A Phase II Single Arm Trial of Induction and Concurrent Vismodegib with Curative Intent Radiation Therapy for Locally Advanced, Unresectable Basal Cell Carcinoma of the Head and Neck

Purpose/Objective(s)

Locally advanced, unresectable basal cell carcinoma (BCC) can be treated with radiation therapy (RT), but locoregional control (LRC) rates are unsatisfactory. Vismodegib is a hedgehog pathway inhibitor (HPI) active in BCC which can radiosensitize cancer cells in preclinical models. We evaluated the combination of vismodegib and RT for patients with locally advanced, unresectable BCC. The hypothesis was that the combination of the vismodegib and RT would yield higher rate of LRC than historically observed with RT or vismodegib alone.

Materials/Methods

In this multicenter, single-arm, phase II study, patients with locally advanced, unresectable BCC of the head and neck ≥2 cm in size and/or with nodal metastasis but without distant metastasis received 12 weeks of induction vismodegib at the FDA approved dose and frequency (150 mg orally once daily) followed by 7 weeks of concurrent vismodegib and RT to 66-70 Gy in 33-35 fractions. The primary endpoint was LRC rate at 1 year after the end of treatment. Secondary endpoints included objective response according to RECIST, progression-free and overall survival (PFS and OS), adverse events according to CTCAE v4.1 and patient reported quality of life (PRQOL) according to the Skindex-16. Tumor genomic sequencing was an exploratory endpoint in a subgroup of patients.

Results

Twenty-four patients received vismodegib; 5 were unable to complete 12 weeks of induction therapy. LRC was achieved in 91% (95% CI 68-98%) of patients at 1 year. Response rate was 63% (95% CI 38-84%) after induction vismodegib and 83% (95% CI 59-96%) following concurrent vismodegib and RT. With median follow up of 5.7 years, 1-year PFS and OS rates were 100% and 96%, and at 5-year PFS and OS rates 78% and 83%. Distant metastasis or BCC-related death has not been observed. The most frequent treatment-related adverse events were dysgeusia, fatigue and myalgias occurring in 83%, 75% and 75% of patients. Seven serious adverse events occurred in 4 patients, none of which were related to protocol therapy. No grade 4-5 treatment-related adverse events occurred. PRQOL demonstrated clinically meaningful improvements in all subscales, with emotions and functioning improvements persisting for a year after the end of treatment. All patients that underwent tumor sequencing were found to have an oncogenic loss of function mutation in PTCH1, but no functional alterations were detected in SMO, SUFU or GLI1.

Conclusion

This is the first prospective trial of RT for locally advanced, unresectable BCC of the head and neck and demonstrated the combination of vismodegib and RT yielded high rates of LRC and PFS, and durable improvements in PRQOL. In practice, this combined modality approach may improve the outcomes of select patients with locally advanced, unresectable BCC of the head and neck.