A Future for PI3K Inhibitors?

In my reading about cancer (which I do way more of than I would like), I've been seeing some articles about PI3K Inhibitors. Coincidentally, the journal Blood and Lymphatic Cancer: Targets and Therapy just published a review of PI3K inhibitors for CLL and Indolent Lymphomas. As a review article, it isn't offering any new research. It's more of a "here's where we are" article. But it's been a little under a year since the FDA pulled its support for PI3K Inhibitors for Follicular Lymphoma, so it's worth thinking about their possible future.

The article is called "PI3k Inhibitors in NHL and CLL: An Unfulfilled Promise," and I think that's a really great way of describing this class of treatments. One of the things that always struck me about this type of treatment was how excited oncologists got when they discussed it (at least in the videos I have seen, many of which I have posted). In theory, it's an excellent treatment. "Inhibitors" are things that inhibit, or stop something from happening. PI3K inhibitors stop an enzyme called Phosphatidylinositol 3-kinase. This is an important part of a chain of enzymes and proteins that turn switches on and off in a cell that allow the cell to grow and live. When something does wrong with the chain, the cell refuses to die. That's what cancer is, in its simplest form -- a bunch of cells that refuse to die. A PI3K Inhibitor stops that process. That's exciting -- especially since some of them were given as pill that a patient could take every day on their own.

The discovery of that chain of events, and the role of Phosphatidylinositol 3-kinase, was very important for Follicular Lymphoma research, since PI3K was especially important in B cells (the cells that become cancerous in FL). Several PI3K Inhibitors were developed, with slight but important differences between them.

Eventually, four of them were approved for Follicular Lymphoma patients. Because they showed promise in early trials, and were treating cancer in new ways than treatments that were already available, they were given accelerated approval by the FDA. This meant that they could be given to patients based on the results of a small phase 2 clinical trial. However, this approval came with the understanding that a larger phase 3 trial would be necessary for full approval.

And that's where the problems started showing up. You can go back and read what I wrote about the PI3K Inhibitors having problems and then having their temporary approvals taken away by the FDA -- Duvelisib in December 2021, Idelalisib in January 2022, Parsaclisib also in January 2022, and Umbralisib in February 2022.  then in March 2022, the FDA discouraged the makers of Zandelisib from seeking Accelerated Approval.

The reason for all of this? Some of the phase 3 trials, which were supposed to confirm the good results from the smaller phase 2 trials, did the opposite -- they showed some new problems with side effects, including an decreased Overall Survival. In other words, instead of keeping people alive longer, there were a greater number of people dying in the trial than had died in the trial that they were comparing themselves to.

The FDA's solution to this was to cancel its temporary approval and insist that full approval would only come with a phase 3 Randomized Control Trial. What does that mean? The trials that had been set up were single-arm trials. A number of patients were given the treatments, and the results were compared to a trial from another treatment (the trial probably took place years before). The makers of the Inhibitor could then say, "See? Our treatment is more effective and/or safer than that other one." A Randomized Control Trial has two arms -- instead of looking back at the trial for another treatment, it's set up so that half the people in the trial get that other treatment directly, and half get the PI3K Inhibitor. This way, there can be more control over which patients are in the trial, and a direct comparison can be made. 

But RCTs are expensive, time-consuming, and complicated. They are also the best way to know if a treatment is safe and effective.

However, one by one, the makers of the PI3K inhibitors announced that they were withdrawing their treatments. This was all happening at the height of the Covid-19 pandemic, and they were having trouble getting patients to enroll in their trials. Most decided that the extra expense and time wasn't going to be worth it. It seemed like they had planned on making money and recovering their research costs right away, and they weren't able to. Personally, I think there was too much competition as well, with too many PI3K Inhibitors on the market without enough to distinguish between them. 

Business decisions aside, there were still problems with the treatments that needed to be overcome. As this article says, there are still some possible changes to PI3K Inhibitors that could make them safer without being less effective.

