Combined cemiplimab and radiotherapy for advanced basal cell carcinoma: A case report

Abstract

Advanced basal cell carcinoma may be treated with systemic therapies such as hedgehog pathway inhibitors or programmed cell death protein 1 inhibitors, namely cemiplimab. We report a case of a 70-year-old man with a nodulo-infiltrative advanced basal cell carcinoma over the right posterior neck and scapula. The patient had a partial response to the hedgehog pathway inhibitor, vismodegib. The tumour progressed, and the patient was switched from vismodegib to radiotherapy combined with cemiplimab, which led to a significant reduction in pain, bleeding, and tumour size. A combined treatment approach with radiotherapy and cemiplimab may be beneficial for advanced basal cell carcinoma cases that progress after treatment with hedgehog pathway inhibitors.

Introduction

Basal cell carcinoma (BCC) is the most common skin cancer, with a reported 1.2 million cases diagnosed globally in 2019. ¹ Fortunately, BCC is highly curable and unlikely to metastasize. ² Treatment options include topical agents (imiquimod and 5-fluorouracil), photodynamic therapy, surgical removal including Mohs micrographic surgery, and radiotherapy. ³ Metastatic and/or locally advanced tumours, hereby termed advanced basal cell carcinoma (aBCC), represent 1%–10% of BCC cases, ⁴ and can be challenging to treat due to tumour factors such as size, extent of invasion, anatomical location, and/or expected morbidity or mortality with conventional surgery or radiotherapy.^3,5 These cases may respond to systemic treatment with a hedgehog pathway inhibitor (HHI) such as vismodegib ² (Hoffmann-La Roche, Mississauga, ON, Canada). Advanced BCCs that are resistant, intolerant, or progressive despite HHI treatment may be treated with cemiplimab (Sanofi, Toronto, ON, Canada), a programmed cell death protein 1 (PD-1) inhibitor. ²

Strategies to enhance the efficacy of existing treatment options are also being explored. ² Multiple reports have described a combination of radiation with systemic therapy for a variety of advanced skin cancers. For instance, combined ipilimumab and radiotherapy was found to reduce tumour size in patients with advanced melanoma, including at tumour sites outside of the radiated field. ⁶ This phenomenon is referred to as the abscopal effect, whereby localized radiotherapy triggers tumour regression at distant sites. ⁷ Combined radiotherapy and HHIs have also been trialled for a small number of aBCC patients.^8,9 Here, we report a case of aBCC managed with combined cemiplimab and radiotherapy after initial HHI therapy.

Case report

A 70-year-old man presented to a dermatologist with a 20-year history of a slowly enlarging tumour over his shoulder, associated with pain and bleeding (Figure 1). Physical examination revealed a large, 17 cm by 13 cm, deeply ulcerated tumour with a rolled, shiny edge over his right posterolateral neck and scapula. Inferiorly, over his right upper back, there was a second 6 cm by 4 cm, ulcerated tumour with a rolled edge, which had been developing for 3–4 months. There was no associated cervical or axillary lymphadenopathy. Medical comorbidities included hypertension, type 2 diabetes, and a 55-year history of cigarette smoking. There was no family history of skin cancer. Incisional biopsies of both tumours on the back revealed a diagnosis of nodulo-infiltrative BCC. A computed tomography (CT) scan revealed a large soft-tissue defect infiltrating into the right trapezius, a second 4.7 cm by 3.1 cm mass abutting the deltoid muscle, and a third lesion measuring 16 mm invading into the C2 spinous process. A multidisciplinary team determined that the patient was not a suitable candidate for surgery or curative radiotherapy due to the size and depth of the tumours. The patient was started on vismodegib at a dose of 150 mg daily. After 4 months of treatment, the largest tumour decreased to 10 cm by 9 cm. However, the patient discontinued vismodegib for 4 months due to intolerable side effects, including nausea and vomiting, requiring hospitalization. He then restarted vismodegib on a reduced dose schedule of 150 mg daily for 1 week each month, which was subsequently increased to 10 days each month.

Figure 1.

Timeline of clinical evolution and treatment.

