This article will review the evidence for first-, second- and third-line chemotherapy treatment regimes currently in use for the treatment of advanced-stage NSCLC. Evidence for the benefits of novel approaches to current chemotherapy treatment regimens relating to taxanes, new targeted therapies and Asian patient sub-populations will be highlighted.
First-line Chemotherapy for Advanced Non-small-cell Lung Cancer
Commonly used cytotoxic agents in first-line chemotherapy for advanced NSCLC patients include the taxanes (paclitaxel and docetaxel), gemcitabine, vinca-alkaloids (vinorelbine and vindesine) and platinum (cisplatin and carboplatin). A platinum-based combination chemotherapy is considered the standard of care worldwide in patients with advanced NSCLC.3,4,8 Combination chemotherapy produces a one-year survival rate of 30–40% and is superior to single agents or best supportive care. Several comparative studies have evaluated combination regimens, including carboplatin/paclitaxel, cisplatin/paclitaxel, cisplatin/vinorelbine, gemcitabine/cisplatin and docetaxel/cisplatin (see Table 1).5–7 Many of these comparison studies examining the various combinations of platinum-based therapies with cytotoxic agents have confirmed the efficacy of these doublet therapies to be similar; this is also true for the novel modifications such as triplet therapy and non-platinum-based therapies, which are discussed later in this article.7–11 Evidence of a benefit in overall survival (OS) with a docetaxel-based regimen (docetaxel/cisplatin) over a vinca-alkaloid-based regimen (vinorelbine/cisplatin) was demonstrated in phase III by the Taxotere® (TAX) 326 study group.6 A meta-analysis of individual patient data (IPD) including 2,867 patients from seven clinical trials confirmed a significant OS benefit of docetaxel-based regimens over vinca-alkaloid-based regimens in the first-line treatment of advanced NSCLC patients. This confirmed the docetaxel benefit in OS with a 10% reduction of the risk of death. The docetaxel-based regimens also resulted in fewer toxic side effects and an improved quality of life.12
Combination therapy with cisplatin and gemcitabine is also an effective, widely used regimen for the first-line treatment of NSCLC.11 Building on this, Scagliotti et al. recently conducted a phase III study comparing cisplatin/gemcitabine with cisplatin/pemetrexed, a potent inhibitor of thymidylate synthase and other folate-dependent enzymes, as first-line treatments in 1,725 chemotherapy-naïve patients with stage IIIb or IV advanced NSCLC.13 This non-inferiority randomised study demonstrated that cisplatin/pemetrexed provided similar efficacy to cisplatin/ gemcitabine, with better tolerability, a reduced need for supportive therapies and more convenient administration. Patients received either cisplatin 75mg/m2 and pemetrexed 500mg/m2 on day one every three weeks (n=862) or cisplatin 75mg/m2 on day one and gemcitabine 1,250mg/m2 on day eight every three weeks (n=863) for up to six cycles. For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anaemia, thrombocytopenia (p≤0.001), febrile neutropenia (p=0.002) and alopecia (p<0.001) were significantly lower, whereas grade 3 and 4 nausea (p=0.004) were more common than in cisplatin/gemcitabinetreated patients. However, OS rates were similar (median survival 10.3 versus 10.3 months, hazard ratio [HR] 0.94, confidence interval [CI] 0.84–1.05), although statistically significant differences in survival rates were seen based on histological types: in the cisplatin/gemcitabine group, a significant improvement in survival was observed in patients with squamous cell histology, whereas cisplatin/pemetrexed treatment was associated with superior OS in patients with adeonocarcinoma and large-cell histology.13
