Immune Checkpoint Inhibitor Therapy for Orbital and Ocular Adnexal Squamous Cell Carcinomas: International Society of Ocular Oncology President's Lecture, 2022

Abstract

To summarize an invited lecture topic from the proceedings of the International Society of Ocular Oncology meeting in Leiden in 2022. Mechanism of action, indications, and the authors’ clinical experience with immune checkpoint inhibitors in patients with locally advanced ocular adnexal squamous cell carcinoma are summarized. Several cases of locally advanced conjunctival, eyelid, and lacrimal sac/duct squamous cell carcinoma that were successfully treated with immune checkpoint inhibitors (PD-1 directed) are shared. Immune checkpoint inhibitors are effective at reducing tumor size and enabling eye-preserving surgery in patients with locally advanced ocular adnexal squamous cell carcinoma with orbital invasion. They present a new strategy for the treatment of locally advanced squamous cell carcinoma of the ocular adnexa and orbit.

In the past 10 years, our group has had an interest in studying a relatively new class of drugs known as immune checkpoint inhibitors for the treatment of locally advanced and/or metastatic conjunctival and ocular adnexal melanomas and squamous cell carcinomas (SCCs). In June 2022, I had the honor of giving a president's lecture at the 20th congress of the International Society of Ocular Oncology focused on the clinical applications of immune checkpoint inhibitor therapy for conjunctival and periocular SCCs. Here I present the same data and summarize the take-home points from my lecture, and I also review the most recent publications of clinical relevance on immune checkpoint inhibitor therapy for orbital and ocular adnexal carcinomas. 

Background

The orbit and ocular adnexal structures can harbor a variety of malignant tumors, including cutaneous SCC (cSCC). cSCC is the second most common skin cancer after basal cell carcinoma.¹ cSCC accounts for 5% to 10% of all eyelid cancers, and the incidence of periorbital SCC is estimated to be 1.37 cases per 100,000 individuals per year.^1–3 Most patients with periorbital SCC are at least 60 years of age at diagnosis and fair-skinned with significant sun exposure.² 

Most cases of periorbital SCC are amenable to surgical resection, and in most cases, the eye and its function can be preserved. In a small proportion of cases, however, SCC of the conjunctiva or periocular skin becomes locally advanced with orbital invasion or involvement of most of the ocular surface, which makes eye-preserving surgery difficult or, in some cases, impossible. Furthermore, there is a significant risk of nodal metastasis with SCCs involving the eyelid or periocular region that are T2C or more advanced per the criteria in the eighth edition of the American Joint Committee on Cancer (AJCC) staging manual. Thus, systemic treatments that may decrease tumor size in the case of locally advanced SCCs of the conjunctiva or eyelid with orbital invasion and/or have efficacy against metastatic carcinomas would be of great interest. Immune checkpoint inhibitors are an example of such treatments. 

Immune Checkpoint Inhibitors for Cancer Therapy

The availability of immune checkpoint inhibitors has revolutionized cancer therapy in the past decade.^4–10 Cancer cells can activate immune checkpoint pathways to suppress the host's anticancer immune response⁴; immune checkpoint inhibitors interrupt these inhibitory signaling pathways to allow immune-mediated elimination of cancer cells.⁵ Immune checkpoint molecules that can be targeted clinically include programmed cell death 1 (PD-1) on T cells, programmed cell death ligand 1 (PD-L1) on tumor cells, and cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) on T cells.⁶ 

Since 2011, several immune checkpoint inhibitors have been approved by the US Food and Drug Administration (FDA) for treatment of various cancers, including cSCC. Commonly used immune checkpoint inhibitors include nivolumab, pembrolizumab, and cemiplimab, which are anti–PD-1 inhibitors; avelumab and atezolizumab, which are anti–PD-L1 inhibitors; and ipilimumab, an anti–CTLA-4 inhibitor.^7–10 The 2018 Nobel Prize in Physiology or Medicine was given to Dr. James P. Allison and Dr. Tatsuku Honjo for their discoveries of cancer therapy through inhibition of CTLA-4 and PD-1, respectively. 

Neoadjuvant Use of Immune Checkpoint Inhibitors for cSCC

In September 2018, the FDA approved cemiplimab (Libtayo; Regeneron, Tarrytown, New York) for the treatment of locally advanced or metastatic cSCC in patients ineligible for curative surgery or radiation therapy, on the basis of results of a phase I trial (NCT02383212) and the EMPOWER-CSCC-1 phase II trial (NCT02760498). These trials showed an objective response in 44% to 50% of patients, with durable responses and favorable safety profiles.^11,12 

