Early Results Suggest Opdivo Combo May Help People with Advanced Pancreatic Cancer

Early Results Suggest Opdivo Combo May Help People with Advanced Pancreatic Cancer

Adding cabiralizumab to Opdivo (nivolumab) induced durable clinical benefit in heavily treated pancreatic cancer patients, a group largely insensitive to immunotherapy, early results from an ongoing Phase 1a/1b trial show.

The combination also appears to be safe and well-tolerated, and may be a promising approach for pancreatic cancer patients who are resistant to anti-PD-1/PD-L1 immunotherapies.

These preliminary findings — in more than two dozen people with advanced pancreatic cancer — were recently released at the Society for Immunotherapy of Cancer (SITC) 32nd Annual Meeting, in National Harbor, Maryland. The oral presentation was titled “First-in-human phase 1 dose escalation and expansion of a novel combination, anti–CSF-1 receptor (cabiralizumab) plus anti–PD-1 (nivolumab), in patients with advanced solid tumors.

Cabiralizumab, formerly known as FPA008, is being developed by Five Prime Therapeutics in collaboration with Bristol-Myers Squibb. It is designed to block the colony-stimulating factor 1 receptor (CSF1R), which is found at the surface of immunosuppressive tumor-associated macrophages (TAMs).

Because TAMs participate in tumor progression by suppressing the ability of immune system T-cells to kill tumor cells, high levels of TAMs are often linked with poor prognosis. Using cabiralizumab  to deplete TAM may be a means of improving natural immune responses and the efficacy of immune checkpoint inhibitors.

Preclinical studies have shown that inhibition of CSF1R signals reduces tumor burden, while promoting the anti-tumor immune activity. And when combined with other drugs that boost the immune system, like anti-PD-1 antibodies, cabiralizumab improved the overall therapeutic effect.

“Cabiralizumab depletes immunosuppressive TAMs that regulate T cells in the tumor microenvironment. TAM depletion may be synergistic to PD-1 blockade,” Helen Collins, chief medical officer of Five Prime Therapeutics, said in a press release.

The Phase 1a/1b trial (NCT02526017) is assessing the safety, tolerability, pharmacokinetics (the way a drug distributes in the body), and the overall clinical benefit of cabiralizumab in combination with Opdivo, developed by Bristol-Myers Squibb.

Being conducted in 39 clinical sites across the United States, it expects to enroll 280 patients with advanced lung, head and neck, pancreatic, and ovarian cancers, renal cell carcinoma, malignant glioma, or other solid tumor type. (Enrollment and other information is available by clicking on the trial’s identification number.)

In the first part of the study, investigators gave patients with ascending doses of cabiralizumab alone to determine the dose with higher efficacy and fewer side effects. Next, cabiralizumab was tested in combination with Opdivo.

To date, 229 patients have received the treatment, with 205 being given 4 mg/kg cabiralizumab and 3 mg/kg Opdivo once every two weeks.

Preliminary efficacy data, collected from 31 patients with pancreatic cancer, found that three experienced a partial response and one had stable disease. Also, one patient with disease progression — and so not considered among those responding to treatment — saw a reduction in target lesions by over 40 percent.

The six‐month disease control rate was 13 percent, and objective response rate was 10 percent.

The most common treatment-related adverse events were elevations in liver enzymes, which were reversible. The researchers thought this was likely due to the depletion of macrophages, which normally metabolize these enzymes.

An additional group of 30 patients with pancreatic cancer are being enrolled and treated to further evaluate this combination in this population.

Bristol-Myers Squibb will soon open to recruitment a Phase 2 clinical trial (NCT03336216) testing cabiralizumab plus Opdivo exclusively in about 160 pancreatic cancer patients. That study is taking place at sites in Arizona, Maryland and New York.

“In our robust Immuno-Oncology clinical program, we are focused on discovering ways to leverage the complex tumor microenvironment to help restore the body’s natural ability to fight cancer,” said Fouad Namouni, head of development, Oncology, at Bristol-Myers Squibb. “These preliminary results support our additional evaluation of the combination of cabiralizumab and Opdivo in patients with advanced pancreatic cancer.”