A combination therapy of zimberelimab and lenvatinib (Lenvima) has demonstrated promising clinical activity in patients with advanced cervical cancer who experienced disease progression after prior immune checkpoint inhibitor (ICI) therapy, according to new data presented at the 2025 Society of Gynecologic Oncology Annual Meeting on Women's Cancer (SGO).
The phase 2 trial (NCT05824468) evaluated 30 patients and reported an objective response rate (ORR) of 33.3% (95% CI, 17.3%-52.8%), consisting entirely of partial responses. Notably, the disease control rate (DCR) reached an impressive 96.7% (95% CI, 82.8%-99.9%), indicating that nearly all patients experienced at least stable disease with the combination treatment.
"Zimberelimab plus lenvatinib showed promising antitumor activity in patients with advanced cervical cancer who have experienced disease progression after prior ICI therapy," stated lead investigator Chunyan Lan, MD, PhD, from the Department of Gynecologic Oncology at Sun Yat-sen University Cancer Centre in Guangzhou, China. "The combination therapy had a favorable and manageable safety profile."
Treatment Efficacy Across Biomarker Subgroups
The study analyzed response rates across different biomarker subgroups. Among PD-L1–positive patients, 4 achieved a response while 10 did not. In the PD-L1–negative group, 4 patients responded and 5 did not. For patients with human papillomavirus (HPV)-16–positive or HPV-18–positive disease, 6 responded and 11 did not, while in the other high-risk HPV subtype group, 3 patients had a response compared to 5 who did not.
The median progression-free survival (PFS) was 7.1 months (95% CI, 5.1-not reached). Interestingly, researchers found no statistically significant correlation between PFS outcomes and either PD-L1 expression status (P = .771) or HPV subtypes (P = .614), suggesting the combination may benefit patients regardless of these biomarker statuses.
Trial Design and Patient Population
This multicenter, single-arm phase 2 trial was designed to assess the efficacy and safety of rechallenging ICI therapy in patients with advanced cervical cancer who had previously received ICIs. The study included a safety run-in phase where patients received either lenvatinib at 16 mg once daily plus zimberelimab at 240 mg intravenously every 3 weeks (dose level 1) or lenvatinib at 12 mg once daily plus the same dose of zimberelimab (dose level 2).
Eligible patients were between 18 and 75 years old with histologically confirmed metastatic, recurrent, or persistent cervical cancer not amenable to curative therapy. All patients had experienced disease progression on or after prior ICI therapy with treatment exposure exceeding 6 months.
The median patient age was 54 years (range, 32-70), with most patients having an ECOG performance status of 1 (86.7%) and squamous cell carcinoma (63.3%). The majority had received two prior lines of systemic therapy (43.3%), with common prior ICIs including tislelizumab (Tevimbra; 36.7%), camrelizumab (Airuika; 16.7%), and sintilimab (Tyvyt; 16.7%). All patients (100%) had received prior platinum-based treatment, and 90% had undergone radiotherapy.
Safety Profile
The safety profile of the zimberelimab-lenvatinib combination was favorable, with most treatment-related adverse effects (TRAEs) being mild or moderate in severity. Only 10% (n = 3) of patients experienced grade 3/4 TRAEs, which included proteinuria (3.3%), hand-foot syndrome (3.3%), increased aspartate aminotransferase levels (3.3%), and increased alanine aminotransferase levels (3.3%).
Clinical Context and Significance
Cervical cancer remains a significant global health concern, with limited treatment options for patients who progress after initial immunotherapy. The high disease control rate observed in this study is particularly encouraging for this difficult-to-treat population.
The combination of zimberelimab, an anti-PD-1 monoclonal antibody, with lenvatinib, a multikinase inhibitor targeting VEGFR, FGFR, PDGFR, RET, and KIT, represents a rational approach to overcoming resistance to single-agent immunotherapy. The synergistic effect may be attributed to lenvatinib's ability to modify the tumor microenvironment, potentially making tumors more responsive to immune checkpoint inhibition.
With patient enrollment occurring from May 2023 to May 2024 and a median follow-up of 6.9 months (range, 1.9-14.2), longer-term data will be necessary to fully assess the durability of responses and overall survival benefit. Nevertheless, these early results suggest that this combination could become an important treatment option for patients with advanced cervical cancer who have progressed on prior immunotherapy.
