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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.

New Warnings

Labels for lisinopril (Prinivil, Zestril) and lisinopril/hydrochlorothiazide (Zestoretic) feature updated “Warnings” and “Precautions,” according to AstraZeneca based on recent literature concerning angiotensin-converting enzyme inhibitor (ACEI) use during the first trimester of pregnancy and a possible increased risk for major congenital malformations. Women of childbearing age should be apprised of potential pregnancy outcomes from ACEI-exposure and report pregnancy to healthcare providers as soon as possible.

New Name

Lovaza is the new name for omega-3-acid ester gelcaps, formerly known as Omacor. The name change has occurred in response to reports of prescribing and dispensing errors when confused with Amicar (aminocaproic acid).—MK

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

Rash as a Marker

There appears to be some evidence of a relationship between HER1/EGFR efficacy and associated rash severity. There have been at least 19 trials and additional compassionate use centers that have found the relationship of a positive correlation between rash and response/survival.

For example, in a Phase II study in 57 patients with non-small cell lung cancer, those with grade zero rashes had a median survival of 1.5 months, those with rash grade one had a median survival of 8.5 months, and those with rash grades two or three had a 19.6 month survival. In another study with erlotinib monotherapy, patients with a skin rash had significantly greater survival rates (approximately 80%) than those without skin rashes. In trials of cetuximab in patients with different cancer types, those who developed a rash lived substantially longer than those who did not.

There are also data supporting gefitinib and cetuximab. Many of the studies note a poorer clinical outcome in those patients without rash. These findings suggest that lack of a rash after a specific period of therapy may be an early indicator of treatment failure and the need for another treatment.

Rash Treatment

While receiving treatment with these agents, patients should be advised to moisturize dry body areas twice daily with a thick alcohol-free emollient. Patients should minimize sun exposure and wear a broad-spectrum sunscreen (SPF 15). Zinc oxide or titanium dioxide is preferred over chemical sunscreens. The following treatment interventions are suggested:

  • Mild toxicity: topical hydrocortisone 1% to 2.5% cream or clindamycin 1% gel. The HER1/EGFR dose should not be adjusted;
  • Moderate toxicity: topical hydrocortisone 2.5% cream, clindamycin 1% gel, or pimecrolimus 1% cream (Elidel) with doxycycline 100mg orally twice a day or minocycline 100mg orally twice a day. The HER1/EGFR dose should not be adjusted; or
  • Severe toxicity: topical hydrocortisone 2.5% cream, clindamycin 1% gel, or pimecrolimus 1% cream (Elidel) with doxycycline 100mg orally twice a day or minocycline 100mg orally twice a day. Also add methylprednisolone dose pack.

Reduce the HER1/EGFR dose, if after two to four weeks the toxicities have not sufficiently abated, then the HER1/EGFR therapy should be interrupted. Once the skin reactions have resolved or diminished in severity, the HER1/EGFR dose may typically be restarted or re-escalated.

Results of a recent double-blind, placebo-controlled study suggest tetracycline may be effective in decreasing EGFR-associated rash severity and improving some quality-of-life parameters (e.g., irritation, burning, stinging).7 Remaining alert to these reactions in patients receiving HER1/EGFRs is important for monitoring treatment and managing patients. TH

Michele B. Kaufman is a freelance medical writer based in New York City.

References

  1. Castillo L, Etienne-Grimaldi MC, Fischel JL, et al. Pharmacologic background of EGFR targeting. Ann Oncol. 2004;15(7):1007-1012.
  2. Robert C, Soria JC, Spatz A et al. Cutaneous side effects of kinase inhibitors and blocking antibodies. Lancet Oncol. 2005;6(7):491-500.
  3. Peréz-Soler R, Saltz L. Cutaneous adverse effects with HER1/EGFR-targeted agents: Is there a silver lining? J Clin Oncol. 2005;23(22):5235-5246.
  4. Seiverling EV, Fernandez EM, Adams D. Epidermal growth factor receptor inhibitor associated skin eruption. J Drugs Dermatol. 2006;5(4)368-369. Available at http://findarticles.com/p/articles/ mi_m0PDG/ is_4_5/ai_n16361317Accessed August 7, 2007
  5. Tyrosine Kinase Inhibitors. www.oncolink.com/treatment/article.cfm?c=12&s=90&id=268. Accessed August 7, 2007
  6. Lynch TJ, Kim ES, Eaby B, et al. Epidermal growth factor receptor inhibitor-associated toxicities: An evolving paradigm in clinical management. Oncologist 2007;12(5):610-621.
  7. Jatoi A, Rowland K, Sloan JA, et al. J Clin Oncol 2007; ASCO Annual Meeting Proceedings Part I. Vol. 25(18S);June 20:LBA9006.

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