One is to change dosage. When they were approved, most had a daily dosing schedule -- the patient took a pill every day. But that constant treatment meant that their immune system was always suppressed. This led to more infections, some of which were fatal. Zandelisib was designed to get around this, with a different dosing schedule, with the patient getting the treatment for a couple of weeks, and then stopping for a couple of weeks. This seemed like it was helping with side effects. But its makers decided that it would be too expensive to continue to develop the treatment, and stopped all of its research (except in Japan). 

So that's where we are -- an "unfulfilled promise."

It's too bad. From what I read, this does seem to be a business decision more than a medical decision -- the investment just isn't worth what it would cost to make the treatment safer and more effective (or at least, to find out if it can be made safer and more effective).

But the authors of the article still seem to cling to a small amount of hope that maybe something can come of it. My hope is that a small company will take this on, one that hasn't already spent millions of dollars, and will find ways to improve on this promising treatment. 

I also think that failed research is never a failure, and that even if these treatments are never resurrected, researchers will still have learned something that will make some other treatments better. 

We'll move forward, one way or another.

Goodbye to the Last PI3K Inhibitor

Well, the last of the several PI3K Inhibitors for Follicular Lymphoma is no more. The manufacturer of Copanlisib voluntarily pulled it off of the market yesterday.

It's been a while since I wrote about the sad saga of PI3K inhibitors for FL. They showed lots of promise in early trials. They work by inhibiting, or stopping, an enzyme called PI3K, or Phosphatidylinositol 3-kinase. PI3K is a part of a chain of enzymes and proteins that turn switches on and off in a cell that allow the cell to grow and live. So when one part of that chain has a problem, the cell refuses to die which is what cancer is -- a bunch of cells that refuse to die. A PI3K inhibitor stops that process so the cell can die as it is supposed to, after doing its job. 

And the PI3K inhibitors that were tested and approved did a pretty good job of stopping the things they were supposed to stop. But they ran into a bunch of other problems, too. One of them was safety. Side effects were more severe than expected, including some related to digestion. (One reason Copanlisib may have lasted as long as it did was because it was intravenous, rather then the once-a-day pill like the others. There was some speculation that helped Copanlisib bypass the stomach issues.) But another trial also found that there was a slightly higher risk of death among patients taking the inhibitor than there was in a comparison group. Not good at all.

I've written a lot about these in the past, so if you want to read more, you can go to this post, and then look for the links to take you to previous posts about the individual inhibitors and the problems they had.)

It seems to me that a lot of the problems with PI3K inhibitors came from the accelerated approvals they got from the FDA. (And as I give you this opinion, I will remind you yet again that I am not an oncologist, or a cancer researcher, or a pharma or FDA employee, or anyone else who is trained to know about these things. I'm just a cancer patient who reads a lot.)

The problem with the accelerated approvals was that, like all accelerated approvals, they were based on small phase 2 clinical trial results. The approval allowed the developers to start marketing the treatment, with the idea that a larger phase 3 trial was necessary for final approval. Those results were mixed. Copanlisib, for example, says that their phase 3 trial did not meet its primary endpoint -- the results did not show what they had hoped to show. No more details than that, but that's the issue.

Another problem, it seems to me, was that there were so many PI3K inhibitors developed at once. They were all slightly different -- different enough that the FDA approved them all.  But in practical terms, they were all competing for patients to join their phase 3 trials.  So a couple of them voluntarily pulled their inhibitor from the market because they couldn't get enough patients. The pandemic was a factor there, too, but having so much competition couldn't have helped.

With Copanlisib being withdrawn, that looks like the end for PI3K inhibitors for Follicular Lymphoma. I suppose it's possible that someone could try to develop a new one, or improve upon those that already exist, or keep trying them in combination with other treatments. But with the amount of time and money that goes into research, testing, and marketing for a new treatment, that doesn't seem likely to me.

Which is a real shame. PI3K inhibitors were one of those treatments that got oncologists really excited, based on early trial results. I always hate to see a treatment option be taken off the table.

I try to take hope in knowing that there are a bunch more treatments in the pipeline. Not all of them will get past stage 1 or stage 2 trials. Some of them might end up like these above, with early promise that's never fulfilled. But maybe a few will be available to us in the next few years.

All the more reason to get to those ASH abstracts.....  

Some Final Thoughts on PI3K Inhibitors (for now)

 One more post about PI3K Inhibitors, and then I'll do my best to stop writing about them for a while. 

