618P Efficacy and safety of vactosertib and pembrolizumab combination in patients with previously treated microsatellite stable metastatic colorectal cancer

Vactosertib (TEW-7197), a highly selective and potent inhibitor of TGF-β receptor type 1, combined with PD-1 inhibition could induce immune restoration and enhance anti-tumor responses in patients with microsatellite stable metastatic colorectal cancer (mCRC). MP-VAC-204 is a phase 1b/2a study evaluating the combination of vactosertib with pembrolizumab in previously treated MSS mCRC. Here we report the updated safety and efficacy data of this phase 1b/2a study (NCT03724851). Eligible patients were >18 years old with ECOG performance status 0-1 and who had disease progression after treatment with all available therapies including fluoropyrimidine and oxaliplatin or irinotecan. The MSI testing was conducted by local or central tests. Tumor biomarkers including granzyme B+ CD8+T cells were measured in serial tumor samples by multiplex immunofluorescence staining and deconvolution-based immune cell analysis. Circulating proteins, TGF-b, CTGF, PAI-1 and PDGF-AB were evaluated from serial blood samples. A total of 105 patients (36 in 200mg BID, 30 in 200mg QD, 7 in 200mg TID and 32 in 300mg BID) were enrolled. In all patients (N=105), the overall objective response rate was 13.3% [95% confidence interval (CI), 7.5- 21.4] and median duration of response was 6.0 months (95% CI, 2.9-Not Reached [NR]). Median PFS and OS were 1.3 months (95% CI, 1.2-1.4) and 15.8 months (95% CI, 7.9-NR) respectively. Overall PFS rate at 6 months was 17.1% (95% CI, 10.5-25.7) and overall survival rate at 12 months was 61.0% (95% CI, 51.0-70.3). Rash, headache and decreased appetite were the most frequent treatment emergent adverse events (TEAEs), but all were manageable. No fatal serious TEAEs were observed in any cohort. The levels of TGF-β signaling related circulating cytokines, TGF-b, CTGF, PAI-1, and PDGF-AB/BB were significantly decreased after treatment. Tumor-infiltrating and microenvironmental granzyme B secretion by CD8+ cells were significantly increased after treatment. Vactosertib combined with pembrolizumab showed anti-tumor activity, prolonged overall survival and manageable safety profiles in patients with MSS mCRC. The phase 2 part is still ongoing.