NMPA Grants Conditional Approval to Fruquintinib Plus Sintilimab for pMMR Endometrial Cancer

The National Medical Products Administration of China has granted conditional approval to a new drug application seeking the use of fruquintinib (Elunate) plus sintilimab injection (Tyvyt) in patients with mismatch repair–proficient (pMMR), advanced endometrial cancer who had previous systemic therapy fail and who are not candidates for curative surgery or radiation.¹

The decision is based on findings from the endometrial cancer registration cohort of the phase 2 FRUSICA-1 study (NCT03903705), in which the combination (n = 87) elicited an objective response rate (ORR) of 35.6% (95% CI, 25.6%-46.6%) by independent review committee (IRC) assessment; this included a complete response rate of 2.3% and a partial response rate of 33.3%.² The disease control rate (DCR) achieved with the regimen was 88.5% (95% CI, 79.9%-94.3%). Moreover, the duration of response (DOR) rate at 9 months was 80.7% (95% CI, 56.3%-92.3%) and the median time to response (TTR) was 1.6 months (95% CI, 1.4-2.8).

At a median follow-up of 7.9 months, the median progression-free survival (PFS) by RECIST v1.1 criteria and IRC assessment was 9.5 months, and the 6-month PFS rate was 59.5% (95% CI, 48.1%-69.2%). Further, the median PFS was 13.8 months in those who previously received bevacizumab (Avastin; n = 22) and 9.5 months in those who did not (n = 76). The median overall survival (OS) was 21.3 months, and the 12-month OS rate was 69.4% (95% CI, 58.2%-78.2%). In those with or without prior bevacizumab history, the median OS was not calculable and 21.0 months, respectively.

“This approval of fruquintinib plus sintilimab could represent a paradigm shift in managing this challenging disease. This innovative combination not only leverages the synergistic effects of targeted therapy and immunotherapy, but also addresses a critical gap in treatments available for patients with limited responses to traditional therapies,” Xiaohua Wu, MD, director of the Department of Gynecologic Oncology at Fudan University Affiliated Cancer Hospital and principal investigator of the FRUSICA-1 study, stated in a news release.¹ “With the promising efficacy and manageable safety profile observed in clinical trials, we are eager to have this treatment option available to patients. It brings us closer to our goal of improving survival and enhancing quality of life for patients living with advanced endometrial cancer.”

For this specific cohort of the open-label, single-arm, registrational phase 2 study, investigators enrolled patients with histologically or cytologically confirmed, inoperable or metastatic advanced endometrial cancer who progressed on or were intolerable to up to 2 previous lines of systemic platinum-based therapy.² Patients were between the ages of 18 years and 75 years, had an ECOG performance status of 0 or 1, measurable disease by RECIST v1.1 criteria, and acceptable organ function. They also needed to be able to provide a tumor tissue sample for MMR testing.

Participants received oral fruquintinib at 5 mg once daily on a 2-week-on/1-week-off schedule paired with intravenous sintilimab given at 200 mg every 3 weeks as part of 3-week cycles. Treatment continued until progressive disease or intolerable toxicity. Sintilimab treatment was permitted for no longer than 24 months. The primary end point of the study was ORR by RECIST criteria and IRC assessment, and key secondary end points included DCR, DOR, TTR, PFS, and OS. Other end points included investigator-assessed ORR, safety and immunogenicity, pharmacokinetics, and efficacy-related biomarkers.

As of November 15, 2023, a total of 98 patients had confirmed pMMR. The median age within this group was 57.8 years (range, 29.5-75.5). Regarding ECOG performance status, 54.1% had a status of 1 and the remainder had a status of 0. In terms of histology, 64.3% had endometrioid carcinoma, 27.6% had serous carcinoma, and 8.2% had other. More than half of patients (64.3%) had 1 to 2 metastatic sites, and 35.7% had 3 or more. Most patients (73.5%) had a PD-L1 combined positive score under 1.

Forty-eight percent of patients had prior adjuvant or neoadjuvant treatment. Most (71.4%) had radical surgery and 31.6% had prior palliative surgery. Additionally, 33.7% of patients previously received pelvic radiotherapy. About one-third of patients (30.6%) had received 3 or more prior lines of therapy, and prior treatment included platinum plus paclitaxel (100%) and/or a bevacizumab-containing regimen (22.4%). Moreover, 53.1% of patients had a platinum-free interval of less than 6 months.

The median duration of treatment exposure was 6.01 months (range, 0.7-35.9), and 98% of patients experienced any treatment-related adverse effect (TRAE); 60.2% of these effects were grade 3 or higher. Serious TRAEs were reported in 20.4% of patients. TRAEs led to dose reduction of fruquintinib in 40.8% of patients, interruption of any drug in 52.0% of patients, and discontinuation of any drug of 13.3% of patients.

The most common TRAEs experienced by 30% or more of patients were hypothyroidism (52%), proteinuria (43.9%), hypertension (43.9%), palmar-plantar erythrodysesthesia (38.8%), increased aspartate aminotransferase level (33.7%), and asthenia (30.6%). Most TRAEs were grade 1 or 2 except for hypertension, palmar-plantar erythrodysesthesia syndrome, and hypertriglyceridemia.

References

1. HUTCHMED and Innovent jointly announce NMPA conditional approval for ELUNATE (fruquintinib) in combination with TYVYT (sintilimab injection) for the treatment of advanced endometrial cancer. News release. HUTCHMED (China) Limited and Innovent Biologics, Inc. December 3, 2024. Accessed December 3, 2024. https://www.hutch-med.com/fruquintinib-sintilimab-conditional-approval-for-endometrial-cancer/
2. Wu X, Wang J, Wang D, et al. Fruquintinib plus sintilimab in treated advanced endometrial cancer (EMC) patients (pts) with PMMR status: Results from a multicenter, single-arm phase 2 study. J Clin Oncol. 2024;42(suppl 16):5619. doi:10.1200/JCO.2024.42.16_suppl.5619