Novel Molecular Therapies

The following is a brief overview of the dosing and administration guidelines for the various targeted therapy agents discussed in this supplement to the ONCOLOGY Nurse Edition. Please consult the manufacturer's package insert for more information.

Gefitinib

The small-molecule tyrosine kinase inhibitor gefitinib (Iressa), which is approved for restricted use in advanced lung cancer at a dosage of 250 mg/d orally, may be given with or without food. If a dose is missed, it should be made up that day, but two doses should not be taken on the same day. Gefitinib may be handled without protective measures and stored at room temperature.

Clinical trials for gefitinib in head and neck cancer have used a dose of 500 mg. The US Food and Drug Administration (FDA) has not approved gefitinib for use in head and neck cancers, but further studies are under way.[1]

Erlotinib

The usual dose for the small-molecule tyrosine kinase inhibitor erlotinib (Tarceva), which is also under investigation for use in head and neck cancers and is approved for advanced lung cancer, is 150 mg (given orally), the maximum tolerated dose. Pharmacokinetic studies during clinical trials indicate that erlotinib should be administered at least 1 hour before or 2 hours after meals. If a dose is missed, it may be made up during the day, but two doses should not be taken on the same day. Erlotinib may be handled without protective measures and stored at room temperature.[2]

Sorafenib

Sorafenib (Nexavar) is a multikinase inhibitor that prevents tumor growth by inhibition of tumor cell proliferation and tumor angiogenesis. It inhibits the intracellular Raf kinases (cRaf, BRaf, and mutant BRaf) and cell surface kinase receptors (VEGF-2, VEGFR-3, PDGFRB, cKIT, and FLT3). The approved dose for advanced renal cancer is 400 mg twice a day on a continuous, uninterrupted schedule. It has also been dosed at 400 mg twice a day for unlabeled use in non-small-cell lung cancer (NSCLC) and pancreatic cancer. It may be given with or without food, but pharmacokinetic studies show a decreased bioavailability of 29% when sorafenib is administered with a high-fat meal.

If a dose is missed, it should be taken as soon as possible, unless it is almost time for the next dose, in which case the missed dose should be skipped and dosing resumed on the regular schedule. The dose should not be doubled. Sorafenib may be handled without protective measures, but patients are instructed to store it away from heat or dampness, as these may cause the medication to break down.[3]

Lapatinib

Lapatinib (Tykerb), a novel dual tyrosine kinase inhibitor with selective inhibition of both EGFR and HER2, has shown documented activity in solid tumors. More potent inhibition of cell growth results from simultaneous inhibition than from targeting EGFR or HER2 alone. Clinical trials are investigating the activity of lapatinib in breast cancer, NSCLC, and glioblastoma multiforme or gliosarcoma. Clinical activity, as well as stable disease (> 6 months), has been observed in trastuzumab (Herceptin)-resistant breast cancers. Efficacy results are pending in a randomized phase II multicenter trial of chemo-naive patients with advanced or metastatic NSCLC.[4] GlaxoSmithKline expects to submit lapatinib for regulatory approval in late 2006 or early 2007.

Lapatinib is administered orally and reported to be well tolerated in doses up to 1,800 mg/d, with plasma concentrations achieved at a 1,200-mg/d dose.[5] Grades 1and 2 diarrhea and rash are the most commonly reported adverse events from phase II trials. Other adverse events include nausea, fatigue, mild to moderate pruritus, dyspnea, acne, and dry skin. The phase II multicenter NSCLC trial showed no significant drug-related toxicities,[4] and much of the current literature reports fewer side effects related to lapatinib.

