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Early Data Suggest TLR9 Agonist May Combat PD-1 Resistance in Advanced Melanoma


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COMBINING CMP-001, a Toll-like receptor 9 (TLR9) agonist, plus pembrolizumab (Keytruda) appears to overcome resistance to anti–programmed cell death protein 1 (anti–PD-1) therapy, according to a preliminary phase Ib study.1 Adding CMP-001 to pembrolizumab was well tolerated, with antitumor efficacy in patients with metastatic melanoma who failed to respond to or progressed on prior PD-1 therapy. 

Mohammed Milhem, MBBS

Mohammed Milhem, MBBS

CMP-001 is a therapy that is injected directly into a tumor. Using this approach, researchers saw abscopal effects (ie, responses in tumors that were not injected). “The abscopal effect observed in these patients is a hallmark of successful intratumoral immunotherapy treatment,” said lead author Mohammed Milhem, MBBS, Clinical Professor of Internal Medicine at the University of Iowa, Iowa City. “Based on these preliminary findings, the combination of CMP-001 and pembrolizumab appears to have a manageable side-effect profile and meaningful clinical activity. Additional larger studies in this population are needed to further evaluate clinical benefit.” 

CMP-001 comprises two components: CpG DNA in a virus-like particle. The TLR9 agonist leads to activation of plasmacytoid dendritic cells, which promote an immune response. 

At the 2018 Annual Meeting of the American Association for Cancer Research (AACR), Dr. Milhem reported on 44 patients enrolled in the dose-escalation phase and 24 patients of a planned 66 who enrolled in the ongoing dose-expansion phase of the trial. 

Study Details 

DURING THE dose-escalation phase, participants received CMP- 001 injected intratumorally with either 1, 3, 5, 7.5, or 10 mg plus pembrolizumab on 2 different schedules: 1 injection weekly for 7 weeks or 1 injection per week for 2 weeks followed by every 3 weeks until treatment discontinuation. During the dose-escalation phase, the maximal tolerated dose was not reached. The investigators decided to move to the dose-expansion phase using 5 mg weekly plus pembrolizumab, with the option of increasing the dose to 10 mg. 

The best objective response rate in all patients was 22% according to Response Evaluation Criteria in Solid Tumors. A total of 2 patients had a complete response and 13 had a partial response. The objective response rate was 23% in the weekly arm and 15% in the every-3-week arm. The majority of patients had responses lasting more than 6 months, and several patients remained in response at 1 year. Of 18 responders, 13 remain on study, and the median duration of response had not been reached at the time of the AACR meeting. 

“We injected target lesions and saw responses in both injected and noninjected lesions, both local and systemic responses. Responders showed a rapid reduction in target lesions from baseline, and responses were durable,” Dr. Milhem told listeners. “There was a trend toward improved response in the weekly dosing cohort and in the cohort with a lower tumor burden,” he added. Thus, the investigators plan to use a weekly schedule in the phase II trial. 

NOVEL STRATEGY FOR OVERCOMING RESISTANCE TO IMMUNOTHERAPY

  • A novel approach using a TLR9 agonist plus pembrolizumab appears to overcome resistance in some patients with advanced melanoma.
  • Translational evidence supports the immune-boosting activity of this approach.
  • Larger confirmatory studies are needed.

Striking Photographic Evidence 

THE VISUAL ABSCOPAL effects were striking in individual patients, as seen in the photographs Dr. Milhem showed the audience. Dramatic tumor shrinkage was observed within 1 week in a patient with a very large lesion on his head, and photos of a patient with multiple lesions whose disease progressed on three prior lines of therapy showed complete regression of all lesions by 1 year, including injected and noninjected ones. 

The treatment was generally well tolerated. Adverse events included flu-like symptoms of pyrexia, chills, nausea, and vomiting. Grade 3 hypotension was observed. “Most side effects occurred 1 to 4 hours after CMP-001 injection and resolved with symptomatic management,” Dr. Milhem said. 

Translational analysis using immunohistochemistry and RNA-sequence analysis showed more than fivefold increases in CD8 T cells and more than threefold increases in programmed cell death ligand 1 expression with treatment. Responders had a T-cell–inflamed signature not seen in rapid progressors. When the investigators looked at plasmacytoid dendritic cell expression in 16 patients with pretreatment biopsies, higher plasmacytoid dendritic cell levels at baseline were associated with greater responses. 

“Plasmacytoid dendritic cells could be an enrichment biomarker,” Dr. Milhem said. ■

DISCLOSURE: Dr. Milhem has served on a GIST advisory board of Blueprint Solutions. 

REFERENCE 

1. Milhem M, et al: Intratumoral Toll-like receptor 9 (TLR9) agonist, CMP-001, in combination with pembrolizumab can reverse resistance to PD-1 inhibition in a phase 1b trial in subjects with advanced melanoma. 2018 AACR Annual Meeting. Abstract CT144. Presented April 17, 2018.


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COMBINING CMP-001, a Toll-like receptor 9 (TLR9) agonist, plus pembrolizumab (Keytruda) appears to overcome resistance to anti–programmed cell death protein 1 (anti–PD-1) therapy, according to a preliminary phase Ib study.1 Adding CMP-001 to pembrolizumab was well tolerated, with antitumor efficacy ...

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