(But I make no promises.)

OncLive has a new video series on indolent lymphomas, and it includes a couple of brief episodes on Follicular Lymphoma. One in particular caught my eye -- "PI3K Inhibitors in Relapsed/Refractory Follicular Lymphoma." Conveniently, it includes a transcript in case you want to translate it or you have trouble viewing the video.

The video series features several Lymphoma experts giving their take on recent research on several different types of lymphoma. 

One important detail --  the first video in this series was posted in December, so my guess is that the whole thing was put together during the ASCO conference, and is short pieces are being released every week. That means they discuss PI3K Inhibitors before the various FDA actions had taken place.

The most interesting thing to me is that they focus on Copanlisib. As I have been discussing, there have been four PI3K inhibitors approved by the FDA for Follicular Lymphoma, and three of them have run into problems of different kinds. The fourth one, so far relatively trouble-free, is Copanlisib. As the panelists in the video point out, there are some differences between Copanlisib and the other three. One is the way it is administered. The other three are given in pill form, but Copanlisib is given intravenously, once time per week. Taking a pill at home is a whole lot easier than going for an infusion once a week (Quality of Life matters!), but the pill form might also lead to some gastrointestinal side effects that an infusion doesn't have.

(As always, nothing is easy. Every treatment has side effects, and every treatment is going to affect how we live our lives in some way.)

They also briefly discuss the CHRONOS trial, which looks at the combination of Copanlisib and Rituxan. The results seem very positive, and shows again that there seems to be more success with combinations that with just PI3K inhibitors alone. 

The lesson here, for me, is to remember that problems with some treatments within a group or class does not mean that every treatment in that group or class is in trouble. One of the positive things to come out of the troubles with PI3K inhibitors (and I'm always looking for positives) is that researchers may learn to deal with side effects in the next generation of inhibitors. Ideally that means more demand for them, so "business decisions" don't cause treatments to be removed from the market.

One bit of good news in that regard (which I have been aware of since ASCO) is that there are some potentially "better" PI3K inhibitors coming soon. For example, another PI3K inhibitor called Zandelisib is moving its way through trials and toward FDA application. One of the things that makes Zandelisib different from other inhibitors is its dosing -- how often and how much a patient takes. Like some of the others, it is given in pill form. But instead of being taken every day, patients take it for a number of days and then stop taking it for a number of days. This allows the body to recover, especially the immune system. Numbers are good -- effective, with manageable side effects.

Will Zandelisib (or another PI3K inhibitor under development) be a good replacement for the PI3K inhibitors that are no longer (or may soon no longer) be available? Hard to say. I'm always enthusiastic about having more options available for us, especially when they are more effective and safer than what has come before. So I wish Good Luck to everyone working on an FL treatment.

But the bigger point, as I said, is that problems with some treatments doesn't mean problems with all treatments. 

(I promised last time that I'd be more positive. I think I did OK.)

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.)

Good News (for the EU) and Bad News (for PI3K Inhibitors)

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.

 

ASCO: Copanlisib for Follicular Lymphoma

It's that time of year! ASCO abstracts are out!

In early June every year, the American Society of Clinical Oncology (ASCO) holds its annual meeting. It's a big meeting, meant for clinical oncologists -- the people that we see in their offices -- so the research that gets presented is usually pretty practical. It's a meeting for oncologists of all specialties, so there aren't always as many Follicular Lymphoma presentations as there are at a conference like ASH, which focuses on blood cancers. But because it's a big meeting, the presentations are usually significant.

I like to preview some of the more interesting sessions, looking at the abstracts for stuff that gets me excited. Once the conference happens, pharmaceutical companies and universities will start to send out press releases, bragging about their stuff (good clinical trial results, for example). Sometimes, the news is so good, they start talking about it weeks before the meeting.

And that happened this year (sort of). There will be a session called "Copanlisib in Patients with Relapsed or Refractory Follicular Lymphoma." That's good stuff, but even better is the news that the FDA has granted Priority Review to Copanlisib, based on the clinical trial results that are going to be discussed at ASCO.

