Maintenance therapy, a relatively new paradigm in the treatment of NSCLC, constitutes a shift from the past paradigm of treating recurrent disease.10 However, maintenance therapy has been used for years in the treatment of patients with acute lymphocytic leukemia and acute myeloid leukemia to lower the risk of disease recurrence, and it is also being studied in a number of other cancers. 8 His tologic information about the lung carcinoma is particularly useful for tailoring maintenance therapy toward improving outcomes for patients with NSCLC.11 Molecu larly targeted agents, including those that inhibit epidermal growth factor receptor (EGFR) and vascular endothelial growth factor, also represent a crucial inroad into personalized therapy for patients with lung cancer.9

Maintenance therapy has been shown to prolong progression-free survival (PFS) and overall survival (OS) in the appropriate patients, based on randomized, controlled studies of 2 agents—pemetrexed and erlotinib.12-14

Pemetrexed

In July 2009, pemetrexed was the first drug to be FDA-approved for maintenance therapy of advanced or metastatic lung cancer.15 Pemetrexed, a folate analog metabolic inhibitor, received this new indication specifically for patients with nonsquamous NSCLC that has not progressed after 4 cycles of platinum-based first-line chemotherapy.16 Pemetrexed is also indicated for initial treatment in combination with cisplatin, as well as after prior chemotherapy as a single agent in patients with locally advanced or metastatic nonsquamous NSCLC.16

Based on a randomized, double-blind, phase 3 international study (N = 663), patients with stage IIIB or IV NSCLC (without progress after 4 cycles of platinum-based chemotherapy) who were treated with pemetrexed showed a significant improvement in PFS: 4.3 months (95% confidence interval [CI], 4.1-4.7) compared with 2.6 months (95% CI, 1.7-2.8) in the placebo group (hazard ratio [HR], 0.50; 95% CI, 0.42-0.61; P <.001).13 The pemetrexed group also showed a significantly greater OS: 13.4 months (95% CI, 11.9-15.9) versus 10.6 months (95% CI, 8.7-12.0) in the placebo group (HR, 0.79; 95% CI, 0.65- 0.95; P = .012). No pemetrexed-associated mortalities occurred.13 Grade 3 or higher adverse events were more frequent in the pemetrexed group than in the placebo group, and included fatigue (5% vs 1%) and neutropenia (3% vs 0%).13 The most common any-grade adverse reactions compared with placebo were nausea (19% vs 6%) and anorexia (19% vs 5%).16

Erlotinib

In April 2010, the FDA approved an expanded indication for erlotinib, a tyrosine kinase inhibitor (TKI), as a maintenance treatment for patients with locally advanced or metastatic NSCLC whose disease has not progressed after 4 cycles of platinum-based first-line chemotherapy. 17,18 Erlotinib is also indicated for the treatment of locally advanced or metastatic NSCLC after failure of at least 1 prior chemotherapy regimen.18

Results from a randomized, double-blind, international phase 3 study (N = 889) showed a significant median PFS of 12.3 weeks for patients in the erlotinib group versus 11.5 weeks for the placebo group (HR, 0.71; 95% CI, 0.62-0.82; P <.001).14 In patients with EGFR-positive immunohistochemistry treated with erlotinib, compared with EGFRpositive patients receiving placebo, PFS was also significantly longer in the erlotinib group (12.3 weeks) versus the placebo group (11.1 weeks; HR, 0.69; 95% CI, 0.58-0.82; P <.001).14 The study also showed an improvement in OS of 1 month with erlotinib versus placebo as maintenance therapy (HR, 0.81; 95% CI, 0.70-0.95; P = .009).18

Serious adverse events were reported in 11% of the patients in the erlotinib group compared with 8% in the placebo group; the most common serious adverse events were pneumonia (2% with erlotinib vs <1% with placebo).14 The most common grade 3 or higher adverse events included rash (9% in the erlotinib group vs 0% in the placebo group) and diarrhea (2% in the erlotinib group vs 0% in the placebo group).14 The most common any-grade adverse reactions compared with placebo were rash (49.2% vs 5.8%) and diarrhea (20.3% vs 4.5%).18

