I know I (sort of) promised to stop giving bad news about PI3K Inhibitors, but I can't help it if they keep giving me things to talk about. I'll try to balance it with some good news this time, though.
You really haven't needed to have been reading this blog for long to know that PI3K Inhibitors for Follicular Lymphoma have really been having troubles over the last few months. In December, Duvelisib was taken off the market (for FL) by the manufacturer for "business reasons." It was given accelerated approval by the FDA based on a phase 2 clinical trial, but a larger, longer phase 3 trial was basically seen as not worth it. Pretty much the same thing happened in January with Idelalisib. It was trying to conduct a phase 3 trial after getting accelerated approval, but was having trouble getting patients enrolled, which they blamed on Covid (though, given the troubles that other PI3K inhibitors are having, I think it was probably more than that).
Then later in January, the manufacturers of Parsaclisib withdrew from the FDA approval process. This one had not been given FDA approval (unlike the other two), but was in the process of getting accelaterated approval from the FDA when they also made a "business decision" to not go any further in the process.
Then in February, the FDA stopped all clinical trials involving Umbralisib because of a possible increased chance of death. Umbralisib had already been approved, and it looks like this was done out of an abundance of caution, but it just added more bad news to the treatment class.
And just to make sure we didn't break the streak of monthly bad news, this week FDA "discouraged" the maker of the PI3K inhibitor called Zandelisib from seeking accelerated approval. They had conducted what seemed like a successful phase 2 clinical trial (in face, I wrote about it a few weeks ago in an attempt to be positive about PI3K inhibitors). But the FDA told them that the limited data from that small study wouldn't be enough for approval, and suggested that a larger phase 3 trial would be necessary (something they had already begun doing). The FDA also suggested they look more into dosing (how much each patient is given during treatment). The company suggested that the size of the phase 2 trials isn't necessarily the problem. Instead, they are looking for randomized trials, rather than single arm trials. In other words, instead of giving the treatment to 50 patients and then comparing it to a study that was conducted a few years ago, the FDA wants a study with a direct comparison (100 patients in the study, with 50 getting Zandelisib and 50 getting some other treatment). Randomized trials are much more reliable than single-arm studies, since the researchers can control who is in the trial and make sure every patient is as alike as possible. But it takes more time and money to conduct that kind of trial.
For now, the plan is to go forward with the phase 3 trial. Zandelisib might very well end up being approved in the future. The phase 2 trail looks very promising. But they might also decide to stop, for "business reasons."
When I wrote about Parsaclisib, I mentioned the problems with accelerated approvals by the FDA, and how that seemed to be a common issue with PI3K inhibitors. The comments from the maker of Zandelisib say that the FDA's thinking has "evolved" when it comes to accelerated approval for PI3K inhibitors. In other words, we're probably not going to see any more accelerated approvals. That's too bad, in some ways, since it meant getting access to new treatments much sooner. But good, too, in a way, if it means safety will be less of an issue.
I'll keep you updated on any other bad news that comes this way.
(I'm still confused that there is so little discussion of this in the lymphoma research community. I'm waiting for the "What's the Future of PI3K Inhibitors for FL?" article in one of the medical journals. Nothing I've seen so far.)
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I promised good news, too, and this is what I had planned to write about all along:
The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has suggested that the the European Union approve the use of the CAR-T treatment Kymriah (also known as Tisagenlecleucel), for patients with Relapsed or Refractory (R/R) Follicular Lymphoma who have already received two lines of systemic therapy.
The approval is based on the results of the phase 2 ELARA trial, which involved 94 patients. In the trial, 86% of patients had a response, including 69% who had a Complete Response. The response was durable -- 87% of patients who experienced a CR still had a response after nine months.
The Safety profile was also very positive. While 49% of patients experienced cytokine release syndrome (CRS), none were very serious (grade 3 or higher), and only 3% of patients had grade 3 or 4 neurological side effect.
Results from this trail were reported at last year's ASCO conference, and caused a lot of excitement.
It would be pretty wonderful if our friends in the EU had CAR-T as a treatment option. The European Commission plans to review the CHMP recommendation and make a final decision in about two months. Of they approve, CAR-T will be available to R/R FL patients in all 27 EU countries, plus Iceland, Norway and Liechtenstein.
I'll keep an eye out for news about this, too. I look forward to sharing some happy news when I can.
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