Complete response of a large basosquamous carcinoma following treatment with cemiplimab and vismodegib

Abstract

The anti-PD-1 antibody cemiplimab has demonstrated effectiveness in the setting of locally advanced basal cell carcinoma (BCC) and squamous cell carcinoma. We describe a case of a large, locally invasive basosquamous carcinoma, an aggressive type of BCC, invading the left sternocleidomastoid muscle with near compression of the left internal jugular vein producing a severe anaemia secondary to ulceration and chronic blood loss. The patient was initially started on vismodegib monotherapy but failed to respond. He was then started on cemiplimab in addition to vismodegib. Improvement was noted after one cycle. After 21 cycles of cemiplimab, the left shoulder ulcerated lesion was completely re-epithelialised. He remains in complete remission after 31 cycles of cemiplimab in addition to vismodegib.

Background

Basosquamous carcinoma (BSC) is a BCC with histopathological features of both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).^{1 2} BSCs tend to be more aggressive in nature when compared with traditional BCCs with a propensity for distant metastases in up to 7.4% of cases.² Vismodegib, a medication that inhibits the hedgehog pathway, was initially Food and Drug Administration (FDA) approved for the treatment of metastatic and/or advanced BCC. However, vismodegib is poorly tolerated and is frequently discontinued due to intolerable side effects. Furthermore, 50% of patients may not experience an objective response to vismodegib.³ Up until recently there were no second-line options. In February of 2021, the FDA approved the PD-1 inhibitor cemiplimab for locally advanced or metastatic BCC who previously failed or were unable to tolerate vismodegib.^{4 5} Cemiplimab is also FDA approved for metastatic or locally advanced SCC. Little is known about the responsiveness of BSC to immunotherapy. In this case report, we describe a complete response (CR) of a large, locally invasive BSC after initiation of cemiplimab.

Case presentation

A man in his 60s with no prior chronic health issues history presented to the emergency department with worsening shortness of breath and a 22 cm x 15 cm ulcerated, red plaque extending medially to the level of the mandible and laterally to the point of the shoulder, with further extension anteriorly and posteriorly several centimetres onto his anterior and posterior chest wall (figure 1A). One 2.5 cm x 2.5 cm crusted pink nodule and an additional 7 cm x 4 cm ulcerated plaque were also present on his scalp. He was profoundly anaemic with a haemoglobin of 4.5 mg/dL secondary to chronic blood loss from the ulcerating shoulder mass. The patient reported that the mass had slowly grown in size over the past decade and 6 months prior to presentation, the lesion had started to weep requiring bandaging.

Figure 1.

(A) A 22 cm x 15 cm basosquamous carcinoma prior to initiation of cemiplimab and (B) complete re-epithelisation noted after 31 cycles, the patient remains in CR. CR, complete response.

Investigations

Contrast-enhanced CT scan of the neck demonstrated an invasive mass extending from the clavicle to the angle of the mandible with invasion of the left sternocleidomastoid. The mass abutted the left internal jugular vein without compression (figure 2A). Two 1.5 cm wedge-shaped portions of nodular skin were biopsied from the left shoulder mass and demonstrated infiltrative carcinoma with basaloid features and squamous differentiation present at the peripheral and deep specimen edges (figure 3A). At low power, the lesion was composed of smaller basophilic cells with a high nuclear to cytoplasmic ratios, arranged in sheets and larger cells with glassy eosinophilic cytoplasmic contents consistent with keratin arranged in nests. The shave biopsy stained diffusely positive for BerEp4 (figure 3B).

Figure 2.

(A) Mass extending from the clavicle to the angle of the mandible with invasion of the left sternocleidomastoid. The mass abuts the left internal jugular vein without compression. (B) Mild soft tissue thickening at the site of the previous large infiltrating shoulder mass, measuring approximately 9 mm, consistent with scarring.

Figure 3.

(A) Arrow points at the basaloid features of the lesion. Arrow head points at the squamous features of the lesion (H&E 300×). (B) BerEp4 immunohistochemistry is diffusely positive in the lesional cells, a diagnosis of basal carcinoma with extensive squamous features is favoured, basosquamous carcinoma (500×).

Mutational analysis revealed a mutational burden of 78 mutations/megabase. Histologic examination of the two scalp lesions were consistent with poorly differentiated SCC.