MAINTENANCE THERAPY: BENEFITS, RISKS, AND COSTS

Maintenance therapy is associated with several potential benefits, including preventing the recurrence of cancer, slowing disease growth, and prolonging life.8 However, these benefits must be weighed against potential risks, which include increased side effects, more frequent doctor visits, and drug resistance.8 Maintenance therapy may also be associated with higher treatment costs.8 In addition, the data on the survival benefits associated with maintenance therapy are limited,8 as are data on the quality of life associated with maintenance therapy8,19—in particular, the cumulative toxicity of prolonged chemotherapy.19 Other study limitations include the variability in measurable end points such as the definition of progression (in PFS) and frequency of response assessment; additionally, the use of multiple agents in the poststudy setting may confound the impact of maintenance treatment. 19 Although patients receiving maintenance therapy may not have the opportunity of a reprieve from chemotherapy during the “wait-and-see” period, this period is often accompanied by anxiety about disease progression or recurrence.19

The rising cost of cancer care persists as a major healthcare challenge. The American Society of Clinical Oncology (ASCO) encourages members to discuss the cost of care directly with patients.10 Although maintenance chemotherapy for advanced NSCLC is associated with increased costs, it may decrease costs related to palliative radiotherapy and hospital admissions resulting from deteriorating performance status.12 Furthermore, the concept of extended survival—in terms of additional months, or even weeks of life—may represent an immeasurable benefit for patients and their loved ones.

THE IMPORTANCE OF HISTOLOGY AND MOLECULAR BIOMARKERS

Lung cancer is classified as either non–small cell or small cell, based on its biology, therapy, and prognosis.4 The 5-year survival rate for NSCLC is 17%, compared with a lower survival rate of 6% for small-cell lung cancer.2 NSCLC is categorized into 2 types: nonsquamous carcinoma (adenocarcinoma, large-cell carcinoma, and others) and squamous cell carcinoma.4 Squa mous cell lung carcinoma accounts for 25% of lung cancers in the United States, whereas large cell carcinoma (nonsquamous) accounts for 10% to 20% of all lung cancers.20

Identifying the histologic subtype of NSCLC is an essential step in selecting the appropriate therapy, and it may also be particularly useful when augmented by molecular testing.21 For example, the detection of the bronchoalveolar subtype of NSCLC adenocarcinoma may suggest a specific treatment strategy, particularly if it carries specific mutations in the EGFR tyrosine kinase domain, suggesting it will respond to treatment with an EGFR TKI.21

Several of the key predictive molecular biomarkers in the treatment of NSCLC include4:

  • Presence of the EGFR exon 19 deletion or exon 21 L858R mutation is associated with a treatment benefit from EGFR TKI therapy

  • High levels of ERCC1 expression are associated with a poor response to platinum-based chemotherapy

  • The presence of KRAS mutations is associated with a lack of benefit from platinum/ vinorelbine chemotherapy or from EGFR TKI therapy

  • High levels of RRM1 expression are associated with a poor response to gemcitabine-based chemotherapy.

Patients with EGFR mutations exon 19 deletion and L858R mutation have shown a significantly better response to erlotinib or gefitinib (both EGFR TKI agents), with initial retrospective studies suggesting that an estimated 90% of patients with a tumor response to these agents had mutations, whereas patients without a response did not have these mutations.4

According to the National Compre hen sive Cancer Network (NCCN) practice guidelines for NSCLC, pathologic evaluation should be performed to classify the lung cancer, determine its extent of invasion, determine the status of surgical margins, and identify molecular abnormalities that may predict the benefit of, or resistance to, EGFR TKI therapy.4 Pre operative assessment may include bronchial brushings or washings, fine-needle aspiration biopsy, core needle biopsy, endobronchial biopsy, transbronchial biopsy, as well as sampling of mediastinal lymph nodes to stage the disease and help determine therapeutic options. In traoperative (lobectomy or pneumonectomy) evaluation may include determining the surgical resection margin status, diagnosing any incidental nodules found during the surgery, or checking the status of regional lymph nodes.4 Postoperative pathology provides information necessary for classifying the tumor type, stage, and prognostic factors. Accord ing to NCCN guidelines, the surgical pathology report should use the histologic classifications established by the World Health Organization for lung carcinomas.4

Adequate tissue sampling may provide the key to identifying the treatment most appropriate for a specific patient and improving the likelihood of identifying an effective treatment as early as possible.21 Refinements in histology and the evolving role of molecular testing will undoubtedly play a role in predicting responses to particular treatments for NSCLC.21

