CCR2 Blockade Holds Clinical Promise in Advanced or Metastatic Pancreatic Cancer

Marcus Smith Noel, MD

CCX872-B, a potent, selective oral inhibitor of CCR2, added to FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) was associated with a tumor control rate of 78% at week 12 in a single-arm study of patients with locally advanced or metastatic pancreatic cancer.¹

Data from a poster presented at the 2017 Gastrointestinal Cancers Symposium in San Francisco also showed that progression-free survival (PFS) was 57% at week 24 in the primary analysis population, according to Marcus Smith Noel, MD, assistant professor, Department of Medicine, University of Rochester Medical Center, and colleagues.

CCL2/CCR2 is commonly observed in solid tumors of the breast, ovaries, cervix, pancreas, and other organs, they noted, and may facilitate immune escape. CCL2 can act directly on tumor cells to increase cell survival and migration. Further, macrophages that express CCR2 are abundant in the pancreatic tumor stroma, may act to enhance tumor growth and metastasis, and have been found to be immunosuppressive.

“CCR2 is a major regulator of monocyte migration … effective CCR2 blockade could lower the number of tumor-associated macrophages, increase cytotoxic immune response, and inhibit tumor growth,” the researchers indicated.

CCX872 is an orally administered small molecule that has previously been shown to be safe and well-tolerated when dosed daily up to 300 mg in healthy volunteers. It was shown to block CCR2 in a dose-dependent manner.

There is a precedent for the use of CCR2 inhibition in human cancer. A prior phase 1b trial combined CCR2 blockade with FOLFIRINOX in patients with locally advanced pancreatic cancer, Noel and co-investigators noted. In this study, 49% of 33 patients receiving FOLFIRINOX plus CCR2 inhibition had an objective tumor response on repeat imaging and local tumor control was achieved in 32 patients (97%). Whereas in the FOLFIRINOX alone group, none of 5 patients with repeat imaging achieved an objective response.²

In the study with CCX872-B, 50 patients with locally advanced or metastatic pancreatic cancer and an ECOG performance score ≤2 received FOLFIRINOX every 2 weeks for up to 24 weeks plus 150 mg CCX872-B once or twice daily until disease progression or intolerance to CCX872-B. The primary efficacy endpoint was PFS at 24 weeks. Their mean age at baseline was 59.8 years, 52% were male, and 98% were white. The primary tumor location was the pancreas head in 57%, body/tail in 41%, and other (local recurrence) in 2%. Some 76% had metastatic disease.

Seven patients were not evaluable because they did not have imaging at 12 weeks due to early withdrawal. The primary analysis population included 41 patients. Among all 50 patients, the tumor control rate per RECIST v1.1 criteria was 64.0%, and among the primary analysis population, it was 78.0%. The objective response rate in the 2 populations was 30.0% and 36.6%, respectively, and all were partial responses. No patients had a complete response. Stable disease was experienced by 34.0% of the entire cohort and by 41.5% of the primary analysis cohort. Twenty-two percent of patients in each cohort had progressive disease.

In the primary analysis population, the PFS at 12 weeks was 81%, and at 24 weeks, 57%. The median time to progression was 179 days.

The study is ongoing. In the primary analysis population, the overall survival rate at week 24 was 83%, and 52% at week 48. The median survival is 348 days.

No safety concerns that prevent further development of CCX872 in pancreatic cancer were recorded. The incidence of adverse events (AEs) associated with FOLFIRINX did not increase with the addition of CCX872. Grade 3 or higher AEs with the combination included fatigue in 18.0%, vomiting in 14.0%, diarrhea in 10.0%, peripheral sensory neuropathy in 8.0%, and febrile neutropenia in 6.0%. The authors observed that these AE rates are similar to, or higher than, with FOLFIRINOX alone in a 2011 study.³

Based on plasma receptor occupancy assays, CCR2 was covered 88%, on average, by CCX872-B.

References:

1. Noel MS, Hezel AF, Linehan D, et al. Orally administered CCR2 selective inhibitor CCX872-b clinical trial in pancreatic cancer. Presented at: 2017 Gastrointestinal Cancers Symposium; January 19-21, 2017; San Francisco, CA. Abstract 276.
2. Nywening TM, Wang-Gillam A, Sanford DE, et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial.Lancet Oncol.2016;17(5):651-662.
3. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.N Engl J Med. 2011;364(19):1817-1825.