Targeted Therapy in Non-Small-Cell Lung Cancer

September 2, 2002

Although treatment of advanced non-small-cell lung cancer has been improved with the availability of such new agents as the taxanes, topoisomerase inhibitors, vinorelbine (Navelbine), and gemcitabine (Gemzar), platinum-

ABSTRACT: Although treatment of advanced non-small-cell lung cancer has been improved with the availability of such new agents as the taxanes, topoisomerase inhibitors, vinorelbine (Navelbine), and gemcitabine (Gemzar), platinum-based combination therapy has appeared to reach a threshold of therapeutic effectiveness. A paradigm shift in approach to non-small-cell lung cancer and other tumors may be heralded by the development of agents targeting specific biologic pathways in tumor development. Such new agents include antibody epithelial growth factor receptor (EGFR) inhibitors (eg, the monoclonal antibodies trastuzumab [Herceptin] and cetuximab [IMC-C225, Erbitux]) and EGFR tyrosine kinase inhibitors (eg, ZD1839 [Iressa] and OSI-774), angiogenesis inhibitors (eg, matrix metalloproteinase inhibitors), vascular endothelial growth factor (VEGF) inhibitors (eg, monoclonal antibody to VEGF ligand and small-molecule tyrosine kinase), and signal transduction inhibitors (eg, ISIS-3521, an antisense oligonucleotide to protein kinase C-a). A number of these agents have entered advanced-phase clinical investigation. It is likely that targeted therapy will have applications in combination with cytotoxic chemotherapy or radiation therapy at all stages of treatment, including maintenance therapy. It is even possible that these new biologic therapies will be used together as rational combinations (based on pathologic diagnosis) for advanced non-small-cell lung cancer. [ONCOLOGY 16(Suppl 9):19-24, 2002]

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 [Taxotere]), topoisomerase inhibitors (topotecan [Hycamtin] and irinotecan [CPT-11, Camptosar]), vinorelbine (Navelbine), and 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/gemcitabine, cisplatin/docetaxel, andcarboplatin (Paraplatin)/paclitaxel with the reference regimen of cis-platin/paclitaxelin more than 1,200 previously untreated non-small-cell lung cancer patientswith advanced disease to determine the most effective platinum-based regimen.The cisplatin/gemcitabine regimen was associated with a significant increase inmedian time to disease progression compared with the reference regimen (4.5 vs3.5 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).[2]

In addition, no clear efficacy benefit has been detected for non-platinum-basedcombinations or platinum-based triplets.[8] These findings suggest that athreshold of benefit may have been reached using the currently available agentsand that a paradigm shift in approach to treatment may be needed to achieveadditional improvement in outcomes.

Advances in understanding molecular and biologic aspects ofcarcinogenesis have led to the development of new agents that act on specificbiologic pathways in the disease in an approach that has been termed"targeted therapy." Biologic agents that are being investigated foruse in non-small-cell lung cancer include agents targeting cell growth factorreceptors, angiogenesis inhibitors, and signal transduction inhibitors (Table1). Such biologic agents initially were described as "cytostatic," incontrast to the cytotoxic agents used in conventional chemotherapy, because itwas believed that they would not produce tumor responses when used alone;however, it has been shown that some are capable of producing objective responsein single-agent use (though in general these numbers are between 10% and 20%).

The currently envisioned goal for targeted therapy is thatagents with activity on biologic pathways for specific tumor types can beintegrated with surgery, conventional chemotherapy, or radiation therapy at allstages of disease, including maintenance therapy and chemoprevention (Figure2).The following discussion focuses on select approaches to targeted therapy in non-small-celllung cancer.

Epithelial Growth Factor Receptor Inhibitors

Human tumors express high levels of growth factors and theirreceptors. Epithelial growth factor receptors (EGFRs), also known as ErbBtyrosine kinase receptors, are among the best-studied growth factor receptors incancer. EGFRs, a family consisting of four receptor types, are overexpressed ina wide variety of tumors. Studies in lung cancer have indicated EGFR expressionin 81% to 93% of patients; overexpression (as measured by 20% of cells stainingpositive for the receptor) was found in 45% to 70%, and was more common insquamous cell carcinoma (57% to 92%) than in non-squamous cell tumors (36% to58%).[9-11] Inhibition of EGFR with anti-EGFR monoclonal antibodies or agentsthat inhibit tyrosine kinase, a key component of the EGFR signaling pathway, isbelieved to result in inhibition of cell-cycle progression, angiogenesis, DNArepair after chemotherapy or radiation, and increased apoptosis.

