Novel Agents Move the Needle Forward in Metastatic Pancreatic Cancer

Raymond Wadlow, MD, discusses the emergence of combination chemotherapy regimens in metastatic pancreatic cancer and the promise of emerging strategies that are under exploration.

While the use of combination chemotherapies has served to improve outcomes for patients with metastatic pancreatic cancer, new research examining novel agents like devimistat (formerly CPI-613) could continue to move the needle forward, according to Raymond Wadlow, MD. 

“There is a lot of excitement surrounding some of these novel agents, a lot of work being done in improving the quality of patients’ lives, and a lot of work being done to find new ways to detect disease when it is still at an early stage or to prevent it,” Wadlow said.

In the phase 3 AVENGER 500 trial (NCT03504423), investigators are evaluating the safety and efficacy of devimistat plus modified FOLFIRINOX vs FOLFIRINOX alone in frontline treatment of patients with stage IV metastatic pancreatic cancer. “The results are eagerly awaited because in a phase 1 study, the investigational drug arm was associated with a response rate of approximately 60%, which is astoundingly high in this disease,” Wadlow noted.

In an interview OncLive®, Wadlow, the co-director of Gastrointestinal Oncology Research, and program director of the Hematology-Oncology Fellowship at Inova Schar Cancer Institute, discussed the emergence of combination chemotherapy regimens in metastatic pancreatic cancer and the promise of emerging strategies that are under exploration.

OncLive®: Could you speak to the emergence of combination chemotherapy regimens in pancreatic cancer?

Wadlow: A combination chemotherapy is a fairly recent phenomenon. Single-agent gemcitabine was the standard of care since a seminal clinical trial published in 1997, which demonstrated that gemcitabine versus what could be considered the older standard of care, 5-FU [fluorouracil] was superior in terms of making patients’ lives better. The investigators used an end point referred to as clinical benefit response, which is a composite measurement of quality of life, weight, and pain control, and they found that clinical benefit response was superior in the gemcitabine-treated patients. 

Subsequently, many negative studies sought to expand on that [benefit] by combining gemcitabine with other drugs that had seen success in other indications, including colon cancer and other gastrointestinal [GI] malignancies, as well as with a host of different investigational compounds. It was only recently, within the past decade, that finally, we saw published clinical trials that demonstrated the value of combination chemotherapy; this is associated with a better response rate, as well as a longer progression-free and overall survival vs gemcitabine alone. 

The combination regimen NALIRIFOX was examined in the phase 3 NAPOLI-3 trial (NCT04083235). How does this regimen measure up to other standards used in practice?

We know that NAPOLI-3 is a trial of a regimen known as NALIRIFOX, which is a combination of nanoliposomal encapsulated irinotecan with 5-FU and oxaliplatin, compared with gemcitabine and nab-paclitaxel [Abraxane] chemotherapy, which is one of the 2 standard regimens in use, the other being FOLFIRINOX. The trial is based on results from the phase 3 NAPOLI-1 trial [that was done in the second-line setting, which demonstrated the superiority of nanoliposomal irinotecan and 5-FU versus 5-FU monotherapy in patients previously treated with gemcitabine.

What we know, based on early phase 1/2 data, is that NALIRIFOX looks to be comparably effective to the other standard regimens, but better tolerated, with less GI toxicity than FOLFIRINOX, and less fatigue and neuropathy than both FOLFIRINOX and gemcitabine with nab-paclitaxel.

If the data remain positive, how do you see NALIRIFOX impacting the paradigm?

The goals are to expand the options that are available for our patients. I do not think that anyone believes that combination chemotherapy is going to dramatically extend survival and cure a substantially greater percentage of patients than what we are already doing. People are realistic about that, [which is] why there is a lot of emphasis on novel treatment approaches.

However, combination chemotherapy remains effective for a subset of patients. To that extent, we can offer [these patients] that [regimen, while] minimizing toxicity; that is a very tractable short-term goal for the research community. That is the promise of NALIRIFOX.

You mentioned the emphasis on novel treatment strategies. What is some of the work that is being done with devimistat? 

The phase 3 Avenger 500 trial is evaluating a novel agent called devimistat, which is a lipoate analog, which is a catalytic cofactor for a couple of the enzymes in the TCA cycle. This is an attempt to disrupt the cancer cells’ manipulation of energy metabolism, which allows the cancer cell to produce the building blocks necessary for cell division, invasion, and metastasis. By disrupting this altered energy metabolism, the thought is that cancer cells will be more susceptible to cytotoxic chemotherapy. Avenger 500, which has completed accrual, is a study of FOLFIRINOX with or without devimistat.

What other emerging agents are you excited about?

There are a host of emerging agents. Some efforts are targeting energy metabolism, while others are targeting different enzymes within the hexose biosynthesis shunt within other aspects of the Krebs cycle. Some agents attempt to disrupt the biophysical barrier that encompasses pancreatic cancer through the stromal desmoplastic reaction, and improve cancer drug delivery, including cytotoxics like liposomal irinotecan, but also, other drugs. Other efforts are being made to augment immunotherapy. Unfortunately, checkpoint inhibitors are not effective for the vast majority of patients with pancreatic cancer when given alone, but in combination with other agents, such as CD40 agonists, there is hope and some preliminary evidence to suggest that these strategies may be effective.


  1. Study evaluating efficacy and safety of FFX versus combination of CPI-613 with mFFX in patients with metastatic adenocarcinoma of the pancreas. Updated April 21, 2020. Accessed March 25, 2021.