CUTANEOUS ADVERSE REACTIONS OF TKIs

Cutaneous Adverse Effects Associated With Tyrosine-Kinase Inhibitor Cabozantinib

Zuo RC, Apolo AB, DiGiovanna JJ, et al

JAMA Dermatol. 2015;151:170-177

Study Summary

With the advent of tyrosine kinase inhibitors (TKIs) for the targeted chemotherapy of malignant neoplasms such as thyroid, pancreatic, gastric, bladder, and renal cell carcinoma,^[1]dermatologists need to know how to recognize and treat TKI-induced toxic skin effects.^[2] In this context, Zuo and colleagues studied the prevalence and clinical spectrum of adverse skin reactions seen in patients with metastatic progressive urothelial carcinoma treated with cabozantinib (Cometriq®). The drug is a multikinase inhibitor that inhibits multiple signaling proteins, including the tyrosine kinases c-MET (hepatocyte growth factor receptor) and RET; vascular endothelial growth factor receptor (VEGF) 2; and c-KIT (mast/stem cell growth factor).

The 41 adult patients in this phase 2 clinical trial (age range: 41-82 years) took oral cabozantinib 60 mg/day (administered in 28-day cycles) for up to 20 months. Most of these patients (73%) experienced at least one TKI-related toxic skin effect during targeted chemotherapy. These included:

1. Hand-foot skin reaction (HFSR) (n=22, 54%)
2. Pigment dilution of skin and hair (graying) (n=18, 44%)
3. Xerosis (n=8, 20%)
4. Scrotal ulcer, erythema, and/or edema (n=6, 15%)
5. Splinter hemorrhages (n=5, 12%)

These skin reactions typically occurred within the first 5 weeks of cabozantinib monotherapy, with the exception of pigment dilution or hair graying (mean onset of 11.4 weeks). Of note, 44% of patients had two or more cutaneous adverse events. Roughly half of these patients (57%) experienced reactions within the first month of treatment while 80% experienced them within the first 2 months.

HFSR was the most common and severe dose-limiting skin toxicity. This study showed a prevalence of 54%, which is slightly higher than the 40% prevalence reported elsewhere.^[3] HFSR occurred with a mean onset of 4 weeks, with characteristic tender, "callus-like" hyperkeratotic lesions, erythema and bullae forming on pressure-bearing acral surfaces such as palms or soles, while sparing dorsal skin.

In this study, patients used emollients (ammonium lactate 12%), and pressure/friction reduction techniques (eg, soft gel shoe inserts) for prophylaxis. Once symptomatic with HFSR, they applied urea 40% cream and an ultrapotent topical corticosteroid. Eight patients (36%) improved with TKI dose reduction, while four (18%) had to discontinue therapy.

Of the six patients who developed scrotal erythema, symptoms were managed with treatment interruption (7-15 days), friction reduction, and use of barrier ointments or pastes such as zinc oxide. No women in this study developed genital skin symptoms.

Pigment dilution/hypopigmentation (skin, n=17; hair, n=6) and splinter hemorrhages did not require treatment disruption, and pigment dilution improved in one patient after dose reduction.

Viewpoint

In this informative cross-sectional study, Zuo and colleagues report the spectrum and prevalence of toxic skin reactions occurring during targeted chemotherapy with the multikinase inhibitor cabozantinib. The most severe of these, HFSR, is likely a consequence of VEGF inhibition and should be differentiated from chemotherapy-induced acral erythema, which is caused by cytotoxic drugs such as cytarabine and features painful acral erythema and swelling that does not spare dorsal and intertriginous skin. In contrast, TKI-induced HFSR localizes to pressure-bearing areas with painful callus-like lesions. Because cabozantinib is a multikinase inhibitor, some of its other skin effects are likely due to inhibition of other cellular targets (eg, pigment dilution due to C-KIT inhibition).

HFSR has been reported with a similar incidence with other TKIs including sunitinib (Sutent®) and sorafenib (Nexavar®)^[4]and may predict a better clinical response^[5] as compared with patients who don't develop HFSR. This has yet to be confirmed in large studies, however.

As Zuo and colleagues note, all patients receiving TKIs should avoid mechanical trauma and friction to palms and soles (eg, wear thick socks and gel sole inserts, avoid pressure-intense exercise) and apply emollients. Mild HFSR may respond to humectants such as urea cream and ultrapotent topical corticosteroids, but as symptoms worsen and become debilitating, dose reduction or even discontinuation may be necessary.