FDA approves new first line treatment option for metastatic pancreatic

(m)Folfirinox is still the gold standard and used first in those patients age 70 or younger and a low ECOG physical assessment score of 0-1. When it begins to wane, Gemzar/Abraxane is the next first-line combination regimen used. If that doesn’t work or effectiveness decreases, Nalirifox gives the oncologist a third, first-line drug to use.

In clinical studies, Nalirifox was shown to be statistically more effective than Gemzar/Abraxane. Clinical studies on how it compares to (m)Folfirinox are not yet available. What makes this drug combination unique is the nab-Paclitaxel. It uses the Onyvide formulation which is liposome-coated nano particles of nab-Paclitaxel which get deep into the malignant cells and the “delivered payload” of drug is released. It results in greater and longer effectively.

A misconception people often have is in trying to understand clinical trial statistics. When it gets reported that the median of 3.4 months was observed, that doesn’t mean everyone is going to only get 3.4 months. There are patients who can be “statistical outliers”- those that received far greater benefit. Everyone has an equal chance of falling on the median, being to the left of it (shorter benefit) or to the right (long-term survivors).

Another thing to consider is that the study used the metric of 12 cycles (6 months). When (m)Folfirinox was compared to G/A, a 6 month period (12 cycles (m)FFX to 6 cycles G/A was used. Consider those patients who advocated for receiving more than 12 cycles of FFX. I did 46 cycles with 24 being FFX. Camille Moses did 37 cycles. Both of use are marking 12 years survival of stage IV disease. We advocated for more aggressive chemotherapy and far exceeded the median that was based on only doing standard of care 12 cycles.

There are other long-term patients whose stories are documented on PanCan.org, LetsWinPC.org. seenamagowitzfoundation.org and other sites. If you do standard of care, don’t expect more than standard results. I was physically strong and otherwise healthy and why I spoke up and advocated for going beyond standard of care.

Hi. I’m 65 and have no other health issues and not even a family history of any type of cancer. They tell me this is “a fluke”. 😕 the hardest time for me was starting chemo while I had a severe bout of pancreatitis. Took months for me to feel like I was making headway.

Doing my best to stay on top of this but it is overwhelming at times. I try to push thru the chemo effects cuz I like being busy AND I feel better if I’m useful and productive. Can’t imagine actually working while dealing with this and those of you that do are my heroes!

The original article link says:

1) FOLFIRINOX is composed of 5-FU, leucovorin, irinotecan and oxaliplatin.

2) NALIRIFOX is ... a combination of THREE previously approved pancreatic cancer drugs, liposomal irinotecan (Nal-IRI or Onivyde®), plus 5 fluorouracil (5-FU)/leucovorin and oxaliplatin.

Statement (2) seems to conflate "5 fluorouracil (5-FU)/leucovorin" as one drug, when they are actually distinct, as far as I can tell, with leucovorin being = folinic acid (same as the FOL in Folfirinox). Sounds like 4 drugs to me.

Lancet lists the NALIRIFOX ingredients and ratios here:
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01366-1/fulltext
- liposomal irinotecan 50 mg/m2
- oxaliplatin 60 mg/m2
- leucovorin 400 mg/m2 (a.k.a. Folinic acid)
- fluorouracil 2400 mg/m2
which is 4 drugs according to my math

This article compares original and modified Folfirinox:
https://jgo.amegroups.org/article/view/20784/17301
Standard FOLFIRINOX consisted of
- Oxaliplatin 85 mg/m2 IV infused over 120 minutes
- Irinotecan 180 mg/m2 IV infused over 90 minutes
- Folinic Acid 400 mg/m2 IV infused over 30 minutes (a.k.a leucovorin)
- 5-Fluorouracil 400 mg/m2 IV in bolus infusion and 5-Fluorouracil 2,400 mg/m2 IV in continuous infusion over 46 hours.

Modified FOLFIRINOX consisted of
- Oxaliplatin 50–85 mg/m2
- Irinotecan 60–180 mg/m2
- Folinic Acid 0–400 mg/m2 (a.k.a leucovorin)
- bolus 5-Fluorouracil 0–400 mg/m2 and continuous infusion 5-Fluorouracil 1,800–2,400 mg/m2.

So, it sounds to me like the main difference between NALIRIFOX and mFOLFIRINOX is just the replacement of old-fashioned Irinotecan with Liposomal Irinotecan.

I have no medical training, so forgive my confusion about why the creators of NALIRIFOX did their study comparing it against Gemcitabine + Abraxane when mFOLFIRINOX is already known to be superior to (G+A) and they could have done a perfectly comprehensible study with only one experimental variable against mFOLFIRINOX instead.

