Recurrent and metastatic nasopharyngeal carcinoma

Nasopharyngeal carcinoma recurs in two ways that are treated differently. Local or regional recurrence after radiotherapy, in the nasopharynx or neck, is potentially curable: endoscopic nasopharyngectomy, shown in a Chinese randomised trial (Lancet Oncology 2021) to give better survival and fewer complications than re-irradiation for resectable recurrence, neck dissection for nodal relapse, and hyperfractionated intensity-modulated re-irradiation, which in a further randomised trial (Lancet 2023) reduced the severe late toxicity of a second course of radiotherapy. Distant metastases, most often to bone, liver and lung, are incurable in most patients, although a minority with oligometastatic disease gain from locoregional radiotherapy of the primary added to chemotherapy, as a Chinese phase 3 (JAMA Oncology 2020) showed.

Systemic therapy for metastatic disease was standardised by the GEM20110714 trial (Lancet 2016), in which gemcitabine and cisplatin beat fluorouracil and cisplatin on progression-free survival (7.0 against 5.6 months) and overall survival. Because EBV-driven tumours are inflamed and PD-L1-rich, PD-1 antibodies were tested next, almost entirely by Chinese companies and investigators: JUPITER-02 (Nature Medicine 2021, JAMA 2023) added toripalimab to gemcitabine-cisplatin in 289 patients and lengthened progression-free survival from 8.0 to 11.7 months with a survival benefit, leading to approval in China in 2021 and in the United States in October 2023, the first approval of a Chinese-developed PD-1 antibody there and the first drug approved for nasopharyngeal carcinoma; CAPTAIN-1st (camrelizumab, Lancet Oncology 2021) and RATIONALE-309 (tislelizumab) showed the same pattern, and penpulimab with gemcitabine-cisplatin was approved in the United States in April 2025. PD-1 antibodies alone are used after platinum failure (nivolumab, pembrolizumab, camrelizumab and toripalimab all have phase 2 data), and later lines include gemcitabine-based or taxane-based chemotherapy, capecitabine and the anti-EGFR antibody nimotuzumab in China. The pipeline is dominated by antibody-drug conjugates, notably the EGFR-directed MRG003 and the EGFR-HER3 bispecific BL-B01D1 and the B7-H3-directed YL201, in phase 3 against chemotherapy, and by EBV-specific T-cell therapies, which have produced durable responses in small trials. Plasma EBV DNA tracks response, and locoregional radiotherapy for de novo metastatic disease with a good chemotherapy response is now guideline-endorsed.