Fruquintinib/Sintilimab Yields Efficacy, Safety in Advanced pMMR Endometrial Cancer

The therapeutic landscape for advanced endometrial cancer (EMC) has historically been divided by molecular subtypes, specifically mismatch repair status. While patients with mismatch repair-deficient tumors often show robust responses to single-agent immunotherapy, the mismatch repair-proficient (pMMR) subset—which constitutes approximately 70% of the EMC population—has faced significantly poorer outcomes and limited second-line options following platinum-based chemotherapy.^1,2

The FRUSICA-1 phase 1b/2 clinical trial (NCT03903705) addresses this gap, evaluating the combination of fruquintinib (Fruzaqla), a selective VEGFR-1, -2, and -3 inhibitor, and sintilimab (Tyvyt), an anti–PD-1 antibody, in Chinese patients with advanced pMMR EMC.

The FRUSICA-1 trial successfully met its primary end point, demonstrating clinical activity that markedly exceeds standard-of-care chemotherapy.

The trial utilized an independent review committee to assess responses, providing a rigorous validation of the treatment's efficacy:

• Total pMMR population (n = 98): 32.7% overall response rate (ORR)
• Pivotal population (n = 76): 31.6% ORR
• Clinical significance: The lower bound of the confidence interval for the pivotal group was 21.4%, which significantly surpassed the prespecified efficacy threshold of 16%.

For pMMR EMC, single-agent immunotherapy has proven largely ineffective, as evidenced by the PHAEDRA study (NCT03015129) where durvalumab (Imfinzi) yielded an ORR of only 3%.3 The rationale for combining an antiangiogenic agent like fruquintinib with an immune checkpoint inhibitor is to modulate the tumor microenvironment. Inhibition of the VEGF pathway can reduce immunosuppression and enhance T-cell infiltration, potentially sensitizing pMMR tumors to PD-1 blockade.¹

Secondary end points further supported the durability of the response. When compared with historical data for second-line chemotherapy, the fruquintinib plus sintilimab combination showed substantial improvements in both progression-free survival (PFS) and overall survival (OS). The median PFS was 8.6 months, and the median OS was 21.8 months.

The safety profile observed in FRUSICA-1 was characterized as manageable and consistent with the established safety data for each individual agent. The most frequently reported grade ≥3 treatment-related adverse event (AEs) was hypertension (17.3%). This is a known class effect of VEGFR inhibitors and generally controllable with standard antihypertensive management. Other AEs were consistent with the expected profiles of antiangiogenesis and anti–PD-1 therapies, including potential immune-related AEs and fatigue.

Patients received fruquintinib (5 mg orally once daily on a 2 weeks on/1 week off schedule) plus sintilimab (200 mg intravenously once every 3 weeks).

The study concluded that the safety profile did not present new or unexpected signals, making it a viable long-term treatment strategy for patients who have progressed on prior lines of therapy.

“A limitation of this study was the nonrandomized design and the lack of a comparator arm,” noted Wu X et al, authors of the study, published in Nature Communications. “The ongoing randomized phase [3] study of fruquintinib plus sintilimab [vs] paclitaxel or doxorubicin in patients with advanced EMC (NCT06584032) will allow further understanding of the baseline patient characteristics that predict better outcomes with this combination. Similarly, a larger patient population will be required to evaluate potential biomarkers related to the efficacy of fruquintinib plus sintilimab.”

Clinical Implications and Future Outlook

The findings of FRUSICA-1 represent a significant shift in the management of pMMR EMC in China. While the combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda) is a standard of care in the US and Europe, its lack of availability in China created a profound unmet medical need.

Based on the robust efficacy and tolerable safety demonstrated in this trial, the combination of fruquintinib plus sintilimab has received conditional approval in China. It stands as the first antiangiogenesis plus anti–PD-1 therapy approved for this specific indication in the region.

REFERENCES

1.Wu X, Wang J, Wang D, et al. Fruquintinib plus sintilimab in patients with advanced endometrial cancer with mismatch-repair proficient status: a multicenter, single-arm, phase Ib/II trial. Nat Commun 17, 658 (2026). December 21, 2025. January 21, 2026. doi: 10.1038/s41467-025-67375-3.

2.A phase Ib/II study to evaluate fruquintinib monotherapy or plus sintilimab in advanced solid tumors. ClinicalTrials.gov. Updated April 6, 2025. Accessed January 21, 2026. https://clinicaltrials.gov/study/NCT03903705

3.Antill Y, Kok PS, Robledo K, et al. Clinical activity of durvalumab for patients with advanced mismatch repair-deficient and repair-proficient endometrial cancer. A nonrandomized phase 2 clinical trial. JImmunother Cancer. 2021 Jun;9(6):e002255. doi: 10.1136/jitc-2020-002255. PMID: 34103352; PMCID: PMC8190057.