Bristol-Myers Squibb and Five Prime Therapeutics confirmed that the randomized Phase II trial testing the combination of cabiralizumab (also known as (BMS-986227, FPA008) + nivolumab (Opdivo®) with and without chemotherapy in patients with advanced pancreatic cancer failed to meet its primary endpoint.
Nivolumab (previously known as BMS-936558) is a monoclonal antibody that binds to PD-1 receptors on T-cells and prevents the inhibition of T-cell mediated anti-tumor responses.
Cabiralizumab is an investigational antibody that inhibits the CSF-1 receptor and has been shown in preclinical models and clinical studies to block the activation and survival of monocytes and macrophages.
Based on early (pre-) clinical models, the inhibition of colony-stimulating factor 1 receptor (CSF1R), a cell-surface tyrosine kinase receptor expressed by macrophages and other cells of the myeloid lineage, reduces the number of immunosuppressive tumor-associated macrophages (TAMs) in the tumor microenvironment of a number of different cancers. This, in turn, facilitates an immune response against tumors. 
The CSF1R tyrosine kinase is activated when bound by its ligands, CSF-1 and IL-34. High levels of CSF1 in tumors stimulate more M2-like macrophages, which further tumor progression through suppressing effector T-cell functions.
High levels of TAMs in tumors are associated with poor prognostic outcomes, and preclinical research suggests that a blockade of CSF1R or inhibition of kinase activity may reduce the tumor burden, with a net effect of promotion of antitumor immunologic effects.
Preclinical studies suggest that targeting the CSF1R pathway in combination with other potentially complementary immune pathways, like PD-1, may be a key strategy to more effectively activate the antitumor immune response.
Although early studies showed cabiralizumab to be potentially synergistic to PD-1 blockade, with early encouraging results, which, may have supported the continued development of the combination in pancreatic cancer, the phase II trial failed to improve progression-free survival (PFS) compared with chemotherapy alone in patients with advanced pancreatic cancer, missing the primary endpoint of a phase II trial.
Bristol-Myers Squibb acquired rights in October 2015 to cabiralizumab under an exclusive worldwide license and collaboration agreement.
While Bristol-Myers Squibb has no near term plans for additional sponsored development of cabiralizumab, the company is expected to continue to support the evaluation of cabiralizumab in select, ongoing investigator-sponsored trials and may continue to assess future development opportunities for the investigational agent.
Difficult to treat
“Pancreatic cancer is a difficult disease to treat, and unfortunately the combination of cabiralizumab and Opdivo with and without chemotherapy did not show any meaningful benefit over standard of care chemotherapy in this randomized, controlled Phase II trial,” said Helen Collins, M.D., Executive Vice President and Chief Medical Officer of Five Prime Therapeutics.
“We are disappointed by this outcome and appreciate the participation of the investigators, staff, patients, caregivers, and our development partner who all contributed to the conduct and completion of this Phase II clinical trial,” Collins added.
The multi-arm, randomized, controlled Phase II clinical trial (NCT03336216) enrolled approximately 160 patients with locally advanced or metastatic pancreatic cancer that has progressed during or after one line of chemotherapy.
A Study of Cabiralizumab Given With Nivolumab With and Without Chemotherapy in Patients With Advanced Pancreatic Cancer – NCT03336216
 Foster C, Luke J, Hseu R, Janisch L, Fleming G, Chmura S. Phase I study of multisite stereotactic body radiotherapy plus nivolumab and urelumab or nivolumab and cabiralizumab in patients with advanced solid tumors.34th Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2019).