Platinum-based regimens have been the mainstay of treatment for non-small-cell lung cancer for many years. Over the past several years, the availability of such new agents as the taxanes (paclitaxel and docetaxel(Drug information on docetaxel) [Taxotere]), topoisomerase inhibitors (topotecan [Hycamtin] and irinotecan(Drug information on irinotecan) [CPT-11, Camptosar]), vinorelbine (Navelbine), and gemcitabine(Drug information on gemcitabine) (Gemzar) has improved outcome for patients with advanced non-small-cell lung cancer. However, all recent randomized studies of platinum-based combinations with these newer agents have yielded similar results, with findings indicating median survival of 8 to 9 months and 1-year survival of 33% to 39%.[1-7]
For example, a recent Eastern Cooperative Oncology Group (ECOG) phase III trial compared cisplatin(Drug information on cisplatin)/gemcitabine, cisplatin/docetaxel, and carboplatin(Drug information on carboplatin) (Paraplatin)/paclitaxel with the reference regimen of cis-platin/paclitaxel in more than 1,200 previously untreated non-small-cell lung cancer patients with advanced disease to determine the most effective platinum-based regimen. The cisplatin/gemcitabine regimen was associated with a significant increase in median time to disease progression compared with the reference regimen (4.5 vs 3.5 months), but no differences among regimens in objective response rates (15.3% to 21.3%), median survival (7.4 to 8.2 months), or 1-year survival (31% to 36%) were observed (Figure 1).
In addition, no clear efficacy benefit has been detected for non-platinum-based combinations or platinum-based triplets. These findings suggest that a threshold of benefit may have been reached using the currently available agents and that a paradigm shift in approach to treatment may be needed to achieve additional improvement in outcomes.
Advances in understanding molecular and biologic aspects of carcinogenesis have led to the development of new agents that act on specific biologic pathways in the disease in an approach that has been termed "targeted therapy." Biologic agents that are being investigated for use in non-small-cell lung cancer include agents targeting cell growth factor receptors, angiogenesis inhibitors, and signal transduction inhibitors (Table 1). Such biologic agents initially were described as "cytostatic," in contrast to the cytotoxic agents used in conventional chemotherapy, because it was believed that they would not produce tumor responses when used alone; however, it has been shown that some are capable of producing objective response in single-agent use (though in general these numbers are between 10% and 20%).
The currently envisioned goal for targeted therapy is that agents with activity on biologic pathways for specific tumor types can be integrated with surgery, conventional chemotherapy, or radiation therapy at all stages of disease, including maintenance therapy and chemoprevention (Figure 2). The following discussion focuses on select approaches to targeted therapy in non-small-cell lung cancer.
Human tumors express high levels of growth factors and their receptors. Epithelial growth factor receptors (EGFRs), also known as ErbB tyrosine kinase receptors, are among the best-studied growth factor receptors in cancer. EGFRs, a family consisting of four receptor types, are overexpressed in a wide variety of tumors. Studies in lung cancer have indicated EGFR expression in 81% to 93% of patients; overexpression (as measured by 20% of cells staining positive for the receptor) was found in 45% to 70%, and was more common in squamous cell carcinoma (57% to 92%) than in non-squamous cell tumors (36% to 58%).[9-11] Inhibition of EGFR with anti-EGFR monoclonal antibodies or agents that inhibit tyrosine kinase, a key component of the EGFR signaling pathway, is believed to result in inhibition of cell-cycle progression, angiogenesis, DNA repair after chemotherapy or radiation, and increased apoptosis.
Trastuzumab (Herceptin) is a monoclonal antibody inhibitor of ErbB-2 (also called HER2/neu) that has been approved for treatment of advanced breast cancer with overexpression of HER2/neu. Trastuzumab(Drug information on trastuzumab) has shown some promise in combination with cytotoxic chemotherapy in small studies in non-small-cell lung cancer, and a randomized phase III trial in non-small-cell lung cancer has been proposed by ECOG; ErbB-2 overexpression, however, is not common in non-small-cell lung cancer (2+/3+ overexpression in around 10% of patients in our experience), raising doubts about the practicality of use of this agent in this setting.
Cetuximab (IMC-C225) is an ErbB-1 monoclonal antibody that has shown significant activity in combination with chemotherapy or radiation therapy in non-small-cell lung cancer tumor cell lines overexpressing EGFR (ErbB-1), as well as significant activity in combination treatments in advanced colon, head and neck, and pancreas cancer. Phase II studies of cetuximab(Drug information on cetuximab) combined with carboplatin/gemcitabine or carboplatin/paclitaxel as front-line treatment or with docetaxel in second-line treatment are under way.
