An oral anlotinib-capecitabine regimen plus penpulimab as first-line therapy for recurrent/metastatic nasopharyngeal carcinoma (R/M NPC): A multicenter, single-arm, phase 2 clinical trial.

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Background: Patients with NPC who progress after radical therapy often have poor prognosis and limited tolerance. Adding oral agents to chemo-immuno-targeted triplet therapy may enhance efficacy with reduced toxicity. Methods: This multicenter, single-arm, phase 2 trial evaluated first-line penpulimab (a PD-1 blockade) plus oral anlotinib (a tyrosine kinase inhibitor) and capecitabine in patients with R/M NPC previously treated with radical chemo/radiotherapy for non-metastatic disease. Patients from 4 academic hospitals in China received 4–6 cycles of penpulimab 200 mg IV d1, anlotinib 10 mg PO qd d1–14, and capecitabine 650 mg/m ² PO bid d1–21 q3w, followed by penpulimab-capecitabine maintenance until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), safety, and quality of life (QoL). This trial was to be considered positive if the median PFS significantly reached an expected value of 11 mo than a historical threshold of 7 mo, with a 1-sided α of 2.5% and 80% power. This trial was registered with ClinicalTrials.gov (NCT05807880) and is now ongoing. Results: Between Sept 2023 and July 2025, 59 eligible patients (median [IQR] age, 50 [40–58] yrs; 33.9% women) were included, of which 23 (38.9%) and 41 (69.5%) patients had recurrent and metastatic diseases, respectively. Overall, 74.6% (44/59) of patients completed at least the required 4 cycles of the triple therapy. After a median follow-up of 10 mo (data cutoff: Nov 14, 2025), the median PFS was 13.5 mo (95% CI, 13.1–not reached [NR]) and the 12-mo PFS was 64.4% (95% CI, 50.3–78.5%). The median OS was NR, and the 12-mo OS was 87.8% (95% CI, 78.4–97.2%). As of Feb 10, 2026, ORR was 71.4% among 56 available patients, including 6 (10.7%) complete and 34 (60.7%) partial responses. Patients with baseline EBV DNA ≤ 4000 copies/mL had higher median PFS (NR vs 6.0 mo) and 12-mo PFS rate (71.3% vs 41.7%) than those with EBV DNA > 4000 copies/mL ( p = 0.024). Twelve (20.3%) patients had grade 3–4 acute treatment-related adverse events (trAEs), with the most frequent trAE of palmar–plantar erythrodysesthesia (5.1%). Fifty-seven (96.6%) patients had all-grade trAEs, mainly including palmar–plantar erythrodysesthesia (39.0%), hypothyroidism (37.3%), stomatitis (33.9%), sore throat (32.2%), anemia (27.1%), and leukopenia (23.7%). Two treatment-related deaths were observed. Twenty-nine of 37 QoL domains (78.4%) remained stable or showed clinically meaningful improvement. Conclusions: A first-line combination of penpulimab with oral anlotinib-capecitabine has promising antitumor efficacy, low toxicity, and favorable QoL for patients with R/M NPC. Clinical trial information: NCT05807880 .