Nivolumab/Cabiralizumab Combo Misses PFS Endpoint in Pancreatic Cancer

Helen Collins, MD

The combination of nivolumab (Opdivo) and the investigational CSF-1R inhibitor cabiralizumab with and without chemotherapy did not improve progression-free survival (PFS) compared with chemotherapy alone in patients with advanced pancreatic cancer, missing the primary endpoint of a phase II trial (NCT03336216).¹

Additionally, no new safety signals were observed in the study.

Five Prime Therapeutics, the developer of cabiralizumab, stated in a press release that Bristol-Myers Squibb (BMS), the company manufacturing nivolumab, has no near-term plans for additional sponsored development of cabiralizumab.

In October 2015, BMS acquired the rights to cabiralizumab under an exclusive worldwide license and collaboration agreement. BMS will continue to support the evaluation of cabiralizumab in select, ongoing investigator-sponsored studies and may continue to assess future development opportunities for the investigational asset, Five Prime Therapeutics stated.

“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,” Helen Collins, MD, executive vice president and chief medical officer of Five Prime Therapeutics, stated in the press release. “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.”

Five Prime Therapeutics also stated that, in preclinical models and prior clinical trials, cabiralizumab has been shown to block the activation and survival of monocytes and macrophages. Preclinical data showed that CSF-1R inhibition reduces the number of immunosuppressive tumor-associated macrophages in the tumor microenvironment, which leads to an immune response against tumors.

In the multi-arm, controlled, open-label, randomized, phase II trial, investigators enrolled approximately 160 patients with locally advanced or metastatic pancreatic cancer that progressed during or following 1 line of chemotherapy. Patients are randomized to 1 of 4 arms: investigator’s choice of chemotherapy with gemcitabine/nab-paclitaxel (Abraxane) or 5-flurouracil (5-FU)/leucovorin/irinotecan liposome, cabiralizumab combined with nivolumab, cabiralizumab/nivolumab plus gemcitabine/nab-paclitaxel, or cabiralizumab/nivolumab plus 5-FU)/leucovorin/irinotecan liposome.

To be eligible for enrollment, patients must have had locally advanced or metastatic pancreatic adenocarcinoma, an ECOG performance status (PS) of 0 or 1, adequate organ function, and measurable disease. Those with suspected or known central nervous system metastases; active, known, or suspected autoimmune disease; uncontrolled or significant cardiovascular disease; or prior exposure to selected immune cell-modulating antibody regimens were not eligible to enroll.

The primary endpoint was PFS using RECIST v1.1 criteria; secondary endpoints included Ctrough, objective response rate, duration of response, 2-year overall survival rate, safety, mortality, laboratory abnormalities, and discontinuation due to adverse events (AEs).

A prior, first-in-human phase I trial evaluating this combination demonstrated a 13% ORR in 31 efficacy-evaluable heavily pretreated patients with pancreatic cancer.²

Patients were treated with cabiralizumab monotherapy (n = 24) or in combination with nivolumab (n = 10) in a dose-escalation cohort across several solid tumors. The doses of cabiralizumab ranged from 1 mg/kg to 6 mg/kg; nivolumab was given at a 3-mg/kg dose. Treatment with both agents was administered intravenously every 2 weeks. An optimal dose of 4 mg/kg of cabiralizumab plus 3 mg/kg of nivolumab was further explored in a dose-expansion cohort (n = 195).

In the single-agent cabiralizumab arm, the median age was 65.5 years. Patients had an ECOG performance status (PS) of 0 (29%) or 1 (71%), and 71% of patients had received ≥3 prior regimens. In the combination arm, the median age of patients was 64 years, 27% had an ECOG PS of 0 and 71% had a score of 1. Overall, 45% of patients had received ≥3 prior regimens, 28% had received 2, and 23% had received 1. Seven patients were treated in the first-line setting (3%).

Pharmacokinetic data were similar for cabiralizumab when administered as a single-agent and in combination with nivolumab. Moreover, the 4-mg/kg dose was selected for the expansion cohort after showing similar serum concentrations after the first dose as the higher 6-mg/kg dose. Additionally, depletion of circulating nonclassical monocytes, a pharmacodynamic marker of CSF1R inhibition, was not observed until the dose reached 4 mg/kg.

The reported efficacy findings, which were presented during the 2017 SITC Annual Meeting, included patients with pancreatic cancer; AEs were described across the full study. The pancreatic cancer cohort comprised 33 patients who were treated in the dose-expansion stage of the study. In this cohort, the median age was 64 years, 58% had ECOG PS of 1, and 45% had received ≥3 prior regimens.

Results showed that 3 of the 4 responding patients continued to receive treatment with the combination (range, 168+ to 275+ days) and 1 additional patient had stable disease, leading to a 16% clinical benefit rate. A marked reduction was seen in CA19-9 levels for those with confirmed responses, and there were also reductions in tumor burden.

Across all patients treated with the combination, the most common grade 3/4 treatment-related AEs (AEs) were serum enzyme elevations (20%), pancreatic enzyme elevations (12%), fatigue (5%), rash (4%), pruritus (1%), and periorbital edema (<1%). There were 3 treatment-related deaths in the combination arm, these were due to pneumonitis in a patient with thyroid cancer (n = 1) and respiratory distress (n = 1) and acute respiratory distress (n = 1) in patients with lung cancer. The most frequently observed grade 3/4 TRAEs with cabiralizumab monotherapy were serum enzyme elevation (38%), pancreatic enzyme elevations (8%), and rash (4%).

Regarding safety findings in the pancreatic cancer group, the most common, all-grade, treatment-related AEs (TRAEs) were serum enzyme elevations (52%), fatigue (42%), periorbital edema (30%), rash (21%), and vomiting (21%). The most common grade 3/4 TRAEs were serum enzyme elevations (33%), hyponatremia (9%), and rash (9%). AEs that led to treatment discontinuation occurred in 9% of patients, all of which were grade 3/4 in severity.

References

1. Five Prime Therapeutics provides update on phase 2 trial of cabiralizumab combined with Opdivo in pancreatic cancer [news release]: South San Francisco, CA. Five Prime Therapeutics. Published February 18, 2020. https://bit.ly/2P38N4y. Accessed February 18, 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.