Regorafenib/Sintilimab Show Tolerability and Mixed Efficacy in MSS mCRC

Efficacy results demonstrated by regorafenib and sintilimab in patients with mSS mCRC were dependent on patient characteristics such location of metastasis and RAS type.

Regorafenib (Stivarga) plus sintilimab (Tyvyt) was well-tolerated with limited toxicity, however efficacy results were varied and correlated with specific gene expressions governing tumor metabolism, the abundance of immune cells, and the distance between immune and tumor cells, in patients with microsatellite stable (MSS) metastatic colorectal cancer, according to a phase 2 study (NCT04745130) published in Nature Communications.

At a median follow-up of 19.9 months (95% CI, 12.8-27.0), the median overall survival (OS) was 14.1 months (95% CI, 10.5-17.7), the 6-month OS rate was 85.4% (95% CI, 78.5%-92.4%), and the median progression-free survival (PFS) was 4.1 months (95% CI, 3.4-4.8). The overall response rate (ORR) was 21.4% (95% CI, 13.3%-29.4%), the disease control rate (DCR) was 63.1% (95% CI, 53.6%-72.6%), and the duration of response (DOR) was 13.0 months (95% CI, 2.5-23.5).

Significantly longer median OS was found in patients with RAS or RAS wild-type disease at 23.3 months (95% CI, 10.0-36.6) compared with those who had mutant-type at 12.1 months (95% CI, 8.4-15.8), respectively. It was also noted that the median OS was 19.2 months (95% CI, 15.2–23.2) in patients with liver metastasis and 12.4 months (95% CI, 11.0–13.9) in patients without liver metastasis. The median PFS was 5.4 months (95% CI, 1.1–9.7) in patients with liver metastasis and 3.1 months (95% CI, 1.7–4.5) in patients without liver metastasis.

“In conclusion, the combination of regorafenib and sintilimab was well tolerated in [patients with] advanced MSS colorectal cancer, showing improved antitumor effects compared with the monotherapy of either agent,” lead study author Rui Liu, MD, an associate professor at the Tianjin Medical University Institute and Hospital, Tianjin, China, and fellow investigators wrote in the study. “Moreover, the combination regimen offered a longer survival benefit, particularly in patients with the RAS/RAF wild-type gene.”

A total of 103 patients aged 18 years or older with confirmed inoperable recurrent or metastatic colorectal cancer who experienced progression on at least 2 prior lines of standard systemic therapy were enrolled in the trial. Additional enrollment criteria include an ECOG performance status of 0 to 2, an MSS status, at least 1 measurable lesion per RECIST v1.1, and adequate bone marrow and organ function. Those who received prior treatment with regorafenib or anti–PD-L1/PD-L2/CTLA4 antibodies were excluded.

All patients were administered 80 mg of oral regorafenib daily for 3 weeks followed by a 1-week break plus 200 mg of intravenous sintilimab on day 1 and then every 3 weeks thereafter. Both drugs were given at fixed doses, though adjustments to regorafenib were permitted depending on patient tolerance.

The overall median age was 57 years (range, 28-75), 59.2% were male, and 66.0% had an ECOG performance status of 1. Most patients had a common primary tumor side on the left (84.5%), single-organ metastasis (52.4%), metastasis present in the liver (61.2%), and RAS wild-type disease (51.5%). Also, 83.5% and 45.6% of patients, respectively, received anti-VEGF and anti-EGFR antibodies; 71.8% of patients received 2 prior lines of therapy; 60.2% received no subsequent therapy, 35.0% received targeted therapy, 30.1% received chemotherapy, 5.8% received immunotherapy, and 2.9% received radiation therapy.

OS was the trial’s primary end point. Secondary end points were ORR, DCR, DOR, PFS, and safety.

Regarding safety, the most common treatment-related adverse events (TRAEs) of any grade were asthenia (29.1%), hand-foot syndrome (27.2%), gastrointestinal symptoms (25.2%), mucositis (17.5%), skin rash (16.5%), and hypertension (16.5%). TRAEs of grade 3 were hand-foot syndrome (2.9%), skin rash (2.9%), asthenia (1.0%), mucositis (1.0%), hypertension (1.0%), hypothyroidism (1.0%), and fever (1.0%).

References

Liu R, Ji Z, Wang X, et al. Regorafenib plus sintilimab as a salvage treatment for microsatellite stable metastatic colorectal cancer: a single-arm, open-label, phase II clinical trial. Nat Commun. Published online February 10, 2025. doi:10.1038/s41467-025-56748-3