Abstract: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. About 50% of the patients present locally advanced or metastatic disease at the time of diagnosis. First line therapy usually consists of a combination of cisplatin or carboplatin with a third-generation agent (paclitaxel, docetaxel, gemcitabine, or vinorelbine) that results in less than 5% 5-year survival (Goldstraw et al., 2007). Recently a different approach based on histological subtype has been introduced in the first line treatment of NSCLC: in the non-squamous histotypes, cisplatin plus pemetrexed, compared to the cisplatin plus gemcitabine combination, showed a better outcome, leading to its introduction in the first line treatment setting. In recent years advances in the second and third line treatments have led to a prognostic improvement. Two cytotoxic agents, docetaxel and pemetrexed, are approved as NSCLC second line treatment, and a new class of drugs against specific molecular targets -- tyrosine Kinase inhibitors (TKI) -- has emerged as an alternative to conventional treatment. Many trials are ongoing to assess the activity of new drugs, alone or in combination with other agents, or new combinations of third-generation chemotherapeutic agents.

Introduction

Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancer cases. About 50% of the patients present advanced disease at the time of diagnosis and their 5-year survival is less than 5% (Goldstraw et al., 2007).

First line chemotherapy in advanced NSCLC usually consists of platinum-based doublet with a third-generation agent (paclitaxel, docetaxel, gemcitabine, or vinorelbine) or with pemetrexed in the non-squamous histotypes. About 30% of patients treated in first line with one of these combinations achieve a response lasting 4-5 months. A small minority of patients, who have mutations at exons 19-21 of the epidermal growth factor receptor (EGFR), can benefit from the use of the TKIs, in particular gefitinib, as the first line treatment.

For a long period of time, the results of second line treatment of advanced NSCLC have been disappointing both in terms of response rate and survival, so no further treatment was indicated after failure of first line chemotherapy.

Single Agent Chemotherapy

Docetaxel (Taxotere, Sanofi-Aventis) was the first drug investigated in the second line setting to show better survival and quality of life (QoL) when compared to best supportive care (BSC) (TAX 317 trial) (Shepherd et al., 2000) or to single agent ifosfamide (Ifex, Bristol-Myers Squibb Co.) or vinorelbine (Navelbine, Pierre Fabre Pharmaceuticals) (TAX 320 trial) (Fossella et al., 2000). A better toxicity profile of the weekly compared to three-weekly schedule has been shown in TAX 320 trial and confirmed in several randomized clinical trials and two meta-analyses (Di Maio et al., 2007; Bria et al., 2006), without significant differences in survival.

Later, the multitarget antifolate agent pemetrexed (Alimta, Eli Lilly and Co.) showed similar clinical response compared to docetaxel in second line treatment of NSCLC patients. Both agents provided a median survival of about 8 months, one-year survival of 30%, and a response rate of 10%, with less hematological toxicity in the pemetrexed arm (Hanna et al., 2004). Because of its good toxicity profile, elderly and performance status 3 patients, for which the ASCO guidelines contraindicate any chemotherapy, could benefit from pemetrexed (Weiss et al., 2006; Zinner et al., 2007).

Histology is an important issue in the treatment selection both in the first and in the second line treatment with pemetrexed, due to the higher expression of thymidylate synthase (TS) in adenocarcinoma compared to squamous cell carcinoma. A retrospective analysis of the data of the pemetrexed versus docetaxel phase III study indicated that the squamous cell subgroup patients treated with docetaxel had statistically better survival than patients treated with pemetrexed. Conversely in the non-squamous subgroup pemetrexed was statistically superior to docetaxel (Peterson et al., 2007).

Gemcitabine (Gemzar, Eli Lilly and Co.) and paclitaxel are two third-generation drugs that in phase II studies showed some therapeutic activity and an acceptable toxicity profile as single agents in the second line treatment of advanced NSCLC (Crinò et al., 1999; Berghmans et al., 2007). Patients with stable disease after a first line platinum-based therapy, or a longer time-to-relapse, seem to benefit more than others from a second line treatment with paclitaxel. Table 1 shows some meaningful phase III trials performed in most recent years.

