A novel two-drug combination has demonstrated significant antitumor activity in women with advanced endometrial cancer who progressed after platinum-based chemotherapy, according to data presented at the 2025 Society of Gynecologic Oncology (SGO) Annual Meeting on Women's Cancer.
The combination of cadonilimab, a bispecific monoclonal antibody targeting both PD-1 and CTLA-4, with lenvatinib (Lenvima), a multitargeted tyrosine kinase inhibitor, achieved an objective response rate (ORR) of 42.9% in evaluable patients, offering a potential new treatment option for this challenging patient population.
Study Design and Patient Population
The open-label, multicenter phase 2 trial (NCT05824481) enrolled 32 women with histologically confirmed advanced, recurrent, or metastatic endometrial cancer who had experienced disease progression after prior platinum-based chemotherapy. All patients had measurable disease according to RECIST 1.1 criteria.
The median age of participants was 56 years (range, 39-76), with most patients (71.9%) having an ECOG performance status of 1. The predominant histologic subtype was endometrioid adenocarcinoma (62.5%), followed by serous adenocarcinoma (21.9%), carcinosarcoma (9.4%), clear cell adenocarcinoma (3.1%), and undifferentiated endometrial adenocarcinoma (3.1%).
Three-quarters of patients had received only one prior line of therapy, while 21.9% had received two prior lines, and 3.1% had received four prior lines.
Dr. Chunyan Lan, from Sun Yat-sen University Cancer Center in China, and colleagues utilized a 3+3 dose de-escalation design during the safety run-in period to evaluate two lenvatinib doses—12 mg daily or 16 mg daily—combined with 10 mg/kg intravenous cadonilimab administered every three weeks.
With no dose-limiting toxicities observed during the safety run-in period, investigators selected 16 mg daily lenvatinib as the phase 2 dose for all 32 patients.
Efficacy Results Across Molecular Subtypes
After a median follow-up of 7.6 months (range, 3-14.5), 14 patients remained on treatment while 18 had discontinued due to adverse events (n=6), disease progression (n=4), patient refusal (n=5), or death (n=3).
Among the 28 evaluable patients, 12 achieved partial responses and none achieved complete responses, resulting in an ORR of 42.9% (95% CI, 24.5-62.8%). Fourteen patients exhibited stable disease and only two had progressive disease, yielding an impressive disease control rate of 92.9% (95% CI, 76.5-99.1%).
"Cadonilimab plus lenvatinib showed promising antitumor activity in patients with advanced endometrial cancer who have experienced disease progression after prior systemic platinum-based therapy," Dr. Lan stated during her presentation.
Notably, the combination demonstrated activity across molecular subtypes, with no statistically significant difference between groups (P=0.698). Analyses by molecular subtype revealed numerically higher ORR among patients characterized as having no specific molecular profile (50%) compared to those with mismatch repair-deficient/microsatellite instability-high tumors (33.3%) or those with p53 abnormalities (16.7%).
At the time of data cutoff, the median duration of response and median progression-free survival had not been reached.
Safety Profile
The combination therapy demonstrated a manageable safety profile, with seven patients (21.9%) experiencing grade 3 or 4 treatment-related adverse events. The most common serious adverse events included intestinal obstruction (6.3%), increased alanine aminotransferase (6.3%), hypertension (3.1%), and increased aspartate aminotransferase (3.1%).
Clinical Context and Implications
The findings are particularly significant given the current treatment landscape for advanced endometrial cancer. Since 2019, the combination of lenvatinib and pembrolizumab (Keytruda), a PD-1 inhibitor, has been the standard of care for patients with advanced mismatch repair-proficient endometrial cancer who progress after platinum-based chemotherapy.
This standard was established following the pivotal phase 3 KEYNOTE-775 trial, which demonstrated improved progression-free survival (HR, 0.60; P<0.0001) and overall survival (HR, 0.68; P=0.0001) compared to chemotherapy.
The current study sought to determine whether a PD-1/CTLA-4 bispecific antibody like cadonilimab could offer comparable or potentially superior benefits to a PD-1 inhibitor alone when combined with lenvatinib in this setting.
"The combination therapy had favorable efficacy and a manageable safety profile," Dr. Lan concluded, suggesting that this novel regimen could potentially expand treatment options for women with advanced endometrial cancer who have limited therapeutic alternatives after progression on platinum-based chemotherapy.
Future Directions
While these results are promising, longer follow-up will be necessary to determine the durability of responses and overall survival benefit. Additionally, ongoing biomarker analyses may help identify patient subgroups most likely to benefit from this combination.
The investigators noted that blood samples were collected for circulating tumor DNA analysis at screening, during treatment, and at disease progression to explore potential biomarkers associated with treatment efficacy.
As endometrial cancer rates continue to rise globally, particularly in developed countries, the development of effective therapies for advanced disease represents an important area of unmet medical need. The cadonilimab-lenvatinib combination may offer a valuable addition to the therapeutic armamentarium for this challenging malignancy.