Differential diagnosis

A non-melanoma skin neoplasm such as SCC or BCC was strongly suspected, given the location, presentation and known prevalence of these neoplasms in his demographic. However, histologic examination of the left shoulder mass revealed basaloid features with squamous features. In addition, immunostaining with Ber-EP4 was diffusely positively and the mutational analysis revealed a high mutational burden. These findings were strongly suggestive of BSC as BSC demonstrates an infiltrative growth pattern and may show areas of both BCC and SCC with or without a transition zone.⁶ Furthermore, the basaloid cells typical demonstrate a higher mitotic activity compared with the indolent growth of the superficial nodular BCCs, and the squamoid components often contain eosinophilic cytoplasms, with frequent mitoses and intercellular bridges.⁶ Immunostaining with the monoclonal antibody Ber-EP4 demonstrates strong and diffuse staining to the basaloid cells and is useful in differentiating between BSC and basaloid SCC, as SCC does not typically stain with Ber-EP4.^{7 8} The presence of a transition zone is variable and staining with Ber-EP4 may demonstrate gradation from the strongly positive basaloid areas to weakly positive in the intermediate zone as the tumour transitions towards a squamous phenotype.⁸ As demonstrated in our case, the biopsy obtained from the left shoulder mass was diffusely positive for Ber-EP4, with basaloid features and squamoid differentiation, consistent with a BSC and dissimilar to a poorly differentiated SCC with basaloid phenotype.

Treatment

He was started on vismodegib 150 mg daily, however, he returned to the hospital with a left clavicle fracture with the medial aspect of the clavicle protruding through the skin neoplasm. Given the poor initial response of his BSC to vismodegib, cemiplimab was started in addition to daily vismodegib. This was not considered off-label use of cemiplimab as it was FDA approved for BCC at the time and although controversial, BSC has traditionally been considered an aggressive BCC variant.^{4 6} The patient was not part of a clinical trial. Although there is limited evidence in the literature supporting the effectiveness of dual therapy with vismodegib and immune checkpoint inhibition, the patient was tolerating vismodegib. Furthermore, there is no evidence to suggest that cemiplimab, in addition to vismodegib, leads to increased toxicity.

Outcome and follow-up

Improvement was noted at his first follow-up visit 3 weeks following cycle number one of cemiplimab with re-epithelisation noted at the edges of the shoulder lesion. His anaemia had resolved. After 21 cycles, the ulcerated lesion of the left shoulder was completely re-epithelialised (figure 1B) along with the two lesions on his head. Repeat contrast enhanced CT scan approximately 24 months after starting cemiplimab demonstrated mild soft tissue thickening at the site of the previous large infiltrating shoulder mass, approximately 9 mm in diameter, consistent with scarring (figure 2B). Natera Signatera, an mPCR-next-generation sequencing assay used to detect circulating tumour DNA in the plasma of patients with previously diagnosed cancer, was performed and was negative. He remains in complete remission after 31 cycles (24 months) of cemiplimab and 26 months of vismodegib 150 mg daily. He continues to live independently with minor limitations that do not impair his ability to perform activities of daily living to include the inability to fully abduct his left arm and neck stiffness.

Discussion

CRs have been reported with cemiplimab in the setting of BCC (table 1). Five CRs were reported in the phase II trial leading to cemiplimab’s FDA approval for metastatic or advanced BCC, and two other cases were described in case reports.^{5 9 10} During the phase II trial, the overall time to response (partial and complete) was 4.3 months. For those with a CR, the time to CR ranged from 6 to 14 months with a durability of response ranging from 1 to 16 months at the time of data cut-off. There were no cases of disease progression in the CR group. The median duration of response had not been met at the time of publication.⁵ De Giorgi et al describe a CR of a BCC of the ear after approximately 20 months of every 3 week dosing of cemiplimab. The patient was in remission 8 months after stopping therapy.⁹ Dumman et al describe a CR of a 20 mm x 45 mm BCC of the nasolabial fold that demonstrated a CR after 12 months of cemiplimab therapy.¹⁰ The patient remained in CR 4 months after discontinuing therapy.¹⁰ It is worth noting that these case reports described smaller, localised BCCs confined to either the face or the ear. In addition, we describe a BCC with basaloid features and squamous differentiation that stained diffusely positive for BerEp4, consistent with a BSC, an aggressive type of BCC. In our case report, not only was the skin neoplasm a BSC, but extensive, causing significant morbidity to include profound anaemia and an extruded clavicular fracture.

Table 1.