The use of platinum-based drugs, which have substantial toxic side effects, in combination therapy in a first-line setting is not always appropriate for all advanced NSCLC patients, such as patients with a poor performance status and/or renal dysfunction. However, a suitable alternative is a non-platinum-based doublet such as gemcitabine in combination with taxanes. Kosmidis et al. reported a phase III study comparing the gemcitabine/paclitaxel combination with a platinumbased combination (paclitaxel/carboplatin). Five hundred and nine chemotherapy-naïve patients were enrolled. The two regimens were similar in terms of response rate (35 versus 28%), median time to progression (6.1 versus 6.3 months) and median survival (9.8 versus 10.4 months). The authors concluded that this non-platinum-based combination was equally effective as the platinum-based regimen.9 A study of a similar nature compared docetaxel/cisplatin (n=219) with a docetaxel/gemcitabine combination (n=222). The tumour response rate was 31 and 30.2%, respectively. Again, there was no significant difference between the OS (10 versus 9.5 months, respectively) and time to progression (eight versus nine months, respectively) in the two treatment groups. The non-platinum-based combination was associated with less severe neutropenia, nausea and vomiting.10
First-line Chemotherapy in Combination with a Molecular-targeted Agent
Erlotinib and gefitinib are two new therapies that target the tyrosine kinase (TK) epidermal growth factor receptor (EGFR), which is frequently overexpressed in many cancers.14 Erlotinib is approved for second- and third-line treatment of patients with locally advanced or metastatic NSCLC, and has demonstrated longer survival compared with placebo after first- and second-line chemotherapy.15,16
In a randomised, placebo-controlled phase III trial in advanced NSCLC after failure of previous chemotherapy, erlotinib proved superior compared with placebo in both PFS (2.2 versus 1.8 months) and OS (6.7 versus 4.7 months).16 The combination of erlotinib with a standard carboplatin plus paclitaxel regimen did not confer any survival advantage in patients with previously untreated advanced NSCLC (Tarceva responses in conjunction with paclitaxel and carboplatin [TRIBUTE] trial),17 although a survival benefit was seen in patients who had never smoked.18 Negative survival effects in unselected, untreated patients were confirmed by a large phase III trial (Tarceva Lung Cancer Investigation [TALENT] trial) that added erlotinib to cisplatin plus gemcitabine.19 Similarly, the first EGFR TK inhibitor (TKI), gefitinib, demonstrated no survival benefit when combined with platinum-based chemotherapy in unselected and untreated patients in two phase III trials (INTACT).20,21 Interestingly, preliminary data from the phase III Iressa Pan-Asia Study (IPASS) study, presented in abstract form, suggest that gefitinib may be beneficial as first-line therapy in certain Asian patients with advanced lung adenocarcinoma. IPASS, an open-label, randomised, parallel-group study, assessed the efficacy, safety and tolerability of gefitinib versus carboplatin/paclitaxel as first-line treatment in 1,217 chemo-naïve patients with advanced NSCLC with adenocarcinoma histology. The patients in the study had never smoked or had smoked very little, and the majority (79%) were female. The study exceeded its primary objective and demonstrated superiority of gefitinib relative to carboplatin/paclitaxel in terms of PFS. At 12 months, 25% of patients treated with gefitinib remained progression-free compared with 7% of those on carboplatin/paclitaxel (HR 0.74). Interestingly, PFS at five months favoured chemotherapy for the first five months.22
