Cadonilimab Combo Shows Encouraging Activity in Advanced Endometrial Cancer

“Cadonilimab plus lenvatinib showed promising antitumor activity in patients with advanced endometrial cancer who have experienced disease progression after prior systemic platinum-based therapy,” according to lead study author Chunyan Lan, MD, PhD.

Encouraging efficacy and safety were reported among previously treated patients with advanced endometrial cancer of any molecular subtype who received cadonilimab in combination with lenvatinib (Lenvima), according to findings from a phase 2 study (NCT05824481) presented at the 2025 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (SGO).¹

At the data cutoff of July 31, 2024, and median follow-up of 7.6 months (range, 3.0-14.5), the objective response rate (ORR) was 42.9% (95% CI, 24.5%-62.8%) in the efficacy-evaluable set (n = 28) and 37.5% (95% CI, 21.3%-56.3%) in the full analysis set (n = 32) of patients. Best responses within the efficacy evaluable and full analysis sets, respectively, were partial response (n = 12; n = 12), stable disease (n = 14; n = 14), and progressive disease (n = 2; n = 2).

The respective disease control rates (DCRs) were 92.9% (95% CI, 76.5%-99.1%) and 81.3% (95% CI, 63.6%-92.8%).

“Cadonilimab plus lenvatinib showed promising antitumor activity in patients with advanced endometrial cancer who have experienced disease progression after prior systemic platinum-based therapy,” lead study author Chunyan Lan, MD, PhD, of the Department of Gynecologic Oncology at Sun Yat-sen University Cancer Center in Guangzhou, China, said in a presentation of the data.

Study Rationale and Design

The combination of lenvatinib and pembrolizumab (Keytruda) has been the standard of care for patients with advanced mismatch repair–proficient (pMMR) endometrial cancer and disease progression following platinum-based chemotherapy since its 2019 accelerated approval in the US.² The regimen received full approval from the FDA in 2021 after demonstrating an improvement in progression-free survival (PFS; HR, 0.60; 95% CI, 0.50-0.72; P < .0001) and overall survival (OS; HR, 0.68; 95% CI, 0.56-0.84; P = .0001) vs investigator’s choice of doxorubicin or paclitaxel in the pivotal phase 3 KEYNOTE-775 trial (NCT03517449).²

Despite improved survival with the combination, investigators of the current trial questioned whether a PD-1/CTLA-4 bispecific antibody could demonstrate comparable benefits to that of a PD-1 inhibitor alone in this setting.¹

The multi-center, single-arm, phase 2 trial was borne out of this question, evaluating the combination of cadonilimab and lenvatinib as second- or later-line therapy in patients with advanced endometrial cancer. Eligibility criteria required that patients have histologically confirmed advanced, recurrent, or metastatic endometrial cancer with disease progression after prior platinum-based chemotherapy and measurable lesions per RECIST 1.1 criteria.

During the safety run-in phase, patients received 10 mg/kg of intravenous cadonilimab every 3 weeks plus either 16 mg of lenvatinib once daily (dose level 1) or 12 mg of lenvatinib once daily (dose level 2). A 3+3 dose-escalation design was used to determine the recommended phase 2 dose for lenvatinib.

ORR was the primary end point. Secondary end points were DCR, duration of response, PFS, OS, and safety. Potential biomarkers associated with efficacy were evaluated in an exploratory fashion. “Blood samples were collected for circulating tumor DNA analysis at screening, cycle 3, day 1, and at progressive disease to explore potential biomarkers associated with the treatment efficacy,” Lan stated.

Patient Enrollment Breakdown

A total of 32 patients were enrolled between May 8, 2023, and March 4, 2024, comprising the full analysis and safety analysis sets, and all patients were treated at dose level 1. A total of 18 patients discontinued treatment due to disease progression (n = 4), adverse effects (AEs; n = 6), patient refusal (n = 5), and death (n = 3). Fourteen patients remain on therapy. Four patients were not evaluable and were excluded from the efficacy-evaluable set (n = 28).

Notably, no dose-limiting toxicity was seen in the first 3 patients treated on study.

Regarding baseline characteristics the median age was 56 years (range, 39-76). Histologic subtypes included endometrioid adenocarcinoma (62.5%), serous adenocarcinoma (21.9%), clear cell adenocarcinoma (3.1%), carcinosarcoma (9.4%), and undifferentiated endometrial adenocarcinoma (3.1%). Most patients had received 1 prior line of therapy (75.0%) vs 2 (21.9%) or 4 (3.1%). Additionally, ECOG performance status was 0 (28.1%) or 1 (71.9%) and molecular profiling revealed the presence of mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) disease (9.4%), disease with no specific molecular profile (37.5%), P53 disease (37.5%), and unknown disease (15.6%). Lan noted that no cases of poly-oncomutation were included in the study.

Further Efficacy and Safety Findings

Additional efficacy results illustrated that the median PFS was not reached. Moreover, the combination was also active regardless of molecular subtype, with no statistically significant difference between groups (P = .698). In the dMMR/MSI-H population (n = 3), the ORR was 33.3%. Patients with no specific molecular profile (n = 12) had an ORR of 50.0% and those with aberrant P53 (n = 12) had an ORR of 16.7%.

“The combination therapy had favorable efficacy and a manageable safety profile,” Lan stated.

Grade 3 or 4 treatment-related AEs (TRAEs) occurred in 21.9% of patients. The most frequent grade 3 or 4 TRAEs included intestinal obstruction (6.3%), increased alanine aminotransferase levels (6.3%), increased aspartate aminotransferase levels (3.1%), and hypertension (3.1%).

Disclosures: Lan had no financial disclosures and did not discuss unlabeled/investigational drug use.

References

1. Lan C, Yang X, Zhao J, et al. Cadonilimab plus lenvatinib in patients with advanced endometrial cancer: a multicenter, single-arm, phase II trial. Presented at: 2025 SGO Annual Meeting on Women’s Cancer; March 14-17, 2025; Seattle, WA. Abstract 864114.
2. FDA grants regular approval to pembrolizumab and lenvatinib for advanced endometrial carcinoma. FDA. Updated February 1, 2022. Accessed March 15, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-pembrolizumab-and-lenvatinib-advanced-endometrial-carcinoma#:~:text=On%20July%2021%2C%202021%2C%20the,who%20have%20disease%20progression%20following