If NALIRIFOX is superior to mFOLFIRINOX, then great -- we have a new champion. If it's only shown to be better than G+A, which is already inferior to mFOLFIRINOX, what's the point?

I was also confused about the text citing NALIRIFOX as a treatment for metastatic PC. Shouldn't it also be considered an option in NON-metastatic PC, as mFOLFIRINOX and G+A already are?

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And just for clarity, I was a little thrown off by @stageivsurvivor 's comment "What makes THIS drug combination unique is the nab-Paclitaxel."

It's a little ambiguous whether "THIS drug combination" is referring to the new one (NALIRIFOX which seems to be touted as unique) or to the SoC treatment of Gemzar/Abraxane.

nab-Paclitaxel is the same thing as Abraxane, so in the above context, the G+A would be the 'unique' combination rather than the subject drug of this article (NALIRIFOX).

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In summary, I (lacking better biochemical understanding) am not yet impressed by this development.

As an academic side curiosity, I didn't get as much benefit from mFOLFIRINOX (which contains the platinum-based drug Oxaliplatin) as I have from G+A plus the platinum-based drug Cisplatin. Platinum-based drugs are believed to be effective in patients with ATM mutations (as I have). It's not an apples-to-apples comparison because of possible synergy with all the other drugs, but I wonder if the Cisplatin cocktail has worked better for me because of Cisplatin being a smaller molecule than Oxaliplatin, possibly penetrating better into the tumor. Fewer side effects as well. 🙂 I'd like to see a study of mFOLFIRINOX against "FOLFIRINcis" (Folfirinox replacing the Oxaliplatin with Cisplatin).

Here is a reason why the NAPOLi trial was done comparing Nalirifox to Gemzar/Abraxane first and not to Folfirinox. The first goal of a clinical trial is to prove an investigational new drug or drug combo (IND) is more effective then a currently approved drug. If it is, it gets approval-if not, then it doesn’t unless it shows it is at least equivlent in effectiveness with less side effects and adverse reactions are of a lower grade than the drug or regimen it is compared against.

If Nalirifox was first compared to Folfirinox and found it was not better, then it wouldn’t receive approval. However, if it was proved first that Nalirifox outperformed G/A in a number of metrics and side effects and adverse events were better, it could be approved and patients could begin gaining benefit. Now the next step is in a comparison with Folfirinox to see if is better. Some of those questions might already be answered looking at the Waterfall plots and Meier-Kaplan data and other statistical metrics in comparing with G/A. Those same metrics already exist between Folfirinox and G/A and can be interpreted as to whether study is warranted now between Nalirifox and Folfirinox.

With respect to efficacy of Oxaliplatin and cis-platin, there were comparison studies done more than a decade ago comparing the two. Oxaliplatin was found to be more effective in providing more overall survival and progression free survival but does have more neurotoxicity. Between 30-35% of treatment cohorts respond to either Folfirinox or Gemzar/Abraxane. It could just as well have been that you did not respond to 5-FU and not the Oxaliplatin.

(m)Folfirinox is still the gold standard and used first in those patients age 70 or younger and a low ECOG physical assessment score of 0-1. When it begins to wane, Gemzar/Abraxane is the next first-line combination regimen used. If that doesn’t work or effectiveness decreases, Nalirifox gives the oncologist a third, first-line drug to use.

In clinical studies, Nalirifox was shown to be statistically more effective than Gemzar/Abraxane. Clinical studies on how it compares to (m)Folfirinox are not yet available. What makes this drug combination unique is the nab-Paclitaxel. It uses the Onyvide formulation which is liposome-coated nano particles of nab-Paclitaxel which get deep into the malignant cells and the “delivered payload” of drug is released. It results in greater and longer effectively.

A misconception people often have is in trying to understand clinical trial statistics. When it gets reported that the median of 3.4 months was observed, that doesn’t mean everyone is going to only get 3.4 months. There are patients who can be “statistical outliers”- those that received far greater benefit. Everyone has an equal chance of falling on the median, being to the left of it (shorter benefit) or to the right (long-term survivors).

Another thing to consider is that the study used the metric of 12 cycles (6 months). When (m)Folfirinox was compared to G/A, a 6 month period (12 cycles (m)FFX to 6 cycles G/A was used. Consider those patients who advocated for receiving more than 12 cycles of FFX. I did 46 cycles with 24 being FFX. Camille Moses did 37 cycles. Both of use are marking 12 years survival of stage IV disease. We advocated for more aggressive chemotherapy and far exceeded the median that was based on only doing standard of care 12 cycles.

There are other long-term patients whose stories are documented on PanCan.org, LetsWinPC.org. seenamagowitzfoundation.org and other sites. If you do standard of care, don’t expect more than standard results. I was physically strong and otherwise healthy and why I spoke up and advocated for going beyond standard of care.