So let's look at the ASCO abstract first. Copanlisib is a PI3K inhibitor.There are lots of different inhibitors out there for cancer, and for FL. Haters hate, as they say, and inhibitors inhibit -- they keep something important from happening in a cell. Different inhibitors focus on different things.

PI3K inhibitors focus on the PI3K enzyme, which is needed for a cell to do some important things like grow normally. When there is a problem with the pathway, the cell grows uncontrollably (resulting in cancer). By inhibiting the enzyme, the uncontrollable growth is stopped.

(There's more to it than that -- it involves something called the PI3K/AKT/mTOR pathway, which is really important to cell growth. But we'll just keep it simple. Let's all agree that this is a really important thing to target with an inhibitor.)

Another really important thing about Copanlisib that makes this a big deal is that PI3K actually comes in a few different forms (called isotopes). Most inhibitors only target one of those forms -- Copanlisib targets two of them.

So, the ASCO presentation is going to discuss the results of a phase II clinical trial. A total of 141 patients were in the trial, but the 104 with Follicular Lymphoma are the real focus. These patients were relapsed/refractory (their last treatment didn't work, or stopped working), and had at least 2 prior treatments.

The results were impressive -- Overall Response was 58.7% (14.4 % had a Complete Response and 44.2% had a Partial Response), with another 33.7% having stable disease. The median duration of response was just over 1 year.

Side effects were "manageable," and included diarrhea, reduced neutrophils, fever and fatigue. There were 6 deaths in the group, with "3 attributed to Copanlisib" (a lung infection, a respiratory failure, and a blood clot).

Even with those problems, the researchers point out that Copanlisib did not show some of the problems that other PI3K inhibitors have shown, including infections, colitis (inflammation of the colon), and hepatic enzymopathy (problems with liver enzymes).


Which brings us to the big news about the FDA granting Copanlisib a Priority Review designation. This designation means that the FDA plans to take action within six months (a regular review takes 10 months). Getting the designation means that the FDA thinks it is important that the treatment becomes available quickly, because it's doing something that other treatments aren't doing.

In this case, it seems like the combination of effectiveness and safety is what makes this a better option than some others that are available. I'm guessing that the lack of problems that get seen in other PI3K inhibitors was a big factor.

The question that I had (and that you might have too) is something like "Wait -- didn't it say that 3 people died?" Yes, and that does seem to be downplayed in the reports that I have seen about the FDA approval (though it is certainly mentioned in the ASCO abstract).

It's important to remember that this is a fairly narrow FDA approval, and that is still pending -- it is only for FL patients with refractory/relapsed disease, and who have had at least 2 prior treatments. In other words, this is potentially being approved for patients who are running out of options. So the deaths among trial participants might not be quite as significant. If this were an approval for a first-line treatment, there would be much more attention paid to those unfortunate "adverse events."

So, there's your first ASCO preview. I'll keep looking at the abstracts for more interesting news. Stay tuned.

ASCO: PI3K Inhibitors

More from ASCO.

PI3K Inhibitors have been an area of excitement in blood cancers for a few years. Like all inhibitors, PI3K inhibitors stop something from happening. Cancer cells go through a series of paths or steps to grow and live. Researchers have been able to identify what those paths are, and then how to interrupt or inhibit those paths.

PI3K stands for Phosphoinositide 3-kinase, which is a group of enzymes that are necessary for cancer cells to live and grow.

There are actually three PI3K inhibitors that have been approved (by the FDA) for Follicular Lymphoma.  Duvelisib was approved in 2018 for relapsed/refractory FL, and Copanlisib was approved about a year before that for relapsed FL. Idelalisib was approved in 2014 for relapsed FL.

There were a couple of nice presentations at ASCO this year that dealt with PI3K inhibitors.

One was about Copanlisib: "Long-Term Follow-Up of Patients (pts) with Relapsed or Refractory (R/R) Follicular Lymphoma (FL) Treated with Copanlisib." Interestingly, the reserach deals with both relapsed (a treatment worked for w while, then stopped working) and refractory (a treatment didn't work at all) patients.

