US Pharm. 2007;32(10)(Oncology suppl):5-13.

ABSTRACT: Non–small cell lung cancer (NSCLC) continues to be the leading cause of cancer death in the United States, and treatment for patients with advanced NSCLC remains an important, clinically complex challenge. Although chemotherapy alone or in combination with radiotherapy is considered the standard of care, overall prognosis for these patients is poor, with a five-year survival rate of 15%. The advent of new molecular targeted agents in the last decade has introduced a new and interesting setting, but thus far, the results of clinical trials have not provided the panacea scientists are seeking. This article aims to educate and update pharmacists about the three FDA-approved agents for use in NSCLC--gefitinib, erlotinib, and bevacizumab--as well as recent advances in targeted pharmacology for NSCLC, including recent clinical trial data.

Lung cancer is the leading cause of cancer death in the United States for both men and women. In 2003, lung cancer accounted for more deaths than breast cancer, prostate cancer, and colon cancer combined.1 Lung cancer is divided into two major types: small cell and non–small cell lung cancer (NSCLC). NSCLC comprises approximately 80% of diagnosed cases and is made up of four histological types--epidermoid, squamous carcinoma, adenocarcinoma, and large cell carcinoma.2 Table 1 represents the American Joint Committee on Cancer staging system for lung cancer.3,4


Despite advances in the molecular understanding and management of lung cancer, the overall five-year survival rate for all types of lung cancer remains about 15%. If left untreated, most patients with NSCLC will die within one year of diagnosis. 2 Only a small number of NSCLC patients are suitable candidates for radical curative treatment. The majority present with locally advanced or metastatic disease at diagnosis and can obtain only a modest survival benefit from palliative platinum-based chemotherapy with or without radiotherapy.5 Conventional treatment in NSCLC--combination chemotherapy with cisplatin or carboplatin and third-generation agents (e.g., docetaxel, gemcitabine, irinotecan, paclitaxel, vinorelbine)--has apparently reached a plateau of effectiveness in improving survival.6-11

In the last decade, increased understanding of cancer biology has revealed numerous cellular targets for therapeutic intervention, including epidermal growth factor receptors (EGFRs), angiogenesis inhibitors, proteasome inhibitors, and various signal transduction inhibitors.5,12,13 This article aims to educate and update pharmacists about the three agents approved by the FDA for use in NSCLC (gefitinib, erlotinib, and bevacizumab), as well as the recent advances in targeted pharmacology for NSCLC, including recent clinical trial data.

FDA- Approved Medications for NSCLC
EGFR Inhibitors
The ErbB (human epidermal receptor [HER]) family of transmembrane tyrosine kinase type I receptors, also known as EGFRs, have an important role in processes such as cell growth, proliferation, survival, and differentiation. The receptors contain an extracellular domain and an intracellular protein tyrosine kinase core and must form dimers to initiate signaling.14,15 The EGFR-dependent autocrine pathway is known to have a significant impact in the development and progression of human epithelial cancers, including NSCLC. 16

There are two classes of anti-EGFR agents that have demonstrated clinical activity in NSCLC. They are the low-molecular-weight tyrosine kinase inhibitors that inhibit the tyrosine kinase activity of EGFR by competing with adenosine triphosphate (ATP) for the ATP-binding site and the monoclonal antibodies directed at the extracellular domain of the EGFR.16 The antitumor effects of EGFR inhibitors in human cancer models include inhibition of cancer cell proliferation with cell cycle arrest, induction of apoptosis, antiangiogenesis, inhibition of invasion and metastasis, and potentiation of antitumor activity of cytotoxic drugs and radiotherapy.16,17

Low-Molecular-Weight Tyrosine Kinase Inhibitors: Erlotinib (Tarceva) is a HER1/EGFR tyrosine kinase inhibitor. Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated with the EGFR. Erlotinib is an oral tablet approved by the FDA as monotherapy for the treatment of patients with locally advanced or metastatic NSCLC after disease progression with at least one prior chemotherapy regimen.18

There are three significant clinical trials that led to the FDA approval of erlotinib. The BR.21 trial, carried out by the National Cancer Institute of Canada, consisted of 731 patients with NSCLC whose disease had progressed after chemotherapy. There was a statistically significant increase in the overall survival among patients who took erlotinib, compared to the placebo group (6.7 vs. 4.7 months).19

