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TLR9 agonist may overcome resistance to anti–PD-1 therapy in melanoma



– A TLR9 agonist called CMP-001 can reverse resistance to anti–programmed death-1 (PD-1) therapy in patients with melanoma, a phase 1 trial suggests.

John Kirkwood, MD University of Pittsburgh (Penn.) Medical Center Jennifer Smith/MDedge News

Dr. John Kirkwood

Combination CMP-001 and pembrolizumab produced durable responses in patients who had progressed on prior anti–PD-1 therapy, and the combination was considered well tolerated.

CMP-001 is a CpG-A TLR9 agonist packaged in a viruslike particle, John Kirkwood, MD, of University of Pittsburgh Medical Center, explained in a late-breaking abstract at the annual meeting of the Society for Immunotherapy of Cancer. CMP-001 activates tumor-associated plasmacytoid dendritic cells and induces systemic tumor-specific CD8+ T-cell responses.

Dr. Kirkwood and associates are investigating CMP-001, given alone or in combination with pembrolizumab, in a phase 1 trial (NCT02680184) of patients with metastatic or unresectable melanoma who are refractory to anti–PD-1 therapy.

Data were presented on 144 patients who received CMP-001 in combination with pembrolizumab. About 40% of patients (39.6%) had elevated lactate dehydrogenase at baseline, and 32.6% had BRAF mutations.

All patients had received prior anti–PD-1 therapy alone (75%) and/or in combination (50%). For most patients (93.1%), their last response to anti–PD-1 therapy was progression.

For this study, the patients received intratumoral CMP-001 injections at a range of doses (1 mg, 3 mg, 5 mg, 7.5 mg, and 10 mg). CMP-001 was given weekly for either 2 weeks or 7 weeks, then every 3 weeks until discontinuation. There were two different formulations of CMP-001 given – 0.01% polysorbate 20 (PS20; n = 83) and 0.00167% PS20 (n = 61).


“CMP-001 in combination with pembrolizumab is very well tolerated, with no apparent increase in autoimmune toxicities associated with anti–PD-1,” Dr. Kirkwood said.

The most common treatment-related adverse events were flulike symptoms, including chills (72%), pyrexia (56%), fatigue (51%), nausea (45%), vomiting (29%), and headache (28%). Another common event was injection-site pain (28%).

The most common grade 3 adverse events were hypotension (n = 9) and hypertension (n = 7). Grade 4 events included hypotension, aspartate aminotransferase increase, and alanine aminotransferase increase (n = 1 for all). There were no grade 5 events.

Six patients discontinued treatment because of adverse events.


The overall response rate was 25% (21/83) among patients who received the 0.01% PS20 formulation of CMP-001 and 11.5% (7/61) among patients who received the 0.00167% PS20 formulation.

Responses were similar in injected and noninjected target lesions. The median duration of response has not been reached at a median follow-up of 16.9 months.

“Intratumoral CMP-001 reverses resistance to anti–PD-1 in patients who have progressed on prior anti–PD-1 therapy,” Dr. Kirkwood said, adding that these data support further clinical development of CMP-001.

The research is sponsored by Checkmate Pharmaceuticals. Dr. Kirkwood disclosed relationships with Amgen, BMS, Immunocore, Iovance, Novartis, Elsevier, Castle, Merck, and Checkmate.

SOURCE: Kirkwood J et al. SITC 2019, Abstract O85.

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