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Conference summaries

Skin tumors and cutaneous reactions

Cutaneous Reactions to Targeted Therapies: BRAF/MEK, PI3 Kinase and Hedgehog Inhibitors

Presented by: Dr. Judit Oláh
Dept. of Pediatrics, Erzsébet Hospital, Hódmezővásárhely, Hungary

In the last 10 years, there has been significant progress made in the understanding the molecular signaling pathways which has spawned the development of molecularly targeted drugs and personalization of tailored therapy. This molecular knowledge has led to a paradigm shift of irresectable or metastatic melanoma treatment, especially as 50%-60% of all melanomas are positive for BRAF V600 mutation.1,2 In the past 8 years, 11 new targeted agents have been approved for BRAF or MEK mutations.

Available agents for irresectable or metastatic BRAF V600 mutant melanoma include:

  • Vemurafenib-cobimetinib
  • Dabrafenib-trametinib
  • Encorafenib-binimetinib (FDA).

BRAF inhibitors such as vemurafenib has been associated with a high degree of grade III/IV adverse events. Chapman et al reported significant adverse events such as rash, photosensitivity, cutaneous squamous cell carcinoma (SCC), keratoacanthoma, and skin papilloma with vemurafenib use compared to dacarbazine.3 Instead, Hauschild et al reported dabrafenib-induced adverse events, which included hyperkeratosis, headache, fever, arthralgia, papilloma, SCC, new primary melanoma, and photosensitivity.4

When vemurafenib was combined with cobimetinib, there was a decrease in grade III/IV events compared with vemurafenib alone.5

In comparison with single agent BRAF inhibitors, the combination of BRAF and MEK inhibitors (BRAF-MEK inhibitors) have shown significant improvement in response rates.6 However, grade III/IV adverse events occurred in 58% of patients treated with the full dose combination therapy compared to 43% of patients treated with single agent dabrafenib.6 Frequent complications are folliculocentric morbilliform rash or toxic, erythema-like plaques.7,8

TEN, AGEP, and DRESS are rare complications induced by BRAF inhibitors.7-12

Treatment for severe rash associated with therapy includes use of 1-2 mg/kg of methylprednisolone and a topical corticosteroid.9 In grade III or IV events, BRAF-MEK inhibitors should be interrupted.6,9

Vemurafenib may induce potentially severe acute renal failure, including renal sequelae and persistent kidney disease in some cases.13 Another study, revealed frequent, reversible (80%), moderately severe acute kidney injury with some histological evidence of tubular and interstitial damage in vemurafenib-treated patients, suggesting that renal function should be carefully monitored, especially during the first 3 months.14

Zimmer et al reported the presence of new melanocytic proliferations and new primary melanomas after patients were treated with BRAF-inhibitors.15

Increased photosensitivity has also been demonstrated in multiple studies and thus active protection and discussion of precautions should be instilled in patients.2,16,17 Active discussions should include the use of photoprotective clothing, use of broad-spectrum sunscreen, and use of potent UVA-blocking agents.2,16 It has been noted that there is decreased photosensitivity when vemurafenib and cobimetinib is used in combination therapy.17

Keratosis pilaris-like skin reactions are relatively common and can be treated with gentle skin care, keratolytics, and emollients.2 In the event of hyperkeratotic hand-foot skins reactions, the following management strategies are suggested, depending on the grade:2

  • Grade I: use of keratolytics and emollients
  • Grade II: addition of topical steroids (class I/II), topical anesthetics, and nonsteroidal anti-inflammatory drugs
  • Grade III: addition of antiseptic soaks and treatment interruption.

The upregulation of hedgehog pathways plays a significant role in the development of different tumors including basal cell carcinoma (BCC), breast cancer, pancreatic neuroendocrine tumors, pediatric and adult brain tumors.2,18 The two approved drugs are vismodegib and sonidegib. Their indication includes advanced or metastatic BCC after surgery and irradiation. It is important to note that these are teratogenic drugs.2,18

The PI3K/Akt/mTOR complex plays a significant role in the regulation of cellular growth by controlling differentiation processes in protein synthesis and angiogenesis.2 The two drugs used in oncology are everolimus and temsirolimus. Dysregulation of this pathway is commonly found in kidney, breast, and endometrial cancers as well as neuroendocrine and brain tumors. Adverse reactions to these drugs include a morbilliform rash, stomatitis (44-78%), and aphthous-like lesions appearing as oval shaped, shallow ulcers with erythematous margins.19,20

Mucositis treatment should include general oral hygiene, non-medicated oral rinses, and avoidance of alcohol or peroxidase-based mouth rinses.21 Mild symptoms (Grade I) that do not impair normal diet do not need an intervention., while in Grade II/III is suggested to use topical analgesics with or without topical corticosteroids as needed.21

Key messages

  • Many pathway inhibitor drugs can cause varying degrees of adverse events.
  • Care should be taken to prevent, recognize, and subsequently treat abnormal reactions.
  • The type of inhibitor may play a role in the type of adverse event seen.
  • Dermatologists play a significant role in diagnosis and treatment of skin tumors and cutaneous reactions of oncological drugs.


REFERENCES

Present disclosure: The presenter disclosed that she participated in clinical trials and advisory boards for BMS, Roche, Novartis, and MSD.

Written by: Debbie Anderson, PhD

Reviewed by: Victor Desmond Mandel, MD



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