Both the Tarceva Lung Cancer Investigation (TALENT) trial and the Tarceva Response in Conjugation with Paclitaxel and Carboplatin (TRIBUTE) trials were conducted in patients who were chemotherapy-naïve. The patients first received their respective chemotherapy regimens followed by maintenance monotherapy with erlotinib. In both trials, erlotinib failed to show an increase in survival.20-22 Subset analysis in several clinical trials has suggested that nonsmokers, women, and patients with adenocarcinoma have a higher response rate to erlotinib.16

The most common adverse events associated with erlotinib include acneiform rash and diarrhea, occurring in 9% and 6% of patients, respectively. Other common adverse effects include fatigue, dyspnea, cough, nausea and vomiting, stomatitis, and infection. Liver function test abnormalities have also been reported but were usually transient in nature. Interstitial lung disease (ILD)–like events have occurred in approximately 0.7% of erlotinib-treated patients, including some fatalities. Erlotinib is listed as a category D agent in pregnancy.18

Gefitinib (Iressa) was the first EGFR tyrosine kinase inhibitor approved by the FDA. Gefitinib inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the EGFR. Gefitinib is as an oral tablet and is FDA approved as monotherapy for the continued treatment of patients with locally advanced or metastatic NSCLC who are benefiting or have benefited from gefitinib after failure with both platinum-based and docetaxel chemotherapies.23

In phase II trials, the Iressa Dose Evaluation in Advanced Lung Cancer trials (IDEAL 1, IDEAL 2) included 210 and 221 stage III and IV NSCLC patients, respectively, comparing gefitinib 250 or 500 mg/day versus placebo. The patients had previously failed one or two platinum-based chemotherapy regimens. The objective tumor response rate for both the 250- and 500-mg doses were 8% to 19%, respectively, and a median survival benefit of six to seven months was seen. In addition, 35% to 43% of patients showed symptom improvement.22,24

Phase III trials included the Iressa NSCLC Trial Assessing Combination Treatment (INTACT 1, INTACT 2) and the Iressa Survival Evaluation in Lung Cancer study (ISEL). The INTACT 1 and INTACT 2 trials included 2,130 stage III and IV chemotherapy-naïve NSCLC patients. Patients were randomized to receive 250 mg/day, 500 mg/day, or placebo in combination with platinum-based chemotherapy regimens (gemcitabine plus cisplatin in INTACT 1 and carboplatin plus paclitaxel in INTACT 2). Gefitinib failed to show any increase in tumor response rates, time to progression, or overall survival in comparison to placebo. In the ISEL trial, 1,692 advanced-stage NSCLC patients received either gefitinib 250 mg/day plus best supportive care or placebo plus best supportive care. The patients previously had one or two unsuccessful chemotherapy regimens. Gefitinib failed to demonstrate any significant increase in survival compared to placebo. 25,26

Common adverse events associated with gefitinib include diarrhea, nausea and vomiting, rash, acne, and dry skin. In approximately 1% of patients, ILD has been reported; one third of these cases have been fatal. ILD was seen in patients who received prior radiotherapy and chemotherapy and in patients who had no previous therapy.23

Due to the lack of overall survival benefit in the  aforementioned clinical trials, the FDA issued a public health advisory for gefitinib on June 17, 2005.27 In the advisory, the FDA stated that they have partnered with AstraZeneca to create the Iressa Access Program, which allows the limited distribution of gefitinib to the following patient populations:
• Patients currently receiving and benefiting from gefitinib;
• Patients who have previously received and benefited from gefitinib; and
• Previously enrolled or new patients in non-Investigational New Drug (IND) clinical trials approved by an investigational review board prior to June 17, 2005.

New patients may also be able to obtain gefitinib if AstraZeneca decides to make it available through an IND trial and the patients meet the criteria for enrollment according to the IND application.