Trastuzumab (Herceptin) is a monoclonal antibody inhibitor ofErbB-2 (also called HER2/neu) that has been approved for treatment of advancedbreast cancer with overexpression of HER2/neu. Trastuzumab has shown somepromise in combination with cytotoxic chemotherapy in small studies in non-small-celllung cancer,[12] and a randomized phase III trial in non-small-cell lungcancer has been proposed by ECOG; ErbB-2 overexpression, however, is not commonin non-small-cell lung cancer (2+/3+ overexpression in around 10% of patientsin our experience), raising doubts about the practicality of use of this agentin this setting.[12]

Cetuximab (IMC-C225) is an ErbB-1 monoclonal antibody that hasshown significant activity in combination with chemotherapy or radiation therapyin 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 combined withcarboplatin/gemcitabine or carboplatin/paclitaxel as front-line treatment orwith docetaxel in second-line treatment are under way.

ZD1839 (Iressa) and OSI-774 (Tarceva) are structurally similarquinazoline inhibitors of EGFR tyrosine kinase. ZD1839 was found to produceresponses in multiple non-small-cell lung cancer patients included in severalphase I studies.[13-15] Approximately one-third of non-small-cell lung cancerpatients receiving ZD1839 had stable disease for at least 3 months; patientswith significant pretreatment have had stable disease for more than 1 year.[14]Currently, this agent is being evaluated in two large-scale phase III trials inwhich more than 1,000 chemotherapy-naive patients with stage III/IV non-small-celllung cancer are to receive one of two doses of ZD1839 or placebo in combinationwith 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-celllung cancer patients with progressive disease following prior chemotherapy; theresults were presented at the 2002 annual meeting of the American Society ofClinical Oncology.[16,17] Kris et al conducted a phase II trial in patients whofailed two or more prior regimens containing platinum and docetaxel, giveneither concurrently or separately.[16] Of these patients, 102 received ZD1839 at250 mg/d, and 114 received 500 mg/d.

Response rates were 11.8% (250-mg/d arm) and 8.8% (500-mg/darm); 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 scaleimproved in about 40% of patients. Median survival was not significantlydifferent between arms (6.1 months for the 250-mg/d arm vs 6.0 for the 500-mg/darm). The majority of drug-related adverse events was mild, with grade 3/4events occurring in only 6.9% (250-mg/d arm) and 17.5% (500-mg/d arm). Bothdoses of ZD1839 demonstrated clinically significant antitumor activity andacceptable tolerability profile with chronic dosing.

In another phase II study (IDEAL 1), Fukuoka and colleaguesassessed the efficacy and safety of ZD1839 in 208 evaluable patients with non-small-celllung cancer who had failed one or two chemotherapy regimens (at least oneplatinum-based therapy).[17] There were no significant differences in responserates 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% ofpatients. Drug-related adverse events were generally mild, with fewer patientson 250 mg/d of ZD1839 experiencing grade 3/4 adverse events. The authorsconcluded that ZD1839 at 250 mg/d was equally efficacious as 500 mg/d, with alower frequency/severity of adverse events.

Perez-Soler et al evaluated OSI-774 in a phase II trial in 57non-small-cell lung cancer patients who had at least one prior chemotherapyregimen and progression/relapse after platinum-based therapy. Eligible patientshad to have non-small-cell lung cancer positive for EGFR at a level of >10% of cells on immunohistochemistry.[18] 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 ratewas 48%. Responders had a median of 2 prior treatments (range: 1 to 4), six hadadenocarcinoma 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 acneiformdermatitis, which occurred in 50% of patients in this study (³ grade 3 in only1 patient); some form of skin reaction occurred in all patients. Diarrhea, whichwas easily treated, was observed in 32% of patients (³ grade 3 in only 1patient).

Currently, OSI-774 is being evaluated in two large randomized,double-blind phase III trials. In the United States, 1,050 chemotherapy-naivepatients with stage III/IV non-small-cell lung cancer receive OSI-774 orplacebo in combination with carboplatin/paclitaxel. An international trial isalso studying 330 patients who failed at least one, but no more than two, priorregimens for advanced or metastatic non-small-cell lung cancer. In this trial,patients receive either OSI-774 or placebo, with two patients randomized toOSI-774 for every patient who receives placebo.

