August 2015, Vol 4, No 4

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Sonidegib Responses Improve by Use of Less Stringent Assessment Criteria in BCC


Using less stringent evaluation criteria for sonidegib for the treatment of locally advanced basal cell carcinoma (BCC) improved the complete response (CR) rate observed in the registration trial known as BOLT.

These data, presented in poster format, were reported by Michael R. Migden, MD, at the 2015 World Cutaneous Malignancies Conference. The poster was honored as winner of the Best Poster Abstract at the conference. Sonidegib received FDA approval for the treatment of recurrent locally advanced BCC on July 24, 2015.

When BOLT was being planned, the FDA requested more stringent evaluation criteria than those used for the single-arm, open-label pivotal phase 2 trial of vismodegib, known as ERIVANCE, in patients with advanced BCC.

BOLT was a multicenter, randomized, double-blind, phase 2 study that evaluated 2 dosages of the Hedgehog pathway inhibitor sonidegib (200 mg and 800 mg once daily) in patients with locally advanced BCC not amenable to curative surgery or radiotherapy or those with metastatic BCC. Both dosages of sonidegib demonstrated durable clinical benefit with acceptable safety and tolerability, with the 200-mg dose providing a more favorable benefit-risk profile than the 800-mg dose.

In BOLT, tumor response was determined using modified RECIST (BCC-mRECIST), a novel multimodal evaluation used to integrate assessments from MRI (per RECIST v1.1), standard and annotated color photography, and histology in multiple biopsies based on lesion surface area.

In ERIVANCE, tumor response was determined based on a combination of radiologic (per RECIST v1.0), clinical (photograph and ulceration), and histologic assessments.

“The modified RECIST was requested by the FDA,” said Migden, Associate Professor, departments of Dermatology and Head & Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston. “Having a better assessment includes surface area rather than just 1 long dimension.”

In addition, in BOLT, assessment of the composite overall response was performed by a single, independent review committee who reviewed all MRI, photo, and histology assessments, whereas in ERIVANCE, assessments were made by an independent panel for MRI, an independent panel for photography, and independent pathologists for histologic assessments.

“The biggest difference is that the complete response in BOLT required a CR or CR equivalent by all modalities, in addition to a negative histology,” said Migden. “In ERIVANCE, CR was achievable if you had a CR or partial response in either the photographic measurement or imaging measurement in the setting of a negative histology.”

Switching to the less stringent criteria improved the CR by central review in BOLT markedly. Using the more stringent criteria (BCC-RECIST), the CR was 5%, which jumped to 20% when using the less stringent BCC-RECIST-like criteria similar to those used in ERIVANCE. By investigator review, the respective CR rate increased from 9% to 27%.

“The jump in the CR puts it in the ballpark of the CR of ERIVANCE CR,” said Migden. “But using either assessment criteria produced an objective response rate that was higher numerically by percent than that in ERIVANCE.”

He emphasized that no hard conclusions can be drawn by comparing response rates between the trials by adjusting the evaluation criteria. The different clinical trial settings also prevent accurate comparisons.

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