CLINICAL PRACTICE GUIDELINES FOR MAINTENANCE THERAPY

The NCCN practice guidelines for NSCLC, which were updated in March 2010, added a new section with recommendations on maintenance therapy (Table). Although ASCO released a clinical practice guideline update on chemotherapy for stage IV NSCLC, the guideline went to press in 2009 without the opportunity of a comprehensive data review on recent data supporting the indication/use of pemetrexed for maintenance therapy in patients with advanced NSCLC.22 In this 2009 update, ASCO included an announcement that an update would be forthcoming on consideration of relevant data on the use of pemetrexed in maintenance therapy. Results of 2 studies evaluating erlotinib as maintenance therapy were also anticipated by the ASCO review committee at the time of the 2009 guideline publication.22 In June 2010, the National Institute for Health and Clinical Excellence, based in London, issued guidance to the National Health Service, United Kingdom, recommending pemetrexed for the maintenance treatment of NSCLC.23 The guidance states that pemetrexed is recommended as an option for maintenance therapy in people with locally advanced or metastatic NSCLC other than predominantly squamous cell histology if the cancer has not progressed immediately after platinumbased chemo therapy in combination with gem - citabine, paclitaxel, or docetaxel.23,24 It also states that people who have received pemetrexed in combination with cisplatin as first-line therapy cannot receive pemetrexed maintenance treatment.23,24

NCCN Guideline Recommendations (March 2010) for NSCLC Maintenance Therapy

MAINTENANCE THERAPY CONSIDERATIONS

Treatment considerations include the stage of the cancer and invasion status, the type of cancer, the patient’s performance status, patient-specific preferences, the costs of treatment, as well as other patient- and agent-specific factors. Evidence-based clinical practice guidelines can be a valuable decision-support resource for clinicians.

Selecting the appropriate patient population, as characterized by histologic (nonsquamous) or molecular (EGFR mutation) profile, is a guiding factor in selecting the appropriate maintenance therapy.19 Furthermore, the use of a well-characterized tumor profile as a tool for selecting the appropriate patients for maintenance therapy may improve the therapeutic index, and thereby improve the survival benefit in these patients.19 In addition, identifying predictive biomarkers for specific agents used in maintenance therapy may help to improve the benefits and reduce risks. Pemetrexed is a maintenance therapy option for pa tients with nonsquamous histology.4 Moreover, a molecular-based strategy may be important for selecting the appropriate subgroup of patients best suited for maintenance therapy with erlotinib.19

The risks and benefits of maintenance therapy must be considered and weighed, along with the safety, efficacy, and tolerability of the agents used in this setting. Similarly, the risks associated with delaying additional therapy must also be considered: a delay strategy may be associated with a faster disease progression and shorter survival time than immediate additional therapy.25,26 Extending chemotherapy, particularly with a third-generation regimen, has been shown to improve PFS substantially and OS modestly.26

CONCLUSION

Maintenance therapy represents a new treatment paradigm for patients with advanced NSCLC, given its potential for improved survival. Ideally, the agent selected for maintenance therapy should be well-tolerated by the patient, have minimal side effects/cumulative toxicities, and demonstrate improved patient outcomes.19 The histology of the carcinoma is an important tool in tailoring maintenance therapy for a specific patient. In addition, molecular profiling can help characterize tumors and predict response or resistance after standard or novel therapies.27 Mole cular tests will continue to play an important role in redefining patients with NSCLC into specific subgroups that may respond to different optimal treatment pathways.22

The risks and benefits of maintenance therapy must be considered and addressed with the patient. Similarly, the risks and benefits of a delayed/waitand- see treatment approach must likewise be weighed carefully. The future holds promise, based on recent advances that foster targeted, personalized treatment approaches with the potential to improve response and survival for patients with advanced NSCLC.

References

  1. National Cancer Institute, National Institutes of Health. Common cancer types. www.cancer.gov/cancertopics/types commoncancers. Accessed September 21, 2010.

  2. American Cancer Society. Cancer Facts & Figures 2010. Atlanta, GA: American Cancer Society; 2010.

  3. National Cancer Institute, National Institutes of Health. Surveillance, Epidemiology, and End Results. SEER stat fact sheets: lung and bronchus. http://seer.cancer.gov/statfacts/ html/lungb.html. Accessed September 20, 2010.

