Bristol-Myers Squibb and Five Prime Therapeutics announced preliminary results from a dose escalation and expansion study evaluating the safety, pharmacokinetics and pharmacodynamics of cabiralizumab in combination with Opdivo (nivolumab) in patients with advanced solid tumors. This is the first disclosure of a clinical experience evaluating an anti-CSF-1 receptor antibody, which depletes immunosuppressive tumor associated macrophages (TAMs), in combination with an anti-PD-1 antibody.
Preliminary results show that the safety profile of cabiralizumab plus Opdivo was generally consistent with that of Opdivo monotherapy, and that the combination results in dose-related decreases in circulating monocytes. In a cohort of heavily pre-treated patients with advanced pancreatic cancer (n=31 evaluable patients), a patient population that is generally insensitive to immunotherapy, durable clinical benefit was observed in five patients (16%), including confirmed objective responses in three patients with microsatellite-stable (MSS) disease (objective response rate 10%).
More cancer patients are being treated with immunotherapy, but most patients with advanced pancreatic cancer remain resistant to anti-PD-1/PD-L1 therapy and typically have poor outcomes, with an average one-year survival rate of only 16 percent and five-year survival of less than 3 percent. Pancreatic cancer is known to be associated with TAM infiltration and higher TAM infiltration is in turn associated with worse prognosis, suggesting that suppressed immune response contributes to tumor progression in this patient population. These data show for the first time that combining an anti-CSF-1 receptor antibody with Opdivo may help restore T cell function by a simultaneous reduction of TAMs and inhibition of PD-1 signaling.
“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, M.D., head of development, Oncology, Bristol-Myers Squibb. “These preliminary results support our additional evaluation of the combination of cabiralizumab and Opdivo in patients with advanced pancreatic cancer.”
NCT02526017 is a Phase 1a/1b open-label study to evaluate safety, tolerability, pharmacokinetics (PK), and clinical benefit of cabiralizumab in combination with Opdivo in patients with advanced cancers in single-arm cohorts. In the expansion cohorts, patients received cabiralizumab 4mg/kg plus Opdivo 3mg/kg intravenous (IV) once every two weeks in a 3+3+3 design.
As of data cut-off, 229 patients have been treated, including 205 patients in the combination dose expansion cohorts in advanced solid tumors, of which 33 were pancreatic cancer patients. Cabiralizumab PK activity appears similar as a monotherapy and in combination with Opdivo. The PK of cabiralizumab ≥ 4 mg/kg Q2W approaches the linear dose range, suggesting saturation of target-mediated clearance. Cabiralizumab alone or in combination with Opdivo results in dose-related decreases in circulating monocytes. Treatment-related adverse events (TRAEs) of any grade occurred in 90 percent (n=184) of patients treated with cabiralizumab and Opdivo, with 49 percent (n=100) of patients experiencing Grade 3/4 adverse events. Of the 24 patients in the monotherapy group, 63 percent (n=15) experienced TRAEs of any grade, and 54 percent (n=13) experienced Grade 3/4 adverse events. The most common TRAEs were elevations in creatine kinase and serum liver enzymes.
The efficacy data reported at SITC pertain to an expansion cohort in pancreatic cancer. The ongoing Phase 1a/1b trial has started to enroll and treat an additional 30 pancreatic cancer patients to further evaluate the combination in this patient population in a total of 60 patients. Further, Bristol-Myers Squibb is launching a new study of cabiralizumab plus Opdivo to provide additional insight into the potential benefit of the combination in pancreatic cancer.
Colony-stimulating factor 1 receptor (CSF1R) is a cell-surface tyrosine kinase receptor expressed by macrophages and other cells of the myeloid lineage. 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.