Recently, BeiGene presented the preliminary findings of an ongoing dose-escalation Phase I study of BGB-A317, a checkpoint inhibitor. The presentation was made at the 2016 Annual Meeting of the American Society of Clinical Oncology in Chicago. BGB-A317, a monoclonal antibody, is designed to bind to PD-1, a receptor on the surface of cells that downregulates the immune response to cancer tumors.
When PD-1 is inhibited, T cells can activate an immune response against the tumor and kill tumor cells. PD-1 receptors on T cells are engaged by PD-L1, a surface protein on cancer cells. This binding prevents the T cell from delivering poisonous proteins to the cancer cell. BGB-A317 prevents PD-L1 binding so that the T cell remains activated.
According to preliminary results of the study, BGB-A317 is well tolerated among patients and has the ability to prompt an anti-tumor response in several different types of solid tumors. The molecule has a distinctive binding signature to PD-1, which provides high binding affinity and specificity. The study also found that BGB-A317 does not bind with Fc gamma receptors.
These initial findings seem encouraging, and BeiGene is looking forward to more data from the dose-escalation study, as well as other trials. Currently, researchers are developing combination studies that will look at the efficacy of BGB-A317 with the other compounds in the BeiGene portfolio.
The Phase I Dose Escalation Trial for BGB-A317
The Phase I dose escalation trial for BGB-A317 took place across multiple centers and was an open-label trial. Six facilities in Australia were designated to treat patients with the goal of assessing safety, tolerability, anti-cancer activities, and pharmacokinetics. This trial approached BGB-A317 as a monotherapy for patients with advanced solid tumors.
The study involves more than 60 patients, each of whom received escalating doses of the therapy intravenously on a biweekly basis with dosage ranging from 0.5 milligrams per kilogram up to 10 milligrams. In addition, more than 35 other patients received the therapy every three weeks at elevated doses to explore the impact of an alternative schedule.
The patient population represented 26 different types of solid tumors. At present, four solid tumors indications for PD-1 or PD-L1 antibodies exist. Of these four, no patients with melanoma or non-small cell lung cancer were enrolled, and patients with renal cell carcinoma and urothelial carcinoma combined represented only 15 percent of enrolled individuals.
The initial data on side effects seem rather mild. Among the 60 total patients in the Phase I trial, the most common side effects included fatigue (experienced by 14 individuals), diarrhea (experienced by 11 individuals), pruritus (experienced by 8individuals) and rash (experienced by 7 individuals). In addition, five patients reported nausea. However, nine serious adverse events were reported, including three cases of colitis, two cases of hypotension, and one case each of ketoacidosis, diabetes mellitus, severe diarrhea, and infusion reaction.
Preliminary Results of the Phase I Study
In late May, 94 patients were evaluated for anti-tumor activity using at least one tumor imaging assessment or clinical progression. The anti-tumor assessment is still in early stages considering the amount of time patients had received BGB-A317, but six cases of confirmed partial response and five cases of unconfirmed partial response were reported. In addition, three more patients had signs of tumor reduction significant enough to qualify for partial-response status in one imaging assessment, but the results were not confirmed in a subsequent assessment eight weeks later.
Patients with urothelial carcinoma experienced one confirmed and two confirmed responses out of five total cases, and individuals with gastric cancer experienced one confirmed and one unconfirmed partial responses out of four total cases. Also, one confirmed and one unconfirmed partial responses occurred in the two enrolled patients with Merkel cell carcinoma. The single patient with colorectal cancer had a confirmed partial response.
In addition, responses were recorded in patients with renal cell carcinoma, mesothelioma, penis squamous cell carcinoma, ovarian cancer, and cervical cancer. At the end of the efficacy data stage, nine patients who had responded to the treatment decided to stay on the regimen.
Other Treatments in the BeiGene Pipeline
In addition to BGB-A317, BeiGene has three drugs that are clinical candidates. One of these drugs is BGB-283, an inhibitor that targets rapidly accelerated fibrosarcoma (RAF) kinases. This molecule has the potential to improve treatment of solid tumors and has proven to be more effective than approved first-generation inhibitors, largely because of increased activity against RAF dimers.
BGB-290 is another drug in the BeiGene pipeline. This drug inhibits poly(ADP-Ribose) polymerase-1 and -2. The potent and selective inhibitor has better drug metabolism and pharmacokinetic properties than other options.
The third clinical-stage drug is BGB-3111. A Bruton’s tyrosine kinase (BTK) inhibitor, it is used as a monotherapy or in combination with other drugs to treat B cell malignancies.
All four of the BeiGene clinical candidates, including BGB-A317, are in the dose-expansion stage of clinical trials. The company also has other cancer immunotherapies in the preclinical development stage.