Nab-paclitaxel plus bevacizumab for patients with metastatic extrapulmonary neuroendocrine carcinoma: a phase 2 single-arm study.

Background: Patients with advanced extrapulmonary neuroendocrine carcinoma (EP-NEC) usually present with metastatic disease and have a poor prognosis. No standard therapies have been established beyond the first-line platinum-based chemotherapy. This study aims to evaluate the efficacy and safety of nab-paclitaxel plus bevacizumab in patients with previously treated advanced EP-NEC. Methods: This multicenter, single-arm, phase 2 trial was conducted from January 2021 to March 2024 to evaluate the efficacy and safety of nab-paclitaxel plus bevacizumab in patients with advanced EP-NEC who progressed after prior standard-of-care treatments. Patients were assigned to receive nab-paclitaxel of 150 mg/m2 plus bevacizumab of 5 mg/kg intravenously every 2 weeks in a cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall survival (OS). The secondary endpoints included the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), and safety. The study was registered at ClinicalTrials.gov: NCT04705519 (https://clinicaltrials.gov/study/NCT04705519?cond=NCT4705519&rank=1). Findings: A total of 79 patients were enrolled, with 40 patients receiving ≥2 lines of therapy. After a median follow-up of 22.4 (Interquartile Range [IQR] 14.7-42.9) months, the median OS was 12.8 (95% CI, 8.6-17.4) months. The median PFS was 5.3 (95% CI, 4.2-6.6) months. Among 76 patients with assessable best response, the ORR was 55% (42/76, 95% CI 43-67%), and DCR was 87% (66/76, 95% CI 77-94). The median DoR was 5.7 (95% CI, 3.3-7.2) months. Patients with gastric NEC had a numerically higher ORR compared with those with NEC from other sites, but statistical significance was not achieved (26/39, [67%] vs. 16/37, [43%]; P = 0.068); however, no statistically significant difference in PFS (6.6 [95% CI 3.9-7.5] vs. 4.6 [95% CI 2.6-6.3]; P = 0.13) or OS (14.4 [95% CI 7.7-18.4] vs. 10.0 [95% CI 7.2-20.0]; P = 0.76) was observed. Multivariable analyses identified that metastatic organs >2 was the independent factor significantly associated with worse PFS (HR 2.06, 95% CI 1.20-3.56; P = 0.0092) and OS (HR 1.86, 95% CI 1.04-3.30; P = 0.035). Most treatment-related adverse events (TRAEs) (≥10%) of grade ≥3 were neutropenia (28/79, 35%) and leukopenia (15/79, 19%). Interpretation: Patients with metastatic EP-NEC achieved a high response rate and encouraging survival with tolerable toxicity. The combination regimen has the potential to become a valuable treatment option, if further controlled studies confirm its efficacy for patients who have exhausted standard therapies. Funding: This study was partially supported by Qilu Pharmaceutical Co., Ltd. This work is supported by the Beijing Municipal Science & Technology Commission (No. Z231100007223002).