Cancer Treatment   /   Targeted Therapies

EGFR: Tyrosine Kinase Inhibitors

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Neha Vapiwala, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: July 22, 2004

In Part Two of our series on biologic therapies, we will now perform a more in-depth review of the clinical data on the major targeted therapies that are currently making headlines around the world.

To begin, we will address the three main anti-EGFR drugs: gefitinib, erlotinib, and cetuximab. Please feel free to refer as needed to Part One, which presented the basic science principles behind targeted therapies and outlined the major classes of molecular inhibitors, including EGFR inhibitors. Remember that the drugs have both generic and trade names, but we will use primarily the generic name in the following discussions.

Background

As mentioned in Part One, gefitinib is an oral medication that acts as a small molecule EGFR inhibitor. It was developed by AstraZeneca Pharmaceuticals under the research name ZD1839, and was initially studied in two large, multicenter clinical trials: IDEAL-1, which took place in Japan, and IDEAL-2, which was a U.S.-based study. Based on the results of this latter study, gefitinib was nominated for accelerated approval by the U.S. Food and Drug Administration (FDA) program. This program is designed to allow faster access to promising new drugs for patients with grave, life-threatening diseases. Otherwise, a typical FDA approval could "tie up" a drug in the bureaucratic process for years, preventing some patients from receiving a potentially beneficial treatment. On May 5, 2003, t he U.S. FDA (Food and Drug Administration) granted accelerated approval for the use of gefitinib as a single agent treatment for patients with advanced non-small cell lung cancer. As with all accelerated approvals, the FDA requires that gefitinib continue to be studied to validate its apparent benefit, and thus multiple clinical cancer trials using gefitinib are underway.

About 170,000 new cases of lung cancer are diagnosed each year i n the U.S., and lung cancer is the leading cause of cancer death worldwide, in both men and women. T here are two main categories of lung cancer: non-small cell lung cancer (NSCLC), which represents about 80% of cases, and small cell lung cancer (SCLC), which is the remaining 20%. This distinction of NSCLC vs. SCLC is made based on the appearance of the lung cancer cells under the microscope, as well as the clinical behavior and treatment recommendations for the two different types. Unfortunately, the 5-year survival rates for NSCLC are relatively dismal, with about 15-20% of patients surviving at 5 years from diagnosis. This poor outcome reflects in large part those patients with advanced stage NSCLC who often fail all the standard cancer treatments and eventually succumb to their disease, the very group of patients for whom gefitinib was approved.

Gefitinib is approved for use in patients with NSCLC whose disease has progressed despite chemotherapy treatment with both a platinum-based regimen and a docetaxel regimen. These two chemotherapy regimens are currently considered the standard of care in advanced NSCLC: cisplatin or carboplatin, in conjunction with another chemotherapy agent, is considered "first-line" therapy, and docetaxel is considered "second-line". Thus, gefitinib is indicated as a "third-line" agent, meaning that it is only allowed for use after the two standard chemotherapy regimens have failed. It is not currently approved as first-line treatment of NSCLC. It is currently being studied in other tumor types, such as breast, colorectal, and head and neck, but it is not currently approved for use in these tumor types.

Details of dose, administration, and duration of gefitinib therapy

The daily recommended dose of gefitinib is one 250-mg tablet taken once each day with or without food. No special dose adjustment is needed based on the patient's age, weight, gender, or ethnic background. Also, no special monitoring of drug levels or blood counts is required. Finally, no special premedication or preventive (prophylactic) treatments are needed before starting gefitinib; in other words, there is no mandatory need for intravenous fluids, steroids, anti-nausea drugs, etc..

Patients are supposed to take gefitinib on a daily, continuous basis, until and unless they develop progression of the tumor or a particularly serious side effect from the gefitinib…

So what are the side effects of gefitinib?

The most common side effects associated with gefitinib (250 mg) and the percent of patients in clinical trial experiencing that side effect are as follows:

• diarrhea (48%)
• rash (43%)
• acne, dry skin (25%, 13%)
• nausea and/or vomiting (25%)
• itching (8%)
• loss of appetite (7%)
• weakness (6%)
• weight loss (3%)

These side effects usually happened during the first month of therapy, and are often effectively managed with appropriate medications.

