Subsequent treatment with ipi offers 10-13% ORR (Bowyer 2016, Long 2016) in aPD1 refractory MM. Tilsotolimod, a synthetic TLR9 agonist oligonucleotide, acts on macrophages and dendritic cells to alter the tumor microenvironment. Local drug-induced type 1 interferon response results in increased antigen presentation and downstream T cell activation and proliferation in injected and non-injected lesions (Haymaker, SITC 2017).
The study will enroll up to 60 pts with rMM to receive IT (with/without IG) tilsotolimod (scheduled weeks 1,2,3,5,8,11,17, 23 and 29); ipi is given per the product label starting at week 2. Pts with M1c disease, mucosal melanoma and BRAF mutations were included. The primary endpoint is RECIST1.1 objective response rate (ORR); other endpoints are safety and tolerability and disease control rate (DCR). Immune analyses of T-cell repertoire diversity evaluated by high-throughput CDR3 sequencing. Phase 2 accrual is ongoing.
As of 9 Apr 2018, 26 pts have been treated with tilsotolimod 8mg+ ipi, including 5 pts who received IG injections to deep visceral lesions or lymph nodes. Median age: 65.8 (range 39-91 yrs); 11 IVM1c. 6 pts had irAEs [hypophysitis (2), hepatitis (2), adrenal insufficiency (1), Guillain-Barre syndrome (1), colitis (1), enterocolitis (1)], which responded to standard measures. Injection-related toxicities were grade 1-2 transient fever and flu like symptoms lasting <48 hours. Major expanding T-cell clones are found to be shared in responding local and distant lesions indicating that reactivation is to a shared antigen in responding patients. As of 9 May 2018, 21 pts were assessed for response: 38% ORR and 71% DCR (2 CR, 6 PR, 7 SD). 6 of 8 responses are ongoing including 1 CR > 23 mo. 10 pts had BRAF mutations (1 CR, 3 PR, and 4 SD).
IT tilsotolimod 8mg+ ipi is well tolerated and shows substantial clinical benefit and durable responses. The ORR of 38% compares favorably to ipi in this challenging population, leading to an ongoing global randomized Phase 3 study of tilsotolimod 8mg+ipi vs. ipi in aPD-1 rMM.
Clinical trial identification
Legal entity responsible for the study
All authors have declared no conflicts of interest.