In the past decade, several drugs have been identified with single-agent activity against NSCLC, showing partial response (PR) rates consistently in the range of 20 30%. These include docetaxel (Taxotere, Sanofi-Aventis), paclitaxel, gemcitabine (Gemzar, Eli Lilly), vinorelbine (Navelbine, GlaxoSmithKline), and irinotecan (Camptosar, Pfizer). As they have been identified, followup studies have been conducted with these newer drugs in combination with platinum compounds (cisplatin and/or carboplatin) demonstrating increased efficacy when these drugs are administered concurrently with another chemotherapeutic agent (doublet therapy).
Frontline Therapy
In most cases, phase III trials comparing numerous platinum-based doublets have failed to demonstrate superiority of one single combination regimen. Paclitaxel/cisplatin (PC) was compared to gemcitabine/ cisplatin (GC), docetaxel/cisplatin (DC), paclitaxel/ carboplatin (PCb) in the Eastern Cooperative Oncology Group (ECOG) E1594. This trial reported objective response rate (ORR) of 19%, median survival of 7.9 months, and one- and two-year survival rates of 33% and 11%, respectively, with no significant differences in the ORR and survival between PC and the other three regimens. In contrast, Rosell et al. published the results of a 618-patient trial of the combination of PC versus PCb; the combination of PC was associated with a significantly superior median survival (9.8 vs 8.2 months).Toxicities were low and comparable in the two arms. Moreover, the combination of vinorelbine/cisplatin (VC) was compared to PCb in the SWOG 9509 trial, and demonstrated similar response rates and median survival; less toxicity was noted in the PCb group, although there was no significant difference in quality of life (QOL).
The largest front-line trial reported to date in advanced lung cancer is the TAX 326 trial, which enrolled 1,218 patients with a good performance status; DC or docetaxel plus carboplatin (DCb) was compared with a control regimen of VC every four weeks. The mean age of the patients was 60 years, 75% were men, and approximately two-thirds had stage IV disease. Unlike the previous trials, TAX 326 demonstrated a survival benefit in one of the treatment arms. For DC versus VC, median survival was 11.3 months versus 10.1 months which reached significance (P<0.05); one-year survival was 46% versus 41%; and two-year survival was 21% versus 14%; all favoring DC. Global QOL, measured by the EuroQOL5D Scale, was better for the DC regimen (p=0.016). For DCb versus VC, median survival was 9.4 months versus 9.9 months; one-year survival was 38% versus 40%; and two-year survival was 18% versus 14%. The DCb arm showed global QOL benefits, measured by both the EuroQOL5D (p=0.001) and the Lung Cancer Symptom Scale (p=0.016). Performance status was better maintained in both docetaxel-containing arms, and weight loss of 10% or more was less frequent in these arms (7% vs 15%; p<0.001).
ECOG 4599 (phase II/III trial) recently reported on the addition of bevacizumab to PCb therapy in patients with advanced, metastatic, or recurrent non-squamous cell NSCLC. In this trial, 878 patients were randomized to receive either PC, or the same chemotherapy plus bevacizumab on day one every three weeks. After six cycles, chemotherapy was discontinued and patients in the experimental arm received single-agent bevacizumab. Patients excluded from E4599 were those at an increased risk of bleeding with bevacizumab as demonstrated by the phase II trial: patients with squamous histology, brain metastasis, or gross hemoptysis. Significant improvement in median survival (12.5 months vs 10.2 months),ORR (27% vs 10%), and time-to-tumor progression (TTP) (6.4 months vs 4.5 months) were observed, all favoring the bevacizumab arm. As expected, a higher incidence of bleeding was associated with bevacizumab administration (4.5% vs 0.7%). Salvage Therapy
Treatment of NSCLC has changed dramatically over the past several years as more drugs have been introduced for treating patients who have failed priory chemotherapy. In a phase III study comparing docetaxel to best supportive care, TTP was significantly longer for the patients who received docetaxel (10.6 vs 6.7 weeks, respectively; p<.001), as was median (7.0 vs 4.6 months) and one-year survival (37% vs 11%). In the TAX 320 trial, two different doses of docetaxel (100mg/m2 and 75mg/m2) were compared against vinorelbine or ifosfamide. Although response rates to docetaxel were low (11% for the high dose and 7% for the low dose), they were significantly higher than the vinorelbine or ifosfamide arms (1%). Patients receiving either docetaxel regimen demonstrated a QOL benefit. Furthermore, the one-year survival was significantly greater with docetaxel 75mg/m2 compared with the ifosfamide or vinorelbine treatment (32% vs 19%; p=.025).
