Dual PD-1/CTLA-4 Inhibition With Cadonilimab Plus Lenvatinib Yields Disease Control in Advanced Endometrial Cancer

Cadonilimab/Lenvatinib in Endometrial Cancer

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Results from a phase 2 study (NCT05824481) showed that the addition of cadonilimab to lenvatinib (Lenvima) was active and safe in patients with advanced endometrial cancer who experienced disease progression after receiving platinum-based chemotherapy regardless of molecular subtypes, supporting further evaluation of this novel checkpoint inhibitor combination, according to Chunyan Lan, MD, PhD.1

“Cadonilimab plus lenvatinib demonstrated promising antitumor activity in patients with advanced endometrial cancer who progressed after prior platinum-based chemotherapy,” Lan said in an interview with OncLive®. “The combination had a manageable safety profile, but we will need a larger study to confirm its effectiveness. We also need to understand the potential benefits and risks of adding CTLA-4 targeting, and ctDNA data analysis is still in progress.”

During the interview, Lan detailed the background and rationale of the phase 2 study, key efficacy and safety data with cadonilimab plus lenvatinib presented at the 2025 SGO Annual Meeting on Women’s Cancer, and future directions for investigating the combination in endometrial cancer.

Lan is a member of the Department of Gynecologic Oncology at Sun Yat-sen University Cancer Center in Guangzhou, China.

OncLive: What was the rationale for evaluating cadonilimab plus lenvatinib in patients with advanced endometrial cancer?

Lan: We know that in the phase 3 KEYNOTE-775 study [NCT03517449], pembrolizumab [Keytruda] plus lenvatinib was compared with chemotherapy, demonstrating a median progression-free survival [PFS] of 6.6 months and an objective response rate [ORR] of 30.3%.2 Given this favorable efficacy, the combination was FDA approved [in July 2021] for the second-line treatment [of patients with] advanced endometrial cancer. One of the key questions [to emerge from this research] was whether PD-1 and CTLA-4 bispecific antibodies could provide clinical benefits comparable to a PD-1 antibody in this setting. We investigated this possibility by evaluating cadonilimab, a PD-1 and CTLA-4 bispecific antibody, combined with lenvatinib in patients with advanced endometrial cancer who progressed after platinum-based chemotherapy as a second-line or later treatment.

What was the design and methodology of the trial?

In this multicenter, single-arm phase 2 study, eligible patients had histologically confirmed advanced recurrent or metastatic endometrial cancer. Patients had to progress on or after previous platinum-based chemotherapy. The study consists of a safety run-in period followed by an efficacy evaluation in the phase 2 portion. The safety run-in was used to determine the recommended phase 2 dose [RP2D] for lenvatinib, which was administered at a starting dose of 16 mg once daily. Once the RP2D of lenvatinib was established, it was combined with cadonilimab at 10 mg/kg every 3 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. A Simon’s two-stage design was used to determine the sample size. The primary end point was the ORR, and the secondary end points included the disease control rate [DCR], duration of response [DOR], PFS, overall survival [OS], and safety.

As of that data cutoff [of July 31, 2024], 32 patients were enrolled. No dose-limiting toxicity was observed in the initial 3 patients. Regarding patient characteristics, the median age was 56 years. The most prevalent histology subtype was endometrioid adenocarcinoma, which was found in 62.5% of the patients. Notably, 22% of patients had serous adenocarcinoma, and 9% of the patients had carcinosarcoma, both of which were linked to poor prognoses regarding the molecular subtype. Nine percent of patients had a mismatch repair–deficient [dMMR] or microsatellite instability–high [MSI-H] disease. No specific molecular profile, and P53-mutated disease was each observed in 37.5% of patients. No cases of poly-oncomutation were included.

What were the key efficacy data from the study?

In our study, 12 patients achieved a partial response, 14 had stable disease, and 2 experienced progressive disease. The ORRs were 37.5% in the full analysis set and 42.9% in the efficacy-evaluable set [n = 28]. The DCR was 81.3% in the full analysis set [and 92.9% in the efficacy-evaluable set]. At the data cutoff, the median follow-up was 7.6 months and the median PFS and median DOR were not reached.

What should be known about the regimen’s safety profile?

The most treatment-related adverse effects [TRAEs] were mild or moderate grade 3 or 4 occurred in 21.9% of patients. The most common grade 3 or 4 TRAEs were intestinal obstruction and increased alanine aminotransferase levels, each in 6.3% of patients, followed by increased aspartate aminotransferase levels and hypertension, each in 3.1%.

What are some future directions for this research?

Blood samples were collected for circulating tumor DNA [ctDNA] analysis at screening, on cycle 3, day 1, and at disease progression, to investigate the potential biomarkers associated with treatment efficacy. Next, we will analyze the relationship between antitumor activity and ctDNA status, as well as the trends in ctDNA concentration throughout the treatment.

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. Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med. 2022;386(5):437-448. doi:10.1056/NEJMoa2108330