Sunitinib

Sunitinib (Sutent), another inhibitor of both EGFR and VEGFR, is orally dosed at 50 mg daily for 4 consecutive weeks of a 6-week treatment cycle. Dose increases or reductions are implemented at 12.5-mg increments depending on individual patient tolerance. If given concomitantly with CYP3A4 inhibitors, dose reductions may be necessary. If given with CYP3A4 inducers, dose may need to be increased. Sunitinib may be given without regard to food. It is supplied as 12.5-, 25-, and 50-mg capsules.[6]

ZD6474

Another novel agent expected to be approved shortly is ZD6474 (Zactima), the oral tyrosine kinase inhibitor of EGFR, VEGFR, and RET. It has been used as monotherapy and in combination with standard chemotherapy regimens in multiple solid tumors, including NSCLC and thyroid tumors. It is currently on the FDA fast track for medullary thyroid cancer. The starting dose is 300 mg orally, daily.[7,8]

Cetuximab

Cetuximab (Erbitux) is a monoclonal antibody that must be given intravenously. It is the only IgG1 monoclonal antibody approved by the FDA for the treatment of metastatic colorectal cancer, in combination with irinotecan chemotherapy. As a single agent, it is administered to patients intolerant to irinotecan alone. In addition, cetuximab was approved in March 2006 for locally and regionally advanced squamous cell carcinoma of the head and neck (SCCHN), in combination with radiation therapy. It is also approved as a single agent for recurrent SCCHN in patients who are refractory to platinum-based therapy.

Careful observation to detect infusion reactions is critical throughout each infusion, and medications to treat such reactions should be readily available. Cetuximab is provided in single-use, 50-mL vials (100 mg, 2 mg/mL) that should not be shaken. After reconstitution, it is stable at room temperature for up to 8 hours. An initial loading dose of 400 mg/m² is given over 2 hours, followed by weekly IV administration of 250 mg/m² over 1 hour. Cetuximab should never be administered as an IV push or bolus, and the infusion rate should not exceed 5 mL/min.

Premedication is recommended to prevent infusion reactions. Many clinicians use an H1 antihistamine such as diphenhydramine as premedication, but an H2-blocker such as cimetidine and a steroid are also used. Package insert instructions for cetuximab include administration through a 0.22-micron filter placed as proximal to the patient as possible. The IV line should be flushed with normal saline following the infusion. Patients must be monitored for delayed infusion reactions for at least 1 hour after infusion.[9]

Panitumumab

Panitumumab (Vectibix) is a fully humanized monoclonal antibody that inhibits EGFR through a blockade rather than through a cell-mediated response. It has been used in clinical trials for a variety of solid tumor types but has been studied most extensively in colorectal cancer, for which it has received FDA approval for patients who have failed standard treatment. It is administered intravenously at dosages ranging from 2.5 mg/kg weekly to 9 mg/kg every 3 weeks, alone or in combination with chemotherapy. As a fully human antibody, panitumumab contains no murine protein; therefore, the incidence of allergic reaction is low. Premedication is not required unless a patient experiences hypersensitivity during administration.[10]

Trastuzumab

Trastuzumab (Herceptin) is a humanized monoclonal antibody prepared from mammalian Chinese hamster ovarian cell proteins. Like cetuximab it is given intravenously with a loading dose of 4 mg/kg over 90 minutes. Maintenance doses are given at 2 mg/kg weekly. Subsequent doses may be infused over 30 minutes if the initial 90-minute infusion is well tolerated. Infusion reactions are generally mild, including chills and fever, which may be treated with acetaminophen, diphenhydramine, and meperidine. More severe reactions may include pulmonary events. Allergic reactions may be increased in patients who have received diagnostic or therapeutic monoclonal antibodies. Nursing implications include observation for signs and symptoms of cardiac dysfunction and infusion reactions. Patients who experience infusion reactions may be rechallenged with premedication and careful observation. Infusion reactions may occur up to 24 hours after infusion.[11]

Bevacizumab

Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody that binds to and neutralizes vascular endothelial growth factor, preventing its association with endothelial receptors. It is dosed at 5 to 20 mg/kg IV every 2 weeks for colorectal, prostate, and breast tumors. The currently utilized dose for lung cancer trials is 15 mg/kg every 3 weeks. Initial doses are given over 90 minutes. This time may be reduced by 30 minutes until a 30-minute infusion time is achieved, if well tolerated.

