Two studies published online May 13 in the Lancet Oncology provide data that impacts the clinical management of patients with advanced basal cell carcinoma (BCC).

One study, known as BOLT, profiles a new drug that is awaiting approval: sonidegib (Odomzo, Novartis). The manufacturer has filed for approval in Australia, the European Union, Switzerland, and the United States.

The other study, known as STEVIE, provides long-term safety data for vismodegib (Erivedge, Genentech), which was launched in 2012, from a setting representative of routine clinical practice.

Both drugs act as inhibitors of the Hedgehog signaling pathway.

Vismodegib and sonidegib are both effective and will expand treatment options for patients with advanced basal cell carcinoma, commented Michael R. Migden, MD, from the Mohs Surgery Center, Department of Dermatology, University of Texas M.D. Anderson Cancer Center, Houston. He is lead author on the new study with sonidegib, but has also been involved in clinical trials with vismodegib.

Dr Migden said that individual patients may respond to and tolerate these drugs differently, but it will be difficult to predict which drug will provide more optimal treatment.

Vismodegib Long-term Data

When vismodegib was launched, it was hailed as the “greatest advance yet” and lauded for its “remarkable effects.” Those comments were based on data from the ERIVANCE study, which formed the basis of approval of the drug (N Engl J Med. 2012;366:2171-2179).

Now, Catriona M. Maybury, MBChB, from King’s College London in the United Kingdom, and colleagues write in an accompanying comment that “vismodegib was the first-in-class SMO inhibitor and has delivered good short-come results. However, success has been limited by a high rate of resistance, and many patients discontinue treatment due to intolerable side-effects.”

“The interim report on the STEVIE trial demonstrates that treatment with vismodegib is tolerated in a patient population representative of the real-world situation and confirms the safety profile seen in previous studies,” senior author Johan Hansson, MD, PhD, from the Department of Oncology-Pathology at the Karolinska Institutet in Stockholm, told Medscape Medical News.

However, the high discontinuation rate of 80% with vismodegib in a setting representative of routine clinical practice is worrisome. Most of the treatment-related discontinuations were associated with grade 1/2 adverse events.

“Overall, the side-effect profile and ultimate failure of vismodegib remain barriers to medium and long-term therapy,” Dr Maybury and colleagues note.


When asked whether lowering the dose of vismodegib might increase compliance without sacrificing efficacy, Dr Hansson said: “To my knowledge, there is no documentation of clinical efficacy at a lower drug dose. In the STEVIE study, toxicities were dealt with by treatment interruptions or ‘drug holidays’ of up to 8 weeks. We have no indication that this approach compromised drug activity.”

“Trials are ongoing with alternate dosing schedules, which may increase long-term tolerability,” he added.

Dr Migden indicated that, in his clinical experience, patients with locally advanced disease may decide to discontinue therapy earlier than those with metastatic disease, even though they are experiencing similar adverse events.


“In many cases, the chronicity of specific adverse events may be more relevant in the decision whether to continue treatment than the severity of adverse events,” he said.

“When patients with locally advanced BCC visualize overwhelming improvement in BCC lesions, concern regarding their prognosis may decrease and in the setting of ongoing adverse events, they may decide to stop treatment even though they are benefiting from it,” Dr Migden said.

Dr Hansson concurred and added: “For some class side effects associated with on-target inhibition, such as dysgeusia, muscle spasms, and alopecia, there are no sufficient counter measures.”

BOLT Study With Sonidegib

BOLT was a multicenter double-blind randomized (1:2) phase 2 study in 230 patients with advanced BCC; 79 patients received sonidegib 200 mg daily (the lowest effective dose) and 151 patients received sonidegib 800 mg daily (the maximum tolerated dose) until disease progression or unacceptable toxicity.


Tumor assessments were based on evaluations from central review committee and investigators at baseline, weeks 5 and 9 after treatment, and every 8 weeks after that for the first 12 months. Modified Response Criteria in Solid Tumors (RECIST) was used to evaluate patients with locally advanced disease, and RECIST version 1.1 to was used to assess patients with metastatic disease.

“The modified RECIST complements the MRI findings used in RECIST version 1.1 with standard and annotated color photography, as required by the bidimensional WHO guidelines,” the investigators note.

BOLT Study Outcomes

Ninety-one percent of patients in the 200 mg group and 70% of patients in the 800 mg group were on treatment for 4 months or more.


The primary end point was overall response rate (ORR). Based on central review, 47% and 15% of patients with locally advanced and metastatic disease, respectively, achieved ORR in the 200 mg group; 35% and 17% of patients with locally advanced and metastatic disease, respectively, achieved ORR in the 800 mg group.

Disease control (complete response, partial response, and stable disease) rates were higher in the 200 mg group: 91% and 92% of patients with locally advanced and metastatic disease, respectively, compared with 78% and 83% for the 800 mg group. Investigator-assessed responses were not significantly higher.

Also based on central review, progression-free survival was not reached for patients with locally advanced disease across both groups (due to few patient deaths or disease progression) and was 13.1 months for the 200 mg group and 7.6 months for the 800 mg group of patients with metastatic disease.


Adverse events were experienced by 95% of patients. The most common adverse events were muscle spasms (49%), alopecia (43%), dysgeusia (38%), nausea (33%), increased serum creatine kinase (29%), fatigue (29%), and weight loss (27%).

