Durable tumor regression and restoration of neurologic function after treatment with anti-PD-1 in patients with functionally unresectable cutaneous squamous cell carcinoma with perineural spread into the cavernous sinus

doi:10.21203/rs.3.rs-3220673/v1

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Case Report

Durable tumor regression and restoration of neurologic function after treatment with anti-PD-1 in patients with functionally unresectable cutaneous squamous cell carcinoma with perineural spread into the cavernous sinus

https://doi.org/10.21203/rs.3.rs-3220673/v1

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Journal Publication

published 01 Sep, 2023

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Purpose

To describe tumor response and cranial nerve function outcomes after administration of anti-PD-1 to patients with cutaneous squamous cell carcinoma (CSCC) with perineural spread to cranial nerves (CN) extending into the cavernous sinus.

Methods

Electronic patient records from a single institution were queried for patients with CSCC of the head and neck causing diplopia (ICD-10 H53.2) who were treated with anti-PD-1. Data extracted included demographics, duration of anti-PD-1 therapy, immune-mediated adverse reactions, tumor response per adapted RECIST v1.1, and changes in CN function and symptoms (e.g., pain). All patients were prescribed cemiplimab 350 mg IV q3 weeks.

Results

Four patients met inclusion criteria. They had varying degrees of pain and sensory deficits in branches of the trigeminal nerve (CN V). One, 2, 3 and 1 patients had baseline involvement of CN III, IV, VI and VII, respectively. MRI confirmed perineural cavernous sinus involvement in all patients. Duration of anti-PD-1 therapy ranged 15–60 weeks. All patients experienced an objective anti-tumor response to anti-PD-1; partial response n = 2, complete response n = 2. At a median follow-up of 22 months, responses were ongoing in all patients. All patients demonstrated improvement in ocular motility deficits and pain with resolution of symptoms in 3 and 1 patients, respectively.

Conclusion

Administration of anti-PD-1 to patients with CSCC with perineural spread into the cavernous sinus can generate durable anti-tumor regressions and restore CN function, while sparing the morbidity associated with surgical resection and/or radiotherapy. Our findings add to emerging literature supporting this treatment approach for this patient population.

cutaneous squamous cell carcinoma

perineural spread

trigeminal nerve

cranial nerve palsy

immunotherapy

Cutaneous squamous cell carcinoma (CSCC) is among the most common human cancers[1].CSCC is typically locally invasive and often impacts the skin and nerves of the head and neck, a process termed perineural spread (PNS), resulting in functional deficits and associated morbidity. Locally advanced CSCC of the head and neck often spreads to the trigeminal nerve, which has been described as cancer’s “highway to the brain”[2]. Prior to the modern age of immune checkpoint inhibitor therapies, patients with locally advanced CSCC underwent surgical resection and/or high dose radiotherapy, both of which can be associated with substantial long-term functional morbidity.

Drugs that inhibit the immune regulatory pathway comprised of the programmed cell-death-1 receptor (PD-1) and its ligands have demonstrated promising anti-tumor activity and have changed the standard-of-care for patients with CSCC. In 59 patients with locally advanced unresectable or metastatic CSCC, cemiplimab, a fully human monoclonal antibody blocking PD-1, generated objective anti-tumor responses in 47% of trial subjects[3]. Similarly, pembrolizumab, a humanized PD-1-blocking antibody, brought about tumor regressions in 34% of 105 patients with advanced CSCC[4]. Cemiplimab and pembrolizumab have both been approved by the US Food & Drug Administration for the treatment of patients with advanced CSCC[5]. A more recent trial evaluated the efficacy of neoadjuvant cemiplimab in patients with resectable Stage II - IV CSCC and revealed a pathologic complete response rate of 51%[6].

However, there is a paucity of data about whether administering anti-PD-1 to patients with neurologic deficits from CSCC that has spread to nerves extending into the cavernous sinus can generate tumor regression and restore neurologic function. Herein, we report the largest case series to date describing tumor response and functional outcomes in this patient population.

This study was approved by the Johns Hopkins University Institutional Review Board and adhered to principles of the Declaration of Helsinki. The electronic medical record at Johns Hopkins was searched for patients with CSCC of the head and neck and diplopia. Patients treated with anti-PD-1 were selected for review. Medical records including clinical documentation, imaging studies, and pathology reports were reviewed to confirm nerve involvement by CSCC (i.e., functionally unresectable). Key outcomes investigated included tumor response per adapted Response Evaluation Criteria in Solid Tumors (RECIST) v1.1[7], changes in symptoms (e.g., pain) and nerve function (e.g., ocular motility), and immune-mediated adverse events. Although perineural tumor involvement is not addressed in RECIST v1.1, we adapted these standard criteria and defined target lesions as enhancing nerves that 1) measured ≥ 1 cm in longest diameter and 2) had a short axis diameter that was longer than the contralateral side. Target lesion response was based on percent change of the longest diameter (per standard RECIST v1.1), however, complete response also required normalization of enhancement and short axis diameter (i.e., symmetrical).

