TLR9 Agonist Shows Signs of Reversing Resistance to PD-1 Inhibition in Melanoma

Mohammed Milhem, MBBS

According to phase Ib study findings presented at the 2018 AACR Annual Meeting, combining the intratumoral toll-like receptor 9 (TLR9) agonist CMP-001 and pembrolizumab (Keytruda) showed clinical activity in reversing PD-1 checkpoint inhibition resistance in patients with metastatic melanoma.

While pembrolizumab is the standard of care for this patient population, over 50 percent of patients with metastatic melanoma develop resistance.

Previous studies have shown that tumors with increased interferon gene expression are more responsive to PD-1 inhibition, of which the strongest known inducer of such production is the TLR9 pathway, explained Mohammed Milhem, MBBS, clinical professor of internal medicine at the University of Iowa.

“Toll-like receptors are receptors in the innate immune system. They are displayed on macrophages and dendritic cells and, normally, the toll-like receptors help protect us against viruses and bacteria, so they recognize components of microbes,” said moderator Suzanne L. Topalian, MD, director of the Melanoma Program at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and associate director of the Bloomberg Kimmel Institute for Cancer Immunotherapy.

“In this case, one of the toll-like receptors, TLR9, is being leveraged therapeutically to provide a strong stimulus for immune responses,” she added.

In the ongoing phase Ib study, the researchers evaluated the combination use of CMP-001 with checkpoint inhibition in patients with advanced melanoma who had either not responded to or had progressed during prior anti—PD-1 therapy. As of March 27, 2018, 85 patients have been treated in the trial—44 patients were enrolled in the dose-escalation phase, and 41 patients have been enrolled in the ongoing dose-expansion phase.

During the complete dose-escalation phase of the trial, patients received CMP-001 with direct intratumoral injection at doses of 1, 3, 5, 7.5, and 10 mg in combination with pembrolizumab using 2 dosing schedules: 1 injection per week for 7 weeks followed by every 3 weeks until discontinuation (weekly treatment); or 1 injection per week for 2 weeks followed by every 3 weeks until discontinuation (q3w treatment).

The investigational drug was administered into an accessible lesion(s), and responses were assessed in all target lesions (injected and non-injected) by RECIST v1.1 every 12 weeks. Study therapy was continued until disease progression, toxicity, investigator decision, or withdrawal of consent.

During the dose escalation phase, 1 dose-limiting toxicity occurred. No maximum-tolerated dose was identified. The researchers settled on an expansion dose of 5 mg at the lower concentration weekly plus pembrolizumab; however, they were able to increase the dose to 10 mg upon discretion, Milhem said.

Among the intent-to-treat (ITT) population, the objective response rate (ORR) was 22% (95% CI, 13%-33%), including 2 complete responses and 13 partial responses. The ORR was 23% in the weekly treatment arm and 15% in the q3w treatment arm.

The majority of patients surpassed the 6-month mark of demonstrating clinical responses, while a few cases have surpassed 1 year, Milhem said. “Some of the responders are not receiving any therapy at this time and continue to show a response,” he added.

Among the 18 patients who had responded to the combination regimen, 13 remain on study. Three additional patients that continued study therapy beyond their initial progression had also responded according to iRECIST criteria. The median duration of response has not been reached.

As of December 31, 2017, 68 subjects had been treated, including 44 in the escalation phase and 24 in the expansion.

Among 63 patients, safety data demonstrated a manageable acute toxicity profile consisting predominately of fever, nausea and vomiting, headache, hypotension, and rigors. Grade 3/4 adverse events included hypotension (n = 7), anemia (n = 2), chills (n = 2), hypertension (n = 2), and fever (n = 2).

Of the 10 responders at the December cutoff, 1 progressed at week 36, and 2 withdrew consent by weeks 13 and 25. Regression of non-injected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.

CMP-001 induced TLR9 activation with a median 5.9-fold increase in serum CXCL10 (range, 0.9-276.3; n=39). Immunohistochemical and RNA-sequence analysis of tumor biopsies revealed increases in tumor-infiltrating CD8 T cells more than 5-fold, PD-L1 expression more than 3-fold, and transcriptional signature of inflammation in 2 of 4 patients with analyzable pre-and posttreatment samples. These findings were consistent with activation of plasmacytoid dendritic cells by CMP-001 through TLR9 signaling, Milhem noted.

“The intratumoral TLR9 agonist, CMP-001, in combination with pembrolizumab, can reverse resistance to PD-1 inhibition in melanoma subjects who have progressed on prior PD-1 therapy,” he added. “The combination of CMP-001 and pembrolizumab appears well tolerated and can produce deep and durable systemic clinical responses.”

Enrollment into the expansion phase is ongoing, and clinical investigation in other tumor types is underway.

“This trial looks at a very important group of patients, which are the patients who do not respond to anti—PD-1 [agents], or who have stable disease but don’t make it over the threshold to a complete or partial response, and the question is how can we further activate the immune system in those patients to get them over that threshold to response?” Topalian concluded.

Reference:

M. Milhem, R. Gonzales, T. Medina, 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 Ib trial in subjects with advanced melanoma. Presented at: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, Illinois. Abstract CT0101.