Emerging Agents May Fill Therapeutic Gap in Metastatic Pancreatic Cancer

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.”

OncLive: What are the standard frontline therapies for patients with metastatic pancreatic cancer?

Have any notable advances been made in this setting?

What was the rationale for the study?

Moving to maintenance therapy, what was the rationale for the PRODIGE-35 trial?

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.Mettu: 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.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.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.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.

What are the clinical implications of this trial?

Could you discuss the significance of the NAPOLI-1 trial? What were the key takeaways?

What are the biggest sequencing challenges in the space?

In the study, patients were randomized to 3 different arms: FOLFIRINOX, FOLFIRINOX for a set period of time and then maintenance 5-fluorouracil (5-FU) with leucovorin, or gemcitabine alternating with FOLFIRI for 2 months at a time. The maintenance arm did just as well as the FOLFIRINOX arm, which is pretty exciting. It gives us an option in that patients do not have to undergo the toxicity of FOLFIRINOX for an extended period of time. When they progress, FOLFIRINOX can be reintroduced. Interestingly, the gemcitabine and FOLFIRI arm didn't do as well.It's something that many of us do in clinical practice, so it reinforces that. A lot of it comes down to listening to your patient. If they're experiencing toxicity, you can back off on the drugs that are causing that toxicity.NAPOLI-1 was a study that was done in the second-line setting. Patients who were given a previous gemcitabine-based regimen were randomized 1:1:1 to receive either 5-FU leucovorin with liposomal irinotecan, liposomal irinotecan by itself, or 5-FU and leucovorin. The goal was to investigate what liposomal irinotecan does and whether 5-FU is needed in combination with it. The trial was also done to see if we could develop a better second-line option for our patients. Results showed that the combination of 5-FU with leucovorin and liposomal irinotecan was beneficial over 5-FU and leucovorin itself and that the monotherapy wasn't good enough.It boils down to what patients receive in the frontline setting, because that impacts what they can receive in the second-line setting. For patients who start off with a gemcitabine-containing regimen, you'll want to switch to something different. The option there would be 5-FU, leucovorin, and liposomal irinotecan (Onivyde). If patients already received FOLFIRINOX, they’re probably not going to derive much benefit from getting any of those agents, even the liposomal irinotecan if they've already been given irinotecan. As such, you'll want to switch to a gemcitabine-containing regimen.

What emerging agents are coming down the pike?

Which one is better in which line of therapy? We don't know. It really comes down to what you think your patient can tolerate. If they have a good performance status, they're probably going to go through both lines of treatment.There was a lot of excitement at the 2019 Gastrointestinal Cancers Symposium. Various phase I studies were presented, a couple of phase II studies, and fewer phase III trials. There are several targets that are worth watching out for. One is CPI-613, which is being combined with FOLFIRINOX in a phase III study; it's also being looked at in combination with gemcitabine in a phase II study.

What is the importance of genetic testing in this space?

Another drug that is being looked at is a PEGPH20, which is a hyaluronic acid-targeting drug. Pancreatic cancer has a very dense stroma; this drug breaks down the stroma, thereby improving drug delivery. The one caveat there is that there is an increased risk of thromboembolism, so these patients need to be anticoagulated. There are several other drugs under investigation in phase I studies. We’ll have to wait to see if they pan out.Genetic testing is recommended for all patients with metastatic pancreatic cancer, according to NCCN guidelines. It’s something that we all ought to think about. A certain number of our patients will have defects in genes such as PALB2 and BRCA1/2. For those subsets of patients, treating with platinum-based therapy such as gemcitabine/cisplatin or FOLFIRINOX is indicated. [The results may] also impact the risk of pancreatic cancer for family members. It's something that should be considered. That being said, it's easy to overwhelm our genetic counselors. We have to use that in the context of a good family history.

References

1. Alistar A, Morris BB, Desnoyer R, et al. Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase I trial. Lancet Oncol. 2017;18(6):770-778. doi: 10.1016/S1470-2045(17)30314-5.
2. Hingorani SR, Zheng L, Bullock AJ, et al. HALO 202: randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine versus nab-paclitaxel/gemcitabine in patients with untreated, metastatic pancreatic ductal adenocarcinoma. J Clin Oncol. 2018;36(4):359-366. doi: 10.1200/JCO.2017.74.9564.