This research looked at the patients who were in the trial that resulted in the FDA approval. 104 patents in the trial were given Copanlisib. In the current analysis, 59% had a response, with 20% having a Complete Response. The median for how long the response lasted was a little over a year. The CR numbers are higher than they were for the first analysis -- it was under 15% at that point. That included patients with "higher grade disease." Side effects were manageable, with no new long-term effects popping up after two additional years of study.


It's nice to see long-term results, even after approval.

Another presentation focused on a PI3K inhibitor called ME-401. This one is so new that it doesn't even have a cool name yet. The presentation gave the results of a phase 1b clinical trial. As part of the trial, 48 Follicular Lymphoma patients were given ME-401, by itself or with Rituxan. After a  median follow-up of about 9 months, 28 of the patients remained in the study. Responses were good, with 79% of patients of patients who had ME-401 getting a response, and 78% of patients getting the Rituxan combo getting a response. Patients were either given treatment every day, or for one out of four weeks. Those on the one week out of four had fewer side effects.

This is a very early study, with not many patients in it -- that's how stage 1 trials work. But they are good results, even if they're early, and we may see more of this treatment in the next couple of years, if they are able to move onto phase 2 trials.

It's all a nice reminder that, even if a first treatment doesn't work as well as we'd hoped, we have a lot of options for second and third treatments.

Advancements in FL Treatment (Especially PI3K Inhibitors)

A little follow-up from my last post, which was about PI3K Inhibitors discussed at ASCO:

The American Journal of Managed Care did a special issue on PI3K Inhibitors in Follicular Lymphoma. Very timely.

There are four articles in the special issue. the first is called "Follicular Lymphoma: A Review of Mechanisms, Risk Factors, and Unmet Needs." It's a decent introduction to FL, though its purpose is to go through a lot of information. I think it needs to be read with a very careful eye. (It would be easy to misread this, for example, and think FL has two options -- either watching and waiting, or immunochemotherapy. there are, of course, lots of other options. It's a good intro for the doctors it was written for, but it doesn't present everything it could or should.

Skip it and go to the next article, "The PI3K Pathway: The Benefits of Dual Inhibition in Follicular Lymphoma." This one does a better job of laying out treatment options for FL, and where PI3K Inhibitors (Copanlisib and Duvelisib) fit into the picture. It's as good a summary of the research as you'll find.

The other two articles are interviews with FL experts. The first is "Advancements in Follicular Lymphoma Treatment: Where We Are and Where We Are Going. A Q&A With Andrew M. Evens, DO, MSc." Dr. Evans discusses current treatments for FL, especially PI3K Inhibitors. In some ways, it repeats what the previous article said, but in easier-to-understand language. It also gets into how one doctor would use them on actual patients. Dr. Evans also gives some thoughts on where FL research should go in the next few years. One area is paying more attention to Quality of Life -- and I am in total agreement.

Finally, there is "Evolving Population Health Strategies for an Expanding Treatment Spectrum A Q&A With Sheila M. Arquette, RPh." This article focuses on managed care, which is, of course, the whole focus on the journal it appears in. Managed care is a system of healthcare where a manager has some influence over treatment, making sure it is likely to work (statistically) and that the cost is worth the benefit. So while this article doesn't get into the treatment of FL the way Dr. Evans' interview did, it does provide a pretty fascinating look into how decisions are made by the people who have to pay for them. At its best, managed care reduces the cost of treatment while increasing its effectiveness. Patients don't always see the decisions in the same way. I'll leave it at that.

The special issue is definitely written for a particular group of readers, but it does give some additional insight into how FL gets looked at by people other than patients. That's pretty valuable.

Accelerated Approval for ME-401

I'm certainly paying attention to COVID-19 (and still working through my own anxieties about it), but I'm not sure I have a whole lot more to say about it than I've already said. Thinking and reading about kind of puts me in a holding pattern. I'm focusing on the present, trying to take things day by day.

But, at the same time, I need to look ahead. Hope is all about looking ahead, isn't it? Recognizing that things aren't necessarily great right now, and wishing that the future will be better?

With that in mind, it's time to get back to some Follicular Lymphoma news.

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The FDA has designated ME-401 for Fast Track consideration. I've seen a few notices for this online, but not really any details beyond what you'll see here.