The antifolate agent, pemetrexed, has also been approved for salvage therapy in NSCLC, after previously being approved for mesothelioma with cisplatin. In a 571- patient phase III study comparing pemetrexed to docetaxel, outcomes did not reach significance between the two groups, with ORR approximately 9%, median progression-free survival (PFS) of 2.9 months for each arm, median survival time of 8.3 versus 7.9 months for pemetrexed and docetaxel, respectively, and one-year survival rate of 29.7% for each arm.However, pemetrexed was associated with significantly fewer side effects.
In view of poor outcomes with cytotoxic chemotherapy in salvage treatment, EGFR tyrosine-kinase inhibitors (TKIs) were investigated in second-line therapy for NSCLC. Initial phase II studies with gefitinib appeared promising; however, further studies failed to show a significant survival difference compared with placebo and best supportive care. In contrast, erlotinib has shown efficacy in second-line NSCLC therapy similar to that noted with cytotoxic agents. Shepherd et al. conducted a 731-patient randomized placebo controlled trial of erlotinib versus placebo in second or third line therapy. Significant differences in outcomes, including response rate (8.9% vs <1%), PFS (2.2 months vs 1.8 months), overall survival (6.7 months vs 4.7 months) and QOL, were noted, all favoring the erlotinib arm; only 5% of patients discontinued erlotinib because of toxic effects.
Docetaxel, pemetrexed, and erlotinib are the three currently approved single-agents in the salvage therapy of NSCLC.
Molecular Targeted Therapies
Because of the discouraging survival statistics associated with NSCLC, additional approaches to treatment have been pursued diligently, including the use of targeted agents alone or in combination with chemotherapy. Epidermal Growth Factor Receptor
EGFR is a tansmembrane glycoprotein receptor composed of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain with a TK region.Altered or increased expression of EGFR has been observed in 60 80% of patients with lung cancer and has been linked to disease progression, poor survival, poor response to therapy, development of resistance to cytotoxic agents, advanced tumor stage, and increased risk for metastasis. Overexpression of EGFR is most commonly found in squamous cell (84%), followed by large cell (68%) and adenocarcinoma (65%). The inhibition of EGFR can therefore be accomplished upstream by blocking the ligand-binding domain with monoclonal antibodies (i.e. cetuximab) or downstream by interfering with signal transduction via TK by using small molecule TKIs (i.e. erlotinib and gefitinib).
Erlotinib
Erlotinib, an orally active quinazoline, is a potent selective inhibitor of EGFR TK.The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) conducted the BR.21 trial which evaluated erlotinib in the setting of second- or third-line therapy for advanced NSCLC. This study was the first to demonstrate a statistically significant survival benefit associated with the use of a biologic agent. In BR.21, Shepherd et al. randomized 731 patients with previously treated advanced NSCLC to receive erlotinib 150mg per day or placebo.The ORR and overall survival with erlotinib were 8.9% and 6.7 months, respectively, compared with <1% and 4.7 months for the patients receiving placebo (p=0.001).PFS was 2.2 months in the erlotinib group, compared with 1.8 months in the placebo group (p<0.001), and QOL measurements also significantly favored the erlotinib group. In addition, all subgroups benefited from therapy with erlotinib, including men, women, and those with squamous as well as adenocarcinoma. On the basis of this study, erlotinib was approved by the US Food and Drug Administration (FDA) in November 2004 for the treatment of locally advanced or metastatic NSCLC that has failed to respond to at least one prior chemotherapy regimen. In view of its activity in the salvage setting, a large adjuvant study with erlotinib based on tumor profile is planned to further evaluate its role in the treatment of NSCLC. Gefitinib
Gefitinib (Iressa, AstraZeneca), which gained accelerated approval in May 2003 for the treatment of advanced NSCLC, is also a selective EGFR TKI.Initial studies using this agent were very promising. Recently, ISEL (Iressa Survival Evaluation in Lung Cancer), a placebocontrolled, randomized phase III trial of more than 1,600 patients, reported no statistically significant difference in survival between patients treated with gefitinib and those given placebo. Gefitinib is therefore no longer recommended in the treatment of NSCLC.
