New Combination Is Well-Tolerated in Early-Stage Melanoma

The combination of intratumoral SD-101 and Keytruda (pembrolizumab) was well-tolerated with no dose-limiting toxicites, according to the results of a recent safety, tolerability and dose escalation phase 1b/2 study presented at the 2016 Society for Melanoma Research (SMR) Annual Congress in Boston by Antoni Ribas, M.D., Ph.D., the lead researcher.

Researchers reported an elevation of immune function, which was observed by increases in immune function signals, as well as increases in immune cell infiltrates, in the tumor microenvironment.

“This is very preliminary data, but it seems like the combination may have activity in patients who have not previously received an anti-PD1 agent. We have also seen some changes in patients who are progressing on an anti-PD1 therapy when we administer this combination,” Ribas said, who is a professor of Medicine, Hematology and Oncology at the Ronald Regan UCLA Medical Center.

Primary outcome measures included incidence of dose-limiting toxicities, incidence of injection-site reactions, adverse events (AEs) and serious adverse events in the phase 1b trial and objective response rate in phase 2. Secondary outcome measures in the phase 2 portion of the trial included time to objective response, duration of response and changes in correlative biomarkers, including tumor infiltrating lymphocytes and PD-L1 expression at baseline.

The trial was conducted across five cancer centers and included a total of 18 patients with stage 3c or 4 melanoma. Eight patients were anti-PD-1 naïve, and 11 had previously received an anti-PD-1 therapy. The median follow-up for the anti-PD-1 naïve patients was 188 days, and the median follow-up for patients who were anti-PD-1 experienced was 81 days.

Biopsies and CT scans were taken at baseline and throughout the treatment phase. SD-101 was given weekly for four weeks, and then given every three weeks coinciding with the doses of Keytruda.

At the time of follow-up in the anti-PD-1 naïve group, 20 percent (one patient) had a complete response (CR), 60 percent (three patients) had a partial response (PR), 20 percent (one patient) had progressive disease and 80 percent (four patients) had a PR+CR. For the experienced group, 50 percent (four patients) had stable disease (SD) and 50 percent (four patients) had progressive disease.

In previous preclinical studies, a strong effect was observed between SD-101, an oligonucleotide with immunostimulatory CpG motifs that activate plasmacytoid dendritic cells via the toll-like receptor 9, and anti-PD1 agents, such as Keytruda. SD-101 is designed to mediate anti-tumor effects by triggering both innate and adaptive immune responses, including inducing high levels of Type 1 interferon.

Two key pathways are activated by SD-101, which leads to functional maturation of dendritic cells and substantial production of interferon alpha. When SD-101 is injected into the tumor, it activates cytoxic T cells that are specific to many tumor antigens.

Overall, the combination was well tolerated and had a low toxicity profile. Researchers reported no grade 3-4 adverse events (AEs) in patients (three patients) who received the 1 mg dose, grade 3-4 AEs were reported in 80 percent of patients (five patients) who received the 2 mg dose, 40 percent of patients (five patients) who were given 4 mg, and 50 percent of patients (six patients) who received 8 mg. Overall, two patients discontinued SD-101 due to AEs, and two patients discontinued Keytruda due to AEs. Additionally, there were no dose-limiting toxicities, and no AEs that led to death.

In the overall population of 19 patients, the most common AEs reported were consistent with the engagement of toll-like receptor 9 (TLR9), and included anemia (23 percent), chills (53 percent), fatigue (73 percent), flu-like illness (26 percent), injection site erythema (36 percent), injection-site pain (23 percent), malaise (36 percent), pyrexia (36 percent), myalgia (57 percent) and headache (42 percent).

“In conclusion, in the first 19 patients in the study with stage 3c and 4 melanoma, [the combination] was well-tolerated with no dose-limiting toxicities to date,” said Ribas “The most common AEs are expected with this mechanism of action: fever, chills and other flu-like symptoms.”