The application is for patients with Relapsed or Refractory Follicular Lymphoma (their last treatment stopped working, or didn't work at all) who have received at least 2 prior systemic therapies (chemo, immunotherapy, etc.)

Fast Track designation by the FDA means the treatment is "serious" (likely to result in death if not treated), and the treatments "meets an unmet need" (it is shown to either be more effective or safer than what is available).  Fast Tracking might mean more frequent communication between the FDA and the company making the treatment, so that approval (if it comes) can come sooner.

There's no guarantee, of course, that approval will come at all.

ME-401 is a PI3K, or Phosphoinositide 3-Kinase, inhibitor. As you know from reading, inhibitors work by inhibiting, or stopping, processes that go on in a cell that make it cancerous. Inhibiting Phosphoinositide 3-Kinase means the treatment will stop one of the PI3K enzymes that tell cells to grow. When cells grow without knowing when to stop, they become cancer cells. PI3K inhibitors tell them to stop growing.

ME-401 is, in particular, a PI3K Delta inhibitor. There are four different PI3K enyzmes (alpha, beta, gamma, and delta), and a few different inhibitors that try to target one or more of those different enzymes. They are kind of a common treatment in the Follicular Lymphoma pipeline these days, with some familiar names -- Idelalisib, Duvelisib, and Copanlisib.

The Fast Track designation seems to be based on the results of a phase 1b trial, announced last fall. It's a small trial, with 55 Follicular Lymphoma patients (as of last fall, anyway). But the results were very promising, with 78% of patients in the trial responding. That seems more effective than other PI3K inhibitors.

It will be interesting to see hoe the FDA responds. A phase 1b trial is pretty small, so they may ask for more updated results (it has moved on to a phase II trial now, with 120 participants). I haven't seen a breakdown of how many of the responses were Complete and how many were Partial, which makes me think there were a lot more Partial Responses than Complete Responses. So maybe this ends up being one of those treatments that is taken every day for a year or two to help hold off the need for additional, more aggressive treatment? Certainly patients who would be interested in that.

The good news is, there is another treatment being considered for us. Not the best news, but good news. We'll wait for additional trial results, and more from the FDA, before we start getting especially positive about it.

But we can be hopeful.

Umbralisib Approved by FDA

More good news for Follicular Lymphoma patients:

A few days ago, the FDA approved Umbralisib (also known as Ukoniq) for FL patients who have tried at least three other treatments. 

Umbralisib is a PI3K inhibitor. It is the fourth PI3K inhibitor approved for Follicular Lymphoma -- the others are Idelalisib, Duvalisib, and Copanlisib, which I just wrote about last month). They all work by blocking, or inhibiting, an enyzme called PI3K, which is part of a chain of enzymes and proteins that tell a cancer cell that it's OK to keep growing. By inhibiting it, Umbralisib (like the other inhibitors) turns off that switch and allows the cell to die like a normal cell.

The four inhibitors work the same way in general, but PI3K takes a few different forms in the body, and the different inhibitors work on one or more of those different forms. So there isn't necessarily a lot of overlap between them. They all do a slightly different job.

(Which one is best for you and your Follicular Lymphoma, should you come to a place where a PI3K inhibitor might be an option? No idea. Talk to your oncologist. She or he will know.)

The approval was granted based on a phase 2 trial that included 117 FL patients. (It was also approved for a different type of blood cancer with patients also included in the trial.) The Overall Response Rate for the FL patients was 43%, with 3% of patients getting a Complete Response. The median duration of response was just over 11 months.

Those aren't spectacular numbers compared to some other treatments. One big difference, though, is that is might be safer than other PI3K inhibitors. While it does have similar side effects, it will not come with a "black box" label, which indicates very serious side effects. That said, it still has side effects, including diarrhea, fatigue, nausea, and increased risk of infection, among others. And 18% of patients reported in the trial had serious side effects, especially diarrhea and infection.

My guess (and this is, of course, not coming from a doctor or cancer biologist) is that Umbralisib will end up being used in combination with some other treatment, and those numbers for effectiveness will increase.

The good news, though, is that there is another arrow in the quiver -- another treatment option -- for lots of Follicular Lymphoma patients. And another reason for hope.

