Lung Cancer (2007) 57 (Supplement 2), S12---S17 available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/lungcan

Improving patient management in metastatic non-small cell lung cancer Johan Vansteenkiste * Respiratory Oncology Unit (Pulmonology) and Leuven Lung Cancer Group, University Hospital Leuven, Herestraat 49, 3000 Leuven, Belgium

KEYWORDS Advanced non-small cell lung cancer; First-line therapy; Second-line therapy; Targeted therapy; Pemetrexed; Gemcitabine

Summary The management of advanced non-small cell lung cancer (NSCLC) has progressed over the last 3 decades. Advances in chemotherapeutic drugs and the use of multi-drug combinations, targeted agents and new management strategies have provided modest survival benefits. However, improving quality of life is equally important, and involves a therapeutic strategy that considers the optimal balance between treatment activity (survival; symptom control) and treatment burden (side effects; duration of hospital stay). There remains room for improvement of therapies today, given that 1-year survival is approximately 35%. The option of adding another cytotoxic agent to a platinum-based doublet does not appear to improve survival but increases toxicity. With the advent of targeted drugs, there is much interest in adding a biological agent such as bevacizumab to the current standard. Another strategy of interest is the use of maintenance treatment with a well-tolerated cytotoxic agent such as gemcitabine after first-line therapy. This has been shown to improve progression-free survival compared with best supportive care alone. Ten years ago, few patients with advanced NSCLC were candidates for second-line treatment for progressive or relapsed disease. However, as response rates and toxicity profiles with firstline therapies improved, relapse therapy has become more important. Several single agent chemotherapies have been evaluated in the second-line setting, including the anti-metabolite pemetrexed, which demonstrates comparable survival outcomes to that of the historical standard docetaxel, but a much better toxicity profile. The targeted therapy erlotinib is also being investigated in this setting. Further studies are required to establish the role of newer agents in the management of advanced NSCLC. © 2007 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Improving first-line therapy for advanced NSCLC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Improving relapse therapy for advanced NSCLC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

* Corresponding author. Tel.: +32 16 346 802; fax: +32 16 346 803. E-mail address: [email protected] (J. Vansteenkiste). Web: www.LLCG.be 0169-5002/$ --- see front matter © 2007 Elsevier Ireland Ltd. All rights reserved.

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Improving patient management in metastatic non-small cell lung cancer Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of the funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The management of patients with advanced non-small cell lung cancer (NSCLC) is a matter of achieving the optimal balance between clinical benefit and burden of treatment. In this patient population for whom treatment is mainly palliative, achieving symptom control and good quality of life (QoL) can be at least as important as prolonging survival. Time spent in hospital, as well as the adverse effects associated with therapy can be considered to contribute to the burden of treatment. Thus, in patients with advanced NSCLC, the aim of treatment should be to achieve prolonged survival with a good QoL, rather than just focusing on prolonged survival alone. Having established the aim of therapy in advanced NSCLC, the achievements over the past 3 decades can be viewed against this goal. Although the objective response rate (ORR) and overall survival (OS) achieved today in patients with advanced NSCLC are relatively poor compared with some other solid tumours, the past 3 decades have seen slow but significant improvements in outcome. In the 1980s, first-line chemotherapy for advanced NSCLC was not established and second- or third-line therapy was not even considered. By the 1990s, first-line therapy was well accepted, and options for second-line therapy were being investigated. The ORR for active regimens was approximately 25%, as was 1-year OS. Now in the 2000s, firstand second-line therapies have become established for this patient population, and third-line therapy is considered for selected patients. The ORR for first-line active regimens is approximately 35%, as is 1-year OS. In addition to prolonging OS, current chemotherapies can achieve substantial improvements in symptoms. For example, Cullen et al. demonstrated substantial improvements in cough (70%), hemoptysis (92%), pain (77%), dyspnoea (46%) and anorexia (56%) and an increase in performance status (50% of evaluable responders) in a study in which 74 patients with untreated NSCLC received mitomycin, ifosfamide and cisplatin [1]. In a prospective, randomised phase III comparator study of 169 patients with advanced NSCLC, single agent gemcitabine produced a superior clinical benefit (a composite of symptom score, Karnofsky performance status and weight) compared with cisplatin-based chemotherapy (48% vs 29% of patients, p = 0.03), with a significantly longer median duration of benefit (16 vs 10 weeks, p = 0.01) [2]. These findings compare favourably with earlier phase II studies in which single-agent gemcitabine produced a durable clinical benefit [3]. The development of newer agents has also reduced the burden of treatment compared with agents used decades ago. This partly reflects the fact that newer agents are better tolerated. In addition, better supportive care is now available to manage toxicities. For example, neurokinin 1 antagonists are better anti-emetics than the agents that

