Hedgehog signaling inhibitors show promise for basal cell carcinoma

Issue: November 10, 2015

Two different Hedgehog signaling inhibitors have demonstrated activity for metastatic basal cell carcinoma, according to the results of two phase 2 trials.

Results from the STEVIE and BOLT trials demonstrated vismodegib (Erivedge, Genentech) and erismodegib (sonidegib [Europe], Novartis) may be new treatment options for patients with advanced basal cell carcinoma. These agents block Hedgehog signaling by selective inhibition of SMO expression.

However, vismodegib — which garnered FDA approval following the ERIVANCE study (Sekulic A, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1113713.) — may be limited by its toxicity profile.

The Hedgehog pathway signaling is aberrantly activated in 95% of basal cell carcinomas, according to study background. Hedgehog signaling inhibitors may be a treatment option for patients with unresectable basal cell carcinoma, which often occurs on the head and neck.

STEVIE trial

Nicole Basset-Seguin, MD, a professor of medicine at the Hospital St. Louis in Paris, and colleagues conducted the ongoing, multicenter, open-label STEVIE study to assess the safety and efficacy of vismodegib in a scenario similar to routine practice for patients with an ECOG performance status of 0 to 2 and who were ineligible for surgery.

The analysis included 499 patients (locally advanced disease, n = 468; metastatic disease, n = 31) who received 150 mg vismodegib in 28-day cycles for at least 12 months until disease progression or unacceptable toxicity. Researchers assessed patients on a monthly basis on day 1 of each treatment cycle for safety, which served as the primary endpoint of the study.

Only 20% of the patients continued vismodegib beyond the 12-month period. Forty-six percent of the patients discontinued by choice or due to adverse events, whereas 14% of patients discontinued due to disease progression.

The median duration of vismodegib exposure was 36.4 weeks (range, 17.7-62.0).

Overall, 98% of the patients had adverse events, the most common of which were muscle spasms (64%), alopecia (62%) and dysgeusia (54%). Serious adverse events occurred in 22% of the patients.

Thirty-one patients died, 21 of which were attributed to the adverse events. The researchers deemed 19 of these deaths unrelated to vismodegib, whereas two were possibly treatment related.

Researchers noted the toxicities seemed to be dose-dependent as the rate of adverse events increased as the duration of treatment increased.

The overall response rate (ORR) — which served as the study’s secondary endpoint — was 66.7% (95% CI, 62.1-71) among patients with locally advanced basal cell carcinoma, with a 33.8% complete response rate and a 32.9% partial response rate. The ORR of patients with metastatic disease was 37.9% (95% CI, 20.7-57.7), with a 6.9% complete response rate and a 31% partial response rate.

“Our results show that treatment with vismodegib adds a novel therapeutic modality from which patients with advanced basal cell carcinoma can benefit substantially,” Basset-Seguin and colleagues wrote.

BOLT study

Michael R. Migden, MD, an associate professor in the departments of dermatology and plastic surgery at The University of Texas MD Anderson Cancer Center, and colleagues of the BOLT study evaluated data from 230 patients with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma not eligible for surgery or radiation. Researchers sought to compare 200-mg and 800-mg doses of erismodegib daily in the BOLT study.

The proportion of patients who achieved an objective response after a minimum of 6 months of treatment served as the primary endpoint.

Median follow-up was 13.9 months (range, 10.1-17.3).

The primary efficacy analysis showed that 36% (95% CI, 24-50) of patients assigned 200-mg erismodegib and 34% (95% CI, 25-43) assigned 800-mg achieved an objective response. Among patients with locally advanced disease, 43% (95% CI, 28-59) assigned 200 mg had an objective response, as did 38% (95% CI, 28-48) of those assigned 800 mg.

For patients with metastatic disease, 15% (95% CI, 2-45) of patients assigned 200 mg and 17% (95% CI, 5-39) of the 800-mg group achieved an objective response.

Thirty-two percent of patients in the 200-mg arm had adverse events that led to dose reductions or interruption, and 22% of these patients discontinued treatment. In the 800-mg cohort, 60% of patients experienced an adverse event that led to dose reductions or interruption and 36% discontinued treatment due to an adverse event.

The most common grade 3 to grade 4 adverse events included elevated creatine kinase (200 mg, 6%; 800 mg, 13%) and lipase concentration (5% in both arms). Serious adverse events occurred in 14% of patients assigned 200 mg and 30% of patients assigned 800 mg.

“Quality of life for patients with advanced basal cell carcinoma can be poor because of the emotional distress caused by scarring and disfigurement, particularly for patients with visible lesions,” Migden and colleagues wrote. “Most patients treated with [erismodegib] in our study experienced stable or improved quality of life, which is an important consideration for this population.

“Our findings suggest that 200 mg [erismodegib] could be a promising treatment option for patients with advanced basal cell carcinoma, which is a difficult population to treat,” Migden and colleagues wrote.

‘Rapidly evolving’ treatment

Selection of patients may be a source of bias in both these studies, Catriona M. Maybury, MBChB, MRCP, a research fellow at Kings College in London, and colleagues wrote in an accompanying editorial.

“Patients with Gorlin’s syndrome represented about 20% of the patients in the STEVIE study, although the numbers in the BOLT study is unknown,” Maybury and colleagues wrote. “This subgroup of patients might respond differently to Hedgehog pathway inhibitors than most patients who develop basal cell carcinoma.”

Still, these results point to the recent progress that has been made in the treatment of basal cell carcinoma.

“The management of advanced basal cell carcinoma is rapidly evolving owing to advances in noninvasive imaging techniques, increasing adoption of micrographic surgical techniques, the introduction of SMO inhibitors, and continuing development of other drugs, some of which are in trials,” Maybury and colleagues wrote. “As clinicians become adept at tailoring treatment to the characteristics of patients and tumors, clinical outcomes for patients with basal cell carcinoma will continue to improve.” – by Anthony SanFilippo

References:

Basset-Seguin N, et al. Lancet Oncol. 2015;doi:10.1016/S1470-2045(15)70198-1.

Maybury CM, et al. Lancet Oncol. 2015;doi:10.1016/S1470-2045(15)70233-0.

Migden MR, et al. Lancet Oncol. 2015;doi:10.1016/S1470-2045(15)70100-2.

Disclosure: The BOLT study was funded by Novartis. The STEVIE study was funded by Hoffmann-La Roche. Migden reports personal fees from Eli Lilly, Genentech and Novartis. Basset-Seguin was a visiting scientist at Genentech and reports a consultant role with Roche. Maybury reports no relevant financial disclosures. Please see the full studies for a list of all other researchers’ financial disclosures.