ASCO!

Well, it's finally here -- ASCO (the American Society of Clinical Oncology) annual meeting starts tomorrow and goes through early next week. I look forward to ASCO every year, because it's the largest gathering of oncologists in the U.S., and so many researchers and pharma companies wait for ASCO to make big announcements and show off great research results. Every now and then, one of the very exciting bits of news involves Follicualr Lymphoma. (But not often -- cancer research is usually about small steps forward rather than giant leaps that make the news.)

This year's conference is a little different. For one thing, it's back in person -- thousands of oncologists will travel to Chicago to talk to one another about cancer research. That didn't happen in 2020 and 2021, when the conference was virtual. 

One nice thing about the virtual meetings was that ASCO allowed patient advocates (like me) to register for free, so we could sit in on virtual presentations the same way that all of those oncologists were doing. It was a pretty wonderful thing -- not a lot of medical conferences allow advocates in, especially for free. (And even then, they define "advocate" in a particular way, usually as someone who works for an organization that helps cancer patients.) So, I have lots of love for ASCO. Even this year, with an in-person meeting, ASCO let me register for free for all of the online parts of the meeting. I won't get to see everything live, the way I would if I was there, but I do get to see a lot, and I'll be able to watch recordings after they were presented live. 

The other thing that's different this year is that abstracts were not released until just a couple of days ago. Usually, I can see the abstracts (the summaries of the presentations) a couple of weeks before the conference starts, and I can start writing about them then. (Look back at the May/June posts from the last 5 or 6 years and you'll see what I mean.) This year, there was very little time for that. I'm just getting around to it now.

So, as usual, over the next few weeks I'll write about some of the ASCO presentations that catch my eye. Maybe not the most important ones, but the ones that I think are most interesting or promising. (As I like to remind you all, I am not a doctor or a cancer researcher, I'm just a Cancer Nerd -- a patient who reads a lot.) And because this is such a large conference, there will be lots of commentary over the next few weeks from the actual experts, so I'll report on that, too.

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So one quick look at one of the abstracts for research on Follicular Lymphoma: this one is called "Efficacy and safety of zandelisib administered by intermittent dosing (ID) in patients with relapsed or refractory (R/R) follicular lymphoma (FL): Primary analysis of the global phase 2 study TIDAL."

It caught my eye mostly because I'm seeing it on the same day that I've seen a whole lot of news articles about the FDA officially removing approval for Umbralisib. 

Umbralisib is, of course, one of the PI3K inhibitors that will no longer be available to Follicular Lymphoma patients, whether because of an FDA decision or a decision by the company that makes them. (I've already written a lot about this in the last few months, as you probably know.)

Zandelisib came along at an unlucky time, ready to release results just as all of this PI3K bad news was happening. But Zandelisib is also different from other PI3K inhibitors in some ways, as this presentation shows.  One of the attractive things about some PI3K inhibitors was their oral administration -- instead of sitting in a treatment room for hours, you could take a pill (or two) every day. Unfortunately, a pill a day potentially led to some of the safety issues that had the FDA concerned. Zandelisib tried to deal with that through "intermittent dosing," taking time off from the pill to let the immune system recover. A small phase 1 study showed promise -- the convenience of a pill at home with decent safety and good effectiveness.

The ASCO study reports on a larger phase 2 study. Results are good, and confirm what was shown in the phase 1 study. The Overall Response Rate was 70%, including a 35% Complete Response Rate. It's still early to determine how long the response lasted (which is usually a good sign -- more then half is needed to achieve a median). As for safety, results were OK. About 10% of patients had to drop out of the study due to side effects, and some patients had digestive system issues and blood count issues that were grade 3 (more serious).

The numbers are good enough to warrant more study, either for Zandelisib on its own or in combination (the abstract mentions a phase 3 study of Zandelisib plus Rituxan). 

It's still hard to say where the company will go with this. I hope they will continue. With other PI3K inhibitors dropping out, it seems like there is space for an inhibitor to take their place. It's still too soon to know how oncologists are treating the whole PI3K issue, though I've heard some saying they still believe there is a place for these inhibitors in FL treatment. We will see what the reaction is to this presentation, I guess, and go from there.

