A phase I trial found promising activity and good tolerability with the combination of pembrolizumab and a stimulant of Toll-like receptor 9 (TLR9) known as SD-101 in patients with unresectable or metastatic melanoma, particularly in those who had not received prior anti–programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) therapy.
PD-1/PD-L1 inhibition has improved outcomes in metastatic melanoma, and studies have indicated that combination therapy can increase immune responses further. “Despite the improvement in response rates with combination immunotherapy, a large unmet need remains,” wrote study authors led by Antoni Ribas, MD, PhD, of the University of California, Los Angeles, Jonsson Comprehensive Cancer Center.
SD-101 is a synthetic oligonucleotide targeting TLR9 to stimulate plasmacytoid dendritic cells. Early research in mice showed that intratumoral injections of SD-101 enhanced the effect of pembrolizumab; promising results were also seen with this combination in a small study of patients with non-Hodgkin lymphoma.
In the new phase I dose-escalation study, 22 patients with unresectable or metastatic melanoma were included; 9 had not received prior anti–PD-1/PD-L1 therapy. Patients received intralesional injections of SD-101 along with pembrolizumab; SD-101 dose levels included 1 mg, 2 mg, 4 mg, and 8 mg. The results of the study were published in Cancer Discovery.
Among the nine patients who were naive to anti–PD-1/PD-L1 therapy, seven had at least one evaluation of their tumors; of those, all seven had a confirmed objective response to the therapy, and tumor shrinkage was seen in all target lesions. Responses were observed at all SD-101 dose levels, with complete responses at the 2-mg and 4-mg levels. The median progression-free survival (PFS), duration of response, and overall survival (OS) have not yet been reached, and the estimated 12-month PFS and OS rates were 88% and 89%, respectively. After a median 18 months of follow-up, 86% of the responses were ongoing.
For the 13 patients who had received prior anti–PD-1/PD-L1 therapy, 12 had at least one evaluation. In these patients, only 2 partial responses were observed, 1 in the 1-mg SD-101 cohort and 1 in the 8-mg cohort. Reduction in target lesions was observed in five patients. Ten patients developed progressive disease between 1.5 months and 8 months after enrollment in the study.
The combination was generally well tolerated, though all 22 patients experienced at least 1 treatment-emergent adverse event. Most adverse events were grade 1/2, and there was no relationship between adverse events and SD-101 dose level. The most common grade 3/4 adverse events related to SD-101 included chills, myalgia, and injection site pain, each occurring in 14% of patients. Three patients had new-onset immune-related adverse events, including pneumonitis, polymyalgia rheumatica, and hypothyroidism.
“This early-stage, first-in-human trial of an intratumoral TLR9 agonist with an anti–PD-1 checkpoint inhibitor demonstrated the combination was well tolerated with a high response rate in a small number of patients who were naive to anti–PD-1 therapy at baseline,” the authors concluded. “The correlation of immune activity with response suggests that, independent of prior anti–PD-1/PD-L1 therapy, the addition of SD-101 may have the potential to reverse the resistance to anti–PD-1/PD-L1 monotherapy.”