The STING pathway has been implicated in antitumor immunity and response to immune checkpoint inhibitors. Intratumoral (IT) administration of MK-1454, a cyclic dinucleotide STING agonist, results in complete tumor regression and enhances the efficacy of anti-PD1 therapy in mouse syngeneic models. Initial results of the MK-1454 FIH study as monotherapy (Arm 1) or in combination with pembro (Arm 2) in pts with solid tumors or lymphomas are presented.
A phase 1, open label, multicenter, dose escalation study. Eligible pts had ≥1 measurable-injected and -noninjected lesions. MK-1454 was given IT q1wk x 9 for 3 cycles then q3wk thereafter; dose escalations were 10−3000 ug (Arm 1) and 90−1500 ug (Arm 2) using accelerated titration followed by mTPI design. Pembro was given at 200 mg IV q3wk. Arm 1 pts who progressed were eligible to crossover (n=9) to Arm 2. Study objectives included evaluation of safety, tolerability, PK/PD and tumor responses (RECIST v1.1).
As of Jul 31, 2018, 26 pts in Arm 1 and 34 in Arm 2 were treated. DLTs at 1500 ug were vomiting (1 pt, Arm 1) and injection site reactions (2 pts, Arm 2). An MTD has not been determined; dose escalation is ongoing. Treatment related adverse events (TRAEs) occurred in 83% and 82% of pts in Arms 1 and 2, 9% and 14% were grade ≥3 AEs, and resulted in discontinuation of 7% of pts in Arm 2 (0% in Arm 1); no deaths due to TRAEs occurred. Most common TRAEs in ≥10% of pts in Arms 1 and 2 included pyrexia, chills, fatigue, injection site pain, and nausea (Arm 1) and pruritus (Arm 2). In both arms, dose dependent increases in systemic MK-1454 exposure (t1/2 ≈1.5 hr) and elevations in serum cytokines IL-6 and IP-10 and STING induced gene expression in blood were observed. Of 25 pts (first dosed by May 01, 2018) in Arm 2, 6 (24%) PRs were seen (3 HNSCC, 1 TNBC, 2 anaplastic thyroid carcinoma) with reductions in both target-injected and -noninjected lesions (median -83%); no CR/PR in Arm 1 were observed. DCR was 20% (Arm 1) and 48% (Arm 2).
Combined MK-1454 plus pembro resulted in encouraging efficacy and an acceptable safety profile supporting continued development of the combination regimen.
Clinical trial identification
Clinical trial identification: ClinicalTrials.gov number NCT03010176; originally posted January 4, 2017
Joanne Tomassini, Merck & Co., Inc., Kenilworth, NJ, USA