The promising results in trials of cemiplimab led to interest in using PD-1 inhibitors for neoadjuvant treatment in patients with locally advanced, resectable cSCC. Two prospective phase II trials on this use of PD-1 inhibitors have been published in recent years.^13,14 Ferrarotto et al.¹³ conducted a phase II, single-institution pilot study of cemiplimab as a neoadjuvant therapy prior to curative-intent surgery in patients with newly diagnosed or recurrent stage III to IV (per the eighth edition of the AJCC staging manual) head and neck cSCC. Two cycles of cemiplimab 350 mg were administered intravenously 3 weeks apart, followed by surgery that was planned for at least 21 days after the second dose. Twenty patients were enrolled. Fifty-five percent (11/20) had a pathologic complete response, and 20% (4/20) had a major pathologic response, defined as 10% or less of the tumor still viable. Eleven patients (55%) were not recommended to receive previously planned adjuvant radiation therapy on the basis of their pathologic response. None of these 11 patients had a recurrence at a median follow-up period of 23 months. The 12-month disease-specific survival rate was 95%, the 12-month disease-free survival rate was 89.5%, and the 12-month overall survival rate was 95%. 

More recently, Gross et al.¹⁴ conducted a phase II, multicenter single-group study of cemiplimab as a neoadjuvant therapy prior to definitive surgery in patients with stage II, III, or IV (M0) resectable cSCC, 91% of whom had disease involving the head and neck region. This study was conducted across Australia, Germany, and the United States. Cemiplimab 350 mg was administered intravenously every 3 weeks for up to four cycles. The results were similar to those in the Ferrarotto et al.¹³ study: 51% (40/79) of the patients had a complete pathologic response, and 13% (10/79) had a major pathologic response. 

Pembrolizumab (Keytruda; Merck, Rahway, New Jersey), another anti–PD-1 agent, was approved by the FDA in June 2020 for treatment of patients with recurrent or metastatic cSCC not amenable to curative surgery or radiation therapy, on the basis of evidence from the KEYNOTE-629 trial (NCT03284424). In that trial, in the cohort with locally advanced disease, the objective response rate was 50%; 17% of patients had a complete response, and 33% had a partial response.¹⁵ The exceptional responsiveness of cSCC to immunotherapy may be related to its high tumor mutation burden from ultraviolet-related DNA damage.¹⁶ 

Immune Checkpoint Inhibitors for Conjunctival SCC

In a study by Nagarajan et al.,¹⁷ our group demonstrated PD-L1 expression in 14 of 31 (47%) conjunctival SCC tumor samples, and we found that PD-L1 expression was more prevalent among the cases of invasive SCC than among the cases of SCC in situ. We also found that PD-L1 expression was more prevalent in tumors with a higher AJCC T category (≥T3 vs. ≤T2). These findings support the potential use of anti–PD-L1 therapy in patients with locally advanced conjunctival SCC who are not amenable to other forms of treatment, for example, patients with recurrent disease with orbital invasion in whom the only surgical option may be orbital exenteration and in whom use of high-dose radiation therapy is limited because of concerns about significant ocular toxic effects. 

Case Studies of Immune Checkpoint Inhibitors to Treat SCC in the Periocular Region

Reports on the use of immune checkpoint inhibitors for patients with periorbital cSCC are limited to small case series. There have been two individual case reports on the use of intravenous cemiplimab to treat locally advanced, recurrent, unresectable cSCC.^18,19 In one patient, the tumor was in the left forehead/brow region, and a good clinical response was observed after the fifth cycle of cemiplimab.¹⁸ In the other patient, the tumor was located along the right lateral orbital rim, and a good clinical response was observed after the seventh cycle.¹⁹ 

Although most of the patients in the two prospective clinical trials of neoadjuvant cemiplimab^13,14 had cSCC of the head and neck region, the study reports did not specify the number of patients with periorbital cSCC who were included. 

In a retrospective case series from the University of Texas MD Anderson Cancer Center, we reported on four patients with locally advanced cSCC of the periorbital region who received cemiplimab as neoadjuvant therapy followed by surgery with curative intent.²⁰ After two cycles of cemiplimab given 3 weeks apart, all four patients exhibited a significant clinical and/or radiologic response. Furthermore, all four patients exhibited a pathologic response—complete in three patients and major in one. None of the patients received adjuvant radiation therapy, and all remained disease free with a median follow-up period of 20 months after surgical resection. 

We also observed promising results with use of pembrolizumab for locally advanced cSCC.²⁰ One patient had a T4N0M0 cSCC in the supraorbital region with superomedial orbital and left frontal bone invasion and perineural invasion. This patient had a good clinical and radiologic response after 6 months of treatment with pembrolizumab. However, at the 9-month follow-up visit, when the patient was still being treated with pembrolizumab, tumor progression was noted, so the decision was made to proceed with surgery followed by radiation therapy. The other patient had extensive cSCC involving the right medial orbit that was treated with four cycles of neoadjuvant pembrolizumab, cisplatin, and docetaxel every 3 weeks with significant clinical and radiologic response. We performed surgical resection of all grossly abnormal tissue, including areas that appeared involved on preoperative imaging. The patient was found to have a complete pathologic response. The patient remained disease free at the most recent follow-up visit, 7 months after surgical intervention. We continue to offer either cemiplimab or pembrolizumab to patients with locally advanced periocular SCC in whom curative surgery is not possible and/or would require an orbital exenteration. Immunotherapy can be considered in the neoadjuvant setting prior to surgery, either as single agent or in combination with standard chemotherapy when the tissue of origin of SCC is not as clear and/or when rapid response is needed due to a very large mass that is threatening the eye or orbital structures (Fig.). 

