SD-101 With Immune Checkpoint Inhibition Generates Positive Results in Uveal Melanoma Liver Metastasis

Sapna Patel, MD

Treatment with SD-101 distributed via pressure-enabled drug delivery with immune checkpoint inhibition was tolerated and resulted in the depletion of regulatory T cells (Tregs), monocytic myeloid-derived suppressor cells (M-MDSCs), and M2 macrophages in liver metastases in patients with uveal melanoma, according to data from the phase 1 PERIO-01 trial (NCT04935229) presented at the 2023 SITC Annual Meeting.¹

The results showed that treatment with 2 mg of SD-101 plus nivolumab (Opdivo) led to a median progression-free survival (PFS) of 11.7 months and 1-year overall survival (OS) rate of 86%.

“When we look at this all together, we see the most favorable immune reprogramming happening at the 2 mg plus nivolumab dose level,” Sapna Patel, BA, MD, said in a presentation of the data. “This is demonstrated by a decrease in regulatory T cells and M-MDSCs in the liver tumors, and an increase in systemic activation via cytokine signaling and circulating T cells and NK cells in the periphery,” Patel said.

Patel is the director of the Uveal Melanoma Program and Melanoma Fellowship Program, and an associate professor in the Department of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston.

Tebentafusp-tebn (Kimtrak) is currently the only FDA-approved immunotherapy for patients with metastatic uveal melanoma, and its indication is restricted to patients who present with the HLA-A*02:01 haplotype.² Furthermore, approximately half of patients diagnosed with uveal melanoma will develop metastatic disease, primarily affecting the liver, presenting an unmet need for treatment in this population, Patel said.

Notably, patients with liver metastasis have high levels of MDSCs, which confer resistance to checkpoint blockade. Despite success with TLR9 agonists, administration has been limited to intra-tumoral delivery. In PERIO-01, investigators evaluated whether SD-101, a TLR9 agonist given as a hepatic arterial infusion, plus checkpoint blockade could improve outcomes in this population.

Patients 18 years or older with confirmed metastatic uveal melanoma with liver-only or liver-dominant disease, excluding those with recent cytotoxic chemotherapy, targeted therapy, external radiation therapy, or immunological checkpoint blockade were eligible for enrollment. Participants also had to have measurable liver disease, an ECOG performance status of 1 or less, and a life expectancy greater than 3 months. Adequate organ function was also required.³

Exclusion criteria included recent chemotherapy or investigational agent use; untreated brain metastasis; portal vein thrombosis or severe portal hypertension; extensive liver parenchymal replacement by tumor of both liver lobes; Child-Pugh Class B or C cirrhosis; grade 3 or higher immune-related adverse effects (AEs) from prior checkpoint inhibitor therapy that has not recovered to grade 1; inability to be removed temporarily from chronic anticoagulation therapy; and bleeding disorders. Furthermore, autoimmune diseases; prior exposure to SD-101; and hypersensitivity to TLR9 agonists or checkpoint inhibitors would result in exclusion from the study.²

Eligible patients were enrolled into the phase 1 study where SD-101 was given regionally.

Three cohorts were enrolled in the PERIO-01 study: cohort A (n = 13), which evaluated escalating doses of SD-101; cohort B (n = 26), which evaluated escalating doses of SD-101 and an anti–PD-1 agent; and cohort C (n = 17), which tested escalating doses of SD-101, an anti–PD-1 agent, and a CTLA-4 inhibitor.

Patients in each cohort received SD-101 at 2 mg, 4 mg, and 8 mg every week for 3 weeks, which was followed by a 5-week rest period, before the second cycle. Checkpoint inhibition was administered for 12 months.

Patel noted that disease control, which was defined as stable disease plus partial and complete responses, was seen across all dose levels. An 81% disease control rate (DCR) was seen at the 2-mg dose level. Regarding best circulating tumor DNA (ctDNA) response, 59% of patients had ctDNA clearance; 27% had ctDNA clearance from the highest level on treatment to post treatment. The ctDNA reduction rates were 86% and 65%, respectively. Notably, 5 of the 7 patients treated with 2 mg of the study drug plus nivolumab saw a greater than 50% decrease in ctDNA from baseline, Patel said.

