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Advancing BCC treatment


The success of the Hedgehog inhibitors in treating BCC as well as basal cell nevus syndrome (BCNS) has changed patients’ lives. Traditionally there was little we could do for patients with locally advanced or metastasized disease, but with understanding of the Hedgehog pathway, we can now intervene, experts say.

Recent understanding of the molecular basis of basal cell carcinoma (BCC) has propelled a fairly mundane skin cancer into the spotlight, with one targeted agent approved and another on its way for advanced, inoperable, sporadic BCCs. The success of the Hedgehog pathway inhibitors in treating BCC as well as basal cell nevus syndrome (BCNS) has changed patients’ lives, according to experts who spoke at the 3rd Annual World Cutaneous Malignancies Congress (San Francisco, October 2014).

“The majority of BCCs are simple, but some become locally advanced and even metastasize. Traditionally the options were very limited for these patients, but with understanding of the Hedgehog pathway and its key role in essentially all BCCs, we can now intervene,” said Aleksandar Sekulic, M.D., Ph.D., assistant professor of dermatology at the Mayo Clinic, Scottsdale, Arizona, who led the pivotal trial leading to the approval of vismodegib.[i]

RELATED: Diagnosing, managing aBCC in elderly patients

Hedgehog inhibitors are indicated for metastatic BCC (mBCC) patients or patients with locally advanced BCC (laBCC) where surgery is not considered appropriate. In the ERIVANCE clinical trial, which led to the FDA approval of vismodegib, the laBCC patients  had  (1) a lesion > 1 cm, (2) two or more recurrences and were considered unlikely to be cured with resection, or (3) a high likelihood that surgery will produce substantial morbidity or deformity (Figure).

NEXT: The emerging molecular landscape of BCC 


The emerging molecular landscape of BCC

James Macdonald, M.D., dermatologist at the Central Utah Clinic in Provo (who is also a dermatopathologist), described how molecular insights revolutionized the approach to treating advanced BCC. Nearly all sporadic BCCs have mutations in the Hedgehog pathway components patched (PTCH) or smoothened (SMO). The pivotal role of this signaling pathway was first recognized with the identification of the PTCH1 gene as the site of mutations underlying BCNS, or Gorlin syndrome. Subsequently, it became clear that the majority of sporadic BCCs have inactivating mutations of PTCH as well, and approximately 20% have activating mutations of SMO. These insights were critical for development of targeted therapies, such as vismodegib.

RELATED: Smoothened inhibitors provide new options for BCC treatment

 “We used to think that the defects within the Hedgehog signaling pathway were the primary or even the only driver in carcinogenesis,” Dr. Macdonald says. “Over the last five years we have learned a lot, and have found that BCC is more than a molecular ‘one trick pony,’” he says. “Now we know that in addition to this driver mutation, there are other mutational defects-such as in P53, which evolve over time and with UV exposure-that result in the various subtypes of BCC.” Current studies may elucidate the impact of such molecular defects on clinical behavior of BCC subtypes.

Hedgehog inhibitors, current and future


Hedgehog inhibitors, current and future

“Abnormal Hedgehog signaling appears to be involved in most, if not all, of BCCs, and its ubiquitous expression offers the potential for targeted therapy,” adds Karl D. Lewis, M.D., associate professor of medicine at the University of Colorado, Denver. “The approval of vismodegib and the potential for other agents to become available has changed our ability to treat this disease.”

The phase 2 ERIVANCE trial of vismodegib 150 mg was recently updated. The 30-month analysis showed a median progression-free survival of 9.3 months in metastatic patients and 12.9 months in patients with locally advanced disease; median duration of response of 14.8 months and 26.2 months, respectively; and median overall survival of 22.4 months in metastatic patients and not reached in the locally advanced cohort.[ii]

“Responses can be durable and patients can be treated with vismodegib for quite some time. You can go years without a recurrence,” Dr. Lewis has observes.

RELATED: BCC treatment with laser combination shows promise

A second Hedgehog inhibitor, sonidegib, produced equally impressive results in the phase 2 BOLT trial. The study met its primary endpoint of ≥ 30% objective response rate after a median follow-up of 13.9 months.[iii] With 200 mg (the dose for future trials), responses were observed at 12 months in 58% of patients with locally advanced BCC and in 8% with metastatic disease; the disease control rate was 91% and 92%, respectively; and median progression-free survival was 22 months and 13.1 months.