Figure.

 

A, External photograph in a patient with a massive SCC of the upper eyelid with orbital invasion. The exact tissue source for this SCC is not clear as it could have a tarsal conjunctival tissue source; a cutaneous source from upper eyelid skin is also possible, but given the extent of involvement of the soft tissue by the cancer, it is difficult to determine the exact tissue of origin. Given the size of the mass and the extent of tumor involvement, cemiplimab combined with standard chemotherapy (docetaxel and cisplatin) was planned for four cycles in an effort to decrease the size of the tumor prior to surgery and make eye-sparing surgery with curative intent possible. B, Magnetic resonance imaging of the orbit shows infiltration of the orbital soft tissue. C, External photograph of the same patient after one cycle of chemotherapy combined with immunotherapy. D, Intraoperative photo at the time of surgical resection of the residual lesion. E, External photograph taken during an early postoperative visit after reconstruction of the upper eyelid defect. The patient has been thus far followed for 1 year after surgery without signs of local or regional recurrence. He is under continued surveillance at the time of this communication.

Summary and Future Directions

Our clinical observations thus far suggest that a promising clinical response can be expected following immune checkpoint inhibitor therapy for locally advanced periocular SCC. More studies are needed to confirm the clinical efficacy of anti–PD-1 therapy for locally advanced ocular adnexal and conjunctival SCC, and specifically, prospective trials would be of interest. 

Neoadjuvant therapy with immune checkpoint inhibitors in patients with locally advanced and/or metastatic conjunctival or ocular adnexal SCC with orbital invasion would be of particular interest in geographic areas of the world where the incidence of conjunctival SCC is high and the presentation of disease can be much more advanced than in developed countries. One such area is in sub-Saharan Africa, where the prevalence of conjunctival SCC is estimated to be at least 10 times the prevalence in Western countries. Compared to patients in Western countries, patients in sub-Saharan Africa tend to present with more locally advanced disease and experience more significant morbidity and mortality with the current standard surgical treatments. Identification of molecular markers that are predictive of response to neoadjuvant immunotherapy would aid in patient selection. 

A number of questions remain to be answered regarding neoadjuvant immunotherapy for locally advanced periorbital cSCC. The appropriate duration of neoadjuvant immunotherapy for locally advanced periorbital cSCC has yet to be determined. In most of the cases that we have treated thus far, administering two to four doses of an immune checkpoint inhibitor seems to be effective, especially if the immunotherapy is combined with chemotherapy. Unique to radiation therapy in the periorbital area is significant risk of damage to the eye. Thus, it may be appropriate to administer neoadjuvant immunotherapy for as many cycles as tolerated by the patient and as long as there is measurable tumor shrinkage to maximize the chance of preserving the eye and orbit and to decrease the likelihood of the need for adjuvant high-dose radiation therapy with its expected toxic effects in the periorbital area. In addition, further studies are needed to compare the efficacy of neoadjuvant immunotherapy with that of standard-of-care treatment. Importantly, longer follow-up is needed to determine the durability of the clinical outcome and effect on recurrence and survival. Research is also needed to determine the optimal treatment regimen for immunosuppressed patients. Patients with cSCC who are solid organ transplant recipients or who require immunosuppressants for autoimmune conditions have been excluded from clinical trials of immune checkpoint inhibitors as the use of those drugs would be contraindicated in such patients. Data from case series and case reports showed that response to immunotherapy may be similar between immunosuppressed and immunocompetent patients.^21–23 

Another important consideration is the toxicity of immune checkpoint inhibitors. The frequency of immune-related adverse events depends on the agents used and the individual patient. Fatal immune checkpoint inhibitor–related adverse events are rare and estimated to occur in 0.3% to 1.3% of patients treated with these drugs.²¹ Approximately 10% of patients receiving anti–PD-1 antibodies have grade 3 or greater adverse events, and most tend to occur within the first 6 months of treatment.^22–24 The most commonly reported grade 3 or greater adverse events in patients treated with immune checkpoint inhibitors are fatigue, headache, arthralgia, rash, pruritus, pneumonitis, diarrhea and/or colitis, hepatitis, and endocrinopathies (hypophysitis and thyroid dysfunction).^22–24 

Acknowledgments

Disclosure: B. Esmaeli, None