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.I) Gefitinib (IressaTM, ZD1839)
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.Current FDA-Approved Indications
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.
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…
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:
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:
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
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
4) INTACT-2: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial
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.
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.
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.
Based on phase I tolerability results, the recommended dose of oral erlotinib is 150 mg/day.
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
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
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
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)
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.Breast:
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.
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.
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).
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
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
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.
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.Non-small cell lung cancer:
For further information, please see Targeted Therapy Basics.