ASCO 2025: key highlights in endometrial cancer

A single arm phase II trial led by Dr. Panagiotis Konstantinopoulos evaluated the combination of aromatase inhibitor (AI) letrozole, CDK4/6 inhibitor abemaciclib, and metformin in patients with estrogen receptor (ER)-positive recurrent disease. The rationale for this study were the encouraging results of letrozole and abemaciclib combination in ER-positive endometrial cancer and the suggestion that PI3k inhibition may enhance the activity of AI and CDK inhibitors in this setting. The trial enrolled 25 patients with recurrent ER-positive (defined as ≥ 1% of tumor cell nuclei being immunoreactive by immunohistochemistry) endometrial carcinoma. Regarding the molecular classification, 4 of the patients had p53 abnormal tumor and 21 had no specific molecular profile (NSMP). The majority of patients were pretreated with median number of 2 (range 0–8) previous lines and 72% of patients have received endocrine treatment in the previous lines. As expected, no response was seen in patients with p53 abnormal tumors. In the NSMP cohort, complete response was reached in 3 (12%) and partial response in 5 (20%) patients, stable disease for ≥ 6 or < 6 months was reported in 7 (28%) or 9 (36%) patients, respectively. In summary, an objective response rate (ORR) of 32% was observed in this study with a progression-free survival (PFS) of 19.4 months. Interestingly, responses were observed regardless of prior endocrine treatment. Tumor profiling revealed several predictive markers such as CTNNB1 mutations, while alterations in TP53, RB1, and CCNE1 correlated with the absence of response. Authors concluded that addition of metformin to AI and CDK inhibitor seems to induce deeper and more prolonged responses than the AI/CDK inhibitor combination alone [1].

Dr. Shannon Westin presented a post hoc circulating tumor (ctDNA) analysis of the DUO‑E study cohort. DUO‑E was a randomized phase III trial comparing durvalumab plus carboplatin and paclitaxel followed by durvalumab with or without olaparib as first-line treatment for advanced or recurrent endometrial cancer. As reported previously, DUO‑E met its dual primary endpoints, demonstrating statistically significant and clinically meaningful improvement of PFS with the addition of durvalumab to platinum-based chemotherapy followed by durvalumab ± olaparib versus chemotherapy alone. Furthermore, maintenance olaparib improved PFS in patients without mismatch repair (MMR) deficiency. The biomarker evaluable population included in this post hoc analysis comprised 352 patients and ctDNA was detectable in 80% of them. The presence of baseline ctDNA was associated with shorter PFS across all treatment arms. In both MMR deficient (dMMR) and non-deficient (non-dMMR) patients, combination of durvalumab and chemotherapy led to numerically greater reductions in detectable ctDNA during the chemotherapy phase, compared with chemotherapy alone. Furthermore, continued treatment with durvalumab led to lower ctDNA detection during the maintenance phase due to a lower proportion of patients with rebound (switching from ctDNA− to ctDNA+). The addition of maintenance olaparib to chemotherapy and durvalumab had a limited effect on ctDNA levels in patients with dMMR tumors; however, in patients with non-dMMR tumors, the ctDNA detection rate was lower during the maintenance phase as compared to patients who received chemotherapy or chemotherapy + durvalumab only, which was due to increased ctDNA clearance (change from ctDNA+ to ctDNA−) during the maintenance phase. In summary, this post hoc exploratory analysis showed that baseline ctDNA was associated with shorter PFS. The addition of durvalumab correlated with rapid reductions in ctDNA detection during chemotherapy and the addition of maintenance olaparib was associated with further reduction of detectable ctDNA and increased ctDNA clearance in non-dMMR patients, reflecting an additional activity of the combination in this group of patients [2].

The concept of combination of immune checkpoint inhibitors and antiangiogenic treatment was further investigated by several groups from China, demonstrating synergistic activity of both targeted therapies, especially in patients with non-dMMR tumors.

A phase II study of HB0025—a bispecific antibody targeting programmed cell death protein ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF)—achieved promising preliminary results in first-line treatment of advanced endometrial carcinoma. HB0025 was administered every 3 weeks in combination with platinum-based chemotherapy for 4–6 cycles, followed by maintenance treatment with HB0025. A total of 54 patients were enrolled with a median follow-up time of 5.7 months and a median duration of exposure of 5.1 months. Forty-four patients remained on treatment; the ORR and disease control rate (DCR) were 84.3% and 100.0%, respectively. The ORRs were 85.4% in non-dMMR patients and 100.0% in dMMR patients. Median duration of response (DOR), median PFS, and median overall survival (OS) were not reached; the 6‑month PFS was 98%. Any-grade and grade ≥ 3 treatment-related adverse events (TRAEs) occurred in 98.1% and 59.3% of patients, respectively. Treatment-related serious adverse events (SAEs) were observed in 18.5% of patients and no TRAE led to death. This open-label, multicenter phase II study of HB0025 in combination with chemotherapy showed encouraging antitumor efficacy with good tolerability and safety. Authors reported that a phase III trial of HB0025 is about to start this year [3].

Another phase II study investigated the addition of benmelstobart (a humanized monoclonal antibody against PD-L1) and anlotinib (an anti-angiogenic oral multitarget tyrosine kinase inhibitor) to the first-line carboplatin and paclitaxel chemotherapy for advanced or recurrent endometrial cancer. Patients received chemotherapy and benmelstobart every 3 weeks ± oral anlotinib once daily (2-week on/1-week off), followed by maintenance with benmelstobart ± anlotinib. A total of 67 patients were enrolled: 36 in the benmelstobart + anlotinib arm, and 31 in the benmelstobart arm. The median duration of follow-up was 16.2 months vs. 14.2 months, respectively. The ORR was 86.1% in the combination arm and 80.6% in the benmelstobart only arm with DCR of 100% in both groups. A significant PFS benefit was observed in the benmelstobart + anlotinib arm (HR 0.38 [95% CI 0.18–0.82]); median not reached (NR) vs. 8.41 months compared to the benmelstobart only arm. The median OS (OS) was not reached in either arm (HR = 0.30 [95% CI 0.08–1.07]) showing a favorable trend in the combination arm. The safety profile was comparable between both arms; however, the incidence of any-grade TEAEs was high with 100% in both groups and the incidence of grade ≥ 3 TEAEs was 81.58% vs 75.76%, respectively. The most common AEs were hematologic, increased transaminases, and hypertension. Serious TEAEs occurred in 50% and 48.48% of patients, respectively [4].

Several new agents were introduced during the congress. An interim analysis from a phase I study of INCB123667—a selective CDK2 inhibitor—showed a manageable safety profile along with promising antitumor activity in pretreated patients with metastatic endometrial cancer. The study included 17 patients with 11 patients who previously received immune checkpoint inhibitors. Authors reported ORR of 23.5% and DCR of 47.1% with the median PFS of 3.7 months and median duration of response of 5.7 months [5].

Another early phase study investigated a folate receptor alpha targeting antibody drug conjugate rinatabart sesutecan (Rina-S) in heavily pretreated endometrial cancer, progressing on immune and platinum-based therapy. Investigators reported ORR of 50% with 100 mg/m² Rina‑S and 47.1% with 120 mg/m²; and DCR of 100% and 85.3%, respectively. The safety profile was manageable; the most common AEs were hematologic and were managed with low rates of treatment discontinuation [6].