TLR9 Agent Triggers Durable Response in Metastatic Melanoma

John Kirkwood, MD

John Kirkwood, MD

The use of CMP-001, an intratumoral toll-like receptor 9 (TLR9) agonist, is capable of triggering durable responses when used in combination with pembrolizumab (Keytruda) for patients with PD-1 resistant metastatic melanoma according to results from a phase Ib study presented at the Society for Immunotherapy of Cancer’s 34th Annual Meeting (SITC 2019).¹

CMP-001 is a CpGA DNA TLR9 antagonist that activates tumor-associated plasmacytoid dendritic cells to produce interferon, which in turn induces antitumor systemic immunity.

“CMP-001 in combination with pembrolizumab was very well tolerated with no apparent increases in autoimmune toxicities associated with anti—PD-1,” explained John Kirkwood, MD, Usher Professor of Medicine and Dermatology at the University of Pittsburgh School of Medicine and codirector of the Melanoma and Skin Care Program at the University of Pittsburgh Cancer Institute and UPMC Hillman Cancer Center.

“Intertumoral CMP-001 reverses resistance to anti—PD-1 in melanoma patients who progressed on prior anti–PD-1 therapy,” said Kirkwood. “These data support further clinical development.”

Study Methods

In the ongoing 2-part phase Ib study (NCT02680184), investigators are evaluating intratumoral CMP-001 alone or in combination with pembrolizumab (administered per label; part 1) or as monotherapy (part 2) in subjects with advanced melanoma resistant to prior anti—PD-1.

The two phases of the combination include dose expansion and dose escalation. Patients enrolled in the complete dose-escalation phase of the trial (n = 44) received CMP-001 via 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.

Following dose expansion, patients in the ongoing dose-escalation phase are treated with CMP-001 at 1 of 2 dose levels (5 or 10 mg) and using 2 different formulations of CMP-001 (n = 69). This is then followed by a second dose-expansion phase with CMP-001 at 10 mg and a single, higher concentration formulation of CMP-001 (TABLE).

Treatment continued until progression, toxicity, investigator decision, or withdrawal of consent.

“In the dose-escalation phase, we allowed both stable disease and progressive disease, in the dose expansion phase, only progression of disease on the last PD-1 therapy was allowed,” said Kirkwood. “There is no restriction on the number of prior therapies and the lines of therapy were multiple in most of these patients.” Of the patients enrolled (n = 144), 75% received prior anti—PD-1 monotherapy and 50% received prior anti–PD-1anti–PD-1 combination therapy with some patients having received both.

Combination Demonstrates Clinical Activity

The investigational drug is 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. Two formulations of CMP-001 were evaluated, either 0.01% polysorbate 20 (PS20; n = 83) or 0.00167% PS20 (n = 61). The lower concentration of PS20 was found to be less effective.

As of data cutoff the objective response rate (ORR) was 25% (95% CI, 16%-36%) in patients who received the 0.01% PS20 formulation, including 6 complete responses (CR) and 15 partial responses (PR). Additionally, 4 patients who continued study therapy beyond initial disease progression achieved a PR or CR. In patients who received the lower 0.00167% PS20 formulation the ORR was 11.5%.

The Kaplan Meier estimate for median duration of response (mDOR) is 16.9+ months (95% CI, 5.8-not reached) in the 28 RECIST responders and 25.2+ months (95% CI, 8.6-not reached) in 32 responders, inclusive of the additional 4 patients with post-progression responses. The mDOR has not been reached.

TABLE. Intratumoral CMP-001 +/- Pembrolizumab in Anti—PD-1 Refractory Melanoma Schema

Dose Escalation

(n = 44)

Dose Expansion

First Expansion

(n = 69)

Second Expansion

(n = 31)

Dose

1-10mg

5 or 10mg

10mg

Schedule

Weekly×2 or

Weekly×7 followed by Q3wk

Weekly×7, followed by Q3wk

Weekly×7 schedule, followed by Q3wk

Formulation

0.01% PS20

0.01% PS20 (n = 8)

0.00167% PS20 (n = 61)

0.01% PS20

PS20 indicates polysorbate20; Q3wk, every 3 weeks.

Additionally, similar responses were observed in patients with injected target lesions and non-injected target lesions for the 28 RECIST responders and four patients with post-progression response.

“The toxicities of therapy with this combination were flu-like syndrome in a majority of patients, but very few of these had Grade 3 toxicity of this flu-like category,” noted Kirkwood. The most common all grade treatment-related adverse events (TRAEs) were flu-like symptoms, including chills (69%), pyrexia (56%), fatigue (49%), nausea (44%), vomiting (29%) and headache (27%). TRAEs ≥ Grade 3 included hypotension (6%), hypertension (5%), and back pain (3%).

“There were no grade 5 toxicities and only a handful of grade 4,” he said.

Six patients (4%) discontinued study therapy due to TRAEs.

CMP-001 Monotherapy

Additional data were presented on patients who received CMP-001 monotherapy. Of the 24 patients treated with CMP-001 monotherapy, 5 patients achieved a PR. “This response rate is similar to the response rate of the combination, but the durability is substantially less with CMP-001 alone,” said Kirkwood. Patients who progress on CMP-001 monotherapy can be rolled over onto combination therapy and continue on the study.

Kirkwood concluded by noting a subsequent late-breaking abstract that will be presented at SITC 2019. Diwakar Davar, MD, of UPMC Hillman Cancer Center, will present preliminary results from the phase II trial of neoadjuvant nivolumab and intratumoral CMP-001 in high risk resectable melanoma at 6:15 pm as part of Session 313: Immunotherapy Advances in Skin Cancer in the Cherry Blossom Ballroom.

Reference:

1. Kirkwood J, Milhem M, Zakharia Y, et al. Durable responses in anti—PD-1 refractory melanoma following intratumoral injection of Toll-like receptor 9 (TLR9) agonist CMP-001, in combination with pembrolizumab. Presented at: 34^thAnnual Meeting of the Society for Immunotherapy of Cancer. November 6-10, 2019: National Harbor, MD.