Summary of publications reporting CR of BCC or BSC

Study	Study type	Number of CR	Skin neoplasm	Treatment	Duration of treatment	Time to complete response	Durability of response	Progression
Stratigos et al. Lancet Oncology. 2021	Phase II trial	5	Locally advanced BCC	Cemiplimab 350 mg every 3 weeks	9 cycles	6–14 months	1–16 months at the time of data-cut-off for CR group	None reported at time of data cut-off
De Giorgi et al. Clinical Exp Dermatology. 20219	Case report	1	Locally advanced BCC	Cemiplimab 350 mg every 3 weeks	9 cycles	Not mentioned	8 months after discontinuation of therapy	No
Dumman et al. Jama Dermatology. 202110	Case report	1	Locally advanced BCC	Cemiplimab 350 mg every 3 weeks	14 cycles	12 months	4 months after discontinuation of therapy	No
Sahuquillo-Torralba et al. Indian J Dermatol Venereol Leprol. 201911	Case report	1	Locally advanced BSC	Visdeomegid 150 mg daily	7 months	7 months	9 months after discontinuation of therapy	No
Apalla et al. Eur J Dermatol. 201912	Case series	2	Locally advanced BSC	Visdeomegid 150 mg daily	6 months	6 months	12 and 18 months after discontinuation of therapy	No

BCC, basal cell carcinoma; BSC, basosquamous carcinoma; CR, complete response.

CRs of BSCs have been reported with vismodegib therapy with two separate publications describing a total of three CRs of BSCs to vismodegib monotherapy (table 1).^{11 12} Sahuquillo-Torralba et al describe a large, ulcerated, 13 cm BSC involving the forehead, glabella, dorsum of the nose and inner aspect of the upper and lower eyelids with a CR after 7 months of vismodegib monotherapy.¹¹ The patient remained in CR 9 months after discontinuation of therapy.¹¹ Apalla et al described two CRs after the use of vismodegib for BSC of the nose.¹² In both cases, the response was sustained at 12 and 18 months.¹² It is less likely vismodegib contributed to the patient’s significant response given the initial lack of response after 60 days of vismodegib monotherapy.

PATIENT’S PERSPECTIVE.

• As a young adult, I was involved in a head-on automobile collision that left me hospitalised in excruciating pain for 5 days. The doctors involved in my care paid little attention to me and did not explore the extent of my injuries. I was sent home after 5 days, still in excruciating pain. I spent weeks in bed. Once I started walking, I noticed a clicking sensation in my left hip along with left ankle pain. I was finally sent to an orthopaedic surgeon who discovered a torn gluteus medius muscle requiring surgery. After this surgery, a torn ankle ligament was discovered. Approximately 6 years later, it was discovered my right wrist was likely broken in the accident as well. After this experience, my opinion of the medical profession was low. I noticed the lesions on my head and shoulder months prior to my initial presentation. I took care of the areas on my own and did my best to keep them covered at all times as I did not want to worry my family. My 6-year-old grandson noticed one of the lesions on my head and told me that I need to go to the doctors. I listened to his advice and went to the hospital shortly thereafter. I was told that my case was so severe that the odds of a meaningful recovery were slim. A surgeon told me that surgery was not an option as the shoulder mass was close to the carotid artery and there was a chance I could lose my arm. Radiation was offered to the scalp lesions, but not the shoulder lesion. I declined radiation due to the potential risks. I was offered vismodegib with the chance that it could help. In the meantime, there was discussion about a new therapy called cemiplimab that could help, however, I had to try vismodegib first. A 2 month period went by. I was essentially a dead-man walking. I experienced the clavicle fracture and at this time, I had to tell my family that I was going to try a medication that may kill me. I knew from self-study that the odds of a complete response were possible but very small. What I read showed promised and I was encouraged by Dr Shirai. The response was miraculous and I cannot rule out divine intervention. I have maintained a positive attitude throughout the past two-plus years, even when I am experiencing side effects from the medications. It was not until recently that I told my family just how bad of a situation I was in. I never wanted them to worry about my health. As far as current limitations, I cannot lift my arm straight above my head and I have stiff neck. I can reach up and grab things off the top shelf, however, I cannot tilt my head back to chug a bottle of beer!

Learning points.

• Basosquamous carcinoma (BSC) is a basal cell carcinoma (BCC) with histopathologic features of both BCC and SCC. Although the terminology is controversial, BSC is typically considered an aggressive type of BCC.

• Cemiplimab has shown to be effective in the setting of locally advanced BCC in those who either failed vismodegib monotherapy or were unable to tolerate it.⁵ Little is known about the effectiveness of cemiplimab specifically for BSC.

• We present a patient with locally advanced BSC who initially progressed on vismodegib, but then experienced a complete response after cemiplimab was added.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).