Perhaps the most serious and dreaded potential side effect with gefitinib is something called interstitial lung disease, which has occurred in about 1% of patients. Although this is a very low rate, about one-third of these cases were rapidly fatal. Interstitial lung disease includes things like interstitial pneumonia (infection of the lung) and pneumonitis (inflammation of the lung). Typical symptoms can include sudden shortness of breath, cough, or low-grade fever.

Miscellaneous side effects include:

• harm to the fetus if given to a pregnant woman
• elevation in liver enzymes, which may or may not be associated with symptoms
• in patients who are on warfarin, gefitinib can cause elevated International Normalized Ratio (INR) and/or bleeding events.

Review of the Major Clinical Trials

1) IDEAL-2: This is the study which led to the FDA's accelerated approval. The full study was published in October, 2003 in the Journal of the American Medical Association. It was a double-blind, randomized, phase 2 study conducted at 30 U.S. medical centers. As with all phase 2 studies, this one was designed to evaluate 1) objective tumor response (based on decreased tumor size on CT scan, for example); 2) disease-related symptom response; and 3) safety of gefitinib monotherapy.

Materials & Methods

• Eligible patients had locally advanced and/or metastatic NSCLC, and all had already failed at least two, and as many as five, prior chemotherapy regimens, (including platinum-based therapy and docetaxel).
• 25% of the enrolled patients had previously been treated with four or more chemotherapy treatments
• 216 patients were randomized to one of two arms:
• gefitinib 250 mg per day, orally
• gefitinib 500 mg per day, orally
• 142 patients were evaluable for efficacy

Results

• Objective tumor response rates (all were partial responses) were 12% for the 250 mg/day group and 9% for the 500 mg/day group. The duration of partial responses ranged from 4.6 to over 18.6 months, with a median duration of 8.9 months.
• Symptom improvement rates (measured using a Lung Cancer Subscale to quantify disease-related symptoms) were 43% and 35%, respectively.
• Both doses of ZD1839 were well tolerated in this trial.
• In a retrospective analysis, responses were more frequent in females and in nonsmokers.

Conclusions

The results indicate that gefitinib monotherapy may be given as a single-agent, third-line therapy to patients with advanced NSCLC who have received and progressed on prior chemotherapy.

2) IDEAL-1 : This multicenter study is analogous to IDEAL-2, but was performed internationally, with the majority of patients from Japan. It has a similar study design with similar outcomes and conclusions. Thus it is basically the international version of the above study, and was published in the Journal of Clinical Oncology in June, 2003.

3) INTACT-1: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial

• Randomized phase III multicenter European trial to determine if adding gefitinib to standard first-line platinum-based chemotherapy provides clinical benefit over platinum-based chemotherapy alone in patients with advanced or metastatic non-small-cell lung cancer (NSCLC)
• Double-blind, placebo-controlled trial
• Eligible patients were chemotherapy-naive with inoperable stage III or IV NSCLC
• All patients received up to six cycles of chemotherapy (cisplatin and gemcitabine).
• They were then randomized to get one of three things: 1) gefitinib 500 mg/d, 2) gefitinib 250 mg/d, or 3) placebo. Daily gefitinib or placebo was continued until disease progression.
• 1,093 patients were enrolled
• NO significant difference in overall survival, time to progression, response rates, and safety between the three treatment groups
• Authors concluded that gefitinib in combination with cisplatin-based chemotherapy in previously untreated (chemotherapy-naive) patients with advanced NSCLC did NOT have improved efficacy over cisplatin-based therapy alone. Further studies are needed to understand why this is the case.

4) INTACT-2: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial

• Similar trial purpose and design as INTACT-1, again studying just over 1,000 chemotherapy-naïve, advanced NSCLC patients. And again, no improvement in tumor response rates, time to progression, or overall survival was found with the addition of gefitinib to chemotherapy.
• Please note the following key differences between INTACT 1 and 2:
• INTACT-2 was conducted in the US, at the MD Anderson Cancer Center.
• The platinum-based chemotherapy doublet used here was carboplatin and paclitaxel, a commonly-used regimen in many major academic centers in the U.S.

Current Areas of Cancer Research with Gefitinib: Open Clinical Trials

Now that its role in lung cancer has been well established, researchers are continuing to examine the potential efficacy of gefitinib in fighting other tumor types. Remember, gefitinib is not currently approved for use in tumor types other than non-small cell lung cancer.

