Safety and efficacy of quavonlimab, a novel anti-CTLA-4 antibody (MK-1308), in combination with pembrolizumab in first-line advanced non-small-cell lung cancer

  • Ann Oncol. 2021 Mar;32(3):395-403. doi: 10.1016/j.annonc.2020.11.020.
R Perets  1 ,  J Bar  2 ,  D W Rasco  3 ,  M-J Ahn  4 ,  K Yoh  5 ,  D-W Kim  6 ,  A Nagrial  7 ,  M Satouchi  8 ,  D H Lee  9 ,  D R Spigel  10 ,  D Kotasek  11 ,  M Gutierrez  12 ,  J Niu  13 ,  S Siddiqi  14 ,  X Li  14 ,  J Cyrus  14 ,  A Chackerian  15 ,  A Chain  14 ,  R A Altura  14 ,  B C Cho  16
Affiliations
  • 1. Department of Oncology, Rambam Medical Center, Technion-Israel Institute of Technology, Haifa, Israel.
  • 2. Cancer Center, Chaim Sheba Medical Center at Tel HaShomer, Ramat Gan, and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
  • 3. Phase I, START, San Antonio, USA.
  • 4. Department of Medicine, Samsung Medical Center, Sungkyunkwan University of Medicine, Seoul, South Korea.
  • 5. Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
  • 6. Department of Hemato Oncology, Medical Oncology Center, and Personalized Cancer Medicine Center, Seoul National University Hospital, Seoul, South Korea.
  • 7. Department of Cancer and Hematology, Blacktown Hospital and University of Sydney, Sydney, Australia.
  • 8. Department of Thoracic Oncology, Hyogo Cancer Center, Akashi, Japan.
  • 9. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
  • 10. Department of Medical Oncology, Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, USA.
  • 11. Department of Medical Oncology, Adelaide Cancer Centre and University of Adelaide, Kurralta Park, Australia.
  • 12. Department of Hematology, Hematology Oncology, and Medical Oncology, Hackensack University Medical Center, Hackensack, USA.
  • 13. Department of Medical Oncology, Banner MD Anderson Cancer Center, Gilbert, USA.
  • 14. MRL, Merck & Co., Inc., Kenilworth, NJ, Kenilworth, USA.
  • 15. Department of Discovery Oncology, Merck & Co., Inc., Kenilworth, USA.
  • 16. Division of Medical Oncology, Yonsei Cancer Center, Seoul, South Korea. Electronic address: [email protected].
PMID: 33276076 DOI: 10.1016/j.annonc.2020.11.020
Abstract

Background: Quavonlimab (MK-1308), a novel anti-CTLA-4 antibody, in combination with pembrolizumab was investigated in a phase I study.

Patients and methods: Dose-escalation (DE) phase: patients with advanced/metastatic solid tumors received an initial flat dose of quavonlimab as monotherapy [25 mg (cohort 1), 75 mg (cohort 2), or 200 mg (cohort 3)] followed by four treatments of the same quavonlimab dose plus pembrolizumab every 3 weeks (Q3W). Dose-confirmation phase (DC): patients with stage IIIB/IV non-small-cell lung Cancer (NSCLC) received first-line quavonlimab [25 mg Q3W (arm A), 25 mg Q6W (arm B), 75 mg Q6W (arm C), or 75 mg Q3W (arm E)] plus pembrolizumab. Primary objectives were safety and tolerability and establishment of the recommended phase II dose (RP2D) of quavonlimab when used with pembrolizumab. Objective response rate (ORR) was a secondary endpoint. Efficacy based on PD-L1 expression, tumor mutational burden (TMB), and changes in circulating CD4+/CD8+ cells were exploratory endpoints.

Results: Thirty-nine patients were enrolled in DE [n = 14 (cohort 1); n = 17 (cohort 2); n = 8 (cohort 3)] and 134 in DC [n = 40 (arm A); n = 40 (arm B); n = 40 (arm C); n = 14 (arm E)]. Maximum-tolerated dose was not reached. Grade 3-5 treatment-related adverse events (AEs; graded according to NCI CTCAE v4.03) occurred in 0%, 23.5%, and 75.0% of patients in DE cohorts 1, 2, and 3, respectively, and 35.0%, 30.0%, 35.0%, and 57.1% of patients in DC arms A, B, C, and E, respectively. Efficacy was observed at all dose levels/schedules in patients with NSCLC. ORRs were 40.0% [95% confidence interval (CI), 24.9-56.7; arm A], 37.5% (95% CI, 22.7-54.2; arm B), 27.5% (95% CI, 14.6-43.9; arm C), and 35.7% (95% CI, 12.8-64.9; arm E). PD-L1 expression and total number of circulating CD4+ cells correlated with ORR.

Conclusions: Quavonlimab 25 mg Q6W plus pembrolizumab demonstrated similar efficacy and a better safety profile among all quavonlimab doses/schedules evaluated; this regimen was the chosen RP2D.

Keywords
CTLA-4; MK-1308; immunotherapy; non-small-cell lung cancer; pembrolizumab; quavonlimab.
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