Cancer Medications : Iressa, Kepivance

by National Cancer Institute

(Page 10 of 18)

Iressa®

On June 17, 2005, the FDA approved new labeling for gefitinib (Iressa®, a trademark of AstraZeneca) that limits the indication to cancer patients who, in the opinion of their treating physician, are currently benefiting, or have previously benefited, from gefitinib treatment. The FDA has agreed to AstraZeneca's proposal to limit distribution of this drug under a risk management plan called the Iressa Access Program 24 to the following patient populations:

• patients currently receiving and benefiting from gefitinib
• patients who have previously received and benefited from gefitinib
• previously enrolled patients or new patients in non-Investigational New Drug (IND) clinical trials approved by an IRB prior to June 17, 2005

New patients may also be able to obtain gefitinib if AstraZeneca decides to make it available under the IND and the patients meet the criteria for enrollment under the IND.

Gefitinib, an orally administered epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, was approved for marketing in May 2003 for patients with non-small cell lung cancer (NSCLC) under Subpart H accelerated approval regulations that allow products to be approved on the basis of a surrogate endpoint for clinical efficacy. For gefitinib the surrogate end-point was tumor response rate. The response rate in patients taking the drug was approximately 10 percent.

The approved indication was for the treatment of patients who were refractory to established cancer treatments (both a platinum drug and docetaxel). However, since the initial approval of gefitinib, erlotinib (Tarceva™) has been approved for treatment of this same group. Erlotinib was approved based on improved overall survival.

The FDA has carefully reviewed data from two failed clinical studies of gefitinib, one of which was required by the agency as part of the drug's accelerated approval. This trial enrolled patients with regionally advanced or metastatic NSCLC who had failed one or two prior treatment regimens. In this large study, 1,692 patients were given either gefitinib or placebo. There was no significant survival benefit in the overall study population nor in patients who had high levels of a surface marker called "EGFR". In contrast, the presence of EGFR at high levels appears to predict a good response to erlotinib.

In the second trial in patients with stage III NSCLC, after completion of induction and consolidation chemotherapy and radiation therapy, patients were given either gefitinib or placebo maintenance therapy. No gefitinib survival benefit could be demonstrated.

The FDA is not considering market withdrawal of gefitinib at this time. New clinical trials are being developed, other ongoing trials are being completed, and there will be further analysis of the completed trials described above. These will determine the future role of gefitinib treatment.

Kepivance

On December 15, 2004, the FDA approved a recombinant protein called palifermin (Kepivance™, a trademark of Amgen, Inc.) to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies who receive high doses of chemotherapy and radiation therapy followed by stem cell rescue. Mucositis - sores and ulcers in the lining of the mouth - is a common side effect of certain cancer treatments.

Kepivance is a nonglycosylated, 16.3 kD protein produced by an E. coli strain that has been genetically modified to contain a truncated version of the genetic sequence for human keratinocyte growth factor (KGF). Endogenous KGF is a paracrine growth factor produced by mesenchymal cells and fibroblasts; binding of KGF to the KGF receptor on adjacent epithelial cell tissues results in proliferation and differentiation.

The KGF receptor is present on epithelial cells in many tissues examined including the tongue, buccal mucosa, esophagus, stomach, intestine, salivary gland, lung, liver, pancreas, kidney, bladder, mammary gland, skin (hair follicles and sebaceous gland), and the lens of the eye. The KGF receptor is not present on cells of the hematopoietic lineage.

The following potential mechanisms through which endogenous KGF may protect epithelial cells from injury and/or hasten recovery from injury have been proposed: induction of mitogenesis, tissue thickening and induction of cellular protective mechanisms.

The recommended dose of Kepivance is 60 µg/kg/d by intravenous bolus injection for three consecutive days immediately prior to and for three consecutive days, beginning the day of stem cell re-infusion, following the completion of myeloablative conditioning regimen. Kepivance should not be administered less than 24 hours prior to or less than 24 hours following myelotoxic therapy. Kepivance should not be administered through an IV line containing heparin.

