New Advances in the Treatment of Basal Cell Carcinoma: Targeting the Hedgehog Signaling Pathway
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PRIORITY PRESS - 8th World Congress of Melanoma
Hamburg, Germany / July 17-20, 2013
Hamburg - Until recently, treatment options for advanced basal cell carcinoma (BCC) were limited and suboptimal. Research into novel therapeutic targets identified mutations in the hedgehog signaling pathway as a possible cause of new tumours or tumour acceleration in BCC and development of a class of small-molecule hedgehog pathway inhibitors was initiated. The first in class is now available worldwide for the treatment of adult patients with symptomatic metastatic or locally advanced BCC for whom surgery or radiotherapy is inappropriate. Studies are currently focused on long-term safety and optimizing dosing to minimize side effects and to determine whether these therapies can be administered in earlier stage disease.
Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec
Basal cell carcinoma (BCC) is the most commonly diagnosed malignancy worldwide, accounting for approximately 80% of all non-melanoma skin cancers, about 2 million cases. Surgery is still the most common treatment for BCC, especially early-stage and low-risk cases, but patients with advanced BCC (aBCC) often have lesions that are inappropriate for surgery or for which surgery would result in substantial morbidity or deformity. No effective systemic therapy existed for aBCC until the development of targeted therapies in recent years; the most advanced of these are the hedgehog (HH) signaling pathway inhibitors. The HH signaling pathway is actively repressed under normal circumstances, but it has been found to be altered and activated in almost all BCCs. In most cases, this is due to mutations in the genes expressing the cell membrane receptors Patched (PTCH1) or Smoothened (SMO). Over 90% of all BCCs carry one of these mutations.
“I am convinced that inhibitors of the HH signaling pathway offer new treatment options for patients with advanced BCC,” said Prof. Dirk Schadendorf, University Hospital Essen, Germany. Vismodegib and erismodegib (LDE225) are the furthest along in development, but most of the evidence has come with vismodegib, he noted. Vismodegib was the first HH pathway inhibitor to become commercially available when it was approved in the United States in 2012 for treatment of patients with metastatic BCC (mBCC) or with locally advanced BCC (laBCC) that has recurred following surgery or who are not candidates for surgery. It has since been approved elsewhere, most recently in July 2013 when it became available in Canada and in the European Union. Regulatory approval was based on the “spectacular” results of the pivotal Phase 2 study, ERIVANCE BCC, Prof. Schadendorf recalled, noting the investigator-assessed objective response rates (ORR) of 46% for mBCC and 60% for laBCC and tumour regression seen in the majority of cases (Sekulic A et al. N Engl J Med 2012;366:2171-79). At an 18-month update, ORR were comparable with the primary analysis, at 49% for mBCC and 60% for laBCC (Sekulic A et al. J Clin Oncol 2013;31[suppl]; Abstract 9037). Median duration of response increased from 13 to 15 months for mBCC and from 8 to 20 months for laBCC, “impressive results,” Prof. Schadendorf commented. “Excellent” results were seen for median progression-free survival (PFS) at 9.3 and 12.9 months for mBCC and laBCC, respectively, as well as 1-year survival rates of 79% and 93%. The main toxicities were muscle spasms (mostly mild), taste distortion, fatigue, nausea and weight loss, which affected one-third to one-half of patients. “It depends very much on the motivation of the patient whether this is an issue,” Prof. Schadendorf suggested. “There is definitely a need to find ways to cope with toxicity and also to find alternative strategies for dosing the drug for maintaining efficacy and increasing tolerability,” he stated.
Progress has also been made with erismodegib, Prof. Schadendorf reported. A Phase 1 study demonstrated strong antitumour activity in BCC and the drug was well tolerated with similar in-class adverse effects (Tawbi HA et al. J Clin Oncol 29:2011;29[suppl]:Abstract 3062). In patients with aBCC, 1 complete response (CR) with histologic clearance and 4 partial responses (PR) were seen, as well as “impressive responses” in tumour shrinkage. Erismodegib has also been administered as a topical treatment for 4 weeks in a Phase 2 trial (Skvara H et al. J Invest Dermatol 2011;131:1735-44), but “Although the responses to topical administration showed clear activity, development has slowed because of problems with the formulation,” Prof. Schadendorf noted.
