Citation
Azad DA, Zhang JJ, Emerick KS, Shalhout SZ, Kaufman HL, Miller DM, Lee NG, Yoon MK, Freitag S, Stagner AM, Wolkow N. Immunotherapy for advanced conjunctival squamous cell carcinoma: Treatment failures. Ophthalmic Plast Reconstr Surg. Published March 13, 2025. doi:10.1097/IOP.0000000000002935.
Why this study matters
Immune checkpoint inhibition has produced dramatic responses in some reported cases of advanced conjunctival squamous cell carcinoma. Those successes created understandable enthusiasm for using systemic therapy to preserve the eye and avoid highly morbid surgery.
This cohort provides an important counterweight. All five patients experienced progression during immunotherapy, emphasizing that conjunctival SCC is biologically heterogeneous and that apparent sensitivity in selected case reports should not be assumed to apply broadly.
Immune checkpoint inhibition can be effective in advanced conjunctival SCC, but response is not assured. In this cohort, all patients progressed, all tumors had low tumor mutational burden, and several ultimately required highly morbid local treatment.
The cohort at a glance
Patients with advanced conjunctival SCC
All had cT3N0M0 disease and received systemic immune checkpoint inhibitor therapy.
No objective disease control
Every patient experienced disease progression while receiving immunotherapy.
Required definitive salvage surgery
Exenteration occurred at a median of six months from initial diagnosis.
What the study found
- All five patients progressed during immune checkpoint inhibitor therapy.
- Three patients ultimately required orbital exenteration.
- One patient developed progressive metastatic disease.
- One patient experienced direct intracranial extension.
- All tumors demonstrated low tumor mutational burden.
Why treatment may fail
Low tumor mutational burden
Lower mutational burden may reduce neoantigen generation and contribute to weaker immune recognition.
Anatomically distinct disease
Conjunctival tumors may arise in biologically different sites with different ultraviolet exposure and immune microenvironments.
Small and selective prior literature
Earlier reports may disproportionately reflect exceptional responders and may not capture the full range of outcomes.
Delayed definitive local therapy
Progression during systemic treatment can narrow future surgical options and increase the morbidity of eventual salvage.
The clinical tension
Immunotherapy may offer an opportunity to preserve vision and avoid exenteration, but treatment failure can permit further orbital, metastatic, or intracranial progression. The central challenge is balancing a potentially organ-preserving systemic strategy against the risk of losing a window for more definitive local control.
These data support close clinical and radiographic monitoring, explicit discussion of uncertainty, and early multidisciplinary planning for surgery or radiation if response is not prompt and convincing.
Immune checkpoint inhibition should be considered a treatment strategy—not a guaranteed route to organ preservation. Patients require early response assessment, clear stopping rules, and a predefined salvage plan before therapy begins.
What remains unresolved
- Which clinical or molecular features identify likely responders?
- Whether tumor mutational burden can meaningfully guide patient selection.
- How anatomic site influences tumor biology and immunotherapy sensitivity.
- The optimal number of treatment cycles before declaring lack of benefit.
- How best to sequence immunotherapy with surgery and radiation.
Authors
D. Amee Azad, Jia Jia Zhang, Kevin S. Emerick, Sophia Z. Shalhout, Howard L. Kaufman, David M. Miller, Nahyoung G. Lee, Michael K. Yoon, Suzanne Freitag, Anna M. Stagner, and Natalie Wolkow.