Similar to erlotinib, there were certain subsets of patients who showed an increased response to gefitinib therapy. Among those patients with relapsing NSCLC, Asian patients, women, nonsmokers, patients with adenocarcinoma, and patients who maintained normal activity or were slightly bedridden had the highest response rates from gefitinib treatment.22 Kato and colleagues have created a list of clinical and molecular factors that are predictive of response to the small molecule EGFR tyrosine kinase inhibitors (see Table 2).7


Vascular Endothelial Growth Factor (VEGF) Inhibitors
Angiogenesis is the formation of new blood vessels and is therefore an important mechanism leading to tumor cell proliferation and metastasis in human malignancies. This is a process prompted by various enzymes.28-34 Among these, VEGF is known to be the most important proangiogenic factor, necessary for the development of novel tumor vessels. VEGF mediates its effects by interaction with two high-affinity kinase receptors: VEGFR-1 and VEGFR-2. Clinically active agents against VEGF include the monoclonal antibodies (bevacizumab and VEGF-Trap) and oral small molecule VEGF tyrosine kinase inhibitors (ZD6474, sunitinib, and sorafenib).6,35,36

Monoclonal Antibodies: Bevacizumab (Avastin) is a recombinant, human monoclonal antibody that binds to and inhibits the biologic activity of human VEGF. Once bevacizumab binds to VEGF, it prevents the interaction of VEGF to its receptors. This leads to decreased endothelial cell proliferation, new blood vessel formation, and inhibition of metastatic disease progression. The FDA has approved bevacizumab in combination with carboplatin and paclitaxel as first-line treatment for patients with unresectable, locally advanced, recurrent, or metastatic nonsquamous NSCLC.37

 

In an initial phase II trial, patients with previously untreated stage IIIb/IV NSCLC were randomized to receive 7.5 mg/kg bevacizumab or 15 mg/kg bevacizumab plus carboplatin/paclitaxel or chemotherapy alone. The 15 mg/kg arm demonstrated a better response rate (31.5% vs. 18.8%), longer time to progression (7.4 months vs. 4.2 months), and a slight increase in survival (17.7 vs. 14.9), compared to patients taking chemotherapy alone. Bleeding episodes were the main serious adverse event in this trial; of six patients who developed hemoptysis or hematemesis, four patients died. Squamous cell histology was determined to be an independent risk factor for bleeding.

Subsequent trials evaluated nonsquamous cell NSCLC patients.38-40 In the largest of these trials, 878 chemotherapy-naïve patients with locally advanced, metastatic, or recurrent nonsquamous NSCLC were randomized to receive a combination of carboplatin/paclitaxel plus bevacizumab or carboplatin/paclitaxel alone. Overall survival was significantly higher among patients receiving carboplatin/paclitaxel plus bevacizumab (12.3 months vs. 10.3 months), compared to patients on chemotherapy alone. Although these findings are statistically significant, detailed analysis showed that women, patients ages 65 and older, and patients with 5% or more weight loss at study entry did not have as robust of a response.41


The most serious adverse reactions in patients treated with bevacizumab included gastrointestinal perforations (0.9%), wound-healing complications (0.8%), hemorrhage (fetal hemoptysis in 31% of squamous histology and 2.3% in nonsquamous histology), arterial thromboembolic events (4.4%), hypertensive crisis (8-18%), reversible posterior leukoencephalopathy syndrome (<0.1%), nephrotic syndrome (0.5%), and congestive heart failure (1.7%). Common adverse events included mild to moderate rash, diarrhea, and proteinuria.37

Agents Currently Under Investigation for Use in NSCLC
Medications currently being used or evaluated for NSCLC, along with approved indications, dosages, route of administration, and significant adverse effects, can be found in Table 3.


EGFR Inhibitors
Tyrosine Kinase Inhibitors: Lapatinib (Tykerb) is an orally available dual inhibitor of the intracellular tyrosine kinase domains of both the EGFR and HER2. Lapatinib is presently approved for use in combination with capecitabine for the treatment of advanced or metastatic breast cancer.42 Because of its dual mechanism of action, it has been studied in a variety of cancers, including NSCLC. Data from these trials are not yet published.28

Monoclonal Antibodies: Cetuximab (Erbitux) is a recombinant, human/mouse chimeric monoclonal antibody that binds specifically to the extracellular domain of the human EGFR. Cetuximab is composed of the Fv regions of a murine anti-EGFR antibody with human immunoglobulin G1 (IgG1) heavy and kappa light-chain constant regions. Binding of cetuximab to the EGFR, by competitively inhibiting the binding of epidermal growth factor and other ligands, blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and vascular endothelial factor production.43 Currently, cetuximab is FDA approved for use in colorectal, head, and neck cancers. It is currently being investigated in phase III trials for use in NSCLC, based on encouraging results from phase II studies.

