Updated results of anlotinib combined with penpulimab and nab-paclitaxel as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, open-label phase II clinical trial.

404 Background: PD-1 blockade combined with dual chemotherapy regimens in the first-line setting has exhibited encouraging efficacy for patients with ESCC. However, the safety profile of conventional dual chemotherapy remains unsatisfactory. Therefore, combining PD-1 blockade with anti-angiogenic tyrosine kinase inhibitors (TKIs) and single chemotherapy agent may offer a promising alternative strategy. Anlotinib, a novel multitarget TKI primarily targeting VEGFR1-3, has shown therapeutic activity as first-line combination therapy or second-line monotherapy for ESCC patients in China. Therefore, this study aims to explore the efficacy and safety of anlotinib combined with penpulimab (a PD-1 inhibitor) and nab-paclitaxel as first-line therapy for advanced ESCC. Methods: Patients with previously untreated metastatic or locally advanced ESCC were enrolled and received anlotinib (12 mg, po, d1~14, q3w) and penpulimab (200mg, iv, d1, q3w) plus nab-paclitaxel (220mg/m 2 , iv, d1, q3w) until disease progression or unacceptable toxicity. The primary endpoint was PFS and secondary endpoints included safety, ORR, DCR, and OS. ctDNA MRD substudy was exploratory. Results: A total of 30 patients were enrolled. At the data cut-off date (May, 2025), the best overall response included 1 complete response (CR, 3.3%), 24 partial responses (PR, 80%), 2 stable disease (SD, 6.7%), and 3 non-evaluable cases (NE, 10%), yielding an ORR of 83.3% (95% CI: 65.3-94.4), DCR of 90.0% (95% CI: 73.5-97.9). The median PFS was 11.93 months (95% CI: 7.89-15.97), and the median OS was 22.08 months (95% CI: 8.91-35.25). Additionally, safety profile exhibited that the regimen was tolerable. The most common treatment-emergent adverse events (TEAEs) occurring in ≥20% of patients included anemia (60%), leukopenia (30%), peripheral neurotoxicity (30%), and rash (20%). Grade 3/4 TEAEs occurred in 23% of patients, notably leukopenia. In the first 4 patients with evaluable ctDNA, complete molecular response (undetectable ctDNA) was observed in patients with sustained clinical benefit, whereas ctDNA persistence correlated with disease progression. Conclusions: The combination of anlotinib plus penpulimab and nab-paclitaxel as first-line therapy demonstrated promising efficacy and manageable safety profile in patients with advanced ESCC. These findings warrant confirmation in large randomized trials. Clinical trial information: ChiCTR2400089133 .