Resistance to PD-1 Inhibition Overcome With a Combination

Alexander M. Castellino, PhD

April 18, 2018

CHICAGO — Although immunotherapy with programmed cell death (PD) inhibition has had some great treatment successes in metastatic melanoma, some patients stop responding after the tumor acquires resistance to PD-1 inhibition. But preliminary new data suggest that this resistance can be overcome by adding a toll-like receptor 9 (TLR9) agonist, CMP-001 (under development at Checkmate Pharmaceuticals).

These preliminary data were presented at the American Association for Cancer Research (AACR) 2018 Annual Meeting.

"Many patients either initially respond to checkpoint inhibition and then progress or never respond to this therapy to begin with," Mohammed Milhem, MBBS, clinical professor of internal medicine at the University of Iowa, Iowa City, said in a statement. "Finding safe and effective therapies for these patients is critical," he added.

Milhem explained that tumors with increased interferon gene expression are more responsive to PD-1 inhibition. Because the TLR9 pathway is a strong inducer of interferon production, Milhem and his colleagues thought that ramping up the TLR9 pathway with an agonist along with PD-1 inhibition may be a way to reduce any resistance that develops to PD-1 inhibition. This led them to test CMP-001 in the current study.

CMP-001 consists of CpG-A DNA — a 30-mer native DNA oligonucleotide that is packaged in a nonreplicating viruslike particle. It activates innate immune cells, such as macrophages and dendritic cells, which typically protect against viruses and bacteria, explained Suzanne L. Topalian, MD, associate director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy and director of the Melanoma Program at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine, Baltimore, Maryland. She moderated the AACR press conference at which the new data were highlighted.

Study Details

Milhem and his colleagues tested the new approach in a phase 1a study in patients with metastatic melanoma who had either not responded to or whose disease had progressed after treatment with a PD-1 inhibitor. All patients received pembrolizumab (Keytruda, Merck) as well as the investigational agent, CMP-001, which was administered in two dosing schedules at doses that escalated gradually from 1 mg to a final dose of 10 mg.

In one schedule, CMP-001 was given once weekly for 7 weeks, after which CMP-001 was given every 3 weeks (weekly treatment group). In the second schedule, CMP-001 was initially given for 2 weeks, after which maintenance doses were given every 3 weeks (q3w treatment).

CMP-001 was administered intratumorally — it was injected into an accessible lesion. Milhem explained to Medscape Medical News the challenges for this administration.

For melanoma patients who have visible lesions, Milhem, who is a medical oncologist, delivers the intratumoral injection himself. But for delivery into a lesion that is not externally visible, an interventional radiologist is needed on the team. For example, in a patient with liver lesions, the radiologist delivers the injection into the lesion in real time, guided by imaging.

Another challenge is that all patients experience typical interferon-related flulike symptoms. One hour after the injection, the patient experiences fever, chills, rigors, nausea, and vomiting. Because of this, the patient is kept under observation for ~4 hours and is only then sent home.

So in practice, the patient received CMP-001 first and then received pembrolizumab.

Response was evaluated in all accessible and nonaccessible lesions.

Sixty-eight patients have been treated so far — 44 with dose escalation, and 24 with dose expansion.

Safety data from 63 patients showed manageable acute toxicity — fever, nausea, vomiting, headache, hypotension, and rigors. Grade 3 or 4 adverse events included hypotension (seven patients), anemia (two patients), chills (two patients), hypertension (two patients), and fever (two patients).

The objective response rate (ORR) was 22% (two complete responses and 13 partial responses). Thirteen of 18 patients who responded to treatment remain on study. Milhem also reported that the two patients who showed a complete response withdrew consent and have come off the study drug; responses continue in these patients.

Milhem also reported that TLR9 activation was seen with CMP-001, with a fivefold increase in serum protein CXCL10. In addition, tumor biopsies revealed an increase in tumor-infiltrating T cells and PD-L1 expression.

Milhem indicated that the minimum tolderated dose was not reached, but the dose expansion cohort is receiving CMP-001 at the 5-mg dose level, which can be increased with investigator discretion.

Medscape Medical News asked Topalian about the kind of patients who may be typical candidates for CMP-001. She explained that because the drug is injected intratumorally, likely candidates are those with melanoma, Merkel cell carcinoma, head and neck cancer, and soft tissue sarcoma.

But Milhem suggested that with a good interventional radiologist, the patient population need not be restricted to those with visible lesions.

Dr Milhem has disclosed no relevant financial relationships.

American Association for Cancer Research (AACR) 2018 Annual Meeting. Abstract CT144, presented April 17, 2018.

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