Cetuximab
Cetuximab (Erbitux, ImClone Systems/Bristol-Myers Squibb), a promising monoclonal antibody targeting the EGFR, has been approved for use in colorectal cancer and recently in head/neck squamous cell cancer.
Studies examining cetuximab as a treatment for patients with NSCLC are on-going. In first-line treatment of patients with metastatic disease, the addition of cetuximab to PC, gemcitabine/carboplatin (GCb),VC are currently under way. In the setting of second-line treatment of NSCLC, a recent study reported on the use of docetaxel plus cetuximab in patients with EGFR-positive tumors. The results were encouraging, with a response rate of 25 30% in this chemotherapyrefractory patient population. A phase III trial is ongoing in this patient population with docetaxel or pemetrexed +/- cetuximab. VEGF Signaling Pathway
Angiogenesis plays an important role in the growth and metastasis of solid tumors. vascular endothelial growth factor (VEGF), its isoforms, and its receptor (VEGFR) are important in regulating angiogenesis. Multiple strategies have been developed to target this pathway.
One approach to the modulation of VEGF-mediated angiogenesis is to use antibodies targeted against the VEGF protein itself,or to its receptor.Encouraging results have been reported with the addition of bevacizumab to PCb (ECOG 4599) in patients with advanced, metastatic, or recurrent non-squamous cell NSCLC. A phase II randomized second-line trial of chemotherapy + placebo, chemotherapy with bevacizumab, and erlotinib with bevacizumab was reported at American Society of Clinical Oncology (ASCO) this year. The results demonstrated improved PFS (primary endpoint) in favor of both bevacizumab arms and a better response rate with the bevacizumab and erlotinib combination. This combination of erlotinib and bevacizumab is being studied in a large phase III randomized study in the second-line setting.
ZD6474 (AstraZeneca) is an oral agent with dual kinase inhibitor activity which targets both VEGFR-2 and EGFR TKs. ZD6474 has shown activity in NSCLC and other solid tumor types. This small molecule inhibitor therefore affects two distinct processes involved in tumor growth and survival: cell proliferation and angiogenesis. Phase I studies with ZD6474 have been completed and demonstrated good tolerability at an oral dose =300mg, and manageable side effects. Although phase II studies with ZD 6474 are currently on-going, preliminary data from two studies appear promising.
Other compounds are actively being studied in NSCLC. These include BAY 43-9006 (Sorafenib, Bayer), a potent inhibitor of both Raf kinase signaling pathway (involved in cell proliferation), as well as VEGFR2 and platelet derived growth factor receptor (PDGFR)-ß (involved in angiogenesis). BAY 43-9006 has demonstrated promising anti-tumor activity in a number of tumor types including renal cell carcinoma (RCC), sarcoma, melanoma, and pancreatic, thyroid, and colorectal cancers. Sunitinib (Sutent) is an oral multi-kinase inhibitor (VEGFR, PDGFR-a, PDGFR- ß,RET,KIT, FLT-3) and is approved for use in renal cell cancer and imatinib-refractory GIST. Sunitinib has been studied in NSCLC with response rates of about 10%. Further studies are planned in combination.
Conclusion
The treatment of advanced lung cancer remains an exciting area that reflects a sobering challenge. Cytotoxic chemotherapy doublets have modestly improved survival, and research is now emphasizing QOL issues. Agents targeting VEGF and EGFR have become critical weapons in the treatment of NSCLC. Bevacizumab and erlotinib are the first biologic agents to demonstrate a survival advantage when added to standard chemotherapy. Other strategies are being evaluated including earlier detection, predictive markers, and chemoprevention.As research on genomic and proteomic techniques continues, therapy tailored to specific tumors may offer an opportunity for improved efficacy and disease control with the use of both cytotoxic and biologic compounds.