Treatment across the 3 dose levels showed that the most favorable immune reprogramming was observed at 2 mg. This is due to the decrease in Treg cells in the liver tumors, as well as the monocytic population of MDSCs, and an increase in granzyme B and IL-15 in the periphery, Patel said.

“If you look across all dose levels, if we had done what we do in typical phase 1 trials, which is escalate the dose and take the maximum tolerated dose [MTD], we would have missed this sign of optimal biology,” Patel said. “[Benefit] is shown at the lowest dose level of SD-101. It is important that we don't just ratchet up the treatment and pick the MTD, [rather] we go deep on the biology to ensure that we’re moving forward with the optimal dose.”

A total of 56 patients were enrolled onto the study and the median age was 64 years (range, 35-86); a majority of patients were male (54%); lactate dehydrogenase (LDH) was above the upper limits of normal for 48% of patients; and 80% of patients had an ECOG performance status of 0. Additionally, patients enrolled onto the study had 0 (29%), 1 (30%), 2 (21%), and 3 or more (14%) prior lines of therapy, 16% of whom had received prior tebentafusp.

Looking to pharmacokinetics, Patel noted that across all dose levels, SD-101 was undetectable in the blood beyond 4 hours in more than 95% of patients. In the presentation, Patel also noted the increase in infiltrating CD8 T cells and NK cells in liver tumors following 8 weeks on study (day 57).

“This means that regional delivery of SD-101 is resulting in low and transient drug levels in the periphery and high drug levels in the liver,” Patel said. “RNA sequencing gene expression profile shows an induction of T-cell activation and cytokine signaling in the liver metastasis and a similar signature emerging in the periphery, despite low levels of SD-101 detectable outside of the liver.”

Regarding safety, in cohort A, 38% of patients experienced treatment-related AEs (TRAEs), 8% of which were grade 3 or higher serious AEs. No dose-limiting toxicities (DLTs) occurred in this cohort. The most common AEs included gastrointestinal (GI) disorders (23%), fatigue (15%), fever (15%), and administration site conditions (8%).

In cohort B, 73% of patients experienced TRAEs, 19% of which were grade 3 or higher and 4% were considered serious AEs. Notably, 8% of patients experienced DLTs. The most common AEs recorded in cohort B were GI disorders (31%), fatigue (19%), skin disorders (27%), fever (4%), administration site conditions (15%), increased alanine aminotransferase (ALT; 15%), and increased aspartate aminotransferase (AST; 15%).

Finally, in cohort C, 88% of patients experienced TRAEs, 47% of which were grade 3 or higher and 35% were considered serious AEs. The most common AEs reported were GI disorders (71%), fatigue (59%), skin disorders (47%), fever (35%), administration site conditions (24%), increased ALT (24%), and increased AST (24%).

“The 2 mg dose of SD-101 is moving forward as our optimal dose with the most favorable augmentation of the tumor microenvironment. We believe that SD-101 via pressure enabled delivery device plus [an] immune checkpoint inhibitor does have the potential to address the significant unmet clinical need in patients with uveal melanoma liver metastasis,” Patel concluded.

References

1. Patel SP, Carvajal R, Montazeri K, et al. Clinical activity of SD-101 with immune checkpoint inhibition (ICI) in metastatic uveal melanoma liver metastasis (MUM-LM) from the PERIO-01 phase 1 trial. Presented at: 2023 SITC Annual Meeting; November 1-5, 2022; San Diego, CA. Abstract 1534
2. FDA approves tebentafusp-tebn for unresectable or metastatic uveal melanoma. FDA. January 25, 2022. Accessed December 18, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tebentafusp-tebn-unresectable-or-metastatic-uveal-melanoma
3. Intrahepatic delivery of SD-101 by pressure-enabled regional immuno-oncology (PERIO), with checkpoint blockade in adults with metastatic uveal melanoma. ClinicalTrials.gov. Updated January 31, 2023. Accessed November 27, 2023. https://clinicaltrials.gov/study/NCT04935229