  4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, V.2.2010. March 5, 2010. www.nccn.org/professionals/physi cian_gls/PDF/nscl.pdf. Accessed September 15, 2010.

  5. Wang BH. The financial burden of cancer—NCI benchmarks. April 23, 2010. http://benchmarks.cancer.gov/2010/04/thefinancial- burden-of-cancer/. Accessed September 20, 2010.

  6. Vincent GK, Velkoff VA. The Next Four Decades, the Older Population in the United States: 2010 to 2050. Current Population Reports, P25-1138. Washington, DC: US Census Bureau; May 2010.

  7. US Department of Health and Human Services, Ad - ministration on Aging. A Profile of Older Amer icans: 2007. www.agingcarefl.org/aging/AOA-2007profile.pdf. Accessed August 27, 2010.

  8. American Society of Clinical Oncology. Explaining maintenance therapy. Cancer.net. Updated February 22, 2010. www.cancer.net/patient/All+About+Cancer/Cancer.Net+ Feature+Articles/Treatments%2C+Tests%2C+and+Procedures/ Explaining+Maintenance+Therapy. Accessed September 20, 2010.

  9. Herbst RS, Lippman SM. Molecular signatures of lung cancer— toward personalized therapy [editorial]. N Engl J Med. 2007; 356:76-78.

  10. Peck P. Maintenance pemetrexed extends NSCLC survival by three months. Medpage Today. May 30, 2009. www.med pagetoday.com/tbprint.cfm?tbid=14437. Accessed September 22, 2010.

  11. Lilly receives fourth FDA approval for ALIMTA—first chemotherapy approved as maintenance therapy for nonsquamous non-small cell lung cancer. Medical News Today. July 8, 2009. www.medicalnewstoday.com/articles/156659. php. Accessed September 22, 2010.

  12. Eaton KD. Maintenance chemotherapy in non-small cell lung cancer. J Natl Compr Canc Netw. 2010;8:815-821.

  13. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomized, doubleblind, phase 3 study. Lancet. 2009;374:1432-1440. Epub September 18, 2009.

  14. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomized, placebo-controlled phase 3 study. Lancet Oncol. 2010;11:521-529. Epub May 20, 2010.

  15. Riley K. FDA approves first maintenance drug therapy for advanced lung cancer [press release]. July 6, 2009. US Food and Drug Administration. www.fda.gov/News/Events/Newsroom/ PressAnnouncements/ucm170515.htm. Accessed Sept ember 22, 2010.

  16. Alimta (pemetrexed disodium) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2010.

  17. Waknine Y. FDA approves use of erlotinib as maintenance therapy for advanced non-small cell lung cancer [press release]. April 20, 2010. www.medscape.com/viewarticle/720446. Accessed September 22, 2010.

  18. Tarceva (erlotinib) [package insert]. Melville, NY: OSI Pharmaceuticals Inc; and South San Francisco, CA: Genentech; 2010.

  19. Owonikoko TK, Ramalingam SS, Belani CP. Maintenance therapy for advanced non-small cell lung cancer: current status, controversies, and emerging consensus. Clin Cancer Res. 2010;16:2496-2504.

  20. Cleveland Clinic. Lung cancer overview. Reviewed October 23, 2008. http://my.clevelandclinic.org/disorders/Lung_Cancer/hic _Lung_Cancer.aspx. Accessed September 23, 2010.

  21. Neal JW. Histology matters: individualizing treatment in nonsmall cell lung cancer [editorial]. Oncologist. 2010;15:3-5. Epub January 19, 2010.

  22. Azzoli CG, Baker S Jr, Temin S, et al. American Society of Clinical Oncology clinical practice guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol. 2009;27:6251-6266.

  23. NICE recommends pemetrexed for the maintenance treatment of non-small-cell lung cancer [press release]. Medical News Today. June 23, 2010. www.medicalnewstoday.com/ articles/192709.php. Accessed September 22, 2010.

  24. National Institute for Health and Clinical Excellence (NICE). Final appraisal determination—pemetrexed for the maintenance treatment of non-small cell lung cancer. March 2010. www.nice.org.uk/nicemedia/live/12091/48303/48303. pdf. Accessed Septem ber 22, 2010.

  25. Belani CP, Liao J. Maintenance therapy for non-small cell lung cancer [comment]. Lancet. 2010;375:281-282; comment on Stinchcombe T, West H comment in: Lancet. 2009;374:1398- 1400.

