Regorafenib/Sintilimab shows tolerability and mixed efficacy in MSS mCRC

Regorafenib plus Sintilimab (Tyvyt) was well tolerated with limited toxicity, but efficacy outcomes in patients with microsatellite stable (MSS) metastatic colorectal cancer varied and were related to the expression of specific genes that control tumor metabolism, the abundance of immune cells, and the distance between immune cells and tumor cells, according to a published Phase 2 study (NCT04745130).

The median follow-up time was 19.9 months (95%CI, 12.8-27.0), the median overall survival (OS) was 14.1 months, accounting for 10.5-17.7, the 6-month OS rate was 85.4%, accounting for 78.5%-92.4%, and the median progression-free survival (PFS) was 4.1 months. 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).

Patients with RAS or RAS wild-type disease had significantly longer median OS at 23.3 months compared with 12.1 months for patients with the mutant form (95% CI, 10.0-36.6). It was also noted that the median OS for patients with liver metastases was 19.2 months (95% CI, 15.2-23.2) and for patients without liver metastases was 12.4 months, 95% CI, 11.0-13.9. The median PFS was 5.4 months (95% CI, 1.1-9.7) for patients with liver metastases and 3.1 months (95% CI, 1.7-4.5) for patients without liver metastases.

In conclusion, the combination of regorafenib and Sintilimab was well tolerated in patients with advanced MSS colorectal cancer and showed better anti-tumor effects compared with monotherapy. In addition, the combination regimen provided a longer survival benefit, especially in patients with RAS/RAF wild-type genes.

A total of103 patients aged 18 years or older diagnosed with inoperable recurrent or metastatic cancer who had experienced progression on at least 2 prior lines of standard systemic therapy were enrolled in the trial. Other inclusion criteria included ECOG performance status of 0 to 2, MSS status, at least 1 measurable lesion per RECIST v1.1, and adequate bone marrow and organ function. Those previously treated with regorafenib or anti-PD-L1/PD-L2/CTLA4 antibodies were excluded.

All patients received oral administration of 80 mg of regorafenib daily for 3 weeks, followed by a 1-week break, and intravenous injection of 200 mg of sintilimab on day 1, and every 3 weeks thereafter. Both drugs were administered at fixed doses, but adjustments to regorafenib were allowed based on patient tolerance.

The overall median age was 57 years (range 28-75 years), 59.2% were male, and 66.0% had an ECOG performance status of 1. Most patients had common primary tumor side on the left side (84.5%), single organ metastasis (52.4%), liver metastasis (61.2%), and RAS wild-type disease (51.5%). In addition, 83.5% and 45.6% of patients received anti-VEGF and anti-EGFR antibody treatment respectively; 71.8% of patients received 2 previous treatments; 60.2% did not receive subsequent treatment, 35.0% received targeted therapy, 30.1% received chemotherapy, 5.8% received immunotherapy, and 2.9% received radiotherapy.

OS is the primary endpoint of the trial. Secondary endpoints are ORR, DCR, DOR, PFS and safety.

With regard to safety, the most common treatment-related adverse events (TRAEs) of any grade were fatigue (29.1%), hand-foot syndrome (27.2%), gastrointestinal symptoms (25.2%), mucositis (17.5%), rash (16.5%), and hypertension (16.5%). Grade 3 TRAEs were hand-foot syndrome (2.9%), rash (2.9%), fatigue (1.0%), mucositis (1.0%), hypertension (1.0%), and pyrexia (1.0%).

Reference materials:https://www.cancernetwork.com/view/regorafenib-sintilimab-show-tolerability-and-mixed-efficacy-in-mss-mcrc