Listed below are some of the latest clinical trials that are currently enrolling patients, along with the study sponsors. Note that while gefitinib is still being investigated as a single agent therapy, it is increasingly being incorporated as an adjunctive agent within a whole treatment regimen. Depending on the tumor type, this regimen may contain varying combinations of chemotherapy, radiation therapy, surgery, hormonal agents, and even other targeted therapies.

• Breast : Gefitinib has very little activity as a single agent in the overall breast cancer population, but preclinical data have suggested synergy with tamoxifen and other hormonal agents, as well as other growth factor inhibitors.
• A Pilot Trial Incorporating ZD1839 (IRESSA) into Adjuvant Therapy for Breast Cancer - BRE02-43. Hoosier Oncology Group
• Anastrozole With or Without Gefitinib in Treating Postmenopausal Women With Metastatic or Locally Recurrent Breast Cancer. EORTC
• Gefitinib With or Without Tamoxifen in Treating Patients With Tamoxifen-Resistant Metastatic Breast Cancer. No rris Cotton Cancer Center
• T rastuzumab and Gefitinib in Treating Patients With Metastatic Breast Cancer. Eastern Cooperative Oncology Group (ECOG)

• Colorectal : Four studies in a total of 39 patients with colorectal cancer have shown modest clinical benefit from 3-9 months of gefitinib therapy (12 of the 39 patients). Following single-agent therapy, pain reduction was reported in phase I studies. Following combination therapy of gefitinib and 5-fluorouracil/ leucovorin chemotherapy, a phase 1 trial including 26 chemotherapy-naive patients with metastatic colorectal cancer reported 1 complete response, 5 partial responses, and 12 patients with stable disease.
• Gefitinib and Combination Chemotherapy in Treating Patients With Advanced Solid Tumors or Colorectal Cancer. Stanford University

• Head and neck : A phase II study studied gefitinib monotherapy in patients with advanced head and neck cancer, finding a response rate of 10.6% and a disease control rate of 53%.
• Study Of Zd1839 (Iressa™) Versus Methotrexate For Previously Treated Patients With Squamous Cell Carcinoma Of The Head And Neck. Astra Zeneca
• Gefitinib and Radiation Therapy With or Without Cisplatin in Treating Patients With Stage III or Stage IV Head and Neck Cancer. University of Colorado Cancer Center
• Gefitinib, Paclitaxel, and Radiation Therapy in Treating Patients With Advanced Squamous Cell Carcinoma of the Head and Neck. NCI
• Phase II Study of Gefitinib in Patients With Recurrent and/or Metastatic Head and Neck Cancer. Huntsman Cancer Institute

Background

Erlotinib is a cousin of gefitinib, as both are small molecule inhibitors of the EGFR tyrosine kinase receptor. It is an oral drug that was developed by OSI Pharmaceuticals, Genentech and Roche under the name OSI-774. Erlotinib was granted Fast Track status from the U.S. FDA (Food and Drug Administration) in May 2002 for the treatment of chemotherapy-naïve, advanced-stage NSCLC patients. In September 2002, the Fast Track status was also applied to the use of erlotinib as a second or third-line single agent therapy in patients with incurable NSCLC who have failed standard chemotherapy.

It is important to note that Fast Track FDA status is not the same as a FDA approval, nor does it necessarily lead to a Priority Review or Accelerated Approval. When a drug is placed on Fast Track, there are scheduled meetings with the FDA regarding development plans. Benefits include the option to submit a New Drug Application in multiple parts rather than all at once. The Fast Track status is meant for a drug product and a claimed benefit that addresses an unmet medical need.

However, recently presented data from a randomized phase III trial of erlotinib in advanced NSCLC patients will likely play a big role in FDA approval of this drug for this setting in the very near future. Meanwhile, numerous early stage studies of erlotinib are underway in other solid tumors, including ovarian, colorectal, head and neck, renal cell carcinoma, glioma and gastrointestinal cancers.

Current FDA-Approved Indications

As stated above, erlotinib has not yet received FDA approval, but is presently in Fast Track status. Very promising new study results in advanced NSCLC will likely lead to approval in the coming months.

Details of dose and administration of erlotinib therapy

Based on phase I tolerability results, the recommended dose of oral erlotinib is 150 mg/day.

What are the side effects of erlotinib?

• acneiform rash, dose-related, mainly above the waist
• diarrhea seen with a 200-mg dose
• headache
• nausea/vomiting

Review of the Major Clinical Trials

1) Erlotinib Phase II Trial in NSCLC

The Fast Track status was granted based on the results of this study, first presented as an abstract at the ASCO 2002 conference.