  26. Soon YY, Stockler MR, Askie LM, Boyer MJ. Duration of chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis of randomized trials. J Clin Oncol. 2009;27:3277-3283. Epub May 26, 2009.

  27. Herbst RS, Heymach JV, Lippman SM. Molecular origins of cancer. N Engl J Med. 2008;359:1367-1380.

Maintenance Therapy in NSCLC: Personalized Perspectives

By Corey J. Langer, MD

Director of Thoracic Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia

Maintenance therapy has begun to emerge as a treatment standard for patients with non–small cell lung cancer (NSCLC) whose disease has not progressed after 4 to 6 cycles of frontline chemo - therapy. But some caveats still apply. Although it may be suitable for fit, motivated patients who are highly symptomatic at the time of presentation, it is not yet clear if maintenance therapy should be routine.

Based on the phase 3 data, use of pemetrexed is certainly justified in patients whose advanced NSCLC has stabilized or improved after 4 or more cycles of frontline therapy with a platinating agent, plus either gemcitabine or a taxane. Pemetrexed is particularly well tolerated and convenient, al though its “maintenance” benefits are confined to nonsquamous histology and its utility is as yet unproven in patients who have received pemetrexed and/or bevacizumab as part of their first-line treatment. Similarly, erlotinib has yielded a survival advantage compared with placebo in the maintenance setting, although the extent of its benefit seems less pronounced compared with pemetrexed.

Prolonged Initial Chemotherapy

Prolonged treatment with initial chemotherapy (eg, 6 vs 3 cycles or indefinite treatment vs 4 cycles) has shown no overall survival (OS) benefit1- 3; neither have prior maintenance studies of attenuated dosing or single agents yielded a survival benefit, although “intriguing trends” in time to progression have been observed in underpowered efforts.4,5

Switching to a new compound for maintenance therapy demonstrated some benefit in the welldesigned study by Fidias and colleagues, which evaluated immediate versus delayed docetaxel upon disease progression after first-line carboplatin/ gemcitabine.6 Pro gres sion-free survival (PFS) improved from 2.7 months in the delayed arm to 5.7 months with maintenance (P <.001), and median OS trended better (12.3 vs 9.7 months; P = .085). In addition, a recent metaanalysis documented a 30% reduction in disease progression using maintenance therapy with a third-generation regimen compared with maintenance with older regimens.7

Determining the Optimal Maintenance Therapy Agent

The study by Fidias and colleagues laid the groundwork for pemetrexed as maintenance after chemotherapy,6 which was evaluated in a recent phase 3 study by Ciuleanu and colleagues.8 Patients were randomized 2:1 to pemetrexed or intravenous placebo. Disease progression was reduced by 40% (P <.001) overall and by 53% in patients with nonsquamous histology (P <.001), and deaths were reduced by 21% (P = .012) and 30% (P = .002), respectively. Pemetrexed was reasonably well-tolerated and devoid of cumulative toxicity. Benefits were particularly pronounced in patients with nonsquamous histology (they had a more than 5-month survival advantage); there was no PFS or OS advantage in those with squamous histology.8

Although this was the first randomized, doubleblind, placebo-controlled trial to show a significant survival benefit for maintenance treatment, one still needs to exercise caution in basing clinical decisions on this study.

Maintenance therapy is unrealistic for many patients due to early disease progression, comorbidities, and patient desire to stop treatment. Pemetrexed is of no value to patients with squamous histology and is unproven in patients who have received first-line pemetrexed or bevacizumab. Furthermore, the survival improvement in the Ciuleanu study would be more impressive had there been mandatory crossover to pemetrexed at the time of disease progression in the control arm; unlike the Fidias trial, mandatory crossover was not instituted in this trial. It is noteworthy that <20% of enrollees in the control arm received pemetrexed at the time of disease progression, although a majority received a standard secondline treatment.