Patients were excluded if they had < 12 months of follow-up from initiation of anti-PD-1, underwent radiation, or attempted tumor excision.

Four patients met the above criteria. Age at diagnosis of CSCC and at development of cranial neuropathy ranged from 56–82 and 71–84 years, respectively (Table 1).

Table 1: Baseline features

Case	1	2	3	4
Age at CSCC diagnosis (years)	78	82	72	56
Age at onset of cranial neuropathy (years)	78	84	72	71
Time from diplopia to diagnosis (months)	1	36	24	2
CN5 sensory deficits	V1, V2, V3	V1, V2	V1	V1, V2, V3
Neurotrophic keratopathy	Yes	Yes	No	Yes
CN2 involvement	No	No	No	Yes
Motor CN deficits	CN6	CN6, CN7, CN12	CN3, CN4	CN4, CN6
Clinical localization	Meckel’s cave Infra-temporal fossa	Cavernous sinus	Cavernous sinus	Orbital apex / Meckel’s cave
MRI localization	Infra-temporal fossa, Meckel’s cave, anterior temporal dura	Cavernous sinus, Meckel’s cave, pterygopalatine fossa	Cavernous sinus	Meckel’s cave
Repeat biopsy site / method	Endonasal infra-temporal fossa, pteryoid fossa, pterygopalatine fossa	Infra-orbital V2 nerve via anterior orbitotomy	Anterior orbitotomy	Orbit via craniotomy
CN = cranial nerve; V* = trigeminal branch

Time from onset of diplopia to realization that the cause of neurologic disturbance was CSCC ranged from 1–36 months. At time of diagnosis, all 4 patients had ophthalmic branch (cranial nerve V1) sensory deficits. Three patients had maxillary branch (cranial nerve V2) sensory deficits, and 2 patients had mandibular branch (cranial nerve V3) sensory deficits. Three patients had neurotrophic keratopathy. The abducens nerve (cranial nerve VI) was the most commonly involved nerve, followed by trochlear nerve (cranial nerve IV). Three patients had multiple cranial nerve palsies. One patient had optic nerve dysfunction due to orbital apex syndrome. Clinical evaluation localized disease to the orbital apex in one patient, cavernous sinus in 2 patients, and extension beyond cavernous sinus (intracranial) in 2 patients. The patient with orbital apex syndrome also had clinical findings consistent with intracranial extension.

All patients underwent a biopsy to confirm PNS of CSCC. Two patients had an anterior orbitotomy, one had a transcranial orbitotomy and one had an endonasal approach to biopsy the infra-temporal fossa, pterygoid fossa, and pterygopalatine fossa.

All 4 patients received cemiplimab 350 mg IV with intended frequency of q3weeks, though some cycles were longer due to toxicity or scheduling changes. Median follow-up was 22 months (range 15–39) after start of cemiplimab.

Treatment courses and outcomes are described in Table 2.

Table 2: Treatment course and outcomes

Case	1	2	3	4
Duration of cemiplimab (weeks)	55	15	60	59
Time until patient-reported improvement in pain (weeks)	4	3	12	3
Pain outcome	resolved	improved	resolved	improved
Change in ocular motility	resolved w/ residual esotropia from childhood strabismus	CN6 resolved	improved, ptosis resolved	resolved
Tumor response	CR	PR	PR	CR
Immune-mediated adverse reactions	Thyroiditis (Grade 1)	Dermatitis (Grade 1), pneumonitis (Grade 2)	None	Meningitis (Grade 3)
Length of follow-up from initiation of cemiplimab (months)	18	39	15	26
CN = cranial nerve, PR = partial response, CR = complete response

Median duration of therapy was 57 weeks, (range 15–60 weeks). All 4 patients experienced an objective anti-tumor response to anti-PD-1 based on imaging (Fig. 1); 2 patients experienced a partial response (PR) and 2 patients experienced a complete response (CR).

Pain severity decreased in all patients, 2 of whom experienced resolution. Improvement occurred within 4 weeks of treatment initiation for 3 patients and by 12 weeks in the 4th patient. Ocular motor cranial neuropathies improved in all patients; 3 of 4 experienced resolution. The sole patient who did not have resolution of ocular motor cranial neuropathy did experience resolution of 4th nerve palsy and normalization in primary gaze (esotropia of 30 prism diopter at baseline to orthotropia by Maddox rod) and small residual esotropia in lateral gaze (improved from 35 prism diopter to 5 diopter esophoria). Additionally, the sole patient with optic neuropathy had resolution of visual deficits as measured by visual acuity, color vision, and visual field.