Pre-clinical data suggest that TKI-induced G1-phase cell-cycle arrest may affect the efficacy of chemotherapy when administered simultaneously, whereas sequential administration of EGFR-TKI following chemotherapy may improve efficacy.23,24 The FAST-ACT study evaluated the efficacy of first-line sequential administration of erlotinib with chemotherapy in Asian chemo-naïve stage IIIb/IV NSCLC patients.25 Patients (n=154) were randomised to receive either erlotinib 150mg/day or placebo orally on days 15–28 of four-weekly chemotherapy cycles. Chemotherapy consisted of gemcitabine 1,250mg/m2 intravenous (IV) plus either cisplatin 75mg/m2 or carboplatin five times area under the curve (AUC) for a maximum of six cycles. The primary end-point was non-progression rate at eight weeks using response evaluation criteria in solid tumours (RECIST). Preliminary results, presented in abstract form, showed that sequential administration of erlotinib with chemotherapy resulted in a statistically significant improvement in PFS (p=0.005) compared with placebo plus sequential chemotherapy, demonstrating that first-line sequential administration of erlotinib with chemotherapy provides promising results and that this treatment strategy warrants further investigation in advanced NSCLC. Recently, the addition of targeted agents to first-line chemotherapy options has been investigated in a number of phase III trials. The addition of cetuximab, an EGFR-targeted monoclonal antibody, to a first-line carboplatin/vinorelbine treatment regimen (n=557) demonstrated superior survival rates over carboplatin/vinorelbine alone (n=568) in patients with advanced EGFR-detectable NSCLC.26
Bevacizumab, a monoclonal vascular endothelial growth factor (VEGF) antibody, has demonstrated the greatest promise to date in phase III clinical trials. Targeting and sequestering soluble VEGF (elevated in cancer) in patients is antiangiogenic in nature and in a phase III trial in colorectal cancer in 2003 demonstrated efficacy in terms of improved survival.27 Two phase III randomised clinical trials, E4599 and the European Avastin in Lung Cancer B017704 (AVAiL), have been reported where bevacizumab has been tested as combined therapy with first-line chemotherapy treatment regimens. The first of these two trials (E4599) was a phase II/III trial, where 878 patients with newly diagnosed, non-squamous NSCLC were randomised to receive either carboplatin/ paclitaxel alone or chemotherapy with bevacizumab (15mg/kg) every three weeks. The study demonstrated significant improvements in response rates, PFS (4.5 versus 6.4 months; p<0.0001) and OS (10.3 versus 12.3 months; p=0.003). However, with the addition of bevacizumab there were 15 treatmentrelated deaths in the bevacizumab arm.28 E4599 was a pivotal trial that demonstrated activity of bevacizumab in advanced NSCLC. The beneficial results of bevacizumab in NSCLC treatment were also demonstrated in the AVAiL trial. One thousand and forty-three patients were randomised into one of three arms: cisplatin/gemcitabine with placebo, cisplatin/ gemcitabine with bevacizumab at 7.5mg/kg or cisplatin/gemcitabine with bevacizumab at 15mg/kg. Patients received up to six cycles of chemotherapy with bevacizumab being added until disease progression. PFS, the primary end-point, was improved in both the bevacizumab arms compared with placebo. Response rates were also significantly improved with bevacizumab; however, there was no improvement in OS.29–31
Second-line Chemotherapy for Advanced Non-small-cell Lung Cancer
Second-line therapy is now the standard treatment for patients who continue to exhibit good performance status. The aims of second-line treatment are to palliate symptoms, improve quality of life and prolong survival. The benefits of treatment should outweigh toxicity and inconvenience to the patient due to the limited life span of the patient after completing first-line therapy.
Based on two randomised phase III trials, docetaxel was the first approved second-line therapy associated with longer survival and better quality of life than best supportive care alone32 and vinorelbine or ifosfamide.33 These trials led to registration and adoption in clinical practice in the US, Europe and Asia of docetaxel (75mg/m2 every three weeks) for the second-line treatment of NSCLC.
