“Modified” FOLFIRINOX Regimen Approved by FDA for 2nd Line Treatment of Pancreatic Cancer

On the 22nd of October, 2015, the U.S. Food and Drug Administration approved a new combination therapy that includes the drug Onivyde for patients with metastatic pancreatic cancer (ductal adenocarcinoma of the pancreas) who had earlier been treated until progression of disease while on gemcitabine or a gemcitabine-based regimen. Onivyde is liposomal irinotecan, a topoisomerase I inhibitor (was called CPT-11, and originally derived from the plant extract camptothecin). This liposomal version was earlier known as MM-398 (and still earlier as PEP02). The combination that was approved is similar to the FOLFIRINOX regimen for pancreatic cancer, but without oxaliplatin – the 4th drug.

The liposome portion of the Onivyde refers to a fatty-like or “lipid” substance that covers the drug molecule generally creating a spherical shape. The underlying rationale typical for placing a drug-agent in a liposomal structure is to slow down absorption or to better target the drug to increase its duration or efficacy, and/or to reduce side-effects. The firm that owns Onivyde is Merrimac Pharmaceuticals of Cambridge, Massachusetts. They had or have Onivyde under study for the treatment a number of cancers including as the first line for advanced pancreatic cancer, breast cancer, pediatric sarcoma, brain cancer, and pediatric solid tumors.

This now approved FDA combination includes three drugs:  Onivyde, with 5-FU and leucovorin. The full FOLFIRINOX regimen includes four drugs: irinotecan (standard version), 5-FU, leucovorin, and oxaliplatin. FOLFIRINOX has been in frequent use as first line therapy in advanced pancreatic cancer beginning from the May 12, 2011 study published in the New England Journal of Medicine (NEJM) that demonstrated an overall survival of those with metastatic pancreatic cancer in the FOLFIRINOX treatment arm of 11.1 months compared with 6.8 months in the gemcitabine treatment arm.

Since that time, the Pancreatica Blog has also been interested in a number of studies that have looked at so-called “modified FOLFIRINOX regimens.” For example, one combination that entirely avoided the use of irinotecan. Another, substituted the drug-agent S-1 for 5-FU. Still another study modified the dosages of the agents such that the side-effects might be reduced while still aiming to maintain the efficacy for combating pancreatic cancer.

The most recent previous published article on Onivyde for advanced pancreatic cancer that we have been able to find (anywhere) is a Phase II study published on August 20, 2013 in the British Journal of Cancer by authors including a member of our Science Board, Professor Margaret Tempero. This study was commented on at the time here in the Pancreatica Blog. Onivyde had earlier received orphan drug status with the FDA for pancreatic cancer and was eligible for a Priority (expedited) Review.

It appears that the much of data used by the FDA in determining its decision came from the NAPOLI 1 Phase III randomized open-label clinical trial that was begun on December 14, 2011 (estimated time of completion was June, 2015) for those with pancreatic cancer (417 patients; 79 study locations worldwide) who had become refractory to gemcitabine regimens. The three arms of this clinical trial included one for the use of Onivyde infusion alone, one for 5-FU and leucovorin, and one with Onivyde together with 5-FU and leucovorin. The metastatic pancreatic cancer patients who received the full three-drug combination had a median survival duration of 6.1 months, compared to 4.1 months with just 5-FU and leucovorin. There was not an advantage of Onivyde alone over 5-FU and leucovorin.

The two most common very serious side-effects of the Onivyde regimen resulting in what will be a boxed package warning are severe leucopenia (low white cell count) and diarrhea.

Until now, there has been no generally agreed upon official second line treatment for pancreatic cancer. This three-drug Onivyde regimen, as approved by the FDA, will be the first (of a sort). But there are some points that should be made. The results need to be verified. The liposomal form of irinotecan (Onivyde) may well be superior to the standard form of irinotecan in combination, but this will require more study to fully determine. The Onivyde regimen will need to be compared to the standard FOLFIRINOX regimen (and other modified FOLFIRINOX regimens) in the treatment of pancreatic cancer in those for whom gemcitabine regimens have allowed disease progression.  And it should be noted that the survival advantage of the Onivyde regimen over that of 5-FU and leucovorin was somewhat small.

With these caveats, one might say that this FDA approval likely represents a modest step forward in the treatment of advanced pancreatic cancer in those for whom gemcitabine regimens have failed. And certainly this work establishes a new waypoint by which to compare further research on the range of options for the second line treatment of pancreatic cancer.


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Dale O’Brien, MD