Targeted Therapies in Basal Cell Carcinoma

Jean Tang, MD, PhD

Although basal cell carcinoma (BCC) is the most common type of skin cancer, it typically does not advance beyond locally contained disease. However, in some patients, BCC can progress to a point of significant local invasion such that surgical or radiation treatment is not indicated. A minority of patients with BCC experience an advanced, metastatic form of the disease that is typically fatal.^1,2

Until recently, few options existed to treat patients with significant locally invasive or advanced metastatic BCC. During the past several years, improved understanding of the Hedgehog signaling pathway and its impact on progression and recurrence of BCC has led to development of several new therapies that target this signaling pathway. Specifically, these agents inhibit the pathway by blocking Smoothened (Smo), a 7-pass transmembrane G protein coupled receptor-like protein. Nearly all patients with BCC have defects of the Hedgehog pathway that result in an inability to block Smo; this ultimately results in release of inhibition of glioma-associated protein (Gli) through the suppressor of fused molecule (Sufu). The Gli familyof proteins are transcription factors that are capable of activating a number of target genes that produce an oncogenic effect on the cell. Thus, blocking Smo in patients with Hedgehog signaling pathway defects can reverse this activity.¹

Basal Cell Carcinoma, Superficial

SOURCE: The Web site of the National Cancer Institute

(http://www.cancer.gov)

“A number of targeted agents are currently being evaluated. The first, which was FDA-approved in January 2012, is vismodegib (Erivedge), which is indicated for locally advanced or metastatic BCC,” said Jean Tang, MD, PhD, assistant professor of Medicine, Stanford University Medical Center. “By definition, locally advanced BCCs are those for which surgery or radiation cannot cure the BCC.”

“We have seen a great response rate to vismodegib—somewhere around 50% of overall responders in clinical trials. Overall responders are people who have complete response or partial response,” said Tang. “Several companies are developing agents that also target Smoothened, the key receptor in the Hedgehog pathway. These agents are currently in clinical trials.”

FDA approval of vismodegib was based on a single, open-label, international trial. Of 33 patients with metastatic BCC, approximately 30% showed a partial response, but none had complete response. In patients with locally advanced BCC (n = 63), 22% and 20% showed a partial and complete response, respectively.³Vismodegib was relatively well tolerated; the most frequent adverse events seen in ≥10% of patients in clinical trials were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia.⁴

Other Smo inhibitors in the pipeline include LDE225, BMS-833923, TAK-442, LY2940680, and LEQ506.¹LDE225, a selective and potent inhibitor of Smo, is currently in phase II studies in patients with BCC and other cancers.⁵A phase I dose-escalation study in patients with advanced solid tumors, with positive results, was presented at the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting.⁶A phase II trial for patients with locally advanced or metastatic BCC was initiated in 2011 and is currently ongoing. A second trial is evaluating the efficacy of LDE225 in patients who have progressed on another Smo inhibitor (vismodegib), which should provide information regarding cross-resistance between these agents. The remaining agents are currently in phase I studies.¹

Resistance to Smo inhibitors may occur, resulting in growth of previously-responding tumors or new tumor development. “So far there has been one patient with medulloblastoma treated with a Smo inhibitor who displayed resistance. There can be mutations in the Smoothened itself so it doesn’t bind to the drug,” said Tang. “In preclinical mouse models, resistance due to amplification of Gli, which is a transcription factor downstream of Smoothened, as well as activation of other signaling pathways, such as PI3 kinase, have occurred. It is not well known exactly what is responsible for resistance to these agents.”

Clinical trials are currently seeking to define mechanisms to overcome resistance to Smo inhibitors. “When the patient develops resistance [to Smo inhibitors], there are clinical trials that may be considered. Some inhibitors may prove to be more potent and efficacious against those tumors that have developed resistance to vismodegib, and also to the standard therapy that has been used for years [cisplatin],” Tang said.

Given these new therapeutic options, future opportunities for practicing clinicians to improve outcomes in their patients with BCC are encouraging. “Overall, metastatic advanced BCCs are quite rare, but at least now there are targeted therapies against Smoothened that seem to have a good overall response and progression-free survival so far. Those data look very promising, and it certainly seems to beat the prior standard of care, which is cisplatin,” said Tang. “However, clinical trials really haven’t compared Smoothened inhibitors or targeted therapies against chemotherapy that is cisplatin-based.”

Tang is currently leading clinical trials on arsenic trioxide for patients with advanced BCC at Stanford Medical Center. “Arsenic trioxide hits at the level of Gli—so it works downstream of Smoothened.”

“The overall take-home message is that if you have a patient with advanced or metastatic BCC where surgery or radiation is not indicated, the first choice of therapy should be a Smoothened inhibitor, and the only one that is FDA-approved currently is vismodegib. If that one doesn’t work, second-line therapy would be to consider clinical trials of other Smoothened inhibitors, of cisplatin, or of arsenic trioxide.”

References

1. Cowey CL. Targeted therapy for advanced basal-cell carcinoma: vismodegib and beyond.Dermatol Ther (Heidelb). 2013;3:17-31.
2. Macha MA, Batra SK, Ganti AK. Profile of vismodegib and its potential in the treatment of advanced basal cell carcinoma.Cancer Manag Res.2013;5:197-203.
3. Erivedge [prescribing information]. South San Francisco, CA: Genentech; 2012. Available at:http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203388lbl.pdf. Accessed October 9, 2013.
4. Keating GM. Vismodegib: in locally advanced or metastatic basal cell carcinoma.Drugs.2012;72(11):1535-1541.
5. Pan S, Wu X, Jiang J, et al. Discovery of NVP-LDE225, a potent and selective Smoothened antagonist.ACS Med Chem Lett. 2010;1:130-134.
6. Rodon Ahnert J, Baselga J, Tawbi HA, et al. A phase I dose-escalation study of LDE225, a smoothened (Smo) antagonist, in patients with advanced solid tumors.J Clin Oncol. 2010;28(suppl 15s: abstract 2500).