Q: Over the years, I have had a few patients who have been on epidermal growth factor receptor inhibitors, such as panitumumab (for metastatic colorectal cancer) and erlotinib (for non-small cell lung cancer and pancreatic cancer). Do I need to be concerned about the ocular side effects listed (e.g., corneal perforation) and, if so, who specifically is at greatest risk?

A: Ocular adverse effects associated with panitumumab and erlotinib use are fairly rare, but potentially serious. This is especially true in the case of contact lens wearers, or those who have pre-existing severe dry eye or a history of keratitis—especially ulcerative keratitis—says Kathy Kelley, OD, a medical optometrist specializing in cornea and external disease, and Matthew T. Feng, MD, a cornea, refractive and anterior segment surgeon. Both are part of Price Vision Group in Indianapolis.

Used to treat metastatic colorectal cancers that overexpress epidermal growth factor receptor (EGFR), panitumumab "is a recombinant human IgG2 kappa monoclonal antibody administered intravenously to competitively inhibit EGFR at an extracellular binding site," say Drs. Kelley and Feng. Erlotinib, in contrast, "blocks the EGFR intracellularly via its tyrosine kinase, like other tyrosine kinase inhibitors such as gefitinib, lapatinib and canertinib."

EGFR inhibitors are most frequently associated with cutaneous adverse effects like redness, itching or rashes on the face, neck or torso, Drs. Kelley and Feng explain. This is because EGFR regulates skin growth and regeneration, or "the proliferation, differentiation, migration and apoptosis of epidermal cells, including corneal and conjunctival epithelium."¹ Panitumumab, in particular, carries a black box warning for dermatologic toxicity (seen in 90% of patients), with 15% of cases considered severe.^2,3

In the case of panitumumab use, irritation and conjunctivitis are the most common ocular adverse effects. However, say Drs. Kelley and Feng, there were early reports of one serious case of keratitis and three serious cases of ulcerative keratitis, as well as mild keratitis documented in clinical trials at a rate of 0.2- 0.7%.⁴ This outcome prompted the manufacturer to release a physician warning.4 Other serious adverse effects, including corneal perforation that required penetrating keratoplasty, were also observed during a small case study, Drs. Kelley and Feng add.⁵

Erlotinib users may also experience decreased tear production, redness, pain and inflammation. Although these ocular effects are still quite rare based on the number of reports in literature, they appear to be more common for erlotinib than panitumumab, Drs. Kelley and Feng note. "One theory is that intracellular kinase inhibitor is more potent than competitive extracellular antibodies inhibitors."

Drs. Kelley and Feng recommend that any patients taking EGFR inhibitors should be educated regarding the symptoms of epithelial defects and keratitis and told to report any suspicions immediately. Because EGFR inhibitors impair corneal epithelial healing, "patients who are at greatest risk for epithelial damage may not recover normally, and instead experience persistent defects that rarely progress to non-inflammatory ulceration or even frank perforation," they explain. "Those who present with confirmed epithelial defects or keratitis should be referred emergently to an ophthalmologist. In consultation with the prescribing oncologist, the EGFR inhibitor should be discontinued or at least held."

1. Nakamura Y, Sotozono C, Kinoshita S. The epidermal growth factor receptor (EGFR): role in corneal wound healing and homeostasis. Exp Eye Res. 2001 May;72(5):511-7.
2. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007 May 1;25(13):1658-64.
3. Amgen, Inc. Vectibix (panitumumab) injection for intravenous use prescribing information. Available at: http:// pi.amgen.com/united_states/vectibix/vectibix_pi.pdf. Accessed November 11, 2014.
4. Amgen, Inc. Direct healthcare professional communication on the association of Vectibix (panitumumab) with keratitis and ulcerative keratitis. Cambridge, England; 2011.
5. Saint-Jean A, Sainz de la Maza M, Morral M, et al. Ocular adverse events of systemic inhibitors of the epidermal growth factor receptor: report of 5 cases. Ophthalmology. 2012 Sep;119(9):1798-802.