Lung Cancer (2006) 54S, S15—S18
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Second-line therapeutic options in non-small-cell lung cancer Johan Vansteenkiste 1 Respiratory Oncology Unit, Department of Pulmonology, University Hospital Leuven, Leuven Lung Cancer Group, Leuven, Belgium
KEYWORDS Docetaxel; Erlotinib; NSCLC; Pemetrexed; Second-line; Sequence
Summary Gradual but positive progress is being made in the field of non-small-cell lung cancer (NSCLC) treatment, including the implementation of more effective strategies for the use of second-line therapy. Clinical consideration of the available options for previously treated patients is a relatively recent concept, the application of which looked doubtful even a decade ago due to the poor prognosis of NSCLC patients receiving first-line chemotherapy. However, the 21st century has witnessed improved rates of response, median survival and 1 year survival following second-line treatment of NCSLC, and the therapeutic armamentarium continues to grow in this setting. Therefore, current challenges include the identification of the most appropriate second-line regimen and determination of the best way to position this within a logical, evidence-based treatment sequence. © 2006 Elsevier Ireland Ltd. All rights reserved.
1. The emergence of second-line therapy for NSCLC The limited survival of untreated patients with advanced NSCLC means that maintenance of quality of life is of paramount importance. This includes maximising valuable moments spent at home, which unfortunately, are often negatively influenced by unwanted adverse events such as chemotherapy-associated infections, asthenia and alopecia. Therefore, active treatment in conjunction with the minimisation of side effects and their related hospital admissions is a key goal of second-line therapy for advanced NSCLC. In the late 1990s, a review of clinical trial results in second-line NSCLC therapy by Fossella et al. [1] revealed the
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[email protected]. Author is the holder of the Eli Lilly L. Hertel Chair in Respiratory Oncology at the Catholic University, Leuven, Belgium. 1
benefits of treatment with a variety of chemotherapeutics to be disappointing. No responses were seen in almost half of the studies, and even when observed, objective response rates were less than 15%, with median and 1 year survival rates only rarely reported. However, a notable exception was the agent docetaxel, which is one of the few agents to have been extensively evaluated in the second-line setting. Seven Phase II trials of this agent have been reported, enrolling a total of 312 patients who were treated with docetaxel 100 mg/m2 every 3 weeks [2—9]. Overall response rates ranged from 14—24%, and the median survival time was between 6 and 11 months. These promising results with single-agent docetaxel led to the initiation of two Phase III randomised trials of this agent for patients previously treated with cisplatin-based combination chemotherapy. In the first of these studies (TAX 317), 204 patients were randomised to either treatment with docetaxel 100 mg/m2 every 3 weeks or best supportive care [10]. However, due to an unexpectedly high toxic death rate the dosage was
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S16 reduced to 75 mg/m2 for the second half of the trial. A response rate of 7% was observed (six partial responses, three at each dose level) and a significant prolongation of survival could be seen in the lower-dose group, although no significant quality of life differences were reported. The second study (TAX 320) had a different design, with a control arm using either vinorelbine or ifosfamide, which were being used as investigational second-line agents at that time [11]. This three-arm trial compared docetaxel 100 mg/m2 (n = 120) or 75 mg/m2 (n = 120) every 3 weeks with a control group (n = 118) of either vinorelbine or ifosfamide. Objective response rates for docetaxel were 10.8% for the 100 mg/m2 group and 6.7% for patients receiving the lower dose, each significantly greater than the 0.8% response rate observed with vinorelbine or ifosfamide. Patients who received docetaxel also had a longer time to disease progression and greater progression-free survival rates at 26 weeks. Although overall survival was not significantly different between the three groups, 1 year survival was significantly greater with docetaxel at 75 mg/m2 than in the control arm. The authors indicated that the publication of results relating to quality of life effects would follow, but thus far these have not been reported in the literature. Docetaxel paved the way for second-line treatment in NSCLC, and the 75 mg/m2 dose was approved by the US Food and Drug Administration and the European Medicines Evaluation Agency for this indication. This registration was based on somewhat limited response data that indicated durable disease stabilisation, leading to improved survival and symptom control. Adverse events such as febrile neutropenia, asthenia and alopecia raised concerns regarding the toxicity profile of docetaxel, and there was clearly a need for additional agents in the second-line setting.
