Dermatology Year in Review Part 2: New Treatments

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Hensin Tsao, MD, PhD

 

Dermatologists should remember that most basal cell carcinomas (BCCs) are removed by surgery or with radiation or topical therapies. This past year there has been much more data on hedgehog signaling, which is involved in most BCCs.

Hedgehog Pathway

Vismodegib, which targets the hedgehog pathway, has been studied in BCCs. Of note, the hedgehog pathway is also being studied in other cancers, including pancreatic and brain cancer.

Sekulic, et al. published a study in the New England Journal of Medicine looking at the efficacy and safety of Vismodegib in advanced basal-cell carcinoma looking at 33 patients with metastatic basal-cell carcinoma and 63 patients with locally advanced basal-cell carcinoma, the latter of which is more prevalent in the dermatology setting. The primary endpoint of the study was independent review by an outside dermatologist. The study concluded that Vismodegib is associated with tumor responses in patients with locally advanced or metastatic basal-cell carcinoma.

The most commonly reported adverse events (AEs) were muscle spasms, alopecia, and dysgeusia. Other AEs included decrease in weight, fatigue, nausea, decrease in appetite, and diarrhea.

Tang, et al. studied the results of inhibiting the hedgehog pathway in patients with basal-cell nevus syndrome. (New England Journal of Medicine) There were 41 patients in the study; 26 on Vismodegib vs 15 on placebo. The study looked at cessation of new BCC development while on Vismodegib and the decrease in the diameter of existing lesions while on Vismodegib.

The data from this study demonstrate that one can see no new BCCs form while on Vismodegib and a significant decrease in the diameter of existing lesions while on drug. (Of note, there was a significant attrition of use because of the side effects.) Also of importance is the fact that GLI1 levels diminished on patients taking Vismodegib; therefore, indicating that the drug is hitting its target.

Clinical Pearls
  • This small-molecule hedgehog pathway inhibitor is effective for metastatic, advanced and generalized BCCs
    • Represents nice bench-bedside development of a new cancer agent
  • Side effects, recurrences after drug discontinuation, and cost are limiting factors
    • Although FDA-approved, the role of Vismodegib for common BCC settings is unclear given limitations

 

Head Lice

The emergence of resistance to first line antipediculicides complicates the public health problem of head lice. Dermatologists should remember that second-line treatments, such as lindane and malathion, have limitations related to safety; therefore, newer approaches for the treatment of head lice are needed.

David Pariser and colleagues published a large prospective trial in 2012 in the New England Journal of Medicine looking at topical Ivermectin 0.5% for the treatment of head lice. The study found that Ivermectin has a higher success rate versus the control vehicle.

The side effects for Ivermectin were rather tolerable. AEs included pruritus, excoriation, and erythema.

Clinical Pearls
  • Ivermectin targets glutamate channels whereas permethrin targets sodium channels
  • Topical ivermectin achieved a success rate of >90% with single application
    • Similar to oral ivermectin
  • Nit combing not necessary with ivermectin as opposed to permethrin
  • Nice option for permethrin-resistant louse or even as first line
 Targeted Therapy for Melanoma

Although molecular control of melanoma through targeted therapies has shown tremendous success, relapse is still the general rule; therefore, long-term remission will require immune participation in order to have recognition at the immune surveillance level. Often times, the tumor evades the immune system by circumventing immune checkpoints; yet, recent advances in the studies of targeted therapy for melanoma (Anti-PD-1 and Anti-PD-L1 antibodies) have demonstrated positive efficacy in tumor reduction.This new area of research is at the level of the tumor itself. These therapies, currently under trial, both have major potential in clinical practice and patient outcomes.

Data from Topalian et al, published in the New England Journal of Medicine show that the objective response rates are less than 30 percent as defined by the RESIST criteria. Many patients experienced a drop-off of greater than 30 percent tumor reduction using anti-PD-1.  The anti-PD-L1 shows similar results, but not to as great as an extent as that of anti-PD-1.

Clinical Pearls
  • Anti-CTLA4, anti-PD-1 and anti-PD-L1 represents the triumvirate of immune checkpoint therapies
    • Precise molecule and formulation may be important
    • Tremelimumab (another anti-CTLA4 antibody) did not show any significant survival benefit
  • Anti-PD-1 and anti-PD-L1 treatments appear to be less toxic than ipilimumab
  • Combination molecular therapies for acute control and checkpoint therapies for long-term control may be the wave of the future

 

Overcoming Rejection and Cancer

A small study in the New England Journal of Medicine looked at the role Sirolimus (rapamycin) in secondary skin cancer prevention in the transplant population. Rapamycin, which targets the mTOR pathway, blocks the transduction pathway. This action not only prevents the rejection, but can also prevent SCC from developing.

Patients in the study were randomized to either Sirolimus or cyclosporine, tacrolimus. All patients had at least one prior SCC and were stratified by the number of prior SCCs. Overall there was a significant improvement in the probability of survival-free with Sirolimus compared to the calcineurin inhibitor controls. However, when the data is broken down, one can see that the majority of this effect occurred in the sub-population, i.e., patients with only one prior SCC.

Clinical Pearls
  • Sirolimus is an effective suppressor of transplant rejection and has the added benefit of suppressing development of SCCs
  • The medicine’s positive effects must be balanced against a large number of adverse effects
  • It is less effective in patients who have already had more than one SCC
  • This is not the final word in prevention of skin cancer in transplant recipients