New Neoadjuvant Treatment in Trials

For patients with tumors that are surgically removable or have the potential to be removable, chemotherapy before surgery (known as neoadjuvant treatment) has become an important modality.

The overall goal of neoadjuvant chemotherapy is to potentially shrink certain tumors to make them potentially more amenable to surgery, increase rates of clear surgical margins, and treat microscopic cancer cells so that they do not spread.

Based on trials results, the dominant regimen used for patients who can tolerate it is the combination chemotherapy mFOLFIRINOX. A phase III study called CASSANDRA, based in Italy, compared modified FOLFIRINOX (mFOLFIRINOX) to a new four-drug regimen called PAXG. Although results look promising, more data is still needed.

A New Combination

The four-drug regimen mFOLFIRINOX includes folinic acid, fluorouracil, irinotecan hydrochloride, and oxaliplatin, and is one of the current standard of care options. The new PAXG regimen includes the drugs capecitabine, cisplatin, nab-paclitaxel, and gemcitabine.

Preliminary results of the CASSANDRA phase III trial were presented at the American Society of Clinical Oncology (ASCO) annual meeting in June 2025. Preliminary results showed that neoadjuvant PAXG outperformed mFOLFIRINOX in resectable and borderline resectable disease.

Final results were published in the journal The Lancet in December 2025. According to the report, a total of 260 patients were included, with 132 assigned to PAXG and 128 to mFOLFIRINOX, with a median follow-up of 28.5 months. The trial took place at 17 Italian academic hospitals. Eligible patients were aged 18-75 years with pathologically confirmed resectable or borderline resectable pancreatic cancer. 

PAXG was found to improve event-free survival (EFS) to 16.0 months compared to 10.2 months with mFOLFIRINOX. At one year, EFS was 61 percent for PAXG versus 45 percent for mFOLFIRINOX. And at three years, EFS was 33 percent for PAXG versus 13 percent for mFOLFIRINOX. At least one severe medical event was observed in 87 (66 percent) of 132 patients in the PAXG group and in 78 (61 percent) of 128 patients in the mFOLFIRINOX group, including one fatal event.

PAXG also saw improvements in some secondary outcomes, such as disease control rate and pathological stage, among others.

More Mature Data Needed

Although it appears that PAXG outperforms mFOLFIRINOX in the neoadjuvant setting, the data is “immature,” explains Brian Wolpin, M.D., M.P.H., who was the invited discussant at the ASCO meeting where initial data was presented. Wolpin is the director of the Hale Family Center for Pancreatic Cancer Research at the Dana-Farber Cancer Institute in Boston, director of the Gastrointestinal Cancer Center, and the Robert T. and Judith B. Hale Chair in Pancreatic Cancer.

And although PAXG has the potential to change standard of care in the neoadjuvant setting, there needs to be longer follow-up, Wolpin says. This study measured event-free survival, not the gold standard metric of overall survival, he adds.

Event-free survival is defined as the time from randomization to an event which may include disease progression, discontinuation of the treatment for any reason, or death, according to the National Institutes of Health. It is often used in the neoadjuvant setting. Overall survival is defined as the time from randomization to death. “What we want to do is extend life; we want to cure people,” says Wolpin. “Overall survival is the gold standard. And we need to see what that data shows before anything is changed. I look forward to seeing that data because it’s clear we need better therapies for our pancreatic cancer patients no matter what their stage. I think that the results are interesting and important, but we need more data to fully interpret results.”

Two ongoing trials could also shed more light on neoadjuvant treatment.  One trial, PREOPANC-3, a major, international randomized trial, is looking at whether giving chemotherapy before surgery improves overall survival in patients with resectable pancreatic cancer compared to giving chemotherapy only after surgery. Another trial, dubbed ALLIANCE A021806, is a randomized controlled phase III trial that is evaluating overall survival in patients with resectable pancreatic cancer. The trial compares results in patients treated with mFOLFIRINOX and surgery versus those who receive up-front surgery followed by adjuvant (post-treatment) mFOLFIRINOX.

Wolpin is hopeful about the future of pancreatic cancer treatment. “But we need to do more,” he stresses. Wolpin and colleagues are working on ways to use machine learning and computational modeling to help identify early signals of pancreatic cancer by looking at patterns in patient data and in samples like blood and stool. And targeted therapies like RAS inhibitors, ones focused on overcoming resistance, and more personalized approaches to treatment are also significant areas of research and will help improve outcomes, he believes. “There are a lot of positive things happening right now and I’m excited about the research and how it can potentially help our patients,” he says.