Ivonescimab Combined With Paclitaxel and Cisplatin as Neoadjuvant Therapy Followed by Type A Hysterectomy in Stage IB2 and IIA1 Cervical Cancer

Cervical cancer, one of the three major malignancies of the female reproductive system, poses a significant threat to women's health. According to global cancer statistics, it ranks as the fourth most common cancer in women. The latest NCCN guidelines indicate that early-stage cervical cancer patients meeting SHAPE criteria (squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma; FIGO 2009 stage IA2 or IB1; tumor size ≤2 cm; stromal invasion depth <10 mm on LEEP/cone biopsy or <50% on MRI; any histological grade; no lymph node metastasis) may undergo type A hysterectomy. However, patients with Stage IB2 or IIA1 disease (2 cm < lesion size ≤4 cm) still require radical hysterectomy (type C). Compared to type A hysterectomy, radical hysterectomy carries higher postoperative complication rates and significantly impairs quality of life, including risks of major vascular injury, urinary tract damage and dysfunction, lymphatic complications, and sexual dysfunction. Therefore, there is an urgent need to develop alternative or refined treatment approaches for Stage IB2/IIA1 cervical cancer that ensure survival outcomes while improving quality of life and reducing complications associated with extensive radical surgery.

In recent years, immunotherapy has emerged as a major research focus in oncology. Anti-PD-1/PD-L1 monoclonal antibodies, as immunotherapeutic agents, have demonstrated favorable antitumor efficacy and manageable toxicity in clinical trials. PD-1, a surface immune checkpoint protein, inhibits T-cell activation upon binding to its ligand PD-L1, enabling tumor immune evasion. The NACI study investigated neoadjuvant chemotherapy combined with camrelizumab for locally advanced cervical cancer. Promising results showed an ORR of 98% (83/85, 95% CI: 98%-100%) in the overall population (n=85), with 16 patients (19%) achieving complete response (CR) and 67 (79%) partial response (PR). The pathological complete response (pCR) rate was 38% (32/85, 95% CI: 27%-49%), demonstrating significant clinical benefit with controllable safety, thus ushering in a new era for cervical cancer neoadjuvant therapy. Additionally, a phase II clinical trial reported at the 2024 ASCO Annual Meeting evaluated sintilimab combined with paclitaxel and cisplatin as neoadjuvant therapy for locally advanced cervical cancer, showing a pCR rate of 32.6% (14/43) and an optimal response rate (residual tumor depth <3 mm) of 51.2% (22/43). Regarding toxicity, 15 patients experienced grade 3-4 neutropenia without other severe adverse events, indicating favorable antitumor activity and manageable toxicity for this combination approach. These findings raise the question: Could this immunotherapy-chemotherapy strategy be applied to earlier-stage disease-specifically neoadjuvant treatment for Stage IB2/IIA1 cervical cancer-potentially enabling surgical de-escalation?

Bevacizumab plus chemotherapy constitutes the standard first-line treatment for metastatic or recurrent cervical cancer. Angiogenesis plays a pivotal role in tumor progression by supplying nutrients and oxygen, facilitating tumor growth and dissemination, and remodeling the tumor microenvironment. The phase 3 BEATcc trial published in The Lancet demonstrated that adding atezolizumab (a PD-L1 inhibitor) to standard care (bevacizumab + chemotherapy) significantly improved progression-free survival (PFS) and overall survival (OS) in metastatic, persistent, or recurrent cervical cancer, providing clinically meaningful benefits and suggesting superior efficacy with combined anti-angiogenic and immunotherapy. Another 2024 ASCO report from a randomized phase III trial (NCT04678791) showed that nimotuzumab (an anti-EGFR mAb) combined with concurrent chemoradiotherapy significantly improved ORR in locally advanced cervical cancer, with favorable trends in PFS/OS and an acceptable safety profile. The nimotuzumab group achieved partial response (PR) in 62 patients (43.99%) and complete response (CR) in 57 (40.14%), highlighting the clinical value of anti-angiogenic therapy combined with chemotherapy for locally advanced disease. Given that both angiogenesis and immune escape contribute to treatment resistance, could dual-pathway targeting yield synergistic (1+1>2) effects? However, no studies have yet explored combined anti-angiogenic and immunotherapy as neoadjuvant treatment for Stage IB2/IIA1 cervical cancer.

Ivonescimab, a humanized anti-PD-1/VEGF bispecific antibody with an IgG1-scFv tetrameric structure, represents a novel therapeutic format. As the world's first PD-1/VEGF bispecific antibody to enter phase III trials, it has now gained approval. At the 2024 ASCO meeting, ivonescimab combined with platinum-doublet chemotherapy demonstrated robust antitumor activity and safety not only in first-line treatment of advanced NSCLC without driver mutations but also in EGFR-mutant patients after EGFR-TKI failure and in platinum/PD-(L)1 inhibitor-pretreated advanced NSCLC. This suggests significant efficacy of bispecific antibodies in advanced malignancies. Therefore, given the unmet need for optimized therapies in Stage IB2/IIA1 cervical cancer, this study will explore the efficacy and safety of neoadjuvant ivonescimab combined with paclitaxel and cisplatin. The findings may enable subsequent surgical de-escalation to type A hysterectomy.