4575 - Phase 1 Study of the CTLA-4 Inhibitor MK-1308 in Combination With Pembrolizumab in Patients With Advanced Solid Tumors

Background

Targeting CTLA-4 and PD-1/L1 has been shown to be effective in selective solid tumors. MK-1308 is a novel humanized monoclonal antibody that binds CTLA-4 and blocks interaction with its ligands.

Methods

This ongoing, multicenter, multi-arm, open-label, phase 1b study will evaluate the safety, tolerability, PK/PD, and preliminary efficacy of MK-1308 in combination with pembrolizumab in patients (pts) with solid tumors (NCT03179436). In dose escalation, MK-1308 was given at either 25 mg or 75 mg (cohorts 1, 2) IV Q3W as monotherapy ×1 cycle, in combination with pembrolizumab 200 mg Q3W ×4 cycles, followed by pembrolizumab monotherapy. In dose confirmation, pts with first-line (1L) advanced NSCLC were treated with MK-1308 at 25 mg Q3W (arm A), 25 mg Q6W (arm B) or 75 mg Q6W (arm C), in combination with pembrolizumab 200 mg Q3W. Response was assessed Q9W.

Results

A total of 47 pts were enrolled by Dec 31, 2017: 24 in dose escalation (cohort 1: 14; cohort 2: 11) and 22 in dose confirmation (arm A: 8; arm B: 9; arm C: 5). Median age was 61 years; 53% were male. MTD was not reached at any dose tested. Five DLTs were observed: 2 in cohort 2 (grade 3 rash), 1 in arm A (grade 4 hepatitis), 1 in arm B (grade 3 pneumonitis), and 1 in arm C (grade 3 enterocolitis). Treatment-related adverse events (TRAEs) were observed in 74% of pts. Most common (≥10%) were pruritus (23%), fatigue (17%), rash (17%), diarrhea (11%), and hyperthyroidism (11%), Grade 3/4 TRAEs were observed in 6 pts (12%). Discontinuation due to TRAE was observed in 5 pts. No pts had grade 5 TRAEs. Pharmacokinetics of MK-1308 were comparable to that of an approved CTLA-4 compound. Of the 21 evaluable 1L advanced NSCLC pts in dose confirmation who received at least 1 on-treatment assessment, there were 1 CR, 8 PR, 6 SD, and 6 PD. More mature data, inclusive of 140 pts (90 1L NSCLC) for ORR, DOR, and relationships between PD-L1, tumor mutation burden, and T-cell proliferation with ORR will be presented.

Conclusions

Preliminary results suggest that the combination of MK-1308 and pembrolizumab shows promising responses in a 1L advanced NSCLC population and manageable toxicity in most tumor types evaluated. Enrollment is ongoing.

Clinical trial identification

NCT03179436; trial initiation: June 7, 2017.

Legal entity responsible for the study

Merck & Co., Inc.

Funding

Merck & Co., Inc.

Editorial Acknowledgement

Medical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

B.C. Cho: Advisory board: AstraZeneca, Boehringer Ingelheim, Roche, Yuhan, BMS, MSD, Novartis, Janssen, Ono; Speakers bureau: AstraZeneca, Novartis; Research funding: Bayer, AstraZeneca, Bayer, Janssen, Yuhan, Novartis, Champions Oncology, Ono, MOGAM, Dong-A ST; Honoraria: AstraZeneca, Boehringer Ingelheim, Roche, Yuhan, BMS, MSD, Novartis, Ono. R. Perets: Employment: Musli Thyropeutics; Honoraria: BMS. J. Bar: Advisory board member, Consultant fees: Roche, Boehringer Ingelheim, Novartis, BMS, MSD, Pfizer, AstraZeneca, Takada, Abbvie, VBL; Research funding: Boehringer Ingelheim, AstraZeneca, MSD M-J. Ahn: Advisory board: AstraZeneca, Lilly, Lyzz. K. Yoh: Research funding: MSD. A. Nagrial: Advisory board: MSD; Honoraria: MSD. D.H. Lee: Honoraria: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, CJ Healthcare, Eli Lilly, Janssen, Merck, MSD, Mundipharma, Novartis, Ono, Pfizer, Roche, Samyang Biopharm, ST Cube and Takeda. M. Gutierrez: Stock: Cota; Advisory board member: Eli Lilly, Esanex, Guardant 360; Speaker's bureau: Merck, BMS, Eli Lilly, Foundation Medicine. S. Siddiqi, A. Chain, B.D. Butts, Y. Zhang, X. Li, A. Tse: Employee and stockholder: Merck. J. Cyrus, R.A. Altura: Employee and stockholder: Merck; Travel expenses including accommodations: Merck. D. Rasco: Research funding: Merck. All other authors have declared no conflicts of interest.