Pembrolizumab induced remission of recurrent and metastatic sinonasal squamous cell carcinoma after overcoming checkpoint‐inhibitor pneumonitis: A case report and literature review

Abstract Background For programmed death‐ligand‐1 (PD‐L1) positive recurrent and metastatic head and neck squamous cell carcinoma (R/M‐HNSCC), KEYNOTE‐048 and KEYNOTE‐040 clinical trials recently approved pembrolizumab monotherapy as first‐line treatment. However, recurrent and metastatic sinonasal squamous cell carcinoma (R/M‐SNSCC) was excluded from these clinical trials and treatment reports of immune‐checkpoint inhibitor (ICI) in R/M‐SNSCC are sparse. Immune‐related adverse events (irAEs) are known to occur during ICI treatment and some of these such as checkpoint‐inhibitor pneumonitis (CIP) can be fatal. ICI rechallenge after severe irAEs is debated. Case We describe a case of a 65‐year‐old male with R/M‐SNSCC who is currently in remission with pembrolizumab monotherapy. He developed high‐grade pneumonitis during the course of treatment warranting ICI discontinuation but has since tolerated full‐dose pembrolizumab for 10 months now which is holding his disease stable. Our approach toward restarting full‐dose pembrolizumab was by monitoring the patient's response to an initial low dose of pembrolizumab with concomitant oral steroid immunosuppression to control CIP. Conclusion Clinicians should weigh the risk‐to‐reward ratio of ICI rechallenge after improvement of high‐grade CIP, particularly for selected patients with aggressive tumors such as R/M‐SNSCC and prior treatment response. Under close monitoring, ICI resumption at a low dose and assessing patient tolerance with concomitant immunosuppression may be a reasonable approach to reintroducing ICI after high‐grade CIP in these patients.


| BACKGROUND
Sinonasal squamous cell carcinoma (SNSCC) is an uncommon but aggressive type of head and neck squamous cell carcinoma (HNSCC) affecting fewer than 1 person per 100 000 individuals in the United States. 1 In contrast to oral and laryngeal cancers which constitute the majority of HNSCC, symptoms due to the primary SNSCC tumor are frequently innocuous. This often results in diagnosis once the tumor is advanced and poorer survival rates. 1,2 The therapeutic landscape of recurrent and metastatic (R/M) HNSCC has recently been revolutionized following the discovery of their programmed death-ligand-1 (PD-L1) expression which are targets for immunecheckpoint inhibitor (ICI) therapy. 3,4 However, R/M-SNSCC were excluded from these key trials exploring ICI despite their similar immunogenicity. 5,6 Pembrolizumab is an anti-PD1 class of ICI that enhances the body's immune response to kill tumor cells. However, the same pathway that is responsible for the efficacy of the treatment also causes immune-related adverse effects (irAEs) which are excessive reactions to normal cells due to reinvigoration of the immune system. 7 Checkpoint-inhibitor pneumonitis (CIP) is an uncommon but potentially life-threatening irAE. 7,8 Current literature has mixed evidence regarding ICI rechallenge after improvement of irAEs. [9][10][11] Moreover, reports of ICI treatment, irAE incidence, and ICI rechallenge in HNSCC, particularly in SNSCC, are sparse. This case report describes a case of R/M-SNSCC that is currently under remission following successful ICI rechallenge after overcoming CIP.

