Randomized phase 3 trial of IO102-IO103 plus pembrolizumab versus pembrolizumab alone in patients with previously untreated, unresectable, or metastatic melanoma.

TPS9589 Background: The treatment of melanoma has improved markedly with the emergence of new immune therapies, and both anti-PD-1 monotherapy and the combination of the anti-PD-1 antibody nivolumab and anti-CTLA-4 therapy ipilimumab are now considered standard-of-care in the unresectable or metastatic (advanced) melanoma setting. However, many patients have primary or acquired resistance to these therapies, thereby underpinning the need for more effective approaches. IO102-IO103 is a potentially first-in-class, dual-antigen, immune-modulatory therapy targeting the key cancer immune resistance pathways mediated by IDO and PD-L1. The ability of IO102 and IO103 to respectively activate the specific T cells that recognize these checkpoint molecules and directly modulate immune regulation has previously been demonstrated both preclinically and in human clinical trials. A synergistic anti-tumor response upon treatment against both IDO and PD-L1 has also previously been demonstrated in a preclinical model where IDO and PD-L1 were expressed by different cells in the tumor microenvironment. Due to the distinctive mechanisms of action of IO102-IO103 and anti-PD-1 antibodies, there may be a further synergistic effect when treatment is combined. A previous Phase 1/2 trial investigating the use of IO102-IO103 plus nivolumab in patients with anti-PD-1-naïve metastatic melanoma has demonstrated promising anti-tumor activity with an overall response rate (ORR) of 80%, median progression-free survival (PFS) of 26 months and a manageable safety profile (NCT03047928; Kjeldsen et al, Nat Med 2021). Methods: This is a Phase 3, multicenter, open-label, randomized, 2-arm trial investigating the efficacy and safety of IO102-IO103 plus pembrolizumab versus pembrolizumab alone (EudraCT: 2021-004594-32; ClinicalTrials.gov No: NCT05155254). Inclusion criteria include: adult patients with untreated, unresectable (Stage III), or metastatic (Stage IV) melanoma; > 6 months since last dose of (neo)adjuvant treatment with targeted or immune therapy (in those previously treated); and ≥1 measurable lesion by RECIST v1.1. Primary endpoint is PFS by blinded independent central review. Secondary endpoints include ORR, durable response rate, complete response rate, duration of response, time to response, disease control rate, overall survival, and safety/tolerability. Target enrollment is 300 patients at > 100 sites in 20 countries. Patients are randomized 1:1 to receive either pembrolizumab 200 mg intravenously (IV) every 3 weeks up to 2 years or pembrolizumab 200 mg IV every 3 weeks up to 2 years with dual-antigen IO103-IO102 85-85 µg and Montanide adjuvant subcutaneously on Day 1 and 8 of cycle 1 and 2 and on Day 1 of each cycle thereafter. Enrolment for the study is ongoing. Clinical trial information: EudraCT: 2021-004594-32; ClinicalTrials.gov No: NCT05155254.