3745 - Phase 1b/2, open label, multicenter, study of the combination of SD-101 and pembrolizumab in patients with advanced melanoma who are naïve to anti-PD-1 therapy

Background

SD-101 is a synthetic CpG-ODN agonist of TLR9. Pembrolizumab is a PD-1 inhibitor. SYNERGY-001/KEYNOTE-184 (DV3-MEL-01) assesses the safety and preliminary efficacy of the combination of SD-101 and pembrolizumab in unresectable stage IIIC-IV melanoma.

Methods

SD-101 was evaluated as 2 mg/lesion injected into 1-4 lesions and 1 or 8 mg/lesion injected into 1 lesion as 4 weekly doses followed by 7 doses Q3W. Pembrolizumab was administered as 200 mg IV Q3W. Scans were performed every 9 weeks. Responses were assessed per investigator using RECIST v1.1. Responses and Kaplan-Meier analyses of PFS in the ITT population were compared for patients who received ≤ 2 mg/lesion with 8 mg/lesion.

Results

87 patients (1 mg: n=3; 2 mg: n=44; 8 mg: n=40) have been enrolled with similar baseline characteristics: median age 66 years; male: 68%; stage: IIIC=21%; IVM1a/b=52%; IVM1c=28%; LDH > ULN: 21%; treatment naïve: 71%; PD-L1 negative tumors: 49%. SD-101 safety profile comprises flu-like symptoms. Most frequent grade ≥3 treatment-related AEs were headache (8%), myalgia (7%), malaise (6%), fatigue (6%), chills (6%) and injection-site pain (7%). Immune-related AEs were reported in 17%. One unrelated death occurred in the 8 mg group. The best overall response (ORR) in the ≤ 2 mg group (n=47) was 66% (95% CI: 52, 78) (CR: 11%) and in the 8 mg group (n=40) was 48% (95% CI: 33, 63) (CR: 5%) with responses in both injected and non-injected lesions. ORR in 57 patients with baseline PD-L1 expression data was: PD-L1 positive: ≤ 2 mg=75% (12/16); 8 mg= 62% (8/13); PD-L1 negative: ≤ 2 mg=85% (11/13); 8 mg=33% (5/15); PD-L1 pending: ≤ 2 mg=44% (8/18); 8 mg = 50% (6/12). PFS was higher in the ≤ 2 mg group (median PFS: ≤ 2 mg=not reached [15.2+ months]; 8 mg=10.4 months, p = 0.034; 6 month PFS rate: ≤ 2 mg=86%; 8 mg=62%). Median follow up in this ongoing study is 4.9 months in the ≤ 2 mg group and 7.3 months in the 8 mg group. Tumor biopsies at Day 29 show increases in CD8+, cytotoxic T cells, and NK cells over baseline.

Conclusions

The TLR9 innate immune stimulant, SD-101, in combination with pembrolizumab is showing promising high response rates and prolonged PFS especially in patients who receive lower dose SD-101. The combination has been well tolerated.

Clinical trial identification

NCT02521870

Editorial Acknowledgement