Updates: Instagram, plus PI3K Inhibitors

Just a couple of quick notes today:

First, a final reminder that I'll be on Instagram Live tonight with @MyelomaChick at 7:00pm ETA. We're going to talk about what life is like as a blood cancer patient. If you can, tune in. Feel free to leave comments while we're on. And if you can't make it tonight, I'll send a link where you can watch the recording on YouTube.

Hope you can make it.

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Second, more bad news for PI3K Inhibitors. This week, the makers of Umbralisib decided to withdraw from the market -- in other words, Umbralisib won't be available anymore, and the company that makes it is likely to stop making treatments for cancer. 

The bigger picture for PI3K Inhibitors doesn't look good at all. Today, a meeting is scheduled for the FDA to talk about this type of inhibitor, and they are likely to announce some changes in the way they are approved. If you've been reading this blog for the last few months, you know that there have been issues. 

One big issue has been the way that PI3K inhibitors have been approved. They have received accelerated approval from the FDA. Usually, a treatment goes through steps -- developed in a lab, tested on animals, then on a small number of people in a phase 1 trial to figure out the most effective and safest dose, then a larger phase 2 trial to make sure it is as safe and effective as it seemed, and then a phase 3 trial where it can be compared to other treatments currently available to see if it offers something better than what we already have.

Accelerated approval was developed by the FDA to get treatments to patients more quickly. It can be several years between a phase 2 trial and a phase 3 trial, and if the phase 2 trial shows enough evidence that a treatment is safe and effective, then approval can be given -- the treatment can be offered to patients, as long as the maker agrees to run a phase 3 trial to confirm that the treatment really is safe an effective. The maker gets to start making money a few years sooner than it would have without the accelerated approval.

The potential issue with accelerated approval is that going through the full process, including a phase 3 trial, means more time to discover problems like long-term side effects that don't come out right after a phase 2 trial. 

And that's what has happened with PI3K inhibitors. The FDA issued a report before today's meeting that points out the problems that PI3K Inhibitors have shown. The big one -- even though PI3K Inhibitors improve Progression Free Survival in blood cancer patients, the data from six clinical trials actually shows a decrease in Overall Survival. In other words, compared to other treatments, patients who take these inhibitors have a better chance at going longer in between treatments, but also a better chance of dying sooner. That has never happened before with a cancer treatment, says the FDA.

Let me be very clear here -- this shouldn't be taken as meaning PI3K Inhibitors are going to kill you if you take them. It's more likely that a small number of patients had bad reactions to the treatment and the side effects caused premature death. That's going to mess up the statistics. I've been saying over the last few months that I have been very surprised to hear so little from oncologists about this situation. They're finally talking a little bit. One well-known blood cancer specialist, whom I respect very much, tweeted that he thought PI3K Inhibitors still had a place in blood cancer treatment for a lot of patients. He's probably right -- if anyone would know, it's him.

But the FDA has a responsibility to make sure patients are safe, which we should all be grateful for.They are probably going to make a few changes in the way approvals are made. First, no more accelerated approvals based on phase 2 trials. They will want phase 3 randomized trials. That means a large group of patients, all of them as similar as possible, in terms of their disease and the treatments they have had already, with half getting the new treatment and the other half getting a treatment that has already been approved. Direct comparison. It's the best way to run a trial, and to see if the new treatment is really safer and more effective than the older one. 

Second, the FDA is probably going to want more dosing experiments in phase 1 and phase 2a trials. That means having patients take different amounts of the treatment to see which amount is effective without causing too many harmful side effects. Do that in early phases of the process, and you have fewer problems in the later ones.

Finally, the FDA will probably put more emphasis on Overall Survival. There is a trend in using "surrogate endpoints" in trials -- basically saying, "If PFS is improved after 2 years, then Overall Survival must be improved after 5 years, since that's how it's always been." With the FDA saying this is the first time a cancer treatment has improved PFS but not OS, we'll probably see them asking for more OS data and not surrogate data that is a substitute. That just doesn't hold anymore.

The downside of all of this is that we have lost a bunch of treatment options. Not all of them -- Copanlisib is an effective PI3K Inhibitor, and still safe and effective, and still available. And Zandelisib is making its way through the trial process. They are likely to be told that they will need to do a randomized, phase 3 trial, instead of getting accelerated approval. I hope they decide to take that step -- they seem to have a good product that has taken steps cut down on side effects. But if they make the business decision to withdraw, then we will lost out on that option, too.

The upside, though, is that any treatments that do make it through the phase 3 process will be good treatments, with data that supports their safety and effectiveness. And that's better for us, in the end -- fewer treatments, but safe and effective ones.

(That was not nearly as brief as I had planned, but it's important to talk about. Hope to see some of you on Instagram tonight. Stay well.)