PD-1 blockade in combination with bevacizumab and nab-paclitaxel for second-line treatment in cancer of unknown primary (Fudan CUP-002): A prospective, single-arm phase II study.

Abstract

2529 Background: Cancer of unknown primary (CUP), a heterogeneous tumor characterized by histologically confirmed metastases with undefined primary, accounts for 2-5% of all malignancies. Our previous study, Fudan CUP-001, confirmed that site-specific first-line treatment improves progression-free survival (PFS) in patients with CUP compared to empirical treatment. However, no evidence-based standard of care currently exists for second-line treatment of CUP. We conducted the Fudan CUP-002 study by Simon's two-stage design to evaluate the efficacy and safety of co-administration of F520 injection (anti-PD-1 antibody), bevacizumab, and nab-paclitaxel in patients with CUP who have progressed after first-line treatment. Methods: In this prospective, single-arm phase II study (ClinicalTrials.gov, NCT04848597), patients with previously treated CUP received intravenous F520 injection at a dose of 200 mg and bevacizumab 7.5 mg/kg every 3 weeks for up to 2 years, and intravenous nab-paclitaxel 125 mg/m 2 administered on day 1 and day 8 every 3 weeks for up to 8 cycles. The primary endpoint was confirmed objective response rate (ORR) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The secondary endpoints included PFS, overall survival (OS), disease control rate (DCR), and safety. Results: Between June 2, 2021, and January 10, 2025, a total of 48 eligible subjects were enrolled in the study. In the overall population, the median age was 60 (range: 29 to 72) years, with 31 males (64.6%) and 17 females (35.4%). At the data cutoff on January 10, 2025, the median follow-up was 27.1 months (95% CI, 20.2 to 37.2) and 3 (6.3%) cases continued treatment. The ORR was 54.2% (95% CI, 40.3 to 67.4), and the DCR was 95.8% (95% CI, 86.0 to 98.9), as assessed by BICR per RECIST version 1.1. The median PFS was 16.7 months (95% CI, 12.6 to not available (NA)), with the 12- and 24-month PFS rates at 68.6% and 38.5%, respectively. The median OS was 24.6 months (95% CI, 14.6 to 29.5), and the 12- and 24-month OS rates were 72.5% and 53.0%, respectively. The median duration of response (DoR) was 22.5 months (95% CI, 12.5 to NA), with the 12- and 24-month DoR rates at 78.9% and 47.5%, respectively. Treatment-related adverse events (TRAEs) of any grade were reported by 46 (95.8%) patients. Hematologic toxicity (43, 89.6%) and liver injury (25, 52.1%) of any grade were the most frequently reported TRAEs, and grade 3-4 TRAEs were observed in 25 (52.1%) patients. Grade 3-4 immune-related adverse events (irAEs) occurred in 8 (16.7%) participants, with pneumonitis (2, 4.2%) and endocrine disorders (2, 4.2%) being the most common. Conclusions: Second-line PD-1 blockade in combination with bevacizumab and nab-paclitaxel is an effective and well-tolerated treatment regimen for patients with CUP. Clinical trial information: NCT04848597 .