Angiogenesis Inhibitors

Since angiogenesis is crucial to expansion of the majority ofsolid tumors, and specific cellular agents and factors are known to promoteangiogenesis, 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 werethe first antiangiogenesis agents to be investigated, and some have demonstratedsingle-agent activity in animal models and solid tumors. However, a phase IIItrial of the MMP inhibitor prinomastat in chemotherapy-naive patients withadvanced non-small-cell lung cancer showed no additional benefit of theaddition of this agent to carboplatin/paclitaxel.[19]

Vascular endothelial growth factor (VEGF) is an angiogenicfactor commonly expressed in cancer patients, and VEGF inhibitors may constitutethe most promising antiangiogenesis compounds developed thus far. A recombinanthuman monoclonal antibody to the ligand for VEGF (rhuMAb-VEGF) has shownactivity in phase II trials in non-small-cell lung cancer, colon cancer, andbreast cancer. In a phase II trial by DeVore et al,[20] patients with non-small-celllung cancer received carboplatin/paclitaxel with or without lower-dose orhigher-dose rhuMAb-VEGF, with control patients being able to cross over toreceive 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 diseaseprogression were 4.2, 4.3, and 7.4 months, respectively, and median survivaltimes were 14.9, 11.6, and 17.7 months, respectively.

However, pulmonary hemorrhage occurred in six patients receivingrhuMAb-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 theyare centrally located, the squamous cell lesions are more prone to hemorrhage.Analysis of outcomes among the 25 control patients, 22 lower-dose rhuMAb-VEGFpatients, and 31 higher-dose rhuMAb-VEGF patients with non-squamous cellcarcinoma 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-yearsurvival rates were 52%, 50%, and 68%, respectively.[21] ECOG has initiated aphase III trial in which chemotherapy-naive patients with stage IIIb/IV non-squamouscell non-small-cell lung cancer are to receive carboplatin/paclitaxel alone orcombined with the higher-dose rhuMAb-VEGF.

Signal Transduction Inhibitors

Protein kinase C is involved in cell growth, differentiation,secretion, and exocytosis, as well as immune cell function, receptordown-regulation, and apoptosis. Protein kinase C, for which more than 10isoforms have been identified, is overexpressed in a variety of cancers.Nonspecific inhibitors of protein kinase C exhibit antitumor activity, andantisense oligonucleotides directed against protein kinase C have preclinicallybeen 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,[22] a regimen of carboplatin/paclitaxel plus ISIS-3521produced an objective response rate of 46% in previously untreated patients withnon-small-cell lung cancer; time to disease progression was 6.3 months, mediansurvival was 15.9 months, and 1-year survival was 55%. Grade 3 and 4 neutropeniaoccurred in 26% and 43% of patients, and grade 3 and 4 thrombocytopenia occurredin 21% and 11%. In an ongoing phase III trial, a target population of 600 non-small-celllung cancer patients are being randomized to carboplatin/paclitaxel alone orcombined with ISIS-3521.

Conclusions

A large number of randomized trials of targeted therapy in non-small-celllung cancer are ongoing or planned; the information provided will substantiallyimprove our idea about the effects of these biologic agents and how they canbest be used. Although biologic agents are likely to be used in combination withchemotherapy and combined-modality therapy in most situations, it is also likelythat they eventually will be integrated into every stage of treatment and findroles in maintenance therapy and chemoprevention (Figure3). However, it needsto be emphasized that additional exploration of preclinical models and surrogatemarkers of activity for these new targeted therapies should be undertakenwhenever possible to assist in decisions on which of the investigative agents topursue in clinical development. It will also be critical to validate the trueimportance of each target in patient tissue samples.

Given the molecular complexity of tumors, optimal therapy islikely to require an individualized approach to treatment based on each patient’stumor profile. Ultimately, it may be found that maximal therapeutic effect isachieved by use of a combination of biologic agents—eg, molecular targetedtherapy, antiangiogenesis therapy, and monoclonal antibody therapy—along withcytotoxic chemotherapy. The new paradigm is upon us, which now offers new hopefor lung cancer therapy.

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