ZD1839 (Iressa) and OSI-774 (Tarceva) are structurally similar quinazoline inhibitors of EGFR tyrosine kinase. ZD1839 was found to produce responses in multiple non-small-cell lung cancer patients included in several phase I studies.[13-15] Approximately one-third of non-small-cell lung cancer patients receiving ZD1839 had stable disease for at least 3 months; patients with significant pretreatment have had stable disease for more than 1 year. Currently, this agent is being evaluated in two large-scale phase III trials in which more than 1,000 chemotherapy-naive patients with stage III/IV non-small-cell lung cancer are to receive one of two doses of ZD1839 or placebo in combination with gemcitabine/cisplatin or carboplatin/paclitaxel.
Two randomized, double-blind phase II trials (IDEAL I and II) compared two daily oral doses (250 vs 500 mg/d) of single-agent ZD1839 in non-small-cell lung cancer patients with progressive disease following prior chemotherapy; the results were presented at the 2002 annual meeting of the American Society of Clinical Oncology.[16,17] Kris et al conducted a phase II trial in patients who failed two or more prior regimens containing platinum and docetaxel, given either concurrently or separately. Of these patients, 102 received ZD1839 at 250 mg/d, and 114 received 500 mg/d.
Response rates were 11.8% (250-mg/d arm) and 8.8% (500-mg/d arm); response duration ranged from 3 to 7+ months. Thirty-one percent and 27% of patients had stable disease in the 250- and 500-mg/d arms, respectively. Interestingly, symptom benefit as measured by the lung cancer symptom scale improved in about 40% of patients. Median survival was not significantly different between arms (6.1 months for the 250-mg/d arm vs 6.0 for the 500-mg/d arm). The majority of drug-related adverse events was mild, with grade 3/4 events occurring in only 6.9% (250-mg/d arm) and 17.5% (500-mg/d arm). Both doses of ZD1839 demonstrated clinically significant antitumor activity and acceptable tolerability profile with chronic dosing.
In another phase II study (IDEAL 1), Fukuoka and colleagues assessed the efficacy and safety of ZD1839 in 208 evaluable patients with non-small-cell lung cancer who had failed one or two chemotherapy regimens (at least one platinum-based therapy). There were no significant differences in response rates or overall survival between the 250- and 500-mg/d arms (18.4% vs 19.0%, and 7.6 vs 8.1 months, respectively). Symptom benefit was seen in 40.3% of patients. Drug-related adverse events were generally mild, with fewer patients on 250 mg/d of ZD1839 experiencing grade 3/4 adverse events. The authors concluded that ZD1839 at 250 mg/d was equally efficacious as 500 mg/d, with a lower frequency/severity of adverse events.
Perez-Soler et al evaluated OSI-774 in a phase II trial in 57 non-small-cell lung cancer patients who had at least one prior chemotherapy regimen and progression/relapse after platinum-based therapy. Eligible patients had to have non-small-cell lung cancer positive for EGFR at a level of > 10% of cells on immunohistochemistry. The objective response rate was 12.3% (including 1 complete response and 6 partial responses), and 15 patients (26.3%) had stable disease. Median survival was 37 weeks, and the 1-year survival rate was 48%. Responders had a median of 2 prior treatments (range: 1 to 4), six had adenocarcinoma and two had large-cell carcinoma, and all were 2+/3+ EGFR-positive (mean: 2.7+). As with ZD1839, the most common toxicity was an acneiform dermatitis, which occurred in 50% of patients in this study (³ grade 3 in only 1 patient); some form of skin reaction occurred in all patients. Diarrhea, which was easily treated, was observed in 32% of patients (³ grade 3 in only 1 patient).
Currently, OSI-774 is being evaluated in two large randomized, double-blind phase III trials. In the United States, 1,050 chemotherapy-naive patients with stage III/IV non-small-cell lung cancer receive OSI-774 or placebo in combination with carboplatin/paclitaxel. An international trial is also studying 330 patients who failed at least one, but no more than two, prior regimens for advanced or metastatic non-small-cell lung cancer. In this trial, patients receive either OSI-774 or placebo, with two patients randomized to OSI-774 for every patient who receives placebo.