Combination Chemotherapy

Although second line doublet chemotherapy seems more toxic without an improvement in overall survival compared to single agent chemotherapy (Di Maio et al., 2009), some combinations achieved encouraging results.

Among phase II trials, irinotecan in association to several agents was administered in 373 patients, achieving a mean response rate of 14% (9-26%) and a median survival of 8 months (7-11 months).

Gemcitabine combined with taxanes in 92 patients showed a response rate of about 30% and overall survival of about 9 months.

The results of a phase II randomized trial, comparing pemetrexed plus carboplatin to pemetrexed alone in pretreated NSCLC patients, has been recently published. This trial showed a significant improvement of progression-free survival PFS in the group of patients treated with the combination regimen (4.2 vs. 2.8 months) (Smit et al., 2009).

Targeted Therapies

The development of biologic agents active against specific molecular targets represents an innovation of the antitumoral research.

EGFR is expressed in most of the NSCLC and its tyrosine kinase subunit is the molecular target of a new class of agents, the tyrosine kinase inhibitors, recently introduced in NSCLC treatment. Most randomized trials are focused on gefitinib (Iressa) and erlotinib (Tarceva). Gefitinib, approved in 2003 by FDA for the third line treatment of NSCLC, was then retired because a phase III randomized trial (ISEL) in pretreated patients demonstrated no survival advantage compared to placebo. Survival time favoring gefitinib was very different in the two treatment groups for non-smoker and Asian patients (Thatcher et al., 2005).

The BR.21 trial (Shepherd et al., 2005), comparing erlotinib vs. placebo after failure of first or second line chemotherapy in advanced NSCLC patients, showed a better overall survival and 9% of responses in the erlotinib group. On these data, FDA in 2004 and EMEA in 2005 approved erlotinib for the treatment of patients in second or third line setting. Although response to erlotinib was more frequent in women with adenocarcinoma, never-smokers, or East-Asians, an exploratory analysis of BR.21 study showed smoking status as the most powerful predictor of a survival effect; similar results were seen in the ISEL trial.

Gefitinib and erlotinib are thought to have similar mechanism of action, but they had different outcome in these two large phase III studies, even if without striking differences in response rate and survival benefit. Possible explanations of the different outcomes could be that the ISEL study population had a highly refractory disease, absent in the BR.21 study, or that gefitinib was underdosed, even though higher dose of gefitinib has not shown to be more effective.

Beyond clinical features, two potential biomarkers have been identified as predictive factors, EGFR mutations and EGFR amplifications.

Mutations of exons 19 and 21 are more frequent in never smokers, women, patients of Asian origin, and patients with adenocarcinoma or bronchiolo-alveolar histology, and have been associated with remarkable responses to TKI.

The above mentioned BR.21 trial showed EGFR gene copy number assessed by fluorescence in situ hybridization (FISH) to be the most important predictive factor of response and survival, even if the subsequent INTEREST trial (Kim et al., 2008) raised some doubts about its role as a prognostic instead of a predictive factor.

Some molecular mechanisms involved in primary or acquired TKI resistance has been identified as KRAS and EGFR exon 20 mutations, respectively.

The monoclonal antibody cetuximab (Erbitux, Bristol-Myers Squibb Co.), acting against the extracellular subunit of EGFR, represents an alternative way to target this pathway, but its role in the second line treatment of NSCLC has not been confirmed in any phase III trials. The association of agents targeting different molecular pathways involved in tumor progression seems an innovative therapeutic strategy for patients in this setting.

Bevacizumab (Avastin, Genentech Inc.) is a monoclonal antibody targeting vascular endothelial growth factor (VEGF) involved in angiogenesis. The association of this agent to erlotinib seems to be a promising option in the treatment of relapsed NSCLC after at least one line of chemotherapy (Herbst et al., 2007). Moreover, bevacizumab-based associations recently proved to be a safe option both in the first and in the second line treatment of NSCLC patients with brain metastasis (Socinski et al., 2009).

A new class of multitargeted tyrosine-kinase inhibitors emerged in most recent years and has been studied in NSCLC second line treatment setting.

