Cervical cancer is a significant global health problem, being the fourth most common cancer and the fourth leading cause of cancer death in women. In China alone, a substantial number of new cases and deaths occur annually. The prognosis for patients with metastatic or recurrent cervical cancer is poor, with limited treatment options and a median progression-free survival (PFS) of less than one year after first-line therapy. There's currently no standard of care for second-line and subsequent treatment. Targeting the PD-1/PD-L1 axis is a promising approach, supported by evidence showing human papillomavirus (HPV), the primary cause of cervical cancer, increases PD-L1 expression, leading to immune evasion. Single-agent PD-1/PD-L1 inhibitors like pembrolizumab and nivolumab have shown some clinical activity in PD-L1-positive cervical cancer, but response rates remain modest (under 30%). Before the widespread use of immune checkpoint inhibitors, taxanes and platinum-based chemotherapies were common treatments. Nab-paclitaxel, a nanoparticle albumin-bound paclitaxel, has demonstrated a relatively high objective response rate (ORR) as a single agent in drug-resistant cervical cancer. Given the modest responses to single-agent immune checkpoint inhibitors, combining them with chemotherapy, such as nab-paclitaxel, is an attractive strategy. Serplulimab, a novel humanized anti-PD-1 monoclonal antibody, has demonstrated antitumor activity and a manageable safety profile in various cancers. In a Phase III trial for small cell lung cancer, the combination of serplulimab and chemotherapy significantly improved overall survival compared to chemotherapy alone. This study aims to evaluate the efficacy and safety of combining serplulimab with nab-paclitaxel in patients with advanced cervical cancer who had progressed on or were intolerant to first-line chemotherapy.

The literature demonstrates a significant unmet need for effective second-line and beyond treatments for advanced cervical cancer. While first-line therapies have shown improvement in survival with the addition of bevacizumab to chemotherapy, outcomes remain modest, and toxicities are a concern. Immune checkpoint inhibitors, targeting the PD-1/PD-L1 pathway, represent a significant advance. Several studies have investigated single-agent pembrolizumab, nivolumab, and balstilimab in the second-line setting and beyond, demonstrating some clinical activity but with limited response rates. More recently, cemiplimab has shown improved survival compared to chemotherapy in a phase III trial. However, even with these advancements, the response rates remain modest. The use of nab-paclitaxel as a chemotherapeutic agent in this setting is also supported by its demonstrated efficacy in drug-resistant cervical cancer patients. Existing data suggest that combining immune checkpoint inhibitors with chemotherapy may enhance antitumor activity, a strategy supported by research in other cancer types. The rationale for this combination stems from the potential synergistic antitumor effect of combining these treatment modalities.

This was a single-arm, open-label, multicenter, phase II study conducted in China across 11 sites. Eligible patients were aged 18-75 years, had histologically or cytologically confirmed PD-L1-positive (CPS ≥1) cervical cancer that had progressed after or was intolerant to first-line standard chemotherapy. Patients needed at least one measurable lesion per RECIST v1.1, an ECOG performance status of 0 or 1, adequate organ function, and a life expectancy of ≥12 weeks. Key exclusion criteria included prior nab-paclitaxel or immune checkpoint inhibitor therapy, active malignancies, CNS or leptomeningeal metastases, recent organ or bone marrow transplant, significant cardiovascular disease, and autoimmune disease. Patients received serplulimab 4.5 mg/kg and nab-paclitaxel 260 mg/m² every 3 weeks. Nab-paclitaxel was given for up to six cycles, and serplulimab for up to two years or until disease progression, new therapy, death, unacceptable toxicity, or withdrawal of consent. Tumor imaging and efficacy assessment were performed every 6 weeks for the first 48 weeks, then every 12 weeks. Safety follow-up was at 30 and 90 days after the last dose, and survival follow-up every 12 weeks after treatment. The primary endpoints were safety and ORR (by IRRC per RECIST v1.1). Secondary endpoints included investigator-assessed ORR, PFS (by investigator and IRRC), OS, DOR, and DCR. Statistical analysis was performed on the full analysis set (FAS), per-protocol set (PPS), and safety set (SS) using SAS software. Confidence intervals for ORR were estimated using the Exact (Clopper-Pearson) method, and OS, PFS, and DOR were estimated using the Kaplan-Meier method.

Between December 2019 and June 2020, 52 patients were screened, and 21 were enrolled. At the December 31, 2021 data cutoff, the median follow-up duration was 14.6 months. The IRRC-assessed ORR was 57.1% (95% CI 34.0-78.2%), with 3 (14.3%) patients achieving a complete response (CR) and 9 (42.9%) achieving a partial response (PR). The median duration of response (DOR) was not reached (NR) (95% CI 4.1-NR). The IRRC-assessed median PFS was 5.7 months (95% CI 3.0-NR), and the median OS was 15.5 months (95% CI 10.5-NR). The investigator-assessed ORR was 47.6% (95% CI 25.7-70.2%). The disease control rate (DCR) was 76.2% (95% CI 52.8-91.8%). All patients experienced treatment-emergent adverse events (TEAEs), with 17 (81.0%) experiencing grade ≥3 TEAEs. Grade ≥3 adverse drug reactions (ADRs) were reported in 7 (33.3%) patients. Immune-related adverse events (irAEs) occurred in 12 (57.1%) patients. The most common TEAEs included anemia, decreased white blood cell count, decreased neutrophil count, constipation, alopecia, and asthenia. There were no TEAEs leading to serplulimab discontinuation. Four patients died due to TEAEs, with only one death possibly related to treatment. Among patients with CPS ≥20, the ORR was 64.3%. Four of the five patients with the longest DOR had a CPS >50.

This study provides evidence supporting the combination of an immune checkpoint inhibitor with chemotherapy as a promising treatment strategy for patients with advanced cervical cancer who have progressed on or are intolerant to first-line therapy. The observed ORR of 57.1% (IRRC assessment) is numerically higher than that reported with other immune checkpoint inhibitors used as monotherapy in similar patient populations, suggesting the clinical potential of this combination. The long median DOR (NR) and the encouraging median PFS and OS data further support this conclusion. Although direct cross-trial comparisons are challenging, the data suggest a potential benefit compared to single-agent immune checkpoint inhibitors. The higher ORR observed in patients with CPS ≥20 suggests a potential association between PD-L1 expression and treatment response. The safety profile was manageable, with the most common TEAEs and irAEs consistent with previous reports on immune checkpoint inhibitors and nab-paclitaxel. The absence of infusion-related reactions and the low rate of treatment discontinuation due to TEAEs indicate good tolerability. This is, to the authors’ knowledge, the first published study combining an immune checkpoint inhibitor with chemotherapy in the second-line setting for advanced cervical cancer. This study provides evidence and rationale for combining chemotherapy with an immune checkpoint inhibitor in cervical cancer to maximize clinical efficacy.

This phase II study demonstrates that the combination of serplulimab and nab-paclitaxel shows durable clinical activity with a manageable safety profile in patients with advanced cervical cancer who have progressed on or are intolerant to first-line chemotherapy. This combination represents a potentially valuable option in the second-line treatment setting. Larger randomized controlled trials are needed to confirm these findings and to further investigate the relationship between PD-L1 expression levels and treatment response.

The main limitation of this study is its small sample size and the absence of a control arm. The limited sample size may affect the robustness of the results and prevents definitive conclusions about the association between ORR or PFS and CPS scores. Further confirmatory data from larger randomized trials are needed to confirm these findings and to identify potential biomarkers of response. The study's single-arm design also limits the ability to draw firm conclusions about the comparative effectiveness of this treatment regimen relative to other available therapies.