I hate to keep writing with bad news, but this seems too important not to. Another PI3K inhibitor -- this time it's Umbralisib -- has run into problems. Clinical trials for the treatment have been suspended because of an increased risk of death in a phase trial.
Just to remind you of a few things:
There are currently 4 different PI3K inhibitors approved for Follicular Lymphoma. In the last couple of months, two of them -- Idelalisib and Duvelisib -- have been withdrawn voluntarily because the makers decided it would be too difficult to get final approval by the FDA. Another one -- Parsaclisib -- was withdrawn before it went through the approval process, for similar reasons. All of them were, essentially, business decisions. For whatever reason, it would take more money and/or effort to get final approval and make enough money than was worth it.
The Umbralisib issue is a little different. While it hasn't been taken off the market, clinical trials have been stopped. The trial, called the UNITY-CLL trial, is actually for patients with a different type of blood cancer, Chronic Lymphocytic Leukemia. It's similar to other indolent, slow-growing blood cancers like FL. Similar enough that all FL and Marginal Zone Lymphoma trials for Umbralisib have been stopped, and the FDA is recommending that FL and MZL patients who are currently receiving it should talk to their doctors about risks.
The trial is actually four-armed, meaning patients were given one of four different treatments, including Umbralisib on its own. The results of the trial, in terms of effectiveness, showed some good news. But the increased risk of death was problematic (obviously).
You can look at the links above for some more of my thoughts about this situation and what it means for us as FL patients (keeping in mind that I'm not a cancer researcher or a doctor -- these are just the non-expert opinions of a patient who does a lot of reading. Talk to your own doctor about any concerns you have about any treatments -- that's always the best choice).
But I'll add one more thought to all of this. The three inhibitors that have already been approved went through some form of an accelerated approval by the FDA. The FDA began using accelerated approval a few years ago, in response to many in the cancer community (and other health communities) being frustrated with how long it was taking for new treatments to be approved. The program allows a treatment to be approved based on the results of a small phase 2 trial. But the understanding is that a larger phase 3 trial would need to be conducted and finished, and if the results hold up, then final, permanent approval would be granted.
But there are also many in various healthcare communities who don't like the accelerated approval process. Sometimes the process relies on what are called "surrogate endpoints." This means that, instead of looking at something like Overall Survival after 5 years, the developers of the treatment can use a different statistic, like maybe 2 year Progression Free Survival, as a substitute. This is done when another study has shown that enough patients who made it to that 5 year OS (maybe the first ones enrolled in the trial) also made it to 2 year PFS. So the assumption is that the approval can be given based on that 2 year statistic, and then things will be checked again at 5 years to make sure that 5 year statistic really did match up.
My guess is that there might be more attention paid to accelerated approvals. That might end up being an issue with Umbralisib, if it's shown that the increased risk of death came later on. But it could also end up being an issue with the other inhibitors. Idelalisib was withdrawn because there weren't enough people who signed up for the phase 3 trial. that doesn't necessarily mean anything related to how effective or safe the treatment is. But it does say something about how resources are used. Researchers might think more carefully about how much effort, time, and money to put into a treatment if there's little chance it will be used by doctors.
The whole treatment development process is huge, takes many years, and lots of money, and its far more complicated than I can fully understand. But it seems to me that having 3 of 4 approved treatment options run into big problems says something about the process, even more than it does about the treatments themselves.
And what's especially frustrating is that I really haven't seen a lot of discussion about all of this online. Maybe that will come soon. I'll keep an eye out for those kinds of commentaries (maybe one of those video series that I come across pretty frequently), and if any of you see a Lymphoma expert with an opinion on all of this, please let me know.
I'll try to find something more positive to say next time. But, gosh, they're making it hard.
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