2. Second-line pemetrexed Pemetrexed is a novel, multi-targeted antifolate agent whose activity in multiple tumour types, including NSCLC, is now well established [12]. Observations that pemetrexed had anti-tumour activity of the same order as docetaxel, and that vitamin supplementation with this agent minimised toxicity, led to the initiation of a major Phase III trial to compare pemetrexed with docetaxel in pre-treated NSCLC patients [13]. Response and clinical benefit rates were found to be comparable for both agents, and 1 year survival rates were identical in both study arms. However, the comparable efficacy results were in marked contrast to the significant differences observed in Grade 3 and 4 toxicity. Patients treated with docetaxel experienced significantly higher rates of neutropenia and febrile neutropenia, as well as increased hospitalisation and death rates due to this serious side effect. Growth factors were administered for neutropenia in 19.2% of patients receiving docetaxel compared with just 2.6% of those on pemetrexed, and alopecia was significantly higher in the docetaxel group. Importantly, an analysis of survival time without grade 3/4 toxicity revealed a clear advantage for pemetrexed, indicating that this agent had the potential to offer patients substantial benefit in this regard [14]. Hanna et al. noted that patients who had a clinical benefit with first-line chemotherapy were also more
J. Vansteenkiste likely to experience a benefit from second-line therapy. Another ancillary analysis investigating how the use of first-line chemotherapy may impact on subsequent treatment response compared second-line treatment effects in patients who had previously received a platinum agent plus gemcitabine, a platinum agent plus a taxane, or another (usually platinum-based) regimen as first-line treatment [15]. Interestingly, second-line median survival was found to be better following first-line gemcitabine plus platinum treatment compared with taxane plus platinum or other first-line therapies, while the best response to first-line treatment and length of time since the discontinuation of therapy did not appear to influence the outcome of secondline therapy. The benefits of treatment with pemetrexed in the second-line setting are evident. It has clinically relevant activity with comparable disease control rates and survival outcomes to the established standard of docetaxel, but offers the additional benefit of significantly less toxicity, particularly in relation to neutropenia and its serious consequences. There is significantly less alopecia and a trend towards less diarrhoea with pemetrexed, as well as fewer drug-related hospitalisations and less use of supportive care. In addition, it represents a convenient regimen, administered via a short 10 min IV infusion every 3 weeks, which helps to further minimise patient visits to the hospital. Due to these obvious advantages, pemetrexed is now considered a standard option for second-line treatment of NSCLC by many investigators [13].
