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More than 90% of patients with locally advanced basal cell carcinoma (BCC) of the head and neck achieved locoregional control (LRC) with vismodegib (Erivedge) and radiation therapy (RT), a small clinical trial showed.

LRC at 1 year was 91% after vismodegib induction therapy followed by concurrent vismodegib and RT. The overall response rate was 63% after induction and 83% after concurrent therapy.

After a median follow-up of 5.7 years, both progression-free survival (PFS) and overall survival (OS) were about 80%, reported Christopher A. Barker, MD, of Memorial Sloan Kettering Cancer Center in New York City, at the Multidisciplinary Head and Neck Cancers Symposium in Phoenix.

"About 20% of patients did not complete the induction course of vismodegib due to adverse events," said Barker. "In clinical practice, we think this really necessitates careful selection and monitoring of patients who are undergoing this treatment strategy. We found the adverse events were quite typical for what you would expect with vismodegib and high-dose radiation therapy. The patients enjoy durable, significant, and clinically meaningful improvement in quality of life."

"Future studies may be difficult to perform because this is a relatively rare patient population who is difficult to enroll in clinical trials, but this study does provide some important benchmark data for practice. We really think this represents a novel molecularly targeted drug and curative-intent radiation therapy for locally advanced cancer."

'Remarkable' Study

The study is "remarkable for several reasons," according to Nancy Y. Lee, MD, also of Memorial Sloan Kettering but not an investigator in the trial. In a on the study, she noted that the trial is the first clinical evaluation of RT for unresectable BCC. Second, the study is one of few to evaluate curative-intent RT and an oral targeted therapy. Third, the study showed that an appropriate rationale can lead to a successful trial of combined-modality therapy. Finally, the high rate of disease control and mature follow-up suggest that patients with unresectable, locally advanced BCC should be considered for treatment with vismodegib and RT.

"The authors are to be congratulated for their tremendous work that could set a new standard for these patients," Lee wrote. "The next obvious question is whether this combination can be effective for patients with resectable BCC to improve cosmetic outcomes when complex reconstructive surgery would be otherwise necessary."

In response to a question from the audience, Barker said no patient had any lasting adverse effects from the treatment.

Asked about plans for a phase III trial, given that the phase II study required almost 6 years to complete, Barker said no phase III study is in the works at this point.

"That's an interesting thought. Could we launch a phase III trial and get it done in the career span of anyone in this room?" he said. "We may be looking at other potential strategies incorporating these therapies, but whether we go on to a phase III at this point, it's hard to say."

The most common type of cancer, BCC has a high cure rate when treated early, but locally advanced, unresectable BCC is more difficult to cure, Barker noted. RT alone achieves LRC in about 60% of cases.

The hedgehog inhibitor vismodegib is approved for metastatic BCC or disease that is not amenable to surgery or RT. The agent induces responses in about 60% of patients and a median PFS of 12.9 months, Barker continued. Preclinical studies have suggested that hedgehog inhibition may radiosensitize malignant cells, providing a rationale for evaluating vismodegib and RT in combination to improve outcomes in locally advanced, unresectable BCC.

Investigators enrolled patients with BCC of the head and/or neck that was ≥2 cm or node positive and considered unresectable. Patients with metastatic disease were excluded, as were patients with prior exposure to a hedgehog inhibitor or RT that would preclude safe additional RT.

The treatment regimen consisted of vismodegib daily for 12-14 weeks, then concurrent vismodegib and RT for 7 weeks (50-70 Gy, 25-35 fractions). The primary endpoint was LRC at 1 year, and key secondary endpoints were PFS and OS.

Key Findings

The study population consisted of 24 patients (18 men) who had a median age of 68. Most patients had more than one reason for inability to resect, including large disease burden or excessively morbid, anticipated substantial morbidity and/or deformity, and patient refusal because of anticipated morbidity. Adverse prognostic factors included primary tumor >4 cm (50%), recurrent tumor (67%), perineural spread (42%), and invasion of muscle, bone, or cartilage (67%).

Five patients were excluded from response analysis because of inability to complete vismodegib induction. Response assessment occurred after completion of induction therapy, 3 months after concurrent therapy, and 1 year after completing concurrent therapy.

Objective response rate increased over time, from the end of induction to post-concurrent therapy. The 91% LRC at 1 year compared favorably with the historical rate of 60% with vismodegib alone, Barker noted.

The most common all-grade adverse events (AEs) were dysgeusia (83%), fatigue (75%), myalgia (75%), radiation dermatitis (46%), alopecia (38%), oral mucositis (33%), weight loss (33%), anorexia (25%), and nausea (21%). Grade ≥3 AEs were uncommon and included oral mucositis and hyponatremia in two (8%) patients each.

"The quality-of-life results in this study were notable," he said. "Many patients with unresectable basal cell carcinoma suffer from tumor-related symptoms and other functional aspects. During the induction phase, there was a marked improvement in quality of life. The improvement in quality of life persists after the completion of treatment."

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