Melanoma, Vemurafenib and Ipilimumab.

Vemurafenib 

It has been approved in Europe for use in the treatment of patients with unresectable or metastatic melanoma whose tumors have a BRAF mutation. About 50% of patients with melanoma have this BRAF mutation. A companion diagnostic test, the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems), is already commercially available.A post hoc analysis showed that vemurafenib significantly improved median survival, compared with dacarbazine (13.2 vs 9.6 months): N Engl J Med 2011; 364: 2507-16.       

Potential adverse events include severe allergic reactions, severe skin reactions, cardiac events such as QT prolongation (which can be potentially life-threatening), abnormal liver function tests, eye problems, and new melanoma lesions. Common adverse effects include joint pain, rash, hair loss, tiredness, sunburn or sun sensitivity, nausea, itching, and warts.

Patients with advanced melanoma who are treated with vemurafenib should be tested for RAS mutations!! The testing is important because there is "potential for secondary tumor development" that arises from treatment with vemurafenib. Thus, patients with RAS mutations could also develop secondary cancers in organs beyond the skin, namely cutaneous squamous cell carcinoma and keratoacanthomas.

 Ipilimumab 

 

Ipilimumab is a fully human monoclonal antibody (IgG1) that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), an immune checkpoint molecule that downregulates pathways of T-cell activation. By inhibiting CTLA-4, ipilimumab acts to "release the brake" on the immune system. The role of CTLA-4 is to guard against unwanted and harmful self-directed activities (ie, autoimmunity). 

Treatment Arm	12 months (%)	18 months (%)	24 months (%)
Ipilimumab + gp100	43.6	30.0	21.6
Ipilimumab alone	45.6	33.2	23.5
gp100 alone	25.3	16.3	13.7

Hodi FS, O'Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363(8), 711–723 (2010).
•• First Phase III study to demonstrate the efficacy of ipilimumab in patients with advanced melanoma. 

 

A more recent Phase III trial comparing treatment with ipilimumab with dacarbazine versus dacarbazine alone has also provided evidence for efficacy of ipilimumab in melanoma patients with improved overall survival in the ipilimumab plus dacarbazine group (11.2 months vs 9.1 months) and durable responses in a small number of patients. Robert C, Thomas L, Bondarenko I et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364(26), 2517–2526 (2011).

The current dosing of ipilimumab is 3 mg/kg of body weight, administered by intravenous infusion over 90 minutes once every 3 weeks, for a total of 4 treatments. Disease regression has been reported 3-6 months following treatment initiation. In addition, a partial response followed by stable disease has been noted. Complete responses have been recorded approximately 1 year after receiving therapy.

The most common severe immune-mediated adverse reactions are: enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. These reactions often can be mitigated by withholding or permanently discontinuing ipilimumab, as well as by the administration of corticosteroids.  

Vismodegib for Advanced Basal Cell Carcinoma

Vismodegib is an oral drug that is designed to selectively inhibit abnormal signaling in the Hedgehog pathway, which is an underlying molecular driver of BCC. It binds to and inhibits Smoothened, a transmembrane protein involved in Hedgehog signal transduction.

Vismodegib was reviewed under the US Food and Drug Administration (FDA) priority review program offering an expedited 6-month review. It was approved for use in advanced basal cell carcinoma (BCC) ahead of the prescription user fee goal date, which was March 8, 2012.

 

Clinical Implications

• The FDA has approved vismodegib for treatment of BCC that has metastasized or relapsed after treatment with surgery, or for treatment of BCC in patients who are not candidates for surgery or radiation.

• The recommended dose of vismodegib is one 150-mg capsule orally once daily, with or without food. If a dose is missed, it should not be made up but should be resumed with the next scheduled dose.

• Vismodegib is pregnancy category D and can cause fetal harm. Men as well as women should be advised concerning pregnancy prevention and planning. Breast-feeding mothers should discontinue either vismodegib or breast-feeding, depending on how important the drug is to the mother. The safety and efficacy of vismodegib have not been established in pediatric patients or in patients with hepatic or renal impairment. 

The most common adverse reactions (incidence of 10% or more) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia.

Therapy for Infantile Hemangiomas.

Propranolol vs Corticosteroids for Infantile Hemangiomas: A Multicenter Retrospective Analysis

Price CJ, Lattouf C, Baum B, et al. Arch Dermatol 2011;147:1371-6.