3. Biological agents in NSCLC An active area of cancer research is the investigation of novel biological agents that have the ability to target different cell signalling receptors. The epidermal growth factor receptor (EGFR) family is part of a complex signal transduction network that is central to several critical cellular processes [16]. Recognition that overexpression of EGFR occurs in NSCLC, prompted the investigation of agents with inhibitory activity at this receptor [17]. Two such agents that have been extensively studied are the small molecule tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. Following reports of promising response rates from trials investigating the use of these agents in previously treated NSCLC [18—20], the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) conducted a trial (BR.21) to compare erlotinib with placebo following the failure of standard chemotherapy for NSCLC [21]. Patients with stage IIIB or IV NSCLC, with performance status 0—3, were eligible for the trial if they had received one or two prior chemotherapy regimens. Patients were stratified according to centre, performance status, response to prior chemotherapy, number of prior regimens and prior platinum-based therapy, and were randomly assigned in a 2:1 ratio to receive oral erlotinib, at a dose of 150 mg daily, or placebo. EGFR expression was not a criterion for entry into this trial, and the primary endpoint was a 33% improvement in median survival. Patient characteristics are summarised in Table 1. A response rate of 9% was observed in the erlotinib group, with another 35% of patients experiencing disease
Second-line therapeutic options in NSCLC
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stabilisation. Overall survival was improved with erlotinib (6.7 months) versus placebo (4.7 months), and an improvement in 1 year survival was also observed, leading to the conclusion that erlotinib can prolong survival in patients with NSCLC after first-line or second-line chemotherapy. Grade 3 or 4 rash and diarrhoea, which are known to be the main toxic effects of EGFR inhibitors, occurred in 10% and 6% of patients, respectively, in this trial. Fatigue was reported by 28% of patients receiving erlotinib, while anorexia was observed in 9%, highlighting that this agent is not non-toxic as initial predictions may have suggested. Exploratory multivariate analyses showed that Asian origin, adenocarcinoma on histological examination, and a history of non-smoking were significant independent predictors of survival after adjustment for treatment and other potential predictors in the BR.21 trial [22]. Although expression of EGFR protein has not been shown to be a reliable predictor of responsiveness in previous analysis of EGFR inhibitors [20], in this study, response rate was found to be higher among patients with high polysomy or amplification of EGFR than among those without this characteristic. Therefore, it was concluded that expression of EGFR and an increased number of copies of EGFR, but not mutations in EGFR, are associated with responsiveness to erlotinib, but not with increased survival [22]. Subsequent to the publication of the BR.21 trial data, erlotinib was approved for second- and third-line treatment of NSCLC. However, when considering whether the available evidence suggests that erlotinib will become the next standard therapy for second-line patients, it is important to refer back to the inclusion criteria and patient characteristics for the BR.21 trial, as outlined in Table 1. Half of the patients in the trial were included after two previous lines of chemotherapy, while the other half were patients that were designated as being ineligible for further chemotherapy. However, around half of the patients were below 60 years of age, and approximately two thirds had very good performance status, which causes confusion regarding why they were they not eligible for chemotherapy. In addition, the fact that such a large proportion of patients were less than 60 years of age, ∼20% were non-smokers and 35% were female means that the study population is not reflective of the standard NSCLC patient population observed in the daily clinic. It should also be noted that the superiority of erlotinib was proven versus placebo. This
Table 1
Patient characteristics in the Phase III BR.21 trial
Age <60 years Female Never-smoker Asian race PS 0—1 PS 2—3 Adenocarcinoma Squamous cell EGFR +/−/?
Eriotinib (n = 485)
Placebo (n = 242)
43% 35% 21% 13% 65% 26—9% 50% 30% 24/19/57%
51% 34% 17% 12% 68% 23—9% 49% 32% 28/20/52%
EGFR: epidermal growth factor receptor; PS: performance status.
Fig. 1 Proposed therapeutic strategy for treatment of advanced NSCLC. BAC: bronchoalveolar carcinoma; EGFR-TKI: epidermal growth factor receptor-tyrosine kinase inhibitor.
is not the best standard of second-line care for fit patients with relapsing NSCLC. Therefore, erlotinib may represent an appropriate option for third-line treatment of patients with advanced NSCLC, and perhaps for second-line treatment in patients unable to tolerate the standard approaches with docetaxel or pemetrexed.
4. Conclusion In contrast to previous decades, several therapeutic options are now available for the second-line treatment of NSCLC. This necessitates the implementation of a rational treatment plan for first-, second- and third-line therapy. However, where possible, treatment decisions should be guided by evidence from large-scale studies with well-defined, standard patient populations. An appropriate strategy (outlined in Fig. 1) at this time appears to be a platinum doublet for first-line therapy, followed by second-line pemetrexed, and then an EGRF-TKI inhibitor in the third-line setting, since use of another standard chemotherapy regimen is unlikely to be productive following two previous failures. Emerging work on the preferential activity of targeted agents in certain patient subgroups needs to be continued in order to confirm the promising observations seen in these populations.
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