Since angiogenesis is crucial to expansion of the majority of solid tumors, and specific cellular agents and factors are known to promote angiogenesis, angiogenesis is an attractive target for controlling tumor growth. Matrix metalloproteinases (MMPs) are enzymes that degrade extracellular matrix, promoting tumor progression, angiogenesis, and metastasis. MMP inhibitors were the first antiangiogenesis agents to be investigated, and some have demonstrated single-agent activity in animal models and solid tumors. However, a phase III trial of the MMP inhibitor prinomastat in chemotherapy-naive patients with advanced non-small-cell lung cancer showed no additional benefit of the addition of this agent to carboplatin/paclitaxel.
Vascular endothelial growth factor (VEGF) is an angiogenic factor commonly expressed in cancer patients, and VEGF inhibitors may constitute the most promising antiangiogenesis compounds developed thus far. A recombinant human monoclonal antibody to the ligand for VEGF (rhuMAb-VEGF) has shown activity in phase II trials in non-small-cell lung cancer, colon cancer, and breast cancer. In a phase II trial by DeVore et al, patients with non-small-cell lung cancer received carboplatin/paclitaxel with or without lower-dose or higher-dose rhuMAb-VEGF, with control patients being able to cross over to receive rhuMAb-VEGF if progression occurred. Objective response rates were 19% in the control group (n = 32), 28% in the lower-dose rhuMAb-VEGF group (n = 32), and 31.5% in the higher-dose rhuMAb-VEGF group (n = 35); median times to disease progression were 4.2, 4.3, and 7.4 months, respectively, and median survival times were 14.9, 11.6, and 17.7 months, respectively.
However, pulmonary hemorrhage occurred in six patients receiving rhuMAb-VEGF (five in the lower-dose group) and in none of the control patients. Four of the patients with hemorrhage had squamous cell carcinoma; because they are centrally located, the squamous cell lesions are more prone to hemorrhage. Analysis of outcomes among the 25 control patients, 22 lower-dose rhuMAb-VEGF patients, and 31 higher-dose rhuMAb-VEGF patients with non-squamous cell carcinoma showed objective response rates of 12%, 27%, and 32%, respectively; median times to disease progression were 4.1, 6.3, and 7.2 months, respectively; median survival times were 12.3, 14.2, and 18.0 months, respectively; and 1-year survival rates were 52%, 50%, and 68%, respectively. ECOG has initiated a phase III trial in which chemotherapy-naive patients with stage IIIb/IV non-squamous cell non-small-cell lung cancer are to receive carboplatin/paclitaxel alone or combined with the higher-dose rhuMAb-VEGF.
Protein kinase C is involved in cell growth, differentiation, secretion, and exocytosis, as well as immune cell function, receptor down-regulation, and apoptosis. Protein kinase C, for which more than 10 isoforms have been identified, is overexpressed in a variety of cancers. Nonspecific inhibitors of protein kinase C exhibit antitumor activity, and antisense oligonucleotides directed against protein kinase C have preclinically been found to inhibit mRNA and protein synthesis and to inhibit tumor growth. ISIS-3521 is an antisense oligonucleotide directed against protein kinase C-a. In a phase I/II trial, a regimen of carboplatin/paclitaxel plus ISIS-3521 produced an objective response rate of 46% in previously untreated patients with non-small-cell lung cancer; time to disease progression was 6.3 months, median survival was 15.9 months, and 1-year survival was 55%. Grade 3 and 4 neutropenia occurred in 26% and 43% of patients, and grade 3 and 4 thrombocytopenia occurred in 21% and 11%. In an ongoing phase III trial, a target population of 600 non-small-cell lung cancer patients are being randomized to carboplatin/paclitaxel alone or combined with ISIS-3521.
A large number of randomized trials of targeted therapy in non-small-cell lung cancer are ongoing or planned; the information provided will substantially improve our idea about the effects of these biologic agents and how they can best be used. Although biologic agents are likely to be used in combination with chemotherapy and combined-modality therapy in most situations, it is also likely that they eventually will be integrated into every stage of treatment and find roles in maintenance therapy and chemoprevention (Figure 3). However, it needs to be emphasized that additional exploration of preclinical models and surrogate markers of activity for these new targeted therapies should be undertaken whenever possible to assist in decisions on which of the investigative agents to pursue in clinical development. It will also be critical to validate the true importance of each target in patient tissue samples.
Given the molecular complexity of tumors, optimal therapy is likely to require an individualized approach to treatment based on each patient’s tumor profile. Ultimately, it may be found that maximal therapeutic effect is achieved by use of a combination of biologic agentseg, molecular targeted therapy, antiangiogenesis therapy, and monoclonal antibody therapyalong with cytotoxic chemotherapy. The new paradigm is upon us, which now offers new hope for lung cancer therapy.