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were available in the 1990s; darbepoetin alpha can be given once every 3 weeks to manage fatigue; and the risk of infections can now be reduced with the use of granulocyte colony-stimulating factor (G-CSF) rather than with antibiotics. A further factor is the move to less frequent administration of cytotoxic drugs that have to be administered in hospital. For example, vinorelbine is administered weekly, whereas gemcitabine is administered weekly for 2 out of 3 weeks, and pemetrexed is administered once every 3 weeks. The past 3 decades have therefore seen significant improvements in many aspects of the management of advanced NSCLC. However, with this increase in the available treatments, and the introduction of second- and third-line treatments, the question becomes how to use the available agents to optimise the therapeutic strategy and sequence. It becomes a challenge for physicians to develop a treatment plan for their patients that includes first-, secondand third-line treatment. In this paper we review the data supporting the current recommendations for first-line and relapse therapies and suggest how management is likely to be further improved in the future.

2. Improving first-line therapy for advanced NSCLC The current standard treatment for patients with advanced NSCLC, who have a good performance status (0---1) and acceptable comorbidity, is a platinum-based doublet [4---7]. Both cisplatin and carboplatin are routinely used, with cisplatin being slightly more active and carboplatin being more convenient to administer. Recent US guidelines also suggest that a non-platinum-based doublet can be used [4,5]. Third-generation drugs such as gemcitabine are generally preferable to older drugs, and there are mainly some toxicity differences between the newer drugs [4,6,7]. It is worth noting that such regimens are also appropriate for older patients; comorbidity rather than age determines whether patients can tolerate doublet therapy [4,5,7]. Evidence for the benefit of using two cytotoxic agents rather than one has been confirmed by a meta-analysis that included data from 65 randomised studies published between 1980 and 2003, which involved over 13,000 patients [8]. This meta-analysis found significantly better tumour response and 1-year survival rates for doubletversus single-agent regimens (analysis of data from 31 studies); the odds ratio (OR) for tumour response was 0.42 (95% confidence interval [CI] 0.37---0.47, p < 0.001) and the OR for 1-year OS was 0.80 (95% CI 0.70---0.91, p < 0.001). This meta-analysis also compared tumour response and 1-year OS for treatment with 2 versus 3 cytotoxic agents (data from 35 studies). In contrast to the findings for the addition of a second cytotoxic agent, the addition of a third

