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Hedgehog inhibitors ‘game changers’ for advanced basal cell carcinoma
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NEW YORK — Hedgehog inhibitors have demonstrated high efficacy and durability for patients with advanced basal cell carcinoma, according to a speaker at HemOnc Today Melanoma and Cutaneous Malignancies.
However, these agents — which included FDA–approved agents vismodegib (Erivedge, Genentech) and sonidegib (Odomzo, Novartis) — can have long-lasting negative effects, according to Karl D. Lewis, MD, associate professor of medicine at University of Colorado Denver.
“As common as this cancer is, there is very little in terms of prospective data,” Lewis said.
Although radiation, surgical excision and Mohs micrographic surgery can be appropriate for some patients with high-risk basal cell carcinoma, more complicated cases may require systemic therapy.
The first study that led to an approval of a Hedgehog inhibitor was the ERIVANCE basal cell carcinoma phase 2 trial, which evaluated vismodegib in patients with metastatic or locally advanced disease. The trial met its primary endpoint of overall response rate, which was 42.9% in patients with locally advanced disease and 30.3% in patients with metastatic disease. Median duration of response was 7.6 months in both groups.
“Most patients derived some benefit from the treatment, but there were some patients who had primary resistance, and growth was their best response,” Lewis said. “That needs to be worked out, but the vast majority of patients get some sort of benefit.”
A 30-month update of these data showed duration of response among patients with locally advanced disease increased to 26.2 months, although the response rates remained relatively unchanged. Median OS was 33.4 months for the metastatic cohort and not reached for the locally advanced cohort.
“It’s important to point out that we don’t really know the natural history of metastatic basal cell carcinoma because there really has not been good follow-up for these patients,” Lewis said. “So, whether this 33 months is actually a change in the natural history of this disease is not known.”
The most common adverse events observed in the ERIVANCE trial included muscle spasms (68%), alopecia (64%), dysgeusia (51%) and decreased weight (46%). There were few grade 3 and grade 4 toxicities, and these included decreased weight (5%), muscle spasms (4%), fatigue (4%), decreased appetite (3%), nausea (1%) and diarrhea (1%).
“You would say this is a well-tolerated drug, but it’s very difficult for these patients to maintain their treatment long term,” Lewis said. “Even though the toxicities are relatively low grade, the fact that they are persistent makes it difficult for these patients to stay on treatment.”
Sonidegib was approved based on data from the BOLT study. That trial included patients with locally advanced basal cell carcinoma and metastatic disease randomly assigned to receive 800-mg (n = 128) or 200-mg (n = 66) doses.
Among patients with locally advanced disease, the ORR at 30 months was 56% (median duration, 26.1 months) in the 200-mg group and 45% (median duration, 23.7 months) in the 800-mg group. For patients with metastatic disease, the 30-month ORR was 8% (median duration, 24 months) with the 200-mg dose and 17% (median duration, not reached) with the 800-mg dose.
The FDA approved sonidegib at the 200-mg dose based on the better toxicity profile observed in that arm.
“The hedgehog inhibitors really were game changers,” Lewis said. “These were relatively large patient populations with prospective data showing very high efficacy. There are pros to these drugs: they are oral, they have high efficacy and you can get histologic clearance in some patients.
“But, the cons associated with them are that they are not well tolerated,” Lewis added. “Although most toxicities are low grade … the agents are difficult to stay on long term. You can also have primary and secondary resistance develop.”
There is rationale to evaluate immunotherapy in patients with resistant basal cell carcinoma, Lewis said. Reasons include that the immune system plays a critical role in the surveillance and eradication of nonmelanoma skin cancer, the tumor microenvironment of UV–associated tumors is immunosuppressive, and immunotherapy has activity in other cutaneous malignancies.
“Hedgehog inhibitors have an unclear impact on the natural history of metastatic basal cell carcinoma,” Lewis said. “Future needs include to look at resistance mechanisms and alterative targets. But, really I think the future in the short term is going to be looking at immunotherapy in this disease.” – by Alexandra Todak
Reference:
Lewis KD. Basal cell carcinoma update. Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; March 24-25, 2017; New York.
Disclosure: Lewis reports research funding from Novartis, Regeneron and Roche/Genentech, and consultant roles with Roche/Genentech and Sun Pharma.