Dose interruptions or reductions were reported in 32% and 60% of patients in the 200 mg and 800 mg groups, respectively. Similarly, treatment discontinuations were less frequent in the 200 mg group than in the 800 mg group (22% vs 36%).

“Our findings suggest that 200 mg sonidegib could be a promising treatment option for patients with advanced basal cell carcinoma, which is a difficult population to treat, and support the usefulness of SMO inhibitors,” the investigators conclude.

How Do the Drug Compare?

In their comment, Dr Maybury and colleagues state the inevitable: “The question for clinicians is how well the results compare with those of ERIVANCE, which led to the FDA approval of vismodegib.”


They indicate that the baseline patient demographics were similar across the two studies, and ORR and dropout rates were similar. However, the editorialists also note that “for metastatic basal cell carcinoma, the proportion of patients who achieved an objective response (13 [30%]) with 150 mg vismodegib was double that seen with 200 mg sonidegib.” They also note that “the overall rates of serious adverse events were similar in the two studies (25% with vismodegib and 24% with sonidegib), and the median duration of response was longer with sonidegib (8 months vs 14 months).”

However, BOLT lead investigator Dr Migden told Medscape Medical News: “The two studies should not be directly compared because BOLT used more stringent assessment criteria [modified RECIST] for determining response in patients with locally advanced disease and RECIST versions were different for assessment of the smaller cohorts of metastatic BCC, which is a heterogeneous disease where site of metastasis can significantly impact the response to any treatment.”

Dr Migden, also an investigator on the ERIVANCE study, told Medscape Medical News: “For patients with metastatic BCC, a disease with no known cure that is notoriously difficult to treat, disease control rates, progression-free survival, and duration of response are more significant indicators of benefit.”


In addition, patient selection is a potential source of bias in studies evaluating Hedgehog pathways inhibitors, according to Dr Maybury and colleagues. They point out that patients with Gorlin syndrome (basal cell nevus syndrome) who are also included in these studies may respond more favorably with Hedgehog pathway inhibitors. In addition, the lack of a standard definition of what constitutes locally advanced disease also introduces bias in patient selection.

STEVIE Study of Vismodegib

The STEVIE study was representative of routine clinical practice, the investigators comment. It enrolled 1227 patients with advanced BCC. These were adult patients (18 years and older) with histologically confirmed disease who were ineligible for surgery or whose disease recurred after two or more surgeries (i.e., patients within the approved indication for vismodegib).


All patients received oral vismodegib 150 mg on a continuous basis in 28-day cycles. Safety was the primary end point of the study.

Of the enrolled patients, 501 patients were included in the prespecified interim analysis. “There is no set date for the final analysis. The primary analysis will be done when roughly 1200 patients have the potential to be followed up for at least 1 year,” Dr Hansson told Medscape Medical News.

The evaluable patients had received at least one dose of the drug. Of the patients enrolled at data cutoff, 499 patients (468 with locally advanced disease and 31 with metastatic disease) had the potential to be followed for 12 months. However, the median duration of exposure to vismodegib was 36.4 weeks (36.2 weeks for locally advanced and 52.0 for metastatic disease).


Treatment was discontinued in 400 patients (80%). Of 499 patients, 98% had at least one adverse event. The most frequent adverse events were muscle spasm (64%), hair loss (62%), dysgeusia (54%), weight loss (33%), asthenia (28%), decreases appetite (25%), ageusia (22%), diarrhea (17%), nausea (16%), and fatigue (16%).

Serious adverse events were reported in 22% of patients. Treatment was discontinued for disease progression or adverse events. Discontinuation rates were 21%, 11%, and 2% for grade 1/2, grade 3, and grade 4 adverse events, respectively.

Notably, several patients who discontinued therapy with grade 1/2 adverse events did so despite achieving response. Response data available for patients who discontinued therapy showed that of patients who discontinued due to grade 1/2 adverse events, 73% had achieved a complete or partial response.


Of 482 patients with disease that was measurable by RECIST, 66.7% ORR was reported for patients with advanced basal cell carcinoma and 37.9% with locally advanced disease. Progression-free survival was 20.2 months (24.5 months for locally advanced and 13.1 months for metastatic disease).

“This interim analysis of the STEVIE trial is, to the best of our knowledge, the largest patient series ever reported with advanced basal cell carcinoma and provides important safety and efficacy associated with long-term vismodegib treatment,” the investigators conclude. They also note that no new safety signals were seen.

Most adverse events occurred within the first 6 months of treatment and clinical activity was similar to that seen in the registration ERIVANCE study, the investigators note. An analysis of a subset of patients with Gorlin syndrome was not undertaken in this interim analysis.


Dr Hansson indicated that STEVIE was conducted in an elderly population (median age, 72 years) and, thus, even elderly patients tolerate the drug. “Thus far we have not identified any particular factor associated with increased toxicity,” he told Medscape Medical News.

The BOLT study was funded by Novartis Pharmaceuticals Corporation. The STEVIE study was funded by F. Hoffmann-La Roche. Several investigators in the two studies declared ties with industry. Dr Migden reports receiving honoraria for advisory meetings with industry. One of Dr Maybury’s coauthors, Teresa Guerrero Urbano, PhD, from King’s College London, reports receiving personal fees from several companies.

Lancet Oncol. Published online May 13, 2015. BOLT abstract, STEVIE abstract, Comment