Bevacizumab should not be administered to patients with recent hemoptysis or within 28 days of major surgery(and with complete healing of the surgical incision). There is an increased incidence of arterial thromboembolic events when given in combination with chemotherapy. History of thromboembolism or age > 65 years increases this risk. Patients with central nervous system metastases are excluded from clinical trials because of the risk of bleeding events.

Patients should be monitored closely during the infusion and for at least 1 hour after completion of the infusion for evidence of hypersensitivity reactions. Permanent discontinuation of treatment is recommended by the manufacturer in patients who develop wound dehiscence requiring intervention, gastrointestinal perforation, hypertensive crisis, serious bleeding, or nephritic syndrome. Temporary suspension is recommended in moderate to severe proteinuria, or severe hypertension not controlled by medication. Symptoms generally resolve within days after discontinuation, although neurologic symptoms may be prolonged.

Latest labeling revisions include information about onset of symptoms, which may occur from 16 hours to 1 year after treatment initiation. These may include seizure, confusion, lethargy, and blindness.[12]

As with all other chemotherapy drugs, informed patient consent should be obtained before these agents are administered. At MD Anderson Cancer Center we use preprinted order templates and dosing calculators, available on-line, to reduce errors associated with handwritten orders. Thorough focused patient assessment before and after infusions is important as with any other chemotherapeutic agent. Consistent outpatient follow-up, especially for patients on oral medications, is important for compliance.

Staff education that includes the new agents' mechanism of action, safe handling and storage practices, prescribing information, and expected side effects is necessary for safe use of these agents in clinical practice. As these newer agents are incorporated into practice and patients continue to be treated for extended periods, new toxicities are expected to be identified. All staff should be encouraged to read and stay up to date on current developments and newly identified side effects.

References:

1. Iressa (gefitinib) prescribing information. AstraZeneca Pharmaceuticals, 2005, http://www.astrazeneca-us.com/pi/iressa.pdf

2. Tarceva (erlotinib) prescribing information. Genentech and OSI Pharmaceuticals, 2005, http://www.gene.com/gene/products/information/oncology/tarceva/insert.jsp

3. Nexavar (sorafenib) prescribing information. Bayer Pharmaceuticals, 2006, http://www.univgraph.com/bayer/inserts/nexavar.pdf

4. Heymach JV, Nilsson M, Blumenschein G, et al: Epidermal growth factor receptor inhibitors in development for the treatment of non-small cell lung cancer. Clin Cancer Res 12:4441-4445, 2006.

5. Nelson MH, Dolder CR: Lapatinib: A novel dual tyrosine kinase inhibitor with activity in solid tumors. Ann Pharmacother 40:261-269, 2006.

6. Sutent (Sunitinib Malate) for Health Care Professionals. Pfizer Oncology, 2006.

7. Miller KD, Trigo JM, Wheeler CB, et al: A multicenter phase II trial of ZD6474, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor, in patients with previously treated metastatic breast cancer. Clin Cancer Res 11:3369-3376, 2005.

8. Snyder LC, Astsaturov I, Weiner LM: Overview of monoclonal antibodies and small molecules targeting the epidermal growth factor receptor pathway in colorectal cancer. Clin Colorectal Cancer 5(suppl 2):S71-S80, 2005.

9. Erbitux (cetuximab) prescribing information. ImClone Systems and Bristol-Myers Squibb, 2006, www.erbitux.com

10. Vectibix (panitumumab) prescribing information. Amgen, 2006, http://wwwext.amgen.com/pdfs/products/vectibix_pi.pdf

11. National Cancer Institute Fact Sheet: Herceptin (Trastuzumab): Questions & Answers. NCI Pub 7.45. Issue Date 6/13/06.

12. Avastin (bevacizumab) prescribing information. Genentech, 2006, http://www.gene.com/gene/products/information/oncology/avastin/insert.jsp