Materials & Methods

• 57 patients were enrolled
• All patients had recurrent NSCLC; the vast majority had metastatic disease
• Median age was 62 years old
• Majority of patients had good performance status
• All patients had to be EGFR positive (remember, EGFR is the proposed target for erlotinib, and patients can be tested to see if their tumor cells have EGFR on the surface, and if so, to what degree)
• All patients got erlotinib 150 mg/day as the sole therapy

Results

• 2 patients had complete responses (no visible tumor on physical exam or radiographic scans)
• 5 patients with partial responses
• Overall response rate of 12.3%
• Almost 40% of patients had stable disease
• Duration of response ranged from 18 to 80 weeks
• 40% of patients alive at 1 year, compared to typical survival rate with supportive care only (no treatment) of 11% at 1 year
• Treatment was well tolerated, and most of the side events were acneiform rash and diarrhea

Conclusions

There is some anti-tumor activity with erlotinib in advanced NSCLC patients who have progressed on standard chemotherapy. The one-year survival rate compares favorably to supportive care and to other second-line therapies that have previously been tested. More study is warranted.

2) A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1 st line or 2 nd line chemotherapy

This is the breakthrough study that was recently presented in abstract form at the ASCO meeting in June 2004. The results of this study make erlotinib the f irst and only drug in its class (HER1/EGFR-inhibitors) to show a survival benefit in a randomized phase III trial , and it may very well lead to FDA approval for erlotinib as a third-line therapy for advanced NSCLC. The trial was performed by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG).

Materials & Methods

• Eligible patients had advanced NSCLC (stage IIIB or IV) that progressed despite 1-2 chemotherapy regimens
• 731 pts entered the study
• Median age was 61 years old
• Majority had good performance status
• 50% of patients had received 2 prior chemotherapy regimens: 93% had prior platinum and 37% prior taxanes
• Patients were stratified by the center, performance status, response to chemotherapy, number of prior regimens (1 v 2), platinum (yes v no)
• Patients were randomized 2:1 to receive erlotinib 150 mg/day or placebo

Results

• Overall response to erlotinib was 8.9%
• Median duration of response was 34.2 weeks
• Overall survival 6.7 months with erlotinib, compared to 4.7 months with placebo (p=0.001)
• Progression-free survival was also statistically significantly better with erlotinib compared to placebo
• Rash and diarrhea were the most frequent symptoms

Conclusions

This is the first randomized trial to show that an EGFR inhibitor can prolong survival after 1 st or 2 nd line chemotherapy for NSCLC.

3) TRIBUTE - A phase III trial of erlotinib HCl (OSI-774) combined with carboplatin and paclitaxel (CP) chemotherapy in advanced non-small cell lung cancer (NSCLC)

Materials & Methods

• U.S.-based multicenter trial
• Eligible patients had previously untreated, advanced NSCLC (Stage IIIB/IV)
• 1059 pts were randomized (526 erlotinib, 533 placebo)
• Randomized to receive erlotinib at 150 mg/d (526 patients) or placebo (533)
• All patients received concurrent CP chemotherapy x 6 cycles, followed by maintenance erlotinib or placebo
• Patients were required to have good performance status
• Patients were stratified by stage, weight loss, measurable disease, and medical center

Results

• There was no difference in median overall survival for patients treated with erlotinib + CP over CP alone.
• There was no difference in objective response rates or median time to progression.
• Erlotinib and placebo were equal in terms of overall and serious side effects.

Conclusions

Erlotinib combined with carboplatin and paclitaxel chemotherapy did not result in a survival advantage over carboplatin and paclitaxel alone in patients with previously untreated, advanced NSCLC.

4) TALENT - Results of a phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer (NSCLC)

• Similar trial purpose and design as TRIBUTE, again studying just over 1,000 chemotherapy-naïve, advanced NSCLC patients. And again, no improvement in overall survival or time to progression was found with the addition of erlotinib to chemotherapy.
• Please note the following key differences between TRIBUTE and TALENT:
• TALENT was a German multi-center trial
• The platinum-based chemotherapy used in TALENT was cisplatin and gemcitabine, rather than carboplatin and paclitaxel, as in the U.S.-based TRIBUTE trial.