| CASE PRESENTATION
In March 2018, a 65-year-old male presented to the outpatient department for evaluation of yellow discoloration of eyes and palms for 3-month duration ( Figure 1). PET-CT scan revealed a liver mass measuring 1.5 cm, a mass in the left nasal cavity, and spinal metastases. Biopsy revealed squamous cell carcinoma in the posterior nasal cavity and a liver biopsy confirmed the same pathology. He was initially started on 5-FU, carboplatin, and cetuximab, however, the liver mass continued to progress. The patient was started on pembrolizu- DLCO/VA 4.69 (97% predicted). As similar findings could also be seen with pneumonitis due to drug toxicity, the patient was advised to begin oral prednisone 20 mg daily and to defer pembrolizumab initially for 4 weeks while monitoring response to steroids.
Four weeks later, in March 2021, the patient reported improvement in his cough and shortness of breath and was, hence, taken off steroids. However, the annual restaging PET/CT scan done 1 month later revealed the progression of organizing pneumonia of both lungs compared to the previous CT scan done in February 2021 ( Figure 3).
Re-evaluation for COVID-19 and repeat sputum cultures were negative. Based on these imaging results, a trial of oral prednisone 20 mg daily for 2 weeks was advised while the patient awaited bronchoscopy to evaluate for recurrent cancer. At this juncture, it was decided to proceed with pembrolizumab since his risk of downward clinical course was higher with metastatic cancer compared to drug toxicity. This decision was based on the clinical improvement of the patient's pulmonary symptoms, our doubts if recurrent cancer was the cause of progressive lung findings in the recent CT scan, and prior response to pembrolizumab which had resulted in partial remission. Pembrolizumab was challenged at half-dose 200 mg at this office visit, however, the patient developed hypoxia at the tail end of treatment (SpO 2 dropped to the mid-80s) and had to be rushed to the emergency room.
A week later, the patient underwent bronchoscopy evaluation for lung biopsy. There was no evidence of infectious etiology, metastases or flow immunophenotypic evidence of lymphoproliferative disorder, however, the lung biopsy revealed organizing pneumonia with features of underlying acute lung injury along with patchy fibrosis and honeycombing suggestive of chronic lung disease. Post-bronchoscopy, the patient's SpO 2 dropped to the mid-80s and required intubation followed by ICU admission. Following extubation, his oral prednisone dose was increased to 40 mg daily for 3 weeks.
In May 2021, 3 weeks after the above events, it was decided to pause pembrolizumab until the patient's lung performance had improved and to continue oral steroids with an appropriate tapering dose till that time. The patient understood that while this would put him at risk of tumor progression, the decision had to be weighed against the risk of repeated insult to his compromised lungs with the immunotherapy. He has reported no cough or shortness of breath since April 2022.
PET/CT scan are being planned for future follow-ups. prognosis. 6,12 The incidence of CIP in the patient group receiving pembrolizumab monotherapy was 2.4% and less than 1% in KEYNOTE-040 and KEYNOTE-048 respectively. 3,4 Although rare in incidence, CIP can be fatal and accounts for 35% of PD-1 and PD-L1 inhibitor-related deaths. 7 Clinicians should suspect CIP at its earliest reported symptoms: the most common symptoms are dyspnea and cough while fever and chest pain are less frequently reported. 8,13 The onset of these symptoms during ICI therapy warrants a detailed evaluation to assess disease progression, CIP, or incidental events related to cancer or prior medical conditions. 14 ICI interruption coupled with immunosuppression with steroids is the cornerstone of treatment for CIP. 13,15,16 Current guidelines on ICI rechallenge after irAE are based on clinical observations and expert consensus but not prospective clinical trials. 13,15,16 Our patient initially had Grade 2 CIP warranting temporary Previous studies have suggested that ICI rechallenge may be done with caution following severe irAE. 11,17 Haanen et al have suggested that single-agent rechallenge with concurrent immunosuppression after high-grade irAE may be done in select patients with wellcontrolled initial irAE if the oncologic situation requires it. 11 We did not consider rechallenging with an alternate class of ICI as the patient had shown excellent prior response to pembrolizumab and given the high tumor PD-L1 expression.
It is possible that our patient is treated at significant risk and is fortunate to have cancer under control as a result. However, R/M-SNSCC is an aggressive tumor with limited treatment options.
We would like to reemphasize that the decision to rechallenge pembrolizumab was made after careful consultation with the patient who fully understood the risks of CIP recurrence. Further, the volume and dosing schedule of pembrolizumab were modified from the standard due to concerns about irAE recurrence. As is the case with our patient, the ICI rechallenge should be decided only after evaluating its benefits and risks with the patient. Our patient is being closely monitored for any adverse effects.
There is emerging literature suggesting that irAE development is significantly associated with response to ICI. 18  with this association as patients who are on ICI for longer periods tend to develop irAEs and are hence more likely to respond to treatment. 21

| CONCLUSION
We present this case to discuss the treatment outcomes of anti-PD1 in PD-L1 positive R/M-SNSCC and to emphasize the importance of early diagnosis and management of CIP. Clinicians should weigh the risk-to-reward ratio of ICI rechallenge after improvement of highgrade CIP, particularly for selected patients with aggressive tumors such as R/M-SNSCC and prior treatment response. Under close monitoring, ICI resumption at a low dose and assessing patient tolerance with concomitant immunosuppression may be a reasonable approach to reintroducing ICI after high-grade CIP in these patients. Further work is needed in this area to dictate practice algorithms.