Platinum-resistant recurrent epithelial ovarian cancer carries a bleak prognosis, with single-agent chemotherapy yielding response rates below 20% and median progression-free survival barely reaching 4 months; the A-Plus phase II trial therefore tested a chemotherapy-free, all-oral regimen combining albumin-bound paclitaxel and the multi-kinase inhibitor anlotinib in 44 heavily pre-treated women. Between January 2021 and March 2023, patients aged 32-70 years received nab-paclitaxel 260 mg m⁻² intravenously on day 1 plus anlotinib 12 mg orally once daily on days 1-14 of each 21-day cycle until progression or intolerable toxicity. Eligibility required documented platinum resistance, ECOG performance status 0-1, measurable or evaluable disease by RECIST 1.1 or Rustin criteria, and adequate organ function; prior anti-angiogenic therapy or PARP inhibitors was allowed, reflecting real-world refractory populations.
Investigator-assessed objective response rate, the primary endpoint, reached 56.8% in the intention-to-treat cohort (25/44; 95% CI 41-71%) and 58.1% in the per-protocol set, exceeding the pre-specified 30% benchmark and doubling historical controls. Median progression-free survival was 9.8 months and median duration of response 7.4 months, while six-month PFS probability was 72%. Subgroup analyses showed consistent activity regardless of age, number of prior lines, or previous exposure to bevacizumab or PARP inhibitors: response rates were 55% among 20 bevacizumab-pretreated patients and 60% among 15 PARP-pretreated patients, suggesting limited cross-resistance between vascular-targeting strategies. Disease-control rate was 86 % and one patient achieved a complete metabolic response lasting 11 months. Pharmacokinetic sampling demonstrated that concurrent anlotinib did not alter nab-paclitaxel exposure, while circulating VEGF-A levels fell by 45% at cycle 2, corroborating on-target anti-angiogenic effects.
Safety was generally manageable; the most common any-grade adverse events were fatigue (75%), neutropenia (68%), hypertension (64%), hand-foot syndrome (59%) and mucositis (52%). Grade ≥ 3 events occurred in 57% of participants, led by leukopenia (25%), hypertension (18%), hand-foot syndrome (11%) and gum pain (9%). Febrile neutropenia was seen in only one patient and no grade 4 thrombocytopenia or bleeding was reported. Dose reductions of anlotinib were required in 30% of cycles, mainly for hypertension or skin toxicity, while nab-paclitaxel dose was reduced in 14%. One patient discontinued therapy after cycle 1 due to grade 3 proteinuria, and two withdrew consent during the first two cycles; otherwise, median relative dose intensity exceeded 90%. No treatment-related deaths occurred, and quality-of-life scores remained stable over the first six cycles, indicating that the combination does not impair daily functioning.
Translational endpoints provided mechanistic insights. Baseline circulating tumour DNA (ctDNA) was detectable in 38/44 subjects; variant allele frequency declined ≥ 50% in 18 responders but in only 2 non-responders, yielding a positive predictive value of 82%. Immunoprofiling of peripheral blood showed an early rise in effector CD8⁺ T cells and reduction in myeloid-derived suppressor cells in responding patients, hinting that anlotinib may reverse VEGF-mediated immunosuppression and synergise with taxane-induced immunogenic cell death. Tumour biopsies collected at baseline and week 8 demonstrated decreased micro-vessel density (CD31 staining) and increased apoptosis (cleaved-caspase 3) only in responders, reinforcing the vascular-normalisation hypothesis.
Results position nab-paclitaxel plus anlotinib as a credible chemotherapy-free option for platinum-resistant ovarian cancer, particularly in regions where pegylated liposomal doxorubicin is unavailable or contraindicated. The 9.8-month median PFS compares favourably with 3.4-5.6 months seen in recent phase III trials of single-agent PARP inhibitors or immune checkpoint blockade in similar populations. All-oral maintenance with anlotinib alone is being explored in an extension cohort, and a randomised phase III study versus investigator-choice chemotherapy is planned. Key challenges include optimisation of anlotinib dose to minimise hand-foot syndrome, incorporation of predictive biomarkers such as ctDNA kinetics, and evaluation of the regimen in earlier lines or in combination with PARP inhibitors. For now, A-Plus offers a clinically meaningful, logistically simple and broadly accessible therapeutic strategy for women whose disease has exhausted platinum and targeted options.

DOI
10.1007/s11684-025-1155-1