Two years after an initial partial tumour response to vismodegib, disease progression occurred, with an increase in tumour size, pain, and bleeding. A CT scan revealed a large soft-tissue defect measuring 1.1 cm in maximal thickness, with no evidence of metastatic disease. Vismodegib was discontinued, and the patient was initiated on cemiplimab immunotherapy. After 5 months of cemiplimab monotherapy, the tumours continued to slowly enlarge and bleed, with the largest tumour measuring 30 cm by 10 cm on physical examination. The patient reported a pain rating of 3/10 (0 being no pain and 10 being the worst pain the patient could imagine). Palliative radiotherapy, 20 Gy in five fractions, was administered in concert with cemiplimab, with the goal of reducing bleeding and pain. One month later, there was a significant reduction in bleeding, tumour size, and pain, with the patient reporting a pain rating of 1/10. Three months after combined cemiplimab and radiotherapy, the larger tumour measured approximately 11 cm by 9 cm, with the inferior ulcer measuring 5 cm by 2.5 cm (Figure 2). The patient reported a pain rating of 0/10.

Figure 2.

aBCC tumour with an exophytic component over the right posterolateral neck and scapula. (a) On presentation, (b) prior to treatment with combined cemiplimab and radiotherapy, (c) 1 month after combined cemiplimab and radiotherapy, and (d) 3 months after combined cemiplimab and radiotherapy.

Discussion

To our knowledge, this is the first case report of aBCC treated with combined cemiplimab and radiotherapy. Interestingly, 50% of the patients in the trial leading to the approval of cemiplimab for aBCC had received previous cancer-related radiotherapy, but details about the radiotherapy regimen, including timing relative to cemiplimab initiation, were not reported. ¹⁰ Prior to the approval of cemiplimab, another PD-1 inhibitor, pembrolizumab, had been successfully used as a neoadjuvant treatment for an aBCC patient who did not respond to HHI treatment. ¹¹

HHIs have also been utilized in combination with radiotherapy for aBCC.^12–14 Concurrent vismodegib and multi-site radiotherapy led to a partial response in a case of multifocal BCC. ¹² In addition, HHIs have been used as an induction treatment prior to radiotherapy. A case series of 12 aBCC patients utilized this approach and found that 88.8% of patients were progression-free 40 months after initial HHI treatment. ⁸ Overall, these reports suggest that adjunct and/or concurrent targeted therapy and radiation may provide some clinical benefit for patients with aBCC.

Combined radiotherapy and immunotherapy may increase the likelihood of the abscopal effect, ¹⁵ although this has not been reported for aBCC specifically. Combined cemiplimab and radiotherapy led to a complete response in five out of seven patients with inoperable advanced cutaneous squamous cell carcinoma. ¹⁶ Grimaldi et al. showed that ipilimumab, a cytotoxic T-cell lymphocyte antigen-4 (CTLA-4) antibody, followed by radiotherapy, led to an abscopal response in 52% of patients with advanced melanoma. ⁶ Overall survival was prolonged for patients who had an abscopal response compared to those who did not. ⁶ The median time to achieve an abscopal response was 1 month after radiotherapy in Grimaldi et al.’s study, ⁶ though timing can range from 3 to 39 months. ⁷ Several reports of advanced or metastatic melanoma patients have also observed an abscopal effect of combined radiotherapy and PD-1 blockade. ¹⁵ It is clear from these studies that there is currently no standardized method for achieving an abscopal effect. ¹⁵ It has been observed in cases where radiotherapy was administered before, during, or following immunotherapy.^6,15

Several mechanisms have been proposed to explain the effects of combined radiation and immunotherapy. Radiotherapy causes direct tumour cell death, but it has also been shown to induce cell death by augmenting the immune response.^15,17 Radiation causes tumour DNA damage and subsequent tumour-associated antigen release, including damage-associated molecular patterns, resulting in improved cytotoxic response activation.^15,18 Radiotherapy also increases major histocompatibility complex class 1 expression on tumour cells and releases cytokines that activate C8⁺ T-cells, leading to improved tumour infiltration and destruction.^7,17,19

In summary, this report highlights the potential efficacy of combined cemiplimab and radiotherapy in a patient with aBCC who progressed despite treatment with HHI. Future research on immunotherapy and concurrent radiotherapy in terms of patient selection, dosing, and treatment timing is needed to determine the best management options for aBCC patients who fail treatment with HHI and cemiplimab.