A Phase 1/2 trial of intratumoral (i.t.) IMO-2125 (IMO) in combination with checkpoint inhibitors (CPI) in PD-(L)1-refractory melanoma

Abstract

Background: CPI have transformed melanoma treatment, however many patients remain refractory and subsequent treatment options are limited. IMO, a Toll-like receptor 9 agonist, may improve response to CPI by activating innate and adaptive immune responses to overcome immune escape. Initial clinical experience with IMO + ipi is promising (Uemera, ASCO-SITC 2017). Dose-finding is now complete and is the basis for this updated report. Methods: Adults with unresectable or metastatic melanoma refractory to a PD-(L)1 inhibitor are eligible if they have tumor accessible to biopsy. IMO is administered i.t. to a single tumor at escalating doses during weeks 1,2,3,5,8, and 11 along with ipi or pem per the product label. The primary endpoint of Phase 1 is safety and for Phase 2 is overall response rate using a 2-stage design. Serial biopsies are obtained from both the injected and a non-injected lesion for immune analysis. Results: A total of 22 subjects have been treated with either IMO-ipi (N=18) or IMOpem (N=4) and dose-escalation is now complete for the IMO-ipi arm. Dose-limiting toxicities have not been reported. Immune-related AE were observed in 4 IMO-ipi subjects [hypophysitis (N=2), hepatitis (1), colitis (1)]. These responded well to standard measures. Of 9 patients treated at the RP2D of 8mg, 6 have experienced clinical benefit (1CR, 1PR, 1uPR, 3 SD). Biopsies show maturation of the mDC1 subset (CD1c+CD303-), upregulation of PD-L1 by malignant cells, and an IFNalpha response gene signature. Biopsies of uninjected tumors show expression of CD56+ and Ki67+ effector CD8+T cells in responding patients, indicative of an abscopal effect. Phase 2 accrual using the 8mg IMO dose is ongoing. Conclusions: IMO + ipi is a viable strategy to revive the immune response in CPIresistant tumors and shows preliminary clinical activity worthy of further development.