Managing hedgehog therapies for basal cell carcinoma

While the vast majority of basal cell carcinomas are treated and resolved with surgery, systemic therapy with one of the two hedgehog pathway inhibitors - vismodegib or sonidegib - could be a treatment option for when the basal cell is unresectable or metastasizes, Anne Lynn S. Chang, M.D., reported at the American Academy of Dermatology annual meeting in San Diego this week.

Dr. Chang, who is with Stanford University School of Medicine, said it's unclear whether patients who progress on one hedgehog pathway inhibitor would benefit from treatment with another such inhibitor. Many patients with advanced BCC will have partial or complete responses to vismodegib, the first of the two agents to be approved. However, about half of patients are refractory to treatment, and more than 20% of responders have subsequent disease progression or recurrence.

Dr. Chang and colleagues have looked at whether patients who are resistant to vismodegib would have a response to sonidegib. Results of their open-label, investigator initiated study, which was reported in Clinical Cancer Research, suggest that most patients who develop treatment resistance to vismodegib will continue to experience resistance if switched to sonidegib.

In the study, Dr. Chang and colleagues gave sonidegib to patients with vismodegib-resistant advanced BCC, and after a median follow-up of 6 weeks, 5 of 8 evaluable patients had disease progression, while stable disease was seen in 3 patients, of whom one patient discontinued due to adverse events, according to the published report.

A report appearing recently in JAAD Case Reports showed that a patient with advanced BCC who failed vismodegib went on to experience intracranial regression after treatment with sonidegib and itraconazole, an antifungal treatment recently found to also inhibit the hedgehog pathway by a different mechanism.

Although larger studies are needed to better define tumor mutations or other factors that predict differential response, this patient case suggests that itraconazole or sonidegib “may be an option in the treatment of BCC extension within the brain, and alternative hedgehog inhibitors may produce a positive response even when another has failed,” the authors said in their case report.

Combination therapies are an important area for future research in advanced BCC. Dr. Chang is principal investigator on a currently enrolling, non-randomized phase two trial studying vismodegib with or without pembrolizumab, an immunotherapy agent indicated for melanoma and other cancers, in patients with metastatic or unresectable BCC, with results forthcoming.

“These tumors have lots of mutations and may develop ways to continue to grow despite hedgehog inhibition,” she said.

PATIENT SELECTION

Dr. Chang reviewed the factors associated with selecting a good candidate for Hedgehog pathway inhibitors. These factors include patients who are committed to taking medication daily and patients who have measurable disease so that response to treatment can be measured.

Monthly follow-ups are helpful to track medication usage, side effects, and treatment progress; if tumors are growing, the treatment may be stopped and the patient may go to medical oncology or radiation for further treatment.

“These patients need ongoing surveillance for the side effects of hedgehog pathway inhibitors, and also surveillance for additional skin cancers that may develop, because they are at high-risk for developing tumor resistance within the treated basal cell. They are also at very high risk of getting other skin cancers,” she said.

ADVERSE EVENTS

Muscle spasms are among the most common adverse effects from this treatment occuring in about 70% of patients in clinical trials of vismodegib, and more than 50% of patients in studies on sonidegib. Although more research is needed to confirm efficacy, treatments that might ameliorate muscle spasms include amlodipine, a calcium channel blocker; tizanadine and cyclobenzaprine, both muscle relaxants; and levocarnitine, a dietary supplement.

Due to the potential teratogenicity of hedgehog pathway inhibitors, women of childbearing potential should take two kinds of medically reliable birth control, according to Dr. Chang.

DISCLOSURES

Dr. Chang reported grants/research funding from Galderma Laboratories, L.P., Genentech, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corp., Regeneron, and Nuskin.

REFERENCES

Anne Lynn S. Chang, MD. “Systemic Therapy for Basal Cell Carcinoma.” American Academy of Dermatology 2018 Annual Meeting. Feb. 18, 2018. 1:00-4:00 pm.   

ClinicalTrials.gov. “Pembrolizumab With or Without Vismodegib in Treating Metastatic or Unresectable Basal Cell Skin Cancer.” https://www.clinicaltrials.gov/ct2/show/NCT02690948. Last updated June 22, 2017. Accessed Feb. 2, 2018.

Jaeyoung Yoon, MD, PhD, Anthony J. Apicelli III, MD, PhD, Tricia V. Pavlopoulos, MD. “Intracranial regression of an advanced basal cell carcinoma using sonidegib and itraconazole after failure with vismodegib.” JAAD Case Reports. January 2018. DOI:10.1016/j.jdcr.2017.11.001

Danial C, Sarin KY, Oro AE, Chang AL. “An Investigator-Initiated Open-Label Trial of Sonidegib in Advanced Basal Cell Carcinoma Patients Resistant to Vismodegib.” Clinical Cancer Research. March 15, 2016. DOI:10.1158/1078-0432.CCR-15-1588