Five Prime Therapeutics and BMS's Phase 2 Trial of Cabiralizumab Plus Opdivo Fails in Advanced Pancreatic Cancer

Compiled by Keke

Five Prime Therapeutics’ idea of combining its experimental CSF-1 receptor inhibitor cabiralizumab with BMS’s checkpoint inhibitor Opdivo for the treatment of pancreatic cancer has effectively collapsed.

On February 18, Five Prime Therapeutics announced that the Phase 2 clinical trial (NCT03336216) evaluating the combination of cabiralizumab and Opdivo (nivolumab) for the treatment of advanced pancreatic cancer, conducted in collaboration with Bristol-Myers Squibb (BMS), failed to meet its primary endpoint. Following the announcement, the stock price of Five Prime Therapeutics fell by approximately 10%.

With regard to the goal of treating pancreatic cancer, failure is not surprising. In biopharmaceutical oncology trials, pancreatic cancer is one of the diseases with the lowest success rates.

“Pancreatic cancer is a difficult-to-treat disease. Unfortunately, in this randomized, controlled Phase 2 clinical trial, cabiralizumab in combination with Opdivo, with or without chemotherapy, did not demonstrate greater benefit compared to the standard-of-care chemotherapy regimen,” said Dr. Helen Collins, Executive Vice President and Chief Medical Officer of Five Prime Therapeutics.

It is reported that this multi-arm, randomized controlled Phase 2 study enrolled approximately 160 patients with locally advanced or metastatic pancreatic cancer who had progressed after local chemotherapy or first-line chemotherapy. The patients were divided into four treatment groups, receiving either gemcitabine/paclitaxel (Abraxane), 5-fluorouracil/leucovorin/liposomal irinotecan (ONIVYDE), or leucovorin/fluorouracil/irinotecan hydrochloride (FOLFIRI); cabiralizumab plus Opdivo; cabiralizumab plus Opdivo in combination with gemcitabine and paclitaxel; or cabiralizumab plus Opdivo in combination with oxaliplatin/5-fluorouracil/leucovorin. Specific analytical data from the Bristol-Myers Squibb-led trial have not been disclosed, but the company noted that no new safety concerns associated with the combination therapies were observed in the Phase 2 trial.

In October 2015, Bristol-Myers Squibb (BMS) acquired the development and commercialization rights to cabiralizumab from Five Prime Therapeutics under a global exclusive license and collaboration agreement, with an option to co-promote the drug in the United States. Following the failure of this study, BMS stated that although it had no immediate plans to further sponsor the development of cabiralizumab, it would continue to support ongoing trials of the agent and might continue to evaluate future development opportunities for this investigational drug.

Five Prime Therapeutics Collaborates with BMS on Development Project

Source: Five Prime Therapeutics Official Website

In several preclinical cancer models, inhibition of colony-stimulating factor-1 receptor (CSF-1R) has been found to reduce the number of immunosuppressive tumor-associated macrophages (TAMs) in the tumor microenvironment, thereby promoting anti-tumor immune responses. Cabiralizumab is an investigational antibody that inhibits CSF-1R and has demonstrated the ability to block the activation and survival of monocytes and macrophages in both preclinical models and clinical studies.

Mechanism of Action of Cabiralizumab

Source: Five Prime Therapeutics official website

This failure dealt another severe blow to Five Prime Therapeutics, which has struggled significantly over the past 18 months. In the fall of 2019, CEO Aron Knickerbocker departed the company. Prior to his departure, Knickerbocker implemented sweeping cuts, reducing the workforce by 20% and scaling back early-stage R&D projects to focus on clinical oncology development programs.

Chairman Bill Ringo assumed the role of President and, one month into his tenure, laid off another 70 employees. This round of layoffs also compelled the company to establish a “small research group” focused on advancing clinical candidates with the support of service providers and contractors.

During Knickerbocker’s tenure, a $1.74 billion collaboration with Bristol-Myers Squibb (BMS) was initiated to combine the I-O candidate drug cabiralizumab with Opdivo.

Currently, Five Prime Therapeutics is dedicated to developing immunomodulators and precision therapies for solid tumors. This includes a Phase 3 clinical trial of bemarituzumab (FPA144), a first-in-class investigational FGF2b antibody with enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and isoform selectivity, for the treatment of advanced gastric or gastroesophageal junction cancer, conducted in collaboration with Zai Lab.

Five Prime Therapeutics' Investigational Drug Pipeline

Source: Five Prime Therapeutics official website

The failure of cabiralizumab-based combination therapy follows similar setbacks in pancreatic cancer studies by multiple pharmaceutical companies, including Eli Lilly/Armo, NuCana, GSK, and Halozyme. Recently, only Hutchmed’s surufatinib has yielded positive trial results in this therapeutic area.

Reference Source: Five Prime Therapeutics’ Pancreatic Cancer Combo with Opdivo a Bust