S14 agent was found to produce a significantly better tumour response (OR 0.66, 95% CI 0.58---0.75, p < 0.001) but no statistically significant influence on 1-year OS (OR 1.01, 95% CI 0.85---1.21, p = 0.88). Since the addition of a third cytotoxic agent increased toxicity but did not improve OS, the use of 3 cytotoxic agents is not recommended. Although the addition of a third cytotoxic agent does not improve clinical outcome, there is evidence to suggest that addition of a biological agent may be of benefit. Results from a large randomised, phase III study (E4599), conducted by the Eastern Cooperative Oncology Group (ECOG), showed that addition of the anti-angiogenic agent bevacizumab to carboplatin/paclitaxel resulted in a significantly higher ORR (35% vs 15%, p < 0.001) and OS (12.3 vs 10.3 months, p = 0.003) compared with chemotherapy alone [9]. However, the addition of bevacizumab also increased toxicity. Despite the fact that patients with squamous cell disease, brain metastases and clinically significant hemoptysis were excluded from the study, there still was a problem of major lung bleeding in 19 patients, seven of which were fatal. Thus, the addition of bevacizumab to chemotherapy is an option for selected patients only (nowadays often referred to as `bevacizumab-eligible' patients), and even then, careful toxicity monitoring is needed. An ongoing study is investigating the efficacy and safety of bevacizumab in combination with cisplatin/ gemcitabine, the most common regimen in Europe (AVAiL study). The results are expected to be reported at the 2007 American Society of Clinical Oncology Annual Meeting. The addition of agents that block the activity of the epidermal growth factor receptor (EGFR) has also been investigated in patients with advanced NSCLC, e.g. in a phase III study (n = 1,093) of gefitinib, an oral inhibitor of the tyrosine kinase associated with the EGFR. The addition of gefitinib to cisplatin/gemcitabine did not result in a significant improvement in median survival, median time to progression or ORR [10]. However, the monoclonal antibody cetuximab, which blocks the activity of the EGFR by binding to the ligand-binding domain, has shown promising activity in metastatic colorectal cancer [11,12] and squamous cell carcinoma of the head and neck [13,14], and is currently being investigated in NSCLC in a large ongoing phase III study (FLEX) [15]. Another strategy being investigated to improve the outcome with first-line treatment is the use of maintenance therapy. This approach has recently been examined in a phase III study, which found significantly longer progression-free survival with the administration of gemcitabine as maintenance therapy (plus best supportive care [BSC]) in patients who achieved objective responses or stable disease after cisplatin/gemcitabine therapy compared with BSC alone [16]. Median time to progression was 6.6 months with gemcitabine maintenance compared with 5.0 months with BSC alone (whole study period), and 3.6 months versus 2.0 months (maintenance phase only, p < 0.001, Fig. 1). Maintenance therapy with gemcitabine was feasible and well tolerated. These data suggest that maintenance therapy with well tolerated agents --- such as modern single agent chemotherapy or biological agents --in responding patients may be a further option to improve the clinical outcome of first-line therapy.

J. Vansteenkiste

Figure 1 Median time to progression with gemcitabine maintenance therapy plus BSC compared with BSC alone in patients with advanced non-small cell lung cancer who responded to cisplatin/ gemcitabine first-line therapy. A: Overall and B: Maintenance phase. BSC, best supportive care; GEM, gemcitabine; PD, progressive disease. Reproduced with permission from Elsevier [16].

3. Improving relapse therapy for advanced NSCLC As with first-line therapy, the aim of relapse treatment is to give patients prolonged survival with a good quality of life. Likewise, this includes minimising the adverse effects of treatment, which prevent patients from being able to function normally, and minimising the time spent in hospital for the administration of therapy and treatment of adverse events. The historical second-line treatment for advanced NSCLC was docetaxel. As demonstrated by Shepherd et al. in a randomised study comparing docetaxel and BSC, some patients achieve objective responses to docetaxel (partial response 7.1%) and many achieve disease stabilisation (43%) [17]. Patients receiving docetaxel also had better OS (median 7.0 vs 4.6 months, p = 0.047) and durable symptom control. However, the toxicity of this regimen was of concern; 12% of patients experienced febrile neutropenia, 76% had severe neutropenia (grade 3/4), and 41% had severe asthenia (vs 28% for BSC). Thus, it is important to develop less toxic regimens for treating patients in this setting.

Improving patient management in metastatic non-small cell lung cancer

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Table 1 Incidence of severe toxicities (grade 3/4) during second-line therapy with pemetrexed compared with docetaxel in patients with advanced NSCLC. Adapted from [18]. Toxicity

Pemetrexed (%)

Docetaxel (%)

p

Neutropenia Febrile neutropenia Neutropenia with infection Febrile neutropenia hospitalization Growth factors Alopecia (all grade)

5.3 1.9 0.0 1.5, 29 days 2.6 6.4

40.2 12.7 3.3 13.4, 195 days 19.2 37.7