Monocyte-Targeting Agent Active in Locally Advanced Pancreatic Cancer

Andrea Wang-Gillam, MD, PhD

Almost half of patients with borderline resectable or locally advanced pancreatic cancer had objective responses to treatment with an investigational chemokine receptor antagonist, according to results of a preliminary clinical study.

The results showed that 14 of 29 patients had partial responses, 14 had stable disease, and only one patient had progressive disease as best response to PF-04136309 plus FOLFIRINOX chemotherapy.

Treatment with PF-04136309 was associated with changes in tumor gene expression consistent with the anti-inflammatory effects of the agent, Andrea Wang-Gillam, MD, reported at the 2015 Gastrointestinal Cancers Symposium in San Francisco.

“The combination of FOLFIRINOX plus PF-04136309 was associated with manageable toxicity, and the most frequent treatment-related adverse events are attributable to FOLFIRINOX,” said Wang-Gillam, a medical oncologist at Washington University in St. Louis. “It was a tolerable regimen, as up to 70% of patients completed a total of six cycles of therapy.”

“Antitumor activity was observed in association with depletion of inflammatory monocytes and a repolarized tumor microenvironment,” she added. “This regimen should be explored in a large clinical study,” she continued, at a recommended phase II dose of 500 mg twice daily.

Pancreatic cancer has a high proportion of myeloid-lineage cells, including monocytes. Investigators in a retrospective study of 377 patients with resected pancreatic cancer examined the association between preoperative monocyte count and subsequent survival. They defined low monocyte prevalence as <6% of leukocytes, midlevel prevalence as 6% to11%, and high prevalence as >11%.

Wang-Gillam said the data showed that a low monocyte count was associated with a median overall survival of 35.6 months, declining to 27.6 months with a midlevel monocyte count, and 21.1 months with a high monocyte count.

“The results showed that a low monocyte count is a favorable prognostic factor by multivariate analysis,” she said (HR = 0.58; P = .0246].

Inflammatory monocytes express chemokine C-C motif receptor 2 (CCR2). Cancer cells use chemokine C-C motif ligand 2 (CCL2) to mobilize and recruit inflammatory monocytes from the bone marrow to the peripheral circulation, where they differentiate into macrophages and dendritic cells.

“We felt that if we could block CCR2 and deplete inflammatory monocytes, perhaps we could improve patients’ outcome in pancreatic cancer,” said Wang-Gillam.

In preclinical models, PF-04136309 demonstrated inhibition of tumor growth and delayed development of liver metastasis. Wang-Gillam and colleagues believed the evidence provided a compelling rationale to evaluate PF-04136309 in the treatment of localized pancreatic cancer. They performed a phase Ib clinical trial to identify the maximum tolerated dose (MTD) of PF-04136309 and to determine safety, efficacy, and toxicity of the small-molecule inhibitor.

Investigators enrolled patients with previously untreated borderline resectable or locally advanced pancreatic cancer. A six-patient cohort received only FOLFIRINOX chemotherapy, and eight patients received FOLFIRINOX plus PF-04136309. An expansion cohort of 31 patients was enrolled and treated with FOLFIRINOX and PF-04136309 after the MTD was determined.

Because patients in the dose-finding and expansion cohorts received the same dose of PF-04136309, the cohorts were combined for evaluation of adverse events and efficacy.

Wang-Gillam reported that all six patients treated with FOLFIRINOX alone developed grade ≥3 neutropenia, as compared with 26 of 39 (66.7%) of patients who received FOLFIRINOX plus PF-04136309. Grade ≥3 anemia also occurred more often with FOLFIRINOX alone (33.3% vs 2.6%). Half of patients in the PF-04136309 group received granulocyte-colon stimulating factor, as did three of six patients who received only FOLFIRINOX.

Among nonhematologic toxicities, gastrointestinal adverse events predominated and were consistent with what has been observed in patients treated with FOLFIRINOX.

Three fourths of patients in the PF-04136309 dose-finding and expansion cohorts completed six cycles of therapy. The mean and median number of completed cycles was greater in the PF-04136309 cohorts as compared with the six patients who received only FOLFIRINOX.

Efficacy data for 29 patients in the PF-04136309 expansion cohort showed that 14 patients had stable disease in addition to the 14 who had partial responses, meaning that 96% of the patients had stable disease or better response to PF-04136309. In contrast, data from a historical cohort of 18 patients treated with FOLFIRINOX alone showed partial responses in five patients (28%) and stable disease in nine (50%).

“We felt that 48% partial response was impressive in this group of patients, particularly when you think about targeting the primary tumor,” said Wang-Gillam.

Wang-Gillam A, Nywening T, Sanford D, et al. Phase IB study of FOLFIRINOX plus in patients with borderline resectable and locally advanced pancreatic adenocarcinoma. Presented at: 2015 Gastrointestinal Cancers Symposium; January 15-17, 2015; San Francisco, CA. Abstract 338.

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