Immune mediated adverse reactions occurred in three patients (Table 2). Of note, patient 2 was also diagnosed with COVID in the period shortly preceding identification of pneumonitis. Anti-PD-1 therapy was discontinued in this context. Additionally, patient 4 developed symptoms consistent with aseptic meningitis 2 days after administration of an mRNA COVID vaccine. Aseptic meningitis has been reported as an adverse event associated with this therapy [8]. Meningitis symptoms resolved in this patient following treatment with a steroid taper and the patient was able to successfully resume anti-PD-1 with ongoing tumor response.

This case series – to our knowledge, the largest of its kind to date – illustrates that anti-PD-1 can generate durable tumor regressions and restore neurologic function in patients with functionally unresectable CSCC with perineural extension into the cavernous sinus. These findings add to the emerging literature describing encouraging outcomes in patients treated with anti-PD-1 for CSCC of the head and neck with perineural involvement.

Over the past few years, the utility of anti-PD-1 has been evaluated in patients with locally-advanced CSCC that falls into one or more of the following categories: 1) anatomically unresectable (e.g., carotid artery encasement, invasion into the skull base, pre-vertebral fascia, vertebral body/artery, distant disease), 2) biologically unresectable (e.g., in-transit metastases, recurrence after ≥ 2 prior surgeries, and 3) functionally unresectable (i.e., when resection is feasible but an operation would result in loss of sight or substantial oral competency/speech/swallowing) [9]. Several series have reported excellent outcomes in patients with orbital involvement of CSCC who received immunotherapy and, in so doing, avoided the morbidity associated with surgical resection and radiation therapy[10, 11]. Our series supports the expansion of this approach to patients with CSCC with perineural extension into the cavernous sinus.

The restoration of cranial nerve function and improvement in pain described in this study is a remarkable outcome for patients with this disease. While prior reports have documented improvement in pain among some patients with CSCC with PNS involving the trigeminal nerve who undergo surgical resection, this approach – especially involving the cavernous sinus – is generally unlikely to restore neurologic function and may leave patients with new and irreversible cranial neuropathies. Thus, our findings support consideration of anti-PD-1 as an initial approach in this patient population [12].

Imaging assessment of PNS poses several challenges. RECIST v1.1 are not typically applied to characterize the behavior of perineural target lesions. Thus, alternative systems for classifying changes in perineural disease have been proposed [13]. Our approach to imaging assessment in this study adapts RECIST v1.1 to include perineural disease segments that are most likely to show response and differentiate residual disease from treatment-related inflammation.

Serious immune-related adverse events (irAEs) associated with anti-PD-1 monotherapy occur in 10–15% of patients. Given overall response rates of CSCC to anti-PD-1 are only ~ 50%, clinical decision-making in this patient population requires a multidisciplinary team[14]. Additionally, the CSCC patient population tends to be older with comorbid medical conditions, potentially making management of serious irAEs particularly challenging[15].

The optimal duration of anti-PD-1 therapy is unknown. In this series, 3 patients received 55–60 weeks of cemiplimab, while 1 patient discontinued therapy at 15 weeks due to toxicity. Despite the shorter course of treatment, this patient experienced a durable anti-tumor response, raising the question of whether duration of anti-PD-1 treatment could be safely shortened.

Though our single-institution retrospective series is limited by its small size, modest duration of follow-up, and potential for information bias during selection of cases, our findings support pursuing validation in larger, multi-center, prospective trials.

This series demonstrates anti-PD-1 can generate durable anti-tumor responses and restore cranial nerve function in patients with CSCC of the head and neck with perineural spread extending to the cavernous sinus. Patients treated with anti-PD-1 in this study were able to avoid morbidity and poor disease control rates associated the surgical and high-dose radiation interventions historically utilized in this setting but do face the risk of immune related adverse events. Multidisciplinary involvement to ensure patients understand the risks and benefits of each approach is critical.

This data was presented in part at the North American Neuro-Ophthalmology Society meeting in March 2023 in Orlando, FL.

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No competing interests reported.

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Journal Publication

published 01 Sep, 2023

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Editorial decision: Major revision
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Reviewers agreed at journal
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You are reading this latest preprint version

Durable tumor regression and restoration of neurologic function after treatment with anti-PD-1 in patients with functionally unresectable cutaneous squamous cell carcinoma with perineural spread into the cavernous sinus

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