Current Areas of Cancer Research with Erlotinib: Open Clinical Trials

In addition to looking at erlotinib as a single therapy and in combination with chemotherapy, the latest approach to clinical trials emphasizes combinations of the targeted therapies themselves, and many such studies combine erlotinib with drugs that target other components in the cancer growth pathway. Listed below are some of the major trials that are currently recruiting patients.

• Erlotinib and Gemcitabine in Treating Patients With Metastatic Breast Cancer Previously Treated With An Anthracycline and/or a Taxane, North Central Cancer Treatment Group
• Erlotinib and Bevacizumab in Treating Women With Stage IV Breast Cancer. Memorial Sloan-Kettering Cancer Center
• Trastuzumab and Erlotinib as First-Line Therapy in Treating Women With Metastatic Breast Cancer Associated With HER2/neu Overexpression. Jonsson Comprehensive Cancer Center

• Erlotinib and Combination Chemotherapy in Treating Patients With Metastatic or Locally Advanced Colorectal Cancer. Sidney Kimmel Cancer Center

• Erlotinib and Cisplatin in Treating Patients With Recurrent or Metastatic Head and Neck Cancer. Princess Margaret Hospital
• Erlotinib and Radiation Therapy With or Without Cisplatin in Treating Patients With Mouth or Throat Cancer. Sidney Kimmel Cancer Center
• Bevacizumab and Erlotinib in Treating Patients With Recurrent or Metastatic Head and Neck Cancer. University of Chicago Cancer Research Center

• Erlotinib, Gemcitabine, and Radiation Therapy in Treating Patients With Locally Advanced Unresectable Pancreatic Cancer. Memorial Sloan-Kettering Cancer Center

• OSI-774 to Treat Patients with Recurrent Malignant Glioma (Brain Tumor) and Patients with Glioma After Radiation Therapy. NCI

Background

As we learned in Part One, cetuximab is an antibody type of inhibitor, as opposed to small molecule types of inhibitors like gefitinib and erlotinib. Specifically, cetuximab is a mouse-human monoclonal antibody that binds the outside portion of the EGFR (in other words, the extracellular part, as opposed to the intracellular part). By binding EGFR, it blocks EGF-induced events, thereby disturbing cell cycle progression and tumor growth.

The drug was developed by ImClone Systems, and gained early notoriety in the media as the "Martha Stewart drug", back before its clinical efficacy had been clearly demonstrated to the FDA. Since then, the drug has shown promising activity in advanced colorectal cancer. In February, 2004 it was granted accelerated approval from the FDA, making cetuximab the first monoclonal antibody approved to treat metastatic colorectal cancer.

Colorectal cancer, which is cancer of the colon or rectum, is the third most common cancer affecting men and women in the U.S. Approximately 147,500 new cases were diagnosed in 2003. According to the Centers for Disease Control and Prevention (CDC), it is the second leading cause of cancer-related death, behind lung cancer.

In addition to colorectal cancer, cetuximab appears to have activity in animal models, both as a single agent and in combination with chemotherapy and radiotherapy, in pancreatic, prostate, breast, head and neck, glioma, and ovarian cancers, as well.

Current FDA-Approved Indications

Cetuximab is indicated for the treatment of EGFR-expressing, metastatic colorectal carcinoma in patients who are no longer responding to irinotecan-based chemotherapy. ( Irinotecan is a standard chemotherapy drug approved to fight colorectal cancer.) Cetuximab is approved for use as either a combination treatment with irinotecan, or alone, if patients cannot tolerate irinotecan.

Details of dose and administration of cetuximab therapy

The recommended dose of Erbitux, in combination with irinotecan or as a single therapy, is 400 mg/m 2 intravenously (IV) to start (initial loading dose, first time only). This should be delivered over 120 minutes (as a 2-hour infusion).

The recommended weekly maintenance dose is 250 mg/m 2 IV infusion given over 60 minutes (1-hour infusion).

What are the side effects of cetuximab?

