Abstract
Dear Editor,
The optimal duration of immune checkpoint inhibitors (ICIs) remains one of the major unresolved questions in oncology, particularly in rare tumors where prospective evidence is limited and therapeutic decisions are based on extrapolation from more common malignancies. 1
We present a 73-year-old woman diagnosed in 2018 with programmed death-ligand 1 (PD-L1)–negative (0%) stage cT1N0 vulvar squamous cell carcinoma, initially treated with surgery and adjuvant radiotherapy. She developed early progression with peritoneal and pulmonary metastases. After multiple lines of platinum- and taxane-based chemotherapy, she initiated nivolumab (240 mg every 2 weeks) based on the CheckMate 358 trial. 2 She has completed 140 cycles to date, with radiologically stable disease, excellent tolerability, and no significant immune-related toxicity.
A central clinical dilemma is whether to continue or discontinue immunotherapy in patients with sustained disease control. Continuation is supported by ongoing stable disease without complete response, good tolerability, and uncertainty regarding relapse after withdrawal, particularly in stable disease. Discontinuation may be justified by potential durable immune effects after stopping treatment, cumulative toxicity, treatment burden, and cost. Evidence supports discontinuation mainly in complete responders and in patients with stable disease, decisions should be individualized, considering clinical outcomes, toxicity, and cost.
In rare gynecological tumors such as metastatic vulvar squamous cell carcinoma, evidence derives from small cohorts. The CheckMate 358 trial showed modest and short-lived responses in this setting, while combination immunotherapy trials such as SWOG S1609 DART suggest that only a small subset of patients achieve durable benefit.2,3
Indirect evidence comes mainly from non-small cell lung cancer and melanoma. In these tumors, some studies suggest that immunotherapy discontinuation after a prolonged period of disease control or after complete response may be safe in selected patients, without significantly compromising overall survival. However, data in patients with stable disease remain limited, and the risk of progression after discontinuation appears higher. This highlights the need for careful individualized decision-making.4–7
Emerging biomarkers such as circulating tumor DNA (ctDNA) may help individualize treatment duration. Early reduction or clearance of ctDNA during immunotherapy has been associated with improved clinical outcomes, suggesting a potential role as a predictive tool for durable benefit. However, ctDNA is most useful in complete or minimal residual disease, with limited data in measurable disease.8,9
From a clinical pharmacy perspective, it is essential to evaluate not only the efficacy and safety of prolonged treatments but also their pharmacoeconomic and organizational impact. Clinical pharmacists, particularly in outpatient oncology, can support longitudinal monitoring and multidisciplinary decisions to optimize treatment duration and minimize risks.
In clinical practice, one of the main challenges is the lack of a structured decision point that allows for standardized reassessment of treatment continuation beyond prolonged periods of response or stable disease. Structured reassessment algorithms using radiology, clinical evolution, and biomarkers may reduce variability and improve decisions. Furthermore, the systematic integration of these processes into multidisciplinary tumor boards would allow a more balanced evaluation of clinical benefit, cumulative toxicity, and treatment sustainability.
In conclusion, the lack of clear criteria for discontinuing immunotherapy in patients with prolonged disease control remains a relevant clinical challenge. Dedicated studies, collaborative registries, and predictive biomarkers are needed to individualize treatment duration and avoid both undertreatment and overtreatment.