Sunitinib (Sutent, Pfizer Inc.) is an oral tyrosine kinase inhibitor acting against VEGFR, PDGFR, KIT, RET, and FLT3, approved for the treatment of renal cancer and imatinib-resistant gastrointestinal stromal tumor (GIST). Recent phase II trial showed that Sunitinib has promising single-agent activity in patients with recurrent NSCLC, with an ORR similar to that of currently approved agents and an acceptable safety profile. Further evaluation in combination with other targeted agents and chemotherapy in patients with NSCLC is warranted (Socinski et al., 2008). Sorafenib (Nexavar, Bayer Healthcare Pharmaceuticals) is an oral multi-kinase inhibitor, which targets the Raf/MEK/ERK pathway at the level of Raf kinase and receptor tyrosine kinases. It has been studied in phase II trials, showing promising efficacy in patients with advanced, progressive NSCLC (Adjei et al., 2007; Gatzemeier et al., 2006).

Vandetanib (Zactima, Astra Zeneca Pharmaceuticals) is an antitumoral agent targeting the VEGFR-dependent angiogenesis, and the cell growth and survival mediated by EGFR and RET. The promising results obtained in the phase II led to phase III trials evaluating this agent versus placebo in patients pretreated with EGFR inhibitors, versus erlotinib, and in association with docetaxel or pemetrexed (Groen et al., 2007).

On the basis of promising results by a phase II study, a phase III trial is currently ongoing to assess the efficacy of docetaxel in combination with vandetanib compared to docetaxel as a single agent in NSCLC pretreated patients.

Bortezomib (Velcade, Millennium Pharmaceutical Inc.) is a selective inhibitor of the proteasome recently evaluated in a phase II trial as a single agent or in combination with pemetrexed in pretreated NSCLC patients. The doublet-based therapy showed a good toxicity profile without a significant advantage in terms of response rate and survival compared to pemetrexed monochemotherapy, while bortezomib alone showed no clinically significant activity (Scagliotti et al., 2009).

New Chemotherapeutic Agents

New chemotherapeutic drugs are needed to overcome the intrinsic or acquired drug resistance limiting the efficacy of the most widely used antitumoral agents.

Epothilones A and B (patupilones) and their synthetic analogs (ixabepilone, epothilone B, ZK-EPO, BMS-310705, and KOS-1584) represent a new class of tubulin stabilizing agents, functionally and structurally different from taxanes, that induce the arrest of cell cycle and subsequently cell apoptosis. Although epothilones are active in taxane-resistant preclinical models, it is not clear if their activity is higher than docetaxel or paclitaxel and if they have a different toxicity profile.

Lipoplatin is a new platinum analogue achieving partial responses in 5% and stable diseases in 16% of patients with a median survival of 7 months (Ravaioli et al., 2007). Its toxicity profile leads to a dosage increase in further phase I-II trials.

When compared to docetaxel and vinflunine (a new vinca alkaloid), oral topotecan may be an option for second line treatment of NSCLC patients, as confirmed in phase III trials (Krzakowski et al., 2007; Ramlau et al., 2006).

SNS-595 is a cell cycle inhibitor that damages the DNA, blocks the cell cycle in G2-phase, and induces apoptosis. The dosage of 48 mg/m² is an active dose in the treatment of NSCLC with stable disease in more than 50% of the patients (Burris et al., 2007).

Conclusions

Advanced NSCLC still has a poor prognosis, with a median survival of about 12 months, which is nonetheless an improvement when compared to the 6-month survival reported about 20 years ago. The prognostic improvement in recent years is clearly associated not only with the optimization of the first line treatment but also with the development of second and third line therapies. Docetaxel and pemetrexed are the two agents now commonly used as second line treatment of NSCLC. To date, combination chemotherapy has shown no advantage as compared to single agents. Several trials are ongoing to assess the efficacy of combinations among chemotherapy and targeted therapy drugs. Erlotinib 150 mg/day is now used as third line treatment of NSCLC, and in the second line mainly when chemotherapy is contraindicated or in patients selected by clinical or biomolecular findings.

The choice of a treatment in NSCLC patients who relapsed after a first line chemotherapy has to be carefully evaluated, and while the outcome of second line treatment may be affected by clinical factors as performance status, disease stage, and gender, the response to the second line could be a trustworthy predictor of third line treatment efficacy (Scartozzi et al., 2009).

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