Many patients look forward to the prospect of a therapeutic holiday. If patients are closely monitored once they have completed first-line therapy, there is often enough time to implement secondline treatment when disease progresses before symptoms have taken over. Finally, cost is the 800- lb gorilla in the room. Recent analyses of pemetrexed maintenance suggest a minimum incremental cost of >$120,000 per life-year saved.9

A recent phase 2 study evaluated pemetrexed plus bevacizumab for maintenance after 6 initial cycles of carboplatin, pemetrexed, and bevacizu - mab.9 Median PFS was 9.3 months and median OS was 14 months.10 Many practitioners are using this regimen increasingly in bevacizumabeligible patients. These encouraging findings have led to a large, planned randomized phase 3 trial in the Eastern Cooperative Oncology Group (ECOG) 5508, which just opened and will randomize 1282 patients to bevacizumab, pemetrexed, or to a combination of bevacizumab and pemetrexed after 4 cycles of initial therapy with paclitaxel/carboplatin/bevacizumab. In addition, a separate phase 3 trial, POINT-BREAK, will compare this regimen to the “winning” arm of ECOG 4599 (a combination of paclitaxel, carboplatin, and bevacizumab), which yielded a significant and clinically meaningful survival advantage in this setting compared with chemotherapy alone. Finally, in Europe, pemetrexed maintenance is being compared with “observation” in patients who have stabilized or responded to a “standard” pemetrexed/cisplatin regimen.

Erlotinib Maintenance

Erlotinib has shown value as a maintenance agent in 2 key studies. The Sequential Tarceva® in Unresectable NSCLC (SATURN) trial found that erlotinib reduced the risk of progression by 29% (P <.001) and offered a 1-month OS benefit (P = .0088).11 In the Assessment of Treatment with Lisinopril And Survival (ATLAS) trial, maintenance therapy with erlotinib plus bevacizumab improved PFS by 39%, or by approximately 1 month (P = .0012), but no OS difference was shown.12 Moreover, toxicity associated with this approach is not trivial.

Conclusions

Docetaxel, pemetrexed, and erlotinib are each approved in the second-line setting, and all have shown a PFS benefit as maintenance therapy and at least a trend toward improved survival, if not a statistically significant increase in survival. To date, both pemetrexed and erlotinib are US Food and Drug Administration–approved for maintenance therapy. At the end of the day, treatment should be individualized for all patients, taking into account not only clinical outcomes but patients’ personal preferences, disease burden, and comorbidities.

References

  1. Socinski MA, Schell MJ, Peterman A, et al. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol. 2002; 20:1335-1343.

  2. von Plessen C, Bergman B, Andresen O, et al. Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer. Br J Cancer. 2006;95:966-973.

  3. Smith IE, O’Brien ME, Talbot DC, et al. Duration of chemotherapy in advanced non-small-cell lung cancer: a randomized trial of three versus six courses of mitomycin, vinblastine, and cisplatin. J Clin Oncol. 2001;19:1336-1343.

  4. Belani CP, Barstis J, Perry MC, et al. Multicenter, randomized trial for stage IIIB or IV non-small-cell lung cancer using weekly paclitaxel and carboplatin followed by maintenance weekly paclitaxel or observation. J Clin Oncol. 2003;21:2933-2939.

  5. Brodowicz T, Krzakowski M, Zwitter M, et al. Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial. Lung Cancer. 2006;52:155-163.

  6. Fidias P, Dakhil S, Lyss A, et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small cell lung cancer. J Clin Oncol. 2009;27:591-598.

  7. Soon YY, Stockler MR, Askie LM, Boyer MJ. Duration of chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis of randomized trials. J Clin Oncol. 2009;27:3277-3283.

  8. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non–small-cell lung cancer: a randomized, double-blind, phase 3 study. Lancet. 2009;374:1432-1440.

  9. Klein R, Wielage R, Muehlenbein C, et al. Cost-effectiveness of pemetrexed as first-line maintenance therapy for advanced nonsquamous non-small cell lung cancer. J Thorac Oncol. 2010;5:1263-1272.

  10. Patel JD, Hensing TA, Rademaker F, et al. Phase II study of pemetrexed and carboplatin plus bevacizu mab with maintenance pemetrexed and bevacizumab as first-line therapy for nonsquamous non–small-cell lung cancer. J Clin Oncol. 2009;27:3284-3289.

  11. Capuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non–small-cell lung cancer: a multicentre, randomized, placebo-controlled phase III study. Lancet Oncol. 2010;11:521-529.

  12. Miller VA, O’Connor P, Soh C, et al. A randomized, doubleblind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). Presented at 2009 ASCO Annual Meeting. J Clin Oncol. 2009;27(18 suppl):LBA8002.

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