Targeted Therapy and Immunotherapy for Advanced Malignant Conjunctival Tumors: Systematic Review.

PURPOSE: To review the outcomes of targeted therapy and immunotherapy in advanced conjunctival tumors, including conjunctival squamous cell carcinoma, conjunctival melanoma, and conjunctival lymphoma. METHODS: A Pubmed database systematic search was performed between January 1999 and December 2022. The literature search was limited to studies published in English. RESULTS: This review included 142 patients with advanced malignant conjunctival tumors from 42 articles. In the conjunctival squamous cell carcinoma group, 2 cases of advanced conjunctival squamous cell carcinoma treated with epidermal growth factor receptor inhibitors showed significant tumor size improvement after 7.5 months of follow-up. Among 7 cases treated with systemic immunotherapy, 5 cases (72%) had complete response (CR), 1 case (14%) showed partial response (PR), and 1 case (14%) had stable disease (SD) after 16 months. In the conjunctival melanoma group, among 18 cases treated with combined v-raf murine sarcoma viral oncogene homolog B1/mitogen-activated extracellular signal-regulated kinase inhibitors, 6 (33%) had CR, 5 (28%) had PR, 2 (11%) had SD, and 5 (28%) had progressive disease after 24.8 months of follow-up. Of 44 conjunctival melanoma cases treated with immunotherapy, 12 (28%) had CR, 9 (20%) had PR, 7(16%) had SD, and 16 (36%) had progressive disease after 14.2 months. Systemic Rituximab treatment for conjunctival lymphoma cases resulted in CR in 21 patients (63%), PR in 11 patients (33%), and SD in 1 patient (3%) after 20.5 months of follow-up. Intralesional Rituximab injections in 38 conjunctival lymphoma cases showed CR in 28 patients (75%), PR in 7 patients (19%), SD in 1 patient (2%), and progressive disease in 2 patients (4%) after 20.4 months of follow-up. CONCLUSIONS: Despite limited clinical case reports and short-term follow-ups, targeted therapy and immunotherapy have shown promising results for advanced malignant conjunctival tumors.

Use of Cemiplimab, an Immune Checkpoint Inhibitor for Conjunctival Intraepithelial Neoplasia.

PURPOSE: Immune checkpoint inhibitors (ICIs) have been recently introduced for the treatment of locally unresectable conjunctival squamous cell carcinoma. We present 2 cases with conjunctival intraepithelial neoplasia (CIN) who were treated with ICIs. METHODS: A report of 2 cases with CIN who were treated with systemic cemiplimab (350 mg IV every 3 weeks). RESULTS: A 70-year-old man was treated with cemiplimab for metastatic cutaneous squamous cell carcinoma. The pre-existing CIN continued to progress over the nasal bulbar conjunctiva and cornea, while the other metastatic sites, including parotid glands, and neck lymph nodes showed a complete response after 16 cycles of treatment. An 84-year-old woman had bilateral diffuse CIN involving bulbar and lower eyelid palpebral conjunctiva. Cemiplimab was started because of the extent of involvement. While the bulk of CIN was reduced, it progressed over the cornea and forniceal conjunctiva on OU after 10 cycles of treatment. Excisional biopsies of conjunctival lesions after cemiplimab confirmed CIN in both patients. CONCLUSIONS: Although conjunctival squamous cell carcinoma tumors are reported to be highly responsive to ICIs, a similar effect has not been observed in 2 patients with CIN. Further studies are needed to evaluate ICIs in the management of CIN.

Review of Targeted Therapy, Vismodegib, for the Treatment of Periocular Basal Cell Carcinoma.

PURPOSE: Periocular locally advanced basal cell carcinoma (POLA-BCC) is characterized by orbital involvement and/or extensive invasion of periocular structures. Hedgehog pathway inhibitors have been used for POLA-BCC with promising outcomes. METHODS: The authors reviewed 11 articles published in English literature from January 2012 to July 2022 and reported the outcomes of patients with POLA-BCC who were treated with vismodegib. RESULTS: A total of 384 patients were treated with vismodegib. The mean age was 72 years, and the median treatment duration was 9 months. The overall response rate was 75% with a median follow-up time of 14.4 months. Following vismodegib treatment, the median number of patients who required adjuvant surgery was 43% with a median time to surgery of 6.5 months. The exenteration rate was 6% (overall 8 patients). In total 93.7% of patients experienced grade I adverse events, 26.7% to 37.5% grade II, 8.8% to 10% grade III-IV, and 0.8% to 4.8% grade V. Major side effects included dysgeusia (30-100%), muscle spasm (15-100%), alopecia (47-75%), weight loss (23-83%), and decreased appetite (19-42%). The median percentage of patients who discontinued treatment due to toxicity was 29% with a median interval of 5 months before the development of side effects. The median recurrence rate following discontinuation of vismodegib was 7.8% with a median recurrence duration of 20 months. CONCLUSIONS: In patients with POLA-BCC, vismodegib, a hedgehog pathway inhibitor, provided high rates of orbital preservation, reducing exenteration rates to 6%. Neoadjuvant therapy with vismodegib can also be suggested for patients with POLA-BCC. While extremely effective, side effects lead to temporary or permanent discontinuation of vismodegib in small numbers of patients.

Phase II trial of pazopanib in advanced/progressive malignant pheochromocytoma and paraganglioma.

INTRODUCTION: Pheochromocytomas and paragangliomas (Pheo/PGL) are rare, vascular, sometimes malignant endocrine tumors. Case reports indicate the activity of vascular endothelium growth factor receptor-targeted kinase inhibitors in these cancers. OBJECTIVES: To assess the antitumor activity and tolerability of pazopanib in progressive malignant Pheo/PGL. PATIENTS AND METHODS: This multicenter Phase II trial (MC107C) enrolled individuals ≥18 years old with disease progression ≤ 6 months prior to registration, Eastern Cooperative Oncology Group PS 0-2, and measurable disease (response evaluation criteria in solid tumors 1.0). Pazopanib was administered in 28-day cycles, with the regimen ultimately being as follows: cycle 1: 400 mg daily on days 1-14, cycle 2: 800 mg daily on days 1-14, and then cycle 2 + : 800 mg daily on all days. RESULTS: The study was halted due to poor accrual. Seven patients were enrolled (05/2011-11/2014). One patient withdrew consent prior to treatment, leaving six evaluable patients. Treatment was discontinued, due to the following reasons: disease progression (4); withdrawal (1); and grade 4 (Takotsubo) cardiomyopathy (1). The median number of cycles administered was 4 (range: 2-29, total: 49). Four patients had >1 dose reduction due to the following reasons: fatigue (1), abnormal liver tests (2), hypertension and (Takotsubo) cardiomyopathy (1), and headaches (1). Common severe (Common Terminology Criteria for Adverse Events v3.0 grades 3-5) toxicities were as follows: hypertension (3/6), (Takotsubo) cardiomyopathy (2/6), diarrhea (1/6), fatigue (1/6), headache (1/6), and hematuria (1/6). One confirmed partial response was observed in PGL (17%, duration 2.4 years); median progression-free survival and overall survival were 6.5 and 14.8 months, respectively. CONCLUSION: Pazopanib has activity in Pheo/PGL requiring more study; optimal alpha- and beta-blockade are imperative pre-therapy in patients with secretory tumors, as risk of hypertension and cardiomyopathy are potentially life threatening.