Systemic therapy for metastatic nasopharyngeal carcinoma in the immunotherapy era: A critical review.

Background

The prognosis of metastatic nasopharyngeal carcinoma (mNPC) remains dismal despite recent advances of locoregional and systemic therapy. The incorporation of programmed death-1 (PD-1) inhibitors into first-line chemotherapy has transformed the therapeutic landscape; however, optimal treatment strategies beyond initial chemo-immunotherapy remain undefined.

Methods

We conducted a critical review of prospective clinical trials, large retrospective studies, and translational research evaluating systemic therapies for mNPC in the immunotherapy era, with a focus on treatment sequencing and clinical decision-making.

Results

Multiple phase III trials have established gemcitabine-cisplatin combined with PD-1 blockade as the standard first-line treatment for recurrent or metastatic NPC, with mature follow-up now demonstrating durable overall survival benefits reaching up to 5 years. Subsequent-line treatment options include cytotoxic chemotherapy, anti-angiogenic agents, antibody-drug conjugates (ADCs), and immunotherapy rechallenge strategies. Among these, VEGF-targeted combinations and EGFR/HER3-directed ADCs have demonstrated the most promising activity in PD-1-resistant disease, although toxicity profiles and durability of response vary across regimens.

Conclusions

The treatment paradigm for mNPC is rapidly evolving beyond first-line chemo-immunotherapy. Emerging evidence supports biologically informed treatment selection incorporating angiogenesis inhibition, ADCs, and immune modulation. Prospective trials addressing optimal sequencing, predictive biomarkers, and integration of systemic and local therapies are urgently warranted.