Case
A 56-year-old female patient presented with complaints of sinus congestion, diplopia and right orbital pain associated with proptosis. A magnetic resonance imaging (MRI) scan noted a 6.5 cm mass involving the right maxillary and frontal sinuses. A biopsy demonstrated a poorly differentiated neoplasm that stained positively for cytokeratin (CAM 5.2) and focally for epithelial membrane antigen (EMA), consistent with sinonasal undifferentiated carcinoma (SNUC). She underwent transfacial resection including right orbital exenteration with final staging as pT4bNxM0. Due to a positive posterior margin, she underwent postoperative radiation (5,940 cGy) concurrently with high-dose cisplatin (100 mg/m2, 3 cycles).
One year after initial diagnosis, she presented with cervical radiculopathy and was found to have T1 metastatic recurrence (4.5 x 2 cm) as well as extensive liver metastases (12 lesions, largest 11.5 x 5.2 x 9.5 cm). She received palliative radiation therapy to the T1 metastasis.
Next-generation sequencing of the liver biopsy (Foundation Medicine, Cambridge, MA) revealed several genomic alterations, including equivocal amplifications of CD274 (PD-L1) and PDCD1LG2 (PD-L2). PD-L1 22C3 assay resulted in a tumor proportion score (TPS) of 0%. The liver biopsy was also found to be positive for p16 and therefore potentially indicative of a human papilloma virus (HPV) infection.
The patient completed 6 cycles of carboplatin (AUC 5)/etoposide 100 mg/m2 days 1-3 with peg-filgrastim support. Her best response to therapy was a 65% reduction of the largest liver target lesion. Due to mild progression after the 6th cycle of chemotherapy, single-agent pembrolizumab 2 mg/kg every 3 weeks was started with excellent clinical tolerance; however, a computed tomography (CT) scan after four cycles demonstrated radiographic progression of liver metastases along with elevation of lactate dehydrogenase (LDH) to 1201 U/L (313-618 U/L), alkaline phosphatase (ALP) to 251 U/L (38-126), AST to 74 U/L (14-36), and ALT to 80 U/L (9-52).
Because of atypical clinical benefit, pembrolizumab was continued for a fifth cycle, now in combination with celecoxib 200 mg/day in hopes of suppressing constitutive expression of immunosuppressive molecule indoleamine 2,3-dioxygenase (IDO1).  During the time of progression, repeat genomic testing was done on a lymph node biopsy, which revealed the same alterations of CD274 and PDCD1LG2 though now classified as variance of unknown significance (VUS).
Three weeks after starting celecoxib, LDH decreased to 675 U/L, ALP improved to 158 U/L, and AST and ALT remained stable.  Dual checkpoint inhibition with pembrolizumab 200 mg and ipilimumab 1 mg/kg was started every 3 weeks for the 6th and 7th cycles of treatment.
Three days after the last treatment she experienced grade II autoimmune dermatologic toxicity manifesting as diffuse pruritic rash, which responded to topical steroids. Six days after treatment she was admitted to an outside hospital with polyneuropathy of her upper extremities, generalized weakness, and anorexia. Additionally, she was found to have a sodium of 122 mg/dL secondary to syndrome of inappropriate antidiuretic hormone (SIADH) as well as mildly worsening liver function tests (LFTs). Celecoxib was stopped. An MRI of the brain did not show evidence of metastases but did show meningeal enhancement, concerning for leptomeningeal spread. There was also no evidence of hypophysitis, and adrenocorticotropic hormone (ACTH) and cortisol levels were normal. A lumbar puncture was negative for malignancy or infection in cerebrospinal fluid.
Due to the perceived poor prognosis and the patient’s declining condition, the patient was recommended hospice care by the inpatient team. The treating oncologist, however, requested a subsequent CT scan of the liver to document true disease progression, but the imaging demonstrated marked improvement of hepatic metastases. Because of this significant improvement in target lesions, it was thought that her decompensation was due to an immune-related adverse event (irAE) rather than disease progression.
The patient was started on prednisone 1 mg/kg daily with marked improvement of her performance status and eventually improved to baseline while continuing a steroid taper over two months. 11 weeks after the last immunotherapy, she returned to her oncologist with a CT scan demonstrating continued improvement of liver metastases. LFTs were within normal limits at this time. She did not continue immunotherapy; however, she was advised to restart celecoxib 200mg/day. Two weeks later, she developed the onset of autoimmune hepatitis manifesting as fever: ALP 1445 IU/L, AST 190, ALT 203. She started back on prednisone 1 mg/kg and slowly tapered to 5 mg/day.
A CT scan 24 weeks after last immunotherapy showed continued ongoing durable response with continued regression and/or stability of remaining target liver lesions. LFTs were back to normal despite continuing celecoxib and low-dose prednisone. She was then advised to stop prednisone completely and, within two days, had recurrence of autoimmune hepatitis: ALP 148 IU/L, AST 140 IU/L, ALT 178 IU/L. She was advised to stop celecoxib and resume a prednisone taper, and liver enzymes remained normal thereafter.
Although the patient had oligometastatic recurrences over the subsequent years, she had good disease control and a relatively indolent course managed with single-agent pembrolizumab plus stereotactic body radiation therapy (SBRT). Unfortunately, the patient ultimately died four years after she started immunotherapy due to COVID-19 complications.