Cabiralizumab Misses Primary End Point in Phase II Trial of Advanced Pancreatic Cancer

Although the novel combination of cabiralizumab (FPA008) and nivolumab (Opdivo) with or without the addition of chemotherapy induced an intriguing response rate in previous phase I data as a treatment for patients with advanced pancreatic cancer, the phase II clinical trial did not meet its primary end point of progression-free survival (PFS), according to a press release from Five Prime Therapeutics.¹

“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 2 trial,” said Helen Collins, MD, executive vice president and chief medical officer of Five Prime Therapeutics, in a statement.

Although there are no plans to continue development of cabiralizumab further at this time, the company will continue to support the evaluation of this agent in ongoing investigator-sponsored clinical trials. In the future, the company may assess different opportunities for cabiralizumab.

Approximately 160 patients with locally advanced or metastatic pancreatic cancer who progressed after a prior line of chemotherapy were enrolled in the multi-arm, randomized clinical trial (NCT03336216). The primary end point of PFS was accompanied by secondary end points, including PFS rate, objective response rate, duration of response, overall survival, the incidence of adverse events, and others.

Cabiralizumab was administered in combination with investigator choice of chemotherapy in arm A, with nivolumab in arm B, with nivolumab and gemcitabine plus nab-paclitaxel in arm C, or with nivolumab and oxaliplatin/5- fluorouracil/leucovorin (FOLFOX) in arm D. The purpose of this study was to evaluate the effectiveness of cabiralizumab in combination with nivolumab with or without chemotherapy in patients with advanced pancreatic cancer.

To be included in the trial, patients had to have an ECOG performance status of 0 or 1, adequate organ functions, and measurable disease. If patients had suspected or known central nervous system metastasis or autoimmune disease, uncontrolled or significant cardiovascular disease, or prior exposure to immune cell-modulating antibody therapy, they could not be included in the trial.

At the 2017 SITC Annual Meeting, this combination led to a confirmed objective responsein 4 (13%) of 31 patients who were heavily pretreated in a phase I clinical trial. Patients had received either cabiralizumab plus nivolumab or cabiralizumab alone.²

The most common treatment-related adverse events (TRAEs) of any grade included serum enzyme elevations (20%), pancreatic enzyme elevations, fatigue, rash, pruritus, and periorbital edema. Three deaths in the combination arm were related to treatment, and these were due to pneumonitis in a patient with thyroid cancer, respiratory distress, and acute respiratory distress. In that study, the most common grade 3/4 TRAEs with cabiralizumab alone included serum enzyme elevation, pancreatic enzyme elevations, and rash.²

Cabiralizumab inhibits the CSF-1 receptor. The investigational antibody has demonstrated in preclinical and clinical data that it can block activation of and survival of monocytes and macrophages. The number of immunosuppressive tumor-associated macrophages in the tumor environment can be reduced with inhibition of CSF1R.

“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 2 clinical trial,” Collins stated.

References:

1. Five Prime Therapeutics provides update on phase 2 trial of cabiralizumab combined with Opdivo in pancreatic cancer [news release]. San Francisco, CA: Five Prime Therapeutics; February 25, 2020. https://bwnews.pr/391gi3X. Accessed February 25, 2020.
2. Wainberg ZA, Piha-Paul SA, Luke JJ, et al. 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. Presented at: 32nd SITC Annual Meeting; November 8-12, 2017; National Harbor, MD. Abstract O4 https://go.aws/3c8iEjG.