Niharika B. Mettu, MD, PhD
Since establishing FOLFIRINOX and the combination of gemcitabine and nab-paclitaxel (Abraxane) as frontline therapy for patients with metastatic pancreatic cancer, investigators have been hard-pressed to find alternative agents with the potential for improved survival—until recently, explained Niharika B. Mettu, MD, PhD.
In 2017, a phase I study explored the use of modified FOLFIRINOX in combination with CPI-613 (Devimistat), a novel lipoate analog that inhibits the mitochondrial enzymes pyruvate dehydrogenase and α-ketoglutarate dehydrogenase in the NCI-H460 cell line, in patients with metastatic disease.1
Based on the preliminary safety and efficacy data reported in the trial, the agent is currently being investigated in combination with modified FOLFIRINOX in patients with metastatic disease as a frontline treatment in an ongoing phase III trial (NCT03504423).
The agent’s unique mechanism of action sets it apart from typical cytotoxic combination chemotherapies, according to Mettu, making it a useful target to explore further in patients with metastatic disease.
PEGPH20 has also shown potential in this patient population when used in combination with gemcitabine and nab-paclitaxel, especially in patients with high levels of hyaluronan (HA) expression. Findings from the phase II HALO-109-202 trial showed a median progression-free survival of 9.2 months with the regimen in patients with HA-high tumors compared with 5.2 months in those who received chemotherapy alone.2
Now, PEGPH20 is being explored specifically in patients with HA-high metastatic treatment-naïve disease in the international phase III HALO-109-301 trial (NCT02715804).
“We have good first-line regimens for the treatment of [patients with] metastatic pancreatic cancer, but they're not good enough,” said Mettu. “Clinical trial participation is recommended for patients in any phase of treatment, whether that be the first-line, second-line, or third-line setting. It's always worth looking for a clinical trial to see if your patient can participate.”
In an interview during the 2019 OncLive®
State of the Science Summit™ on Gastrointestinal Cancers, Mettu, an assistant professor of medicine at Duke Cancer Institute, discussed frontline approaches, maintenance therapy, sequencing strategies, and emerging agents for patients with newly diagnosed metastatic pancreatic cancer.
OncLive: What are the standard frontline therapies for patients with metastatic pancreatic cancer?
: We have two first-line treatments for patients with metastatic pancreatic cancer. It really gets to what their performance status is. For patients with good performance status, FOLFIRINOX and gemcitabine/nab-paclitaxel are the 2 category 1 recommendations in the National Comprehensive Cancer Network (NCCN) guidelines.
Have any notable advances been made in this setting?
It's a tough space. We currently have a clinical trial that's open right now in the frontline setting. We need more advances in the frontline setting. There was an exciting phase I paper published in Lancet Oncology
on CPI-613 in combination with FOLFIRINOX, which had some impressive results. It's currently in an ongoing phase III study, so we'll have to see if that [combination will] provide any additional benefit.
What was the rationale for the study?
CPI-613 has a novel mechanism of action that is different from the other drugs that we use. It works on the tricarboxylic acid cycle and inhibits 2 different enzymes. It's a lipoate analog; it's different from standard cytotoxic chemotherapy, and that's what we need in pancreatic cancer. We need something novel that will make a difference for our patients rather than just standard cytotoxic combinations.
Moving to maintenance therapy, what was the rationale for the PRODIGE-35 trial?
Our patients who are on these aggressive regimens derive survival benefit, but not without toxicity. As such, the idea behind this study was to look at ways of administering therapy so that patients could have continued benefit with minimal toxicity.