Hospitalized cancer patient undergoing chemotherapy.
Credit: Fly View Productions/ Getty Images

An international group of researchers have shown that treating metastatic pancreatic ductal adenocarcinoma (mPDAC) with a four-drug chemotherapy regimen prolongs survival by around 2 months compared with a commonly used two-drug regimen.

“This study indicates that the more aggressive chemotherapy approach should be considered for those patients who are able to tolerate it,” said Zev Wainberg, co-director of the UCLA Health GI Oncology Program and a researcher at UCLA Jonsson Comprehensive Cancer Center. He presented the findings of the NAPOLI-3 trial at the ASCO Gastrointestinal Cancers Symposium in San Francisco last week.

Wainberg added: “Metastatic pancreas cancer has long been recognized as a very difficult type of cancer to treat, but this study represents a possible new reference standard for current treatment and for future research and drug development.”

The disease has a notoriously poor prognosis, in part because it is often found too late, once it has already spread. A lack of identifiable actionable genetic targets also play a part.

A previous phase 1/2 study demonstrated promising anti-tumor activity in patients with mPDAC who received a first-line regimen that combined liposomal irinotecan 50 mg/m2 with 5- fluorouracil 2400 mg/m2, leucovorin 400 mg/m2, and oxaliplatin 60 mg/m2, collectively termed NALIRIFOX.

To investigate the efficacy and safety of the regimen further, Wainberg and colleagues carried out the phase 3 NAPOLI-3 trial, in which they compared NALIRIFOX with nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 as first-line therapy in patients with mPDAC from more than 25 countries.

After a median 16.1 months of follow-up, median overall survival (OS) was 11.1 months among the 383 patients randomly assigned to receive NALIRIFOX on days 1 and 15 of each 28-day cycle.

That was the significantly longer than the median OS of 9.2 months observed among the 387 participants given nab-paclitaxel plus gemcitabine on days 1, 8 and 15 of each 28-day cycle. The difference between the two arms corresponded to a significant 16% lower risk for death among individuals given NALIRIFOX.

Wainberg notes that all cancers, and the associated expectations of treatment clinical benefits are different, but he told Inside Precision Medicine that he believes “in this disease a 2-month improvement is in my opinion significant.”

There was also a significant 30% lower risk for disease progression or death in the NALIRIFOX arm relative to the nab-paclitaxel plus gemcitabine arms, with median progression-free survival rates at 7.4 and 5.6 months, respectively. Objective response rates were a corresponding 41.8% and 36.2%.

The investigators found that the safety profile of NALIRIFOX was manageable and consistent with the profiles of the treatment’s individual components. Among the grade 3 or 4 treatment-emergent adverse events that occurred in at least 10% of participants, diarrhea (20.3 vs 4.5%), nausea (11.9 vs 2.6%), and hypokalemia (15.1% vs 4.0%) were more common with NALIRIFOX than with nab-paclitaxel plus gemcitabine. Conversely, anemia (10.5% vs 17.4%) and neutropenia (14.1% vs 24.5%) were both less common among patients who received the study regimen.

For the first time, we have provided proof that a four-drug regimen makes people live longer than a two-drug regimen, this has not been proven until now,” Wainberg remarked.

He added that it is now up to the FDA to determine whether NALIRIFOX will be approved. In the meantime, his team “will continue to test new drugs and new strategies to improve outcomes in this terrible disease.”

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