Two other agents that have also been approved for the second-line treatment of NSCLC are pemetrexed and erlotinib. Pemetrexed is a multitargeted antifoliate agent that acts by inhibiting the three main enzymes in pyrimidine and purine synthesis. The JMEI trial, a randomised phase III clinical trial, compared 500mg/m2 pemetrexed with docetaxel 75mg/m2 as a monotherapy second-line treatment in advanced NSCLC. Non-inferiority for OS was demonstrated according to primary efficacy analysis, response rates and PFS times. Pemetrexed was associated with fewer neutropenic events.34 Pemetrexed is now a commonly used agent for the second-line therapy of advanced NSCLCdue to its favourable toxicity profile over docetaxel and has been considered for combination with the new targeted therapies in the second-line setting.35 The Iressa NSCLC Trial Evaluating Response and Survival versus Taxotere (INTEREST) study compared the efficacy and tolerability of gefitinib with docetaxel as second-line treatment after pre-treatment with platinum-based chemotherapy. This multicentre, open-label phase III trial randomised 1,466 patients (≥1 platinum-based regimen) to receive either gefitinib 250mg/day orally (n=733) or docetaxel 75mg/m2 intravenously in one-hour infusions every three weeks (n=733). Results from the trial established non-inferiority of gefitinib compared with docetaxel for OS (7.6 versus 8.0 months, HR 1.020, 96% CI 0.905–1.150). Response and PFS rates were comparable between the two treatment arms. As in the JMEI trial with pemetrexed, gefitinib was proved to have more neutropenic events than docetaxel, with the most common side effects of gefitinib being rash or acne (49%) and diarrhoea (35%).36
Second-line Chemotherapy in Combination with Molecular Target Agent
With promising efficacy and tolerability data, molecular-targeted agents are increasingly being considered as second-line therapy options not only in the monotherapy setting (JMEI and INTEREST trials), but also as adjuvants to chemotherapeutic regimens. A phase II multicentre, randomised clinical trial evaluated the efficacy and safety of bevacizumab in combination with either chemotherapy (docetaxel or pemetrexed) or erlotinib compared with chemotherapy alone in previously treated NSCLC patients. Results of PFS and OS from the three-armed trial revealed that the combination of bevacizumab plus erlotinib or bevacizumab plus erlotinib versus chemotherapy alone were in favour of the combination regimens. However, the planned sample size of the trial does not allow the data to provide definitive conclusions or reach statistical significance with respect to differences between the arms. The toxicity profile of the bevacizumab and erlotinib combination was more favourable compared with the chemotherapy groups, with fewer patients (13%) in the bevacizumab/ erlotinib arm discontinuing treatment as a result of adverse events than in the chemotherapy alone (24%) or bevacizumab plus chemotherapy (28%) arms.37,38
The BETA Lung trial is investigating what benefits second-line bevacizumab in combination with erlotinib has in comparison with placebo. Hainsworth et al.39 reported that the addition of bevacizumab to erlotinib in second-line therapy did not improve the OS. However, the tumour response rate was higher with the combination (12.6%) compared with erlotinib only (6.2%; p=0.006). The PFS also favoured the combination (HR 0.62; p<0.0001). The improvement was observed in all subgroups. A large portion of patients received subsequent lines of therapy, which may partially account for the lack of difference in OS. Cetuximab has shown activity both as monotherapy and in combination with chemotherapy in the first-line setting. Thus, it is logical to investigate its activity as second-line therapy. A phase II trial assessed cetuximab plus docetaxel in patients with EGFR-overexpressing NSCLC whose disease had progressed or recurred within three months of firstline chemotherapy. A partial response was seen in 13 of 47 evaluable patients, and eight patients achieved stable disease. Acneform rash and neutropenia were the most common toxicities, although the regimen was well tolerated.40 The role of cetuximab in second-line therapy is being investigated in a phase III trial.
A number of other phase III clinical trials of interest currently under way include the evaluation of docetaxel with or without aflibercept and pemetrexed with or without erlotinib.
Novel Schedules for Taxane-based Regimens
With docetaxel, reducing the toxicity, particularly neutropenia and febrile neutropenia, without compromising activity has been the focus of a number of randomised trials in recent years. Five randomised clinical trials comparing a weekly schedule of docetaxel with the standard three-weekly schedule were analysed in a meta-analysis by Di Maio et al.41 None of the trials included in the meta-analysis, nor the meta-analysis itself, was able to demonstrate a clinically relevant or significant difference in survival between the two schedules; however, a significant reduction of grade 3/4 and febrile neutropenia was observed in the weekly schedule.42 A reduced dose of docetaxel at weekly intervals appears to be a good alternative for chemotherapytreated patients with compromised performance status.