Kepivance is recommended for use in patients with hematologic malignancies undergoing hematopoietic stem cell transplantation to reduce the incidence and duration of severe oral mucositis. The safety and effectiveness of Kepivance in patients with solid tumors has not been established.

Approval was based primarily on the results of a randomized, placebo-controlled, multicenter trial in 212 patients. This study confirmed the results of a randomized, placebo-controlled, multicenter, schedule-ranging trial. Both trials were conducted in patients with hematologic malignancies undergoing myeloablative chemotherapy and total body irradiation, with hematopoietic stem cell rescue.

In the primary efficacy study, patients were randomized 1:1 (Kepivance: placebo). The treatment schedule for both studies was: investigational drug (Kepivance/placebo) on Days11, 10, and 9, 1200 cGy total body irradiation in divided doses on Days 8, 7, 6, 5, etoposide 60 mg/kg on Day 4, cyclophosphamide 75-100 mg/kg on Day 2, stem cell re-infusion on Day 0, investigational drug (Kepivance/placebo) on Days 0, 1, and 2, and Neupogen pn Days 0 through 21 or until neutrophil engraftment was documented.

In the primary efficacy study, the median duration of WHO grade 3 and 4 mucositis was significantly shorter (three days vs. nine days, p<0.001, CMH test) in patients receiving Kepivance. The reduction in median duration of severe mucositis reflects both a reduction in the incidence of severe mucositis (67 percent vs. 98 percent) and a shorter median duration in those who experienced severe mucositis (six days vs. nine days).

There was also a reduction in the incidence of WHO grade 4 mucositis (20 percent vs. 62 percent) and a reduction in the requirement for opioid analgesics from initiation of treatment through post-transplant day 28. Patients used a daily diary to record the amount of mouth and throat soreness. Compared with placebo-treated patients, Kepivance-treated patients reported less mouth and throat soreness.

These results confirmed the findings of a phase II study. In that study, as compared with placebo, there was a reduction in median days of WHO Grade 3/4 oral mucositis (four days vs. six days), lower incidence of WHO Grade 3/4 oral mucositis (67 percent vs. 80 percent) and lower incidence of WHO Grade 4 oral mucositis (26 percent vs. 50 percent) among patients receiving Kepivance.

The incidence serious adverse events was similar in Kepivance and placebo-treated patients; the only serious adverse event attributed to Kepivance was skin rash, occurring in <1 percent Kepivance-treated patients. The most common adverse reactions attributed to Kepivance were skin toxicities (rash, erythema, edema, pruritus), oral toxicities (dysesthesia, tongue discoloration, tongue thickening, alteration of taste), pain, arthralgias, and dysesthesia.

The median time to onset of cutaneous toxicity was six days following the first of three consecutive daily doses of Kepivance, with a median duration of five days. In patients receiving palifermin, dysesthesia (including hyperesthesia, hypoesthesia, and paresthesia) was usually localized to the perioral region, whereas in patients receiving placebo dysesthesias were more likely to occur in extremities.

Kepivance-treated patients had an increased incidence of elevated serum amylase (38 percent vs. 31 percent NCI CTC Grade 3/4) and serum lipase (11 percent vs. 5 percent; NCI CTC Grade 3/4) as compared to placebo controls. In phase I studies, modest dose-related increases in blood pressure and in proteinuria were reported; no clear increase in nephrotoxicity or hypertension was reported in the efficacy studies.

Because the KGF receptor is also present on malignant epithelial cells, there is a theoretical risk that Kepivance may also stimulate the proliferation of KGF-receptor bearing malignant cells. There is also a theoretical risk of ocular toxicity as a result of KGF stimulation of cells on the lens of the eye. To date, clinical studies have not demonstrated an increase in second cancers or ocular toxicity. Additional nonclinical and clinical studies characterizing the risks of epithelial-derived tumor stimulation and ocular toxicity are ongoing or planned.

About the Author

www.nci.nih.gov
The National Cancer Institute's research programs are extensive and contain many innovative initiatives. I invite you to explore our Web site to find out more about the exciting work being conducted here at NCI and by NCI-supported scientists throughout the country.