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O85 Durable responses in anti-PD-1 refractory melanoma following intratumoral injection of a toll-like receptor 9 (TLR9) agonist, CMP-001, in combination with pembrolizumab
  1. Mohammed Milhem1,
  2. Yousef Zakharia1,
  3. Diwakar Davar2,
  4. Elizabeth Buchbinder3,
  5. Theresa Medina4,
  6. Adil Daud5,
  7. Antoni Ribas6,
  8. Jiaxin Niu7,
  9. Geoffrey Gibney8,
  10. Kim Margolin9,
  11. Anthony Olszanski10,
  12. Interjit Mehmi9,
  13. Takami Sato11,
  14. Montaser Shaheen12,
  15. Aaron Morris13,
  16. David Mauro13,
  17. Katie Campbell6,
  18. Riyue Bao2,
  19. George Weiner1,
  20. Jason Luke1,
  21. Arthur Krieg13 and
  22. John Kirkwood2
  1. 1University of Iowa, Iowa City, IA, USA
  2. 2University of Pittsburgh Medical Center, Pittsburgh, PA, USA
  3. 3Dana Farber Cancer Institute, Boston, MA, USA
  4. 4University of Colorado Denver, Aurora, CO, USA
  5. 5University of California San Francisco, San Francisco, CA, USA
  6. 6University of California Los Angeles, Los Angeles, CA, USA
  7. 7Banner MD Anderson Cancer Center, Gilbert, AZ, USA
  8. 8Georgetown University, Washington, DC, USA
  9. 9City of Hope, Duarte, CA, USA
  10. 10Fox Chase Cancer Center, Phildelphia, PA, USA
  11. 11Thomas Jefferson University, Philadelphia, PA, USA
  12. 12University of Arizona, Tucson, AZ, USA
  13. 13Checkmate Pharmaceuticals, Cambridge, MA, USA


Background Intratumoral (IT) injection of CMP-001, a CpG-A TLR9 agonist packaged within a virus-like particle, is designed to activate tumor-associated plasmacytoid dendritic cells, inducing an interferon-rich tumor microenvironment and anti-tumor CD8+ T cell responses.

Methods CMP-001-001 is an ongoing Phase 1b trial evaluating the safety and efficacy of CMP-001 in combination with pembrolizumab (Part 1; N = 144) or alone (Part 2; N = 23) in patients with advanced melanoma resistant to prior anti-PD-1 therapy (Tables 1). CMP-001 is administered IT into accessible lesion(s) either with, or without on-site saline dilution (table 1), and response assessed by RECIST v1.1. Monotherapy patients who progress can be rolled over onto combination therapy and continue on study. Baseline and on-therapy serum is analyzed for cytokines, and immunohistochemistry and RNA-Seq are performed on available tumor biopsies.

Abstract O85 Table 1

Advanced anti-PD-1 Refractory melanoma patient population by treatment allocation

Results Adverse events (AEs) attributed to CMP-001 in combination with pembrolizumab or as monotherapy consisted predominately of transient low-Grade flu-like symptoms and injection site reactions: Grade 3+ related AEs were reported in 33% of patients treated with combination therapy and 22% of patients with monotherapy.

The Objective Response Rate (ORR) with undiluted CMP-001 in combination with pembrolizumab was 24% (18/75; 95% confidence interval: 15%-35% (table 1); on-site dilution of CMP-001 was associated with a substantial decrease in ORR to 12% (7/61; 95% confidence interval: 5%-22% (table 1). Three additional patients had a delayed partial response after an initial period of disease progression. Anti-tumor response was comparable between injected and uninjected lesions. The median duration of response to combination therapy has not been reached. The ORR to CMP-001 monotherapy was 22% (5/23; 95% confidence interval: 7%-44% (table 1); time from last anti-PD-1 therapy before CMP-001 was 1.5 to >20 months in responders; 3 of the patients responding to CMP-001 monotherapy achieved PR at the first evaluation, but progressed by the second evaluation.

Serum and tumor biopsy translational studies in the patients receiving combination therapy supported the proposed mechanism of TLR9 activation and identified a possible association between induction of serum CXCL10 and response.

Conclusions IT CMP-001 alone and in combination with pembrolizumab appears well tolerated, can reverse resistance to anti-PD-1 therapy, and can produce deep and durable clinical responses in patients with advanced melanoma.

Ethics Approval CMP-001-001 was centrally approved by the WCG-WIRB, WIRB approval tracking number 20152597.

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