Two phase II trials tested the combination of cetuximab with standard platinum-based doublets in EGFR-positive patients with previously untreated advanced NSCLC. Time to progression of 4.5 and 5.5 months, median survival of 11 and 10.3 months, and a one-year survival rate of 45% were seen in these trials. These results compared favorably to previous trials using chemotherapy alone, and no enhancement in toxicity was noted. A European phase II trial compared cisplatin and vinorelbine with or without cetuximab as first-line therapy in patients with advanced NSCLC. Objective response rates were 35% for cetuximab plus chemotherapy versus 28% in the chemotherapy-only arm. Time to progression was not statistically different between the two groups. Median survival was 8.3 months, with a one-year survival of 32% in the patients treated with cetuximab plus chemotherapy, whereas the chemotherapy-only patients showed a median survival of seven months and a one-year survival of 26%. At two years, 14% of patients in the cetuximab arm were still alive, but there were no survivors in the control arm.44-47

The most frequent side effects with cetuximab include acneiform skin rash (76%), asthenia (45%), fever (29%), anorexia (27%), and diarrhea (19%). ILD is a rarely reported (<0.5%) complication of cetuximab therapy. There are currently two black box warnings for cetuximab--infusion reactions and cardiopulmonary arrest. Approximately 3% of patients develop allergic or anaphylactic reactions, usually during the first infusion. Also, 2% of patients with squamous cell carcinoma of the head and neck developed cardiopulmonary arrest while being treated with cetuximab plus radiation therapy.43

Currently, cetuximab is FDA approved for use only in colorectal, head and neck cancers. Preliminary data from the above phase II trials suggest that cetuximab lends itself to combination chemotherapy and radiation therapy without excessive toxicity and with promising antitumor activity. However, only phase III trial data will determine cetuximab's appropriate place in the treatment of NSCLC.

Trastuzumab (Herceptin) is a recombinant DNA-derived humanized monoclonal antibody that selectively binds to the extracellular domain of the human EGFR-2 protein (HER2). Trastuzumab is FDA approved for use in HER2-overexpressing breast cancer. Utility in NSCLC has been studied in several phase II trials. Overall survival benefit was not seen in the general NSCLC patient population of these studies. Only those patients who were HercepTest 3+ positive showed an increase in progression-free survival time. These data suggest that a very specific small subgroup of NSCLC patients (2-5%) showing HercepTest 3+ positive might indeed benefit by the addition of trastuzumab. In addition, trastuzumab carries black box warnings for cardiomyopathy and infusion reactions.28,48-50

VEGF Inhibitors
Monoclonal Antibodies:VEGF-Trap is a composite, soluble decoy receptor based on VEGFR-1 and VEGFR-2 fused to a Fc segment of IgG1. It has been shown to block outgrowth of new vessels and is capable of disrupting the preexisting vasculature of established metastases. It is currently being tested in phase I and II trials, but no trial data are available at this time.28,51,52

VEGF Tyrosine Kinase Inhibitors
ZD6474 (Zactima): ZD6474 is an oral, small molecule inhibitor of VEGFR and EGFR kinase activity. By targeting both pathways, ZD6474 can inhibit VEGF-dependent tumor angiogenesis and EGFR-dependent cell proliferation and survival.28,53

 

In phase I studies, the drug was generally well tolerated, but dose-dependent diarrhea, rash, and asymptomatic QT prolongation were observed.54

Sorafenib (Nexavar): Sorafenib is an oral, multikinase inhibitor targeting several serine/threonine and receptor tyrosine kinases. It has been shown to interact with multiple intracellular and cell surface kinases, including VEGFR-2 and VEGFR-3. Sorafenib is FDA approved for use in patients with advanced renal cell carcinoma. Due to its effects on the VEGFR, it has been studied as an option in NSCLC. To date, no clinical data have been published for outcomes related to NSCLC patients.55,56

Common adverse events are hand-foot skin reaction and rash. Hypertension, hemorrhage, and wound-healing complications have also been reported as serious adverse events associated with sorafenib use.55