• acne-like rash (88%)
• nausea, vomiting (55%, 41%)
• tiredness or weakness (73%)
• diarrhea (72%)
• abdominal pain (55%)
• more serious side-effects are rarer, but include
• infusion reactions (3%)
• interstitial lung disease (0.5%)
• sepsis (3%)
• kidney dysfunction (2%)
• pulmonary embolism (1%)

Review of the Major Clinical Trials

1) Single agent IMC-C225 (Erbitux™) has activity in CPT-11-refractory colorectal cancer (CRC) that expresses the epidermal growth factor receptor (EGFR)

Materials & Methods

• Phase 2 trial of irinotecan (CPT-11) plus cetuximab (IMC-C225)
• 57 patients with documented progression on irinotecan chemotherapy and with tumors that tested positive for EGFR by immunohistochemistry
• Treated w/ standard doses cetuximab (20 mg test dose, then 400 mg/m 2 loading dose over 2 hours, then 250 mg/m 2 over 1 hour weekly)
• Median ECOG performance status 0, median age 56 years
• Median time from CPT-11 failure to initiation of cetuximab was 2 months

Results

• Objective response rate was 17%, and an additional 31% of patients had minor responses or stable disease
• M ost common side effects were an acne-like skin rash, predominantly on the face and upper torso, and weakness
• Of note, the response rate was significantly higher among patients who experienced skin rash (29%) vs those who did not (3%)
• Median not yet reached @ 4-month median follow-up

Conclusions

Single agent cetuximab is well-tolerated in this patient population and produces major objective responses in some patients with EGFR-positive, irinotecan-refractory colorectal cancer

2) Cetuximab (C225) alone or in combination with irinotecan (CPT-11) in patients with epidermal growth factor receptor (EGFR)-positive, irinotecan-refractory metastatic colorectal cancer (MCRC)

Materials & Methods

• Eligible patients had colorectal cancer that was becoming worse despite conventional chemotherapy with irinotecan
• all had cancer cells with epidermal growth factor receptors (EGFR) on their surfaces, making them more likely to divide excessively
• Of initial 576 patients screened, 470 were EGFR-positive (82%), and 329 were enrolled
• Patients were randomized in a 2:1 ratio
• Arm A - Two-thirds of patients received cetuximab (400 mg/m 2 1st infusion, then 250 mg/m 2 weekly) plus irinotecan at the same dose and schedule on which they had been progressing
• Arm B - One-third received cetuximab alone, with the option to switch to the combination of cetuximab with irinotecan after failure of cetuximab as a single agent

Results

• Arm A response rate = 17.9%, median TTP 126 days (4.1 mos)
• Arm B response rate = 9.9%, median TTP 45 days (1.5 mos)
• Arm A two-drug combination shrank tumors in 22.9% of patients, compared to 10.8% of those who received Arm B, cetuximab alone
• Arm A median survival time was 8.6 mos, vs. 6.9 mos for patients who received only cetuximab
• The one-year survival rates were approximately 30% for both treatment arms
• More patients who received both cetuximab and irinotecan had severe side effects, primarily related to irinotecan therapy: about 65% had diarrhea, weakness, low white blood cell count, rash, or vomiting vs. 49.5% in the cetuximab arm

Conclusions

The combination of cetuximab and irinotecan can effectively shrink tumors and delay tumor progression in some patients with metastatic colorectal cancer. The trial showed that the two-drug combination is more effective than cetuximab alone in patients whose tumors have not responded to chemotherapy. These results have led to changes in the standard of care for patients with metastatic colorectal cancer that has progressed after standard chemotherapy.

Current Areas of Cancer Research with Cetuximab: Open Clinical Trials

In addition to looking at cetuximab as a single therapy and in combination with chemotherapy, the latest approach to clinical trials emphasizes combinations of the targeted therapies themselves, and many such studies combine cetuximab with drugs that target other components in the cancer growth pathway. Listed below are some of the major trials that are currently recruiting patients.

• Paclitaxel, Carboplatin, and Cetuximab in Treating Patients With Stage IIIB or Stage IV Non-Small Cell Lung Cancer. Southwestern Oncology Group (SWOG)
• Cetuximab, Paclitaxel, Carboplatin, and Radiation Therapy in Treating Patients With Unresectable Stage IIIA or Stage IIIB Non-Small Cell Lung Cancer. Radiation Therapy Oncology Group (RTOG)

• Irinotecan and Docetaxel With or Without Cetuximab in Treating Patients With Metastatic Pancreatic Cancer. ECOG
• Gemcitabine With or Without Cetuximab as First-Line Therapy in Treating Patients With Locally Advanced Unresectable or Metastatic Adenocarcinoma of the Pancreas. SWOG

• Cetuximab, Paclitaxel, and Carboplatin in Treating Patients With Advanced Ovarian Epithelial, Fallopian Tube, or Primary Peritoneal Cavity Cancer. Memorial Sloan-Kettering Cancer Center

For further information, please see Targeted Therapy Basics.