“Similarly to other targeted therapies, resistance to HH pathway inhibitors can be expected,” Prof. Schadendorf cautioned. “We are observing resistance in our patients in an average time of 1 year, so we need to systematically collect these resistant tumours for analysis,” he urged.
mBCC with Distant Metastases
Treatment with HH pathway inhibition may have the potential to improve survival of patients with distant metastases, according to the results of a study presented by Dr. Aleksandar Sekulic, Mayo Clinic, Scottsdale, Arizona, USA. Data from 50 treated cases of mBCC with distant metastases previously identified in a retrospective review of case reports and case series published between 1981 and 2011 (McCusker M et al. J Clin Oncol 2012;30[suppl]:Abstract 8585) were compared with those from 45 vismodegib-treated patients who participated in the 18-month update of the Phase 1 and 2 trials. One-year overall survival (OS) was 84% in the clinical trial patients compared with vs 59% for cases in the literature. Median OS was 2.5 years vs 2.0 years, respectively. A total of 24 (53%) trial patients were alive at the last assessment compared with 15 (30%) patients in the literature.
Global Safety Analysis
The latest analysis from a global safety study confirmed the safety profile of vismodegib seen in previous studies, according to Prof. Jean-Jacques Grob, Hôpital de la Timone, Marseille, France. In the STEVIE study, adults with laBCC or mBCC receive vismodegib 150 mg once daily until progressive disease, unacceptable toxicity, or withdrawal. The third interim analysis included 278 patients with laBCC and 22 with mBCC from 10 European countries and Canada. Median treatment duration was 177 days. Treatment-emergent adverse events reported in 93% of patients were typically mild or moderate. The most common were muscle spasm (59%), alopecia (49%), and dysgeusia (41%). Treatment was discontinued in 44% of patients. Preliminary efficacy data in 251 patients showed a high rate of tumour control, with 44 CR, 100 PR, and 98 SD.
Real-world Clinical Practice
Data are limited on treatment of aBCC and Gorlin syndrome in routine clinical practice due to the lack of a universally accepted definition for aBCC, Dr. Sekulic explained. The RegiSONIC disease registry study aims to determine how clinicians define and treat aBCC in the real world by evaluating the effectiveness, safety, and utilization of systemic (HH pathway inhibitors and other chemotherapies) and local (surgery, radiation, destructive, and topical) treatments in patients with aBCC or Gorlin. The definition of aBCC will be left to the discretion of the study clinician so as to evaluate how real-world clinicians determine when BCC is advanced. Enrollment target is 1000 patients at 100 US academic and community practices. “The study is envisioned to run for 8 years,” Dr. Sekulic noted.
Future Combination Therapy
Despite the success seen with HH pathway inhibition in aBCC, “we might want to go further and add another therapy,” suggested Prof. Reinhard Dummer, University of Zurich Hospital, Switzerland. Pharmacologic inhibition of EGFR signalling has been shown to reduce tumour growth in mouse models of HH-GLI driven BCC (Eberl M et al. EMBO Mol Med 2012;4:218-33), “so it might be a good idea to add on EGFR inhibitors,” Prof. Dummer proposed. Interferon-alpha administered by intralesional injection is approved for treatment of BCC,” he added, noting that it has been shown to induce Fas expression and apoptosis in HH pathway activated BCC cells (Chengxin L et al. Oncogene 2004;23:1608-17). BCL2, a downstream target of GLI, is overexpressed in BCC, and targeting BCL2 expression with specific inhibitors might represent another approach. The tumour suppressor gene P53 Wt is present in many BCCs, Prof. Dummer noted, “So it might make sense to use inhibitors of its negative regulator, MDM2.” Adding a PI3K/P13K-mTOR inhibitor has been shown to delay the development of SMO-inhibitor resistance in neuroblastoma in mouse models (Buonamici S et al. Sci Transl Med 2010;2:51-70). Prof. Dummer also recalled that in a recent study in mice, SMO-inhibitor resistant tumours were successfully treated with itraconazole plus arsenic trioxide. (Kim J et al. Cancer Cell 2013;23:23-34).
ERIVANCE BCC and STEVIE have demonstrated the efficacy of HH pathway inhibition in aBCC patients and the 18-month data have shown durability of response. Further trials of this targeted therapy have been carried out into the possibility of reducing adverse events by intermittent dosing. Other issues being addressed are whether it could be used at an earlier stage in the disease, and its potential role in a neoadjuvant setting.