A number of phase II studies have evaluated weekly or bi-weekly schedules of IV docetaxel/platinum doublets, and have reported that this regimen was effective and less toxic than the standard every three-week schedule for advanced NSCLC (see Table 2).
Taxane Regimens in East Asian Populations
A difference in tolerance to taxane treatments between East Asian and white populations has been observed in several trials, indicating that ethnic genetic make-up may also be a predictive factor in terms of response to taxane regimens. Several Chinese and Japanese trials with single agent docetaxel42–48 regimens at reduced dosages of between 35–60mg/m2 for either weekly and three-weekly dosing regimens have consistently reported fewer severe toxicity effects, while not reducing OS (see Table 3).
A phase II study of 68 patients with good performance status with stage IIIb or IV NSCLC at three sites in Australia and Singapore reported a significant difference in response rates between Asian and Caucasian patients following docetaxel 75mg/m2 and carboplatin AUC 6 treatment every three weeks. The overall response rate for the 62 evaluable patients was 42% (95% CI 30–54%). Interestingly, the response rate was significantly related to ethnicity: 65% in Asian patients and 31% in Caucasian patients (p=0.01). Higher rates of toxicity in patients treated in Singapore resulted in reductions of the carboplatin dose to AUC 4.5 in some patients. Although this led to a reduction in cycle 1 neutropenia, there was still a higher rate of febrile neutropenia (six out of 15) in Asian patients compared with Caucasian patients.49
Comparison of the results from this docetaxel and carboplatin combination trial with a similar phase II trial with docetaxel and cisplatin indicate that carboplatin treatment may be better tolerated than cisplatin in Asian patients. The incidence of toxicity-related treatment discontinuations was less than half in patients treated with carboplatin and docetaxel (8%) compared with patients treated with cisplatin and docetaxel (17%).50 A dosage of 60mg/m2 every three weeks was suggested for Japanese patients after a Japanese co-operative study of single-agent docetaxel treatment in chemotherapy-naïve NSCLC patients had been completed.48 The efficacy and reduction in toxicity profile with the titrated dosing schedule of 60mg/m2 every three weeks compared with the standard dosing of 75mg/m2 three-weekly dosing regimen was confirmed by Kunitoh et al., Mukohara et al. and Lai et al.42,44,48
Phase II trials investigating 35mg/m2 as a weekly dosing regimen have shown it to be comparable to other reported three-weekly dosing regimens in terms of activity, but with less toxicity,51–53 although these results have yet to be validated in phase III trials.
These observed differences in the clinical toxicity of docetaxel between Asian and Western patients may be related to pharmacokinetic differences resulting from ethnic diversity of polymorphisms in the CYP3A isoenzyme, which metabolise docetaxel to less active metabolites.54–56
Summary and Conclusion
Cytotoxic chemotherapy remains the cornerstone for first-, second- and third-line therapy for advanced NSCLC. Addition of a moleculartargeted drug such as bevacizumab has improved survival in a select group of patients. However, the concurrent combination of chemotherapy and EGFR TKI failed to demonstrate a benefit. Sequential combination is under investigation. Chemotherapy, particularly docetaxel in second-line treatment of lung cancer, remains the mainstay of lung cancer treatment. The weekly dosing regimen for docetaxel represents a valid alternative to a three-weekly dosing regimen for all patients with NSCLC based on its advantageous toxicity profile and no relevant difference in survival. Pemetrexed or gefitinib was able to attain similar efficacy but with less toxicity than the threeweekly docetaxel regimen. The discovery and validation of predictive markers of the efficacy for both chemotherapy and the newer targeted therapies is of great importance for the future treatment of patients with advanced NSCLC.