Dermatologic adverse events are frequently reported in patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), dual EGFR/human epidermal growth factor receptor 2 (HER2) blockers, and ErbB family blockers. So it is not surprising to learn that afatinib (Gilotrif; Boehringer Ingelheim)—a potent oral irreversible inhibitor of EGFR, HER2, and ErbB4 receptor kinases—is also associated with dermatologic adverse events.
Afatinib was recently approved by the US Food and Drug Administration for first-line treatment of patients who have lung cancer with EGFR mutations. Its approval is based on data from the pivotal LUX-Lung 3 trial, comparing afatinib to chemotherapy with pemetrexed/cisplatin. Data from LUX-Lung 3 showed about a 4.2-month progression-free survival (PFS) advantage compared with pemetrexed/cisplatin. Patients with non–small cell lung cancer (NSCLC) with tumors harboring the 2 most common EGFR mutations (Del19 or L858R) taking afatinib lived for well over a year without disease progression (PFS of 13.6 months) versus just over half a year (PFS of 6.9 months) for those in the comparator arm.
Afatinib is also being studied in breast cancer and head and neck cancer. Because afatinib more widely targets the ErbB family kinases, the drug may replace erlotinib and gefitinib as first-line therapy for patients with advanced NSCLC, explained Mario E. Lacouture, MD, Memorial Sloan-Kettering Cancer Center, New York City. Therefore, it is important to educate patients about these dermatologic adverse events and provide optimal management leading to the best symptom control, thereby promoting adherence.
Lacouture discussed the dermatologic adverse events associated with afatinib, as well as management recommendations, at the 2013 Annual Meeting of the Multinational Association of Supportive Care in Cancer.1 This topic is also the subject of a recent article with Lacouture as the lead author in Expert Reviews in Anticancer Therapy.2
In a large analysis of phase 1, 2, and 3 trials of afatinib in NSCLC (including the LUX-Lung clinical trials program), 4 main dermatologic adverse events were associated with afatinib therapy: (1) papulopustular (acneiform) rash, (2) xerosis, (3) pruritus, and (4) paronychia. These effects have also been reported with other EGFR TKIs, Lacouture said.
Patients taking afatinib (and other EGFR TKIs) should take precautions for skin protection, including using alcohol-free skin-based products, minimizing sun exposure, wearing sun protective clothing and a hat, and using a sunscreen with SPF >30 and UVA/UVB protection when planning to be outdoors.
Dose modifications or interruptions can be used to manage severe dermatologic adverse events (ie, grade 3 or higher), but a hiatus of longer than 28 days of treatment is not recommended. If, however, the adverse event remains at grade 3 or is an intolerable grade 2 reaction despite interventions and a 28-day interruption, afatinib should be discontinued.
In the LUX-1 and LUX-2 NSCLC trials (totaling more than 500 patients), all grades of papulopustular (acneiform) rash were reported in 78% to 94% of patients (severe grade 3 in 14%-28%). Drugs used to treat this rash include topical and oral steroids and antibiotics. For grades 1/2, afatinib can be continued at the current dose.
Nail effects (paronychia) of all grades were reported in 39% to 86% of patients, with grade 3 in 5% to 8% of patients in LUX-1 and LUX-2. These can be treated with topical antibiotics, vinegar soaks, and topical ultrapotent steroids. For more severe paronychia, nail avulsion and systemic antibiotics can be considered.
Pruritus was reported in 18% to 60% of patients enrolled in LUX-1 and LUX-2. Severe pruritus is quite rare, <1%. Topical, oral, or systemic steroids, antihistamines, or gamma-aminobutyric acid (GABA) antagonists are recommended as treatment.
Xerosis is less frequently reported than the other 3 adverse events of interest discussed. In the LUX-2 trial, only 11% of patients had any grade of xerosis and none was severe. Over-the-counter moisturizing cream and ammonium lactate cream or salicylic acid (grade 2 only) are recommended for grade 1/2 xerosis. If grade 3 or higher xerosis occurs, the stated measures plus topical steroid to eczematous areas, as well as afatinib treatment interruption and referral to a dermatologist, are suggested.
An important observation from trials of other EGFR inhibitors is that patients who experience dermatologic adverse events are more likely to benefit from EGFR-inhibitor therapy, and the severity of rash is correlated with improved survival. This association has not yet been established with afatinib, however, but it is likely to be similar.
It is important to maintain an effective dose of EGFR-inhibitor therapy. Therefore, timely identification and appropriate management of dermatologic adverse events will help keep patients on therapy, Lacouture said.
1. Schadendorf D, Lacouture ME, Chu CY, et al. Management of dermatological adverse events associated with afatinib, an oral ErbB family blocker. Support Care Cancer. 2013;21(suppl 1):S248. Abstract 0709.
2. Lacouture ME, Schadendorf D, Chu CY, et al. Dermatologic adverse events associated with afatinib: an oral ErbB family blocker. Expert Rev Anticancer Ther. 2013;13(6):721-728.