Asudemotide

BACKGROUND: Effective maintenance therapy for urothelial carcinoma (UC) is needed to delay progression after first-line chemotherapy. OBJECTIVE: To evaluate S-588410, a cancer peptide vaccine containing five human leukocyte antigen (HLA)-A*24:02-restricted epitope peptides derived from five cancer-testis antigens (DEPDC1, MPHOSPH1, URLC10, CDCA1, and KOC1) in chemotherapy-treated, clinically stable patients with advanced or metastatic UC. MATERIALS AND METHODS: This open-label, international, phase 2 trial enrolled patients with UC who had completed≥4 cycles of first-line platinum-containing chemotherapy without disease progression. Forty-five HLA-A*24:02-positive patients received subcutaneous injections of S-588410 (Montanide ISA 51 VG with 1 mg/mL of each peptide) weekly for 12 weeks then once every 2 weeks thereafter for up to 24 months. Thirty-six HLA-A*24:02-negative patients did not receive S-588410 (observation group). The primary endpoint was the rate of cytotoxic T-lymphocyte (CTL) induction against≥1 of the peptides at 12 weeks. RESULTS: The CTL induction rate in the S-588410 group was 93.3% (p < 0.0001, one-sided binomial test with a rate of≤50% as the null hypothesis). The antitumor response rate was 8.9% in the S-588410 group and 0% in the observation group; median progression-free survival was 18.1 versus 12.5 weeks and median overall survival was 71.0 versus 99.0 weeks, respectively. The most frequent treatment-emergent adverse event was injection-site reactions (47 events, grades 1–3) reported in 93.3% (n = 42/45) of participants. CONCLUSIONS: S-588410 demonstrated a high CTL induction rate, acceptable safety profile, and modest clinical response, as maintenance therapy in participants with advanced or metastatic UC who had received first-line platinum-based chemotherapy (EudraCT 2013-005274-22).

Cancer vaccines induce cancer-specific T-cells capable of eradicating cancer cells. The impact of cancer peptide vaccines (CPV) on the tumor microenvironment (TME) remains unclear. S-588410 is a CPV comprising five human leukocyte antigen (HLA)-A*24:02-restricted peptides derived from five cancer testis antigens, DEPDC1, MPHOSPH1, URLC10, CDCA1 and KOC1, which are overexpressed in esophageal cancer. This exploratory study investigated the immunologic mechanism of action of subcutaneous S-588410 emulsified with MONTANIDE ISA51VG adjuvant (median: 5 doses) by analyzing the expression of immune-related molecules, cytotoxic T-lymphocyte (CTL) response and T-lymphocytes bearing peptide-specific T-cell receptor (TCR) sequencing in tumor tissue or blood samples from 15 participants with HLA-A*24:02-positive esophageal cancer. Densities of CD8+, CD8+ Granzyme B+, CD8+ programmed death-1-positive (PD-1+) and programmed death-ligand 1-positive (PD-L1+) cells were higher in post- versus pre-vaccination tumor tissue. CTL response was induced in all patients for at least one of five peptides. The same sequences of peptide-specific TCRs were identified in post-vaccination T-lymphocytes derived from both tumor tissue and blood, suggesting that functional peptide-specific CTLs infiltrate tumor tissue after vaccination. Twelve (80%) participants had treatment-related adverse events (AEs). Injection site reaction was the most frequently reported AE (grade 1, n = 1; grade 2, n = 11). In conclusion, S-588410 induces a tumor immune response in esophageal cancer. Induction of CD8+ PD-1+ tumor-infiltrating lymphocytes and PD-L1 expression in the TME by vaccination suggests S-588410 in combination with anti-PD-(L)1 antibodies may offer a clinically useful therapy.Trial registration UMIN-CTR registration identifier: UMIN000023324.