These drugs’ abilities to impact the natural history of advanced BCC is unclear, but Dr. Lewis believes that they will have an impact, at least in locally advanced cases. He notes that with vismodegib, 1-year overall survival reached 84%, compared with a historical rate of 58%.

Meeting a need


Meeting a need

In BCNS, or Gorlin syndrome, hundreds of BCCs develop secondary to activation of target genes of the Hedgehog pathway in cells that have lost both normal copies of PTCH.

“Vismodegib has been life-changing for Gorlin patients,” says Jean Y. Tang, M.D., Ph.D., associate professor of dermatology at Stanford School of Medicine in California, who co-led the U.S. Randomized Gorlin Study that tracked a total of 2,000 existing BCCs and followed 694 new BCCs.

RELATED: Vismodegib ‘life-changing’ for BCC patient populations

“Patients randomized to vismodegib had a remarkable reduction in new lesions,” Dr. Tang notes. “We found that vismodegib reduced the per-patient rate of new BCCs from 29 with placebo to 2 (P < 0.001) and reduced the size of existing BCCs by 65% over baseline, compared with an 11% change with placebo (P = 0.003). In some patients, all BCCs clinically regressed, and none progressed during treatment.”

Capturing real-world experience

The RegiSONIC Disease Registry Study is the first cohort study of the real-world treatment of patients with advanced BCC or BCNS. The aim is to follow 750 patients from 75 sites in the United States to determine how patients are being managed in actual clinical practice. As of June 2014, the study had enrolled 312 patients.

“We are asking how patients are being managed, can we treat them indefinitely [with Hedgehog inhibitors], and can we interrupt treatment to manage side effects?” she says.

RELATED: Vismodegib effective for treating challenging basal cell carcinomas

The first 131 patients have lesions mostly on the nose (19.8%), whose median lesion size is 20.5 mm and histopathology is primarily nodular (58.8%) and morpheaform/infiltrative (29.8%).

Neoadjuvant therapy under investigation


Neoadjuvant therapy under investigation

Neoadjuvant treatment might be the next clinical application of Hedgehog inhibitors. An open-label study of 15 patients with large BCCs led by Dr. Tang found that neoadjuvant vismodegib, given for three to six months, reduced the anticipated surgical defect size by 27% (P = 0.006).[iv] (See Figure, page 1). Vismodegib was not effective in patients who received less than 3 months’ treatment.

 “We saw dramatic shrinkage after 4 months of treatment, allowing Mohs surgery in difficult places, such as the eyelid,” Dr. Tang reports. A randomized, double-blind study is now evaluating this strategy.

Dealing with toxicities

Drug-related toxicities are on-target effects of tissues that rely on the Hedgehog signaling pathway. Common toxicities include muscle spasm, hair loss, taste abnormalities, and weight change. Sonidegib has also been shown to increase creatine kinase (CK) enzymes; whether this also occurs with vismodegib is not yet clear.

“The toxicity profile makes it difficult to maintain patients on long-term treatment,” Dr. Lewis says. “Most (toxicities) are low-grade, but over the long term it wears on them. I give dose holidays.”

Side effect management includes hydration and calcium, magnesium and potassium supplementation, muscle relaxants, calcium channel blockers, and drug holidays (intermittent dosing).

In the U.S. Randomized Gorlin Study, 54% of patients receiving vismodegib discontinued drug treatment because of adverse events, however, most patients elect to go back on treatment when tumors return, Dr. Tang says, noting, “The best management seems to be a short period of treatment interruption.” Genentech is sponsoring a trial of intermittent vismodegib: three months on, three months off, three months on.

Dr. Tang suggests that clinicians prepare patients for these toxicities.

“When patients stop treatment, they continue to lose hair for two months, but the hair grows back,” she says. “You can’t avoid these side effects, so it’s best to prepare patients.”



[i] Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171-9.

[ii] Sekulic A, Migden MR, Basset-Seguin N, et al. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: Final update (30-month) of the pivotal ERIVANCE BCC study. ASCO Annual Meeting. Abstract 9013. Presented June 2, 2104.

[iii] Drummer R, Guminski A, Gutzmer R, et al: Randomized, double-blind study of sonidegib (LDE225) in patients with advanced basal cell carcinoma. ESMO 2014 Congress. Abstract LBA33. Presented September 27, 2014.

[iv] Ally MS, Aasi S, Wysong A, et al: An investigator-initiated open-label clinical trial of vismodegib as a neoadjuvant to surgery for high-risk basal cell carcinoma. J Am Acad Dermatol. June 11, 2014 (early release online).


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