The patients were subdivided into 2 treatment groups: those receiving propranolol (n = 68; mean treatment duration, 7.9 months; target dose, 2 mg/kg/d) and those receiving oral corticosteroids (n = 42; mean treatment duration, 5.2 months; target dose, 4 mg/kg/d). To insure comparability, investigators matched these groups for patient age and lesion size, location, and type.
Outcome measures included percentage of IH clearance (< 75% or ≥ 75%), adverse effects, percentage of patients needing subsequent surgical referral, and average treatment cost per IH. Propranolol proved superior in all of these criteria:

1. 82% of patients treated with propranolol achieved ≥ 75% clearance vs 29% of patients treated with oral corticosteroids (P < .01).
2. 1 of 68 patients treated with propanolol had transient hypoglycemia, 2 patients (3%) had nonspecific skin eruptions, all patients completed treatment, and no patients suffered serious adverse events, whereas all patients treated with oral corticosteroids had adverse effects, including cushingoid features (100%), gastroesophageal reflux (n = 4), and hypertension (n = 2). One patient had a life-threatening bleed due to IH ulceration eroding into the external carotid artery.
3. 12% of patients treated with propranolol required surgery after therapy vs 29% of patients treated with oral corticosteroids.
4. The average cost per IH treated (excluding monitoring costs and prophylaxis/treatment of adverse effects) was $205.32 for propranolol vs $416.00 for oral corticosteroids

 Although "propranolol blows away corticosteroids" is the headline here, the investigators of this study also made several other important observations. For example, they found that:

1. Propranolol induced IH regression even when treatment was initiated after the first year of IH growth, confirming previous reports that the drug works to debulk more mature lesions beyond the proliferative phase.
2. Initial treatment with oral corticosteroids followed by oral propranolol showed a trend toward slightly improved efficacy over propranolol alone, although this benefit was not statistically significant.
3. IHs were less likely to relapse if propranolol therapy continued until at least 1 year of age.
4. The risk for propranolol-related side effects can be minimized with proper monitoring (eg, cardiac preclearance and checking for signs or symptoms of bradycardia, hypotension, and hypoglycemia).

Finally, Price and colleagues acknowledged that at least one more critical question remains: We still do not know how propranolol works to slow IH and induce regression. Does it trigger endothelial cell apoptosis, inhibit proangiogenic cytokines, or cause vasoconstriction by reducing nitric oxide levels? As researchers try to solve this complex puzzle, powerful new IH treatments will surely follow.

Neurofibromatosis Type 1

Major Cutaneous Features

•    Neurofibromas (60–90%)    •    Café-au-lait macules (>90%)    •    Axillary and/or inguinal freckling (∼80%)    •    Plexiform neurofibroma (25%)

 

In its fullest expression, NF1 can manifest as thousands of neurofibromas in a patient, hence the appellation neurofibromatosis (Fig. 60.3). Several variants of neurofibromas are observed in NF1. Most commonly, proliferations of spindle cells occur within the dermis, leading to cutaneous neurofibromas (CNFs). CNFs are skin-colored to pink, tan or brown, polypoid or pedunculated nodules that are soft or slightly rubbery in texture and can range from a few millimeters to several centimeters in diameter. They invaginate easily into the skin with gentle external pressure, thereby exhibiting the pathognomonic ‘buttonhole’ sign. Although these soft nodules are usually asymptomatic (except for their appearance), they may become pruritic or, occasionally, irritated. CNFs can appear as early as 4-5 years of age but more typically develop around puberty, with occasional acceleration during pregnancy.

DIAGNOSTIC CRITERIA FOR NEUROFIBROMATOSIS TYPE 1

Two or more of the following must be present:    •    Six or more café-au-lait macules >5 mm in prepubertal individuals and >15 mm in postpubertal individuals    •    Two or more neuro.bromas of any type or one plexiform neurofibroma    •    ‘Freckling’ in the axillary or inguinal regions    •    Optic gliomas    •    Two or more Lisch nodules (iris hamartomas)    •    Osseous lesion, such as sphenoid wing dysplasia or thinning of long bone cortex, with or without pseudarthrosis    •    First-degree relative (parent, sibling or offspring) with NF1 by the above criteria

 Arch Neurol. 1988;45:575–8.