Penpulimab plus oral anlotinib and capecitabine as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (R/M NPC): A multicenter, single-arm, phase 2 clinical trial.

6036 Background: Patients (pts) with NPC progressing after intensive radical treatment often have limited treatment tolerance and poor prognosis. Incorporation of oral agents into triple therapy combining chemotherapy, immunotherapy, and targeted therapy may improve efficacy while reducing 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 pts with R/M NPC previously treated with radical chemo/radiotherapy for non-metastatic disease. Pts 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; assessed by the EORTC and FACT surveys). 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 pts (median [IQR] age, 50 [40–58] yrs; 33.9% women) were included, of which 23 (38.9%) and 41 (69.5%) pts had recurrent and metastatic diseases, respectively. Overall, 74.6% (44/59) of pts 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%). The ORR was 71.4% in 56 pts with available assessments, including complete and partial responses in 5 (8.9%) and 35 (62.5%) pts, respectively. Pts 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%) pts 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%) pts 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: First-line therapy of penpulimab plus oral anlotinib and capecitabine provides promising antitumor efficacy, low toxicity, and favorable QoL for pts with R/M NPC. Clinical trial information: NCT05807880 .