Preliminary results of the first-in-human (FIH) study of MK-1454, an agonist of stimulator of interferon genes (STING), as monotherapy or in combination with pembrolizumab (pembro) in patients with advanced solid tumors or lymphomas

Background: 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. Methods: 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). Results: 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). Conclusions: Combined MK-1454 plus pembro resulted in encouraging efficacy and an acceptable safety profile supporting continued development of the combination regimen. Clinical trial identification: NCT03010176; originally posted January 4, 2017. Editorial acknowledgement: Joanne Tomassini, Merck & Co., Inc., Kenilworth, NJ, USA Legal entity responsible for the study: Merck Sharp & Dohme, Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA Funding: Merck Sharp & Dohme, Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA Disclosure: K.J. Harrington: Honoraria: Amgen, AstraZeneca, BMS, Merck, MSD, Pfizer; Consulted for: Amgen, AstraZeneca, BMS, Merck, MSD, Pfizer; Speakers' bureau: Amgen, AstraZeneca, BMS, Merck, MSD, Pfizer; Research funding: AstraZeneca, MSD; Travel expenses: MSD. J. Strauss: Stock and other ownership interests: Abbott, Abbvie, Bristol-Myers Squibb, Intuitive Surgical, Merck & Co., Inc.; Consulting or advisory role: Tempus. S. Cemerski, M. Wang, A. Tse, A. Khilnani: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock/stock options in the Company. A. Marabelle: Honoraria: Amgen, AstraZen/MedImm, BMS, GSK, MSD, Merck Ser., Roche/Genentech, Sanofi, Servier; Consulting or advisory role: Amgen, Eisai, GSK, Kyowa Hakko Kirin, Merck Ser., Novartis, Pfizer, Pierre-Fabre; Funding (all inst): B. Ingelheim, BMS, Merus, Transgene. T. Golan: Honoraria: Bristol Myers Squibb, MSD, Rafael Pharmaceuticals; Consulting or advisory role: Abbvie, AstraZeneca. All other authors have declared no conflicts of interest.