Sunitinib (Sutent): Sunitinib is an orally available, small molecule that inhibits multiple receptor tyrosine kinases, some of which are implicated in tumor growth, angiogenesis, and metastatic progression of cancer. It has shown activity at VEGFR-1, VEGFR-2, and VEGFR-3. In vivo, sunitinib has been shown to cause inhibition of tumor growth or tumor regression and/or inhibited metastases. Sunitinib is indicated for the treatment of gastrointestinal stromal tumor after disease progression or intolerance to imatinib and for the treatment of advanced renal cell carcinoma.57 Due to actions on multiple VEGF receptors, sunitinib is currently being evaluated for use in NSCLC. The trials are still ongoing as of September 1, 2007.

Similar to other drugs in this category, such as sorafenib, sunitinib has caused hypertension, hemorrhagic events, QT interval prolongation, and diarrhea. A larger percentage of patients receiving sunitinib compared to patients who received placebo or interferon-alpha had a decline in left ventricular ejection fraction. Discontinuation of sunitinib is recommended in those patients who develop clinical manifestations of congestive heart failure.57

Proteasome Inhibitors

The proteasome pathway has a central role in the selective degradation of ubiquitinated proteins involved in cell cycle regulation, apoptosis, and angiogenesis. It has been shown that proteasome inhibitors can stabilize numerous cell cycle inhibitory proteins and cause cell cycle arrest and apoptosis through multiple mechanisms. The discovery that tumor cells appear to be more sensitive to the proapoptotic effects of proteasome inhibitors than normal cells has led to the clinical evaluation of proteasome inhibitors in NSCLC.28,58-61

Bortezomib (Velcade): Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. Inhibition of the 26S proteasome prevents targeted proteolysis, which can affect multiple signaling cascades within cells. This disruption of normal homeostatic mechanisms can lead to cell death. Currently, bortezomib is approved for use in patients with multiple myeloma and patients with mantle cell lymphoma.62

Due to its novel mechanism of action, bortezomib has been evaluated for use in NSCLC as monotherapy and in combination therapy. In a phase II study comparing bortezomib versus bortezomib plus docetaxel in 155 previously treated patients with advanced NSCLC, an 8% response rate for bortezomib versus a 9% response rate for bortezomib plus docetaxel was reported. The time to disease progression was 1.5 months in the bortezomib group, compared to four months in the combination group.63,64 A phase II trial of 114 chemotherapy-naïve patients were given bortezomib plus carboplatin and gemcitabine. A response was seen in 20% of patients, with 45% reporting stable disease. Progression-free survival was five months, and overall survival was 11 months.63,65 While these results are promising, phase III trials are currently being conducted and will further determine bortezomib's place in the treatment of NSCLC. 63

Peripheral neuropathy, hypotension, congestive heart failure, acute respiratory distress syndrome, thrombocytopenia, and neutropenia have all been reported during bortezomib use. 62

Conclusion
NSCLC continues to be the leading cause of cancer death in the U.S., and the treatment for patients with advanced NSCLC remains an important, clinically complex challenge. Although chemotherapy alone or in combination with radiotherapy is considered the standard of care, overall prognosis for these patients is poor, with a five-year survival rate of 15%. The advent of new molecular targeted agents in the last decade has led to a new and interesting setting. Yet, so far, the findings of clinical trials have not provided the panacea scientists are seeking. Among the new agents, the EGFR inhibitors, VEGF inhibitors, and proteasome inhibitors have shown promise in certain subsets of NSCLC patients. Currently, erlotinib (Tarceva), gefitinib (Iressa), and bevacizumab (Avastin) are approved by the FDA for use in NSCLC. Recently, the combination of bevacizumab and erlotinib has been evaluated in phase II studies. Authors concluded that this combination is well tolerated and active in NSCLC. Further investigation into the efficacy and tolerability of combined erlotinib and bevacizumab is ongoing in phase III trials.66 These novel agents also have varying toxicities that can mimic common diseases or conditions such as respiratory illness, bleeding, congestive heart failure, and gastrointestinal disturbances.

As pharmacists, it is extremely important to be educated on the latest therapies for NSCLC, which patients may benefit most from them, and their associated toxicities. Of course, the promotion of smoking cessation--the only proven prevention strategy for lung cancer--cannot be overlooked. 

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