Two-drug regimen active in advanced endometrial cancer
Key takeaways:
- Twelve of 28 evaluable women achieved partial response after treatment with cadonilimab and lenvatinib.
- Seven patients experienced grade 3/grade 4 adverse events.
A novel two-drug combination exhibited antitumor activity among certain women with advanced endometrial cancer, data presented at Society of Gynecologic Oncology Annual Meeting on Women’s Cancer showed.
The combination of cadonilimab (Akeso Inc.) and lenvatinib (Lenvima, Eisai) also exhibited a manageable safety profile, according to investigators.
Lenvatinib — a multitargeted tyrosine kinase inhibitor — plus the PD-1 inhibitor pembrolizumab (Keytruda, Merck) is standard treatment for women with advanced, mismatch repair-proficient endometrial cancer whose disease progressed after platinum-based chemotherapy.
Chunyan Lan, MD, PhD, of Sun Yat-sen University Cancer Center in China, and colleagues conducted a single-arm phase 2 study to evaluate lenvatinib plus cadonilimab — a bispecific monoclonal antibody that targets PD-1 and CTLA-4 — for this patient population.
The open-label, multicenter study included 32 women (median age, 56 years; range, 39-76) with histologically confirmed endometrial cancer. All had ECOG performance status of 0 (28.1%) or 1 (71.9%). Nearly two-thirds (62.5%) had endometrioid adenocarcinoma, and 25% had received at least two prior therapies.
All women had disease progression after receiving platinum-based systemic chemotherapy for metastatic or primary unresectable disease.
Researchers used a 3+3 dose de-escalation design in a safety run-in period to evaluate two lenvatinib doses — 12 mg daily or 16 mg daily — combined with 10 mg/kg IV cadonilimab every 3 weeks.
No dose-limiting toxicities occurred during the safety run-in period (n = 3), leading Lan and colleagues to select 16 mg daily lenvatinib as the phase 2 dose for all 32 patients.
Objective response rate served as the primary endpoint. Secondary endpoints included duration of response, disease control rate, PFS, OS and safety.
After median follow-up of 7.6 months (range, 3-14.5), 14 patients remained on treatment and 18 patients had discontinued. Reasons for treatment discontinuation included adverse events (n = 6), disease progression (n = 4), patient refusal (n = 5) and death (n = 3).
The efficacy analysis included 28 evaluable patients. Twelve patients achieved partial response and none achieved complete response, equating to an ORR of 42.9% (95% CI, 24.5-62.8).
Fourteen patients exhibited stable disease and two had progressive disease, resulting in a disease control rate of 92.9% (95% CI, 76.5-99.1%).
Median duration of response and median PFS had not been reached.
Analyses by molecular subtype showed numerically higher ORR among those characterized as having no specific molecular profile (50%) — characterized by absence of p53 abnormalities and mispatch repair defects — than those with mismatch repair-deficient/microsatellite instability-high tumors (33.3%) or those with p53 abnormalities (16.7%).
Seven patients (21.9%) experienced grade 3/grade 4 treatment-related adverse events. The most common included intestinal obstruction (6.3%; n = 2), increased alanine aminotransferase (6.3%; n = 2), hypertension (3.1%; n = 1) and increased aspartate aminotransferase (3.1%; n = 1).
Perspective
Back to TopA large proportion of these patients had endometrioid histology, and 15% had unknown mismatch repair profiling, which is clinically relevant. Four patients were excluded from the efficacy analysis and, when we look at the ORR, we are pulled to compare to KEYNOTE-775 trial data. The ORR of 37.5% is similar to the 32% ORR by blinded independent central review in KEYNOTE-775. Also, there was a small number of mismatch repair-deficient cases, and the 33% ORR in the mismatch repair-deficient population was less than single-agent IO studies in the recurrent setting.
Further, we are obliged to ask what is the relevance of these data in a world where the treatment paradigm for endometrial cancer has evolved? Many patients with advanced-stage or recurrent disease are receiving immune checkpoint inhibition during initial treatment. Lastly, what is the CTLA-4 component of the bispecific have to do with a nearly 23% rate of grade 3 or grade 4 treatment-related adverse events?
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Lan C, et al. Cadonilimab plus lenvatinib in patients with advanced endometrial cancer: A multicenter, single-arm, phase II trial. Presented at: SGO Annual Meeting on Women’s Cancer; March 14-17, 2025; Seattle.