Human epidural growth factor receptor (HER1/EGFR) signaling pathways are crucial in regulating cell proliferation, survival, and differentiation.
HER1/EGFR is a protein tyrosine kinase with therapeutic applications in cancer treatment.1 Two approved drugs categories target HER1/EGFR: anti-HER1/EGFR monoclonal antibodies (mAb) and HER1/EGFR tyrosine kinase inhibitors (TKIs). The drugs have different complex actions, some leading to disruption of cellular processes at the level of cell division, apoptosis, and angiogenesis.
Approximately 30% to 100% of solid tumors express HER1/EGFR on the tumor surface, while some overexpress it. This is thought to lead to tumor growth.2,3 Increased HER1/EGFR activity has been associated with poor survival in some cancers.
The Agents
A number of HER1/EGFR TKIs are FDA approved and administered orally, including erlotinib (Tarceva), gefitinib (Iressa), imatinib (Gleevec), lapatinib (Tykerb), sorafenib (Nexavar), and sunitinib (Sutent).4-6
Cetuximab (Erbitux) and panitumumab (Vectibix) are approved mAbs given intravenously. Both categories treat different cancers including advanced/metastatic non-small cell lung cancer, colorectal cancer, pancreatic cancer, renal cell carcinoma, myelodysplastic syndrome, and others. The HER1/EGFR targeted agents have a more favorable side effect profile compared with more traditional chemotherapeutic agents with primarily dermatologic toxicities and limited hematopoietic effects. Because many patients are being treated with these oral anti-cancer agents, it is important to remain aware of the agents, their toxicities, and their management.
Adverse Effects
The most common adverse effect associated with HER1/EGFR inhibitors is a dose-dependent, folliculitis-like rash.
The rash affects up to two-thirds of treated patients within the first two weeks of therapy. It is usually on the face, neck, and upper torso and is characterized by inter- and intrafollicular papulopustules of mild-to-moderate severity. The rash develops in three phases: sensory disturbance with erythema and edema (weeks zero to one), papulopustular flare (weeks one to three), crusting (weeks three to five), and erythematotelangiectasias (weeks five to eight).
Dry skin and erythema may remain in the areas after resolution. The skin rash appears to be dose-dependent. The mechanism of the rash is not precisely known. However, HER1/EGFR is expressed by normal keratinocytes and skin fibroblasts, along the outer sheath of the hair follicle, and in many epidermal processes, which probably contributes.
Hair effects occur within two to three months of starting treatment. Scalp hair becomes more brittle, fine, and curly. Frontal alopecia gradually develops, and patients experience progressive trichomegaly of the eyelashes and hypertrichosis of the face. Paronychial inflammation can occur on the fingernails or toenails and be so painful it prevents patients from wearing shoes. Its origin is unknown, and it disappears after discontinuation of the drug. Xerosis is also common, which can be treated with topically applied 5% to 10% urea emollient.
New Drugs
Armodafinil (Nuvigil) has been FDA-approved to treat excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome as adjunct to standard therapy, narcolepsy, and shift-work sleep disorder. Don’t be fooled by this “new” agent—it’s the R-enantiomer of modafinil (Provigil), which will soon lose its U.S. patent. Armodafinil is a stimulant used to provide long-lasting mental arousal.
Cefotetan Disodium for injection (generic Cefotan) has been FDA approved. It can be used to treat infections due to abdominal or vaginal hysterectomy and/or Caesarean section, as well as colorectal surgery, and others.
IN THE PIPELINE
Gabapentin GR, an extended-release, once-daily formulation, is undergoing Phase III clinical trials for treating postherpetic neuralgia. Depomed recently reported results from a randomized, double-blind, placebo-controlled, multicenter trial using 1,800 mg daily that did not meet the primary endpoint (efficacy to reduce average daily pain). Secondary endpoints of sleep interference were all statistically significant in favor of Gabapentin GR. The most common adverse effects were dizziness and peripheral edema.
Natalizumab (Tysabri) received a favorable recommendation for treating moderate-to-severe Crohn’s disease in patients who have failed tumor necrosis factor inhibitor therapies and are not on immunosuppressive therapy—a narrower indication than that proposed by the manufacturers. The recommendation was made at a joint meeting of the Advisory Committees of Gastrointestinal Drugs and Drug Safety and Risk Management. Natalizumab is FDA-approved for the treatment of relapsing forms of multiple sclerosis (MS). Natalizumab is a recombinant, humanized immunoglobulin G4 mAb against alpha4 integrins that is administered via intravenous infusion. Natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral brain infection that usually leads to severe disability or death. A risk-management program is being developed in case the agent is approved for Crohn’s disease.
Raloxifene (Evista), a selective estrogen receptor modulator, originally approved in December 1997 for the treatment and prevention of postmenopausal osteoporosis has been recommended by an FDA advisory panel to add new indications to its label. The new indications include: (1) reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis, and (2) reducing the risk of invasive breast cancer in postmenopausal women at high risk for developing breast cancer.—MK