A phase 2 clinical trial has indicated that the addition of SHR-1701, a TGF-β inhibitor, to first-line capecitabine and oxaliplatin (XELOX) plus bevacizumab shows promising efficacy and manageable safety in patients with unresectable metastatic colorectal cancer (mCRC). The study, conducted across 10 sites in China, suggests that this combination could offer a new treatment option for mCRC patients.
Study Design and Key Findings
The phase 2 portion of the NCT04856787 trial was a single-arm study assessing the efficacy and safety of SHR-1701 in combination with bevacizumab and XELOX as a first-line treatment for patients with unresectable mCRC. Patients aged 18 to 75 years with histologically confirmed colorectal adenocarcinoma who had not previously received systemic therapy for recurrent or metastatic disease were enrolled. The primary endpoint was the investigator-assessed objective response rate (ORR).
The study reported an ORR of 64.9% (95% CI: 51.6-76.8%) and a disease control rate (DCR) of 93.4% (95% CI: 84.4-98.2%). The median duration of response (DoR) was 9.7 months (95% CI: 7.0-13.7), median progression-free survival (PFS) was 11.7 months (95% CI: 9.3-16.5), and median overall survival (OS) was 22.1 months (95% CI: 17.7-28.8).
Treatment and Assessments
Patients received intravenous SHR-1701 (30 mg/kg), bevacizumab (7.5 mg/kg), and oxaliplatin (130 mg/m2) on day 1 of each 21-day cycle, along with oral capecitabine (1 g/m2 twice daily) on days 1-14. Up to eight cycles of induction therapy were administered, followed by maintenance therapy with SHR-1701, bevacizumab, and capecitabine until disease progression or unacceptable toxicity. Radiographic evaluations were performed every six weeks for the first 48 weeks, then every 12 weeks, with clinical responses assessed using RECIST v1.1 criteria.
Genomic Analysis
Comprehensive genomic profiling using a 418-gene panel revealed mutations in genes commonly altered in solid tumors. Tumor mutational burden (TMB) was calculated, and copy number alterations (CNAs) were identified. The genomic integrity of the TGFβ pathway was assessed by examining key regulatory genes. This analysis aimed to identify potential biomarkers predictive of response to SHR-1701.
Safety Profile
The safety profile of the combination therapy was considered manageable. Common adverse events included hematologic toxicities and gastrointestinal symptoms, which are typical with XELOX and bevacizumab regimens. The addition of SHR-1701 did not appear to significantly increase the incidence of severe adverse events.
Clinical Implications
The results suggest that SHR-1701 in combination with XELOX and bevacizumab is a promising first-line treatment option for patients with unresectable mCRC. The observed ORR and DCR warrant further investigation in larger, randomized phase 3 trials to confirm these findings and to better define the role of TGF-β inhibition in the treatment of mCRC.
