¹⁸F-FDG PET/CT Monitoring of Response to PD-1 Blockade in Metastatic Basal Cell Carcinoma

Abstract

A 73-year-old woman with history of metastatic basal cell carcinoma presented with a large spinal mass demonstrating a high mutational burden of 111 mutations/Mb. She underwent T12 corpectomy and T10-L3 posterior spinal fusion followed by adjuvant radiation. After 2 years of surveillance, FDG PET/CT and a contrast enhanced MRI revealed recurrence, prompting salvage therapy with the Hedgehog signaling pathway inhibitor, sonidegib, that only transiently stabilized the disease. An off-label treatment with the programmed death protein 1 (PD-1) inhibitor, pembrolizumab, was initiated. Serial FDG PET/CT showed gradual decline in tumor metabolism over the next 12 months, leading to complete metabolic response.

Figure 1.

Post-contrast T1-weighted turbo spin echo axial 1.5T MR image shows tumor deposit enhancement at left T11 neuroforamina (A); serial fused FDG PET/CT axial images at bone window level show hypermetabolism at left T11 neuroforamina before sonidegib (SUVmax=9.9) (B) with short-term disease stabilization but eventual response failure after 5 months with marked increase in lesion hypermetabolism (SUVmax=30.2) (C) at which time pembrolizumab was started; the lesion metabolic activity decreased after 2 months of PD-1 blockade therapy (SUVmax=7.4) (D) leading to complete metabolic response (SUVmax=1.9) after an additional 6 month of immunotherapy (E). Basal cell carcinoma is the most common nonmelanoma skin malignancy worldwide. However, occurrence of metastases is extremely rare with incidence of less than 0.55% (1). The prognosis for metastatic BCC is generally poor despite treatment (2). Hedgehog signaling pathway mutations are actionable targets for treatment of metastatic disease with small molecule inhibitors, vismodegib and sonidegib (3). A phase 1 nonrandomized study of vismodegib showed a response rate of 30% (95% confidence interval, 16% to 48%, p=0.001) and median response duration of 7.6 months in 33 patients with metastatic BCC (4). Toxicity included alopecia which was also observed in our patient after treatment with sonidegib. Currently there is no standard treatment option for patients with advanced or metastatic BCC after failing Hedgehog inhibition. It has been postulated that due to high tumor mutational burden including immune checkpoint amplification, PD-1/PD-L1 axis blockade may be beneficial (5, 6). Multiple PD-1 inhibitors have shown efficacy in treating advanced cutaneous malignancies, such as melanoma and Merkel cell carcinoma. In a phase II study of 84 patients with BCC that had failed first-line hedgehog inhibitors, treatment with the PD-1 inhibitor, cemiplimab, led to an objective response rate of 31% with estimated progression-free survival of 19 months (7). Given the lack of available treatment options, high burden of pathogenic mutations, and following the case review in a multidisciplinary tumor board, our patient was started on a PD-1 blocker, pembrolizumab, as off-label therapy, upon treatment failure with sonidegib. Metabolic response as documented on FDG PET/CT has been reported only in a single case report of a patient who was treated with vismodegib (8). However, our case illustrated that FDG PET/CT may also be helpful in assessing response in patients with metastatic BCC who fail Hedgehog signaling pathway inhibition and are treated further with immune checkpoint inhibition.