More ASCO news and comments to come over the next few weeks.

 

Copanlisib for Follicular Lymphoma

A couple of Copanlisib-related items have come across my screen in the last few days, so I thought I'd share.

First, to remind you (since Copanlisib hasn't been in the news much lately, from what I have seen):

Copanlisib (also known as Aliqopa) is a PI3K inhibitor. PI3K is short for phosphatidylinositol-3-kinase, which is an enzyme that cancer cells depend on to grow and live. By inhibiting it, or stopping it, cancer cells don't get the signal that they should stay alive, and so they die. There are a few PI3K inhibitors approved for FL, but Copanlisib is thought to be better in one way -- it works on two of the three different forms of PI3K in the body (others only work on one of them). It has been approved by the FDA for relapsed FL patients who have tried at least two other treatments.

As I said, it's not in the news much lately, though it usually gets mentioned by name when lymphoma experts talk about non-chemotherapy treatments and the future of Follicular Lymphoma. (Search this blog and you'll see what I mean.)

The first thing that came around this week was an article from the journal Cancer Management and Research called "Copanlisib in the Treatment of Relapsed Follicular Lymphoma: Utility and Experience from the Clinic," written by Dr. Ayushi Chauhan and Dr. Bruce Cheson. (If you've been reading for a while, you know how much I enjoy Dr. Cheson's work.)

The article isn't describing new research. It's more one of those "here's where we are with things" articles.

Still, it's very helpful in that way. 

Copanlisib was approved by the FDA after only a phase 2 clinical trial, so it is currently in several phase 3 trials. These trials are looking at Copanlisib on its own, with others looking at it in combination with other treatment.

Interestingly, one of the other studies that the authors mention says that there is some evidence that Copanlisib is less effective due to insulin feedback. The treatment may set off a reaction that uses insulin to start the PI3K enyzmes that Copanlisib has inhibited, so slowing down insulin production during treatment may help it be more effective. One way of doing this might be through a keto diet, which I know a lot of people are interested in hearing more about. 

[But let me be very clear -- this article is not saying that a keto diet will stop, cure, or prevent cancer. It is being studied as a way of making one particular treatment more effective, and even that is just a theory. Don't stop eating bread because you think it will cure your cancer. There's no evidence of that. Talk to your doctor about your diet if you have questions.]

The rest of the article talks about the best uses for Copanlisib (it's a useful treatment for patients who have already tried two things and might get some use out of a different approach), and its future (like those trials that use it in combination with other treatments).

Which brings me to the second item that came across my screen recently: a quick video from Targeted Oncology featuring Dr. Mark J. Roschewski, who makes very quick mention of a different trial, this one a phase 2 trial that looks at Copanlisib with Rituxan in FL patients that have not yet had a treatment. I think this is probably part of a larger series of videos with Dr. Roschewski, but he is excited about this trial. So far, he says, every patient in it has had a response of some kind, with fairly quick reduction in the size of tumors. 

That's exciting, especially since the FDA approval was for relapsed FL. Good to see that it has some use in untreated FL, too. Options are good.

My guess is we'll see some of the results of these trials at ASCO in June. I look forward to it. (I'm happy about anything, really, that will get me through this winter and spring.)

More soon. Stay safe.

ASH Reviews: MedPage Today on Follicular Lymphoma

Happy New Year!

I'm excited to be back for another year reading and writing about Follicular Lymphoma and other cancer-related topics. 

For the last few weeks, I've been looking at reviews of the presentations at the this year's ASH meeting. As I said a while ago, with a couple of exceptions, it seems like this year was about incremental progress. Lots of presentations on helping us understand certain treatments better, or improving current treatments in small ways. Which is great -- any forward progress is great.

This will probably be my last ASH review for the year; I'm getting lots of repeated information at this point. But what I'm offering is pretty nice -- MedPage Today's video series on Follicualr Lymphoma.

The series includes multiple videos featuring Lymphoma experts from The Ohio State University Wexner Medical Center. They look at a number of presentations from ASH related To FL (there are 10 videos in the series as I write this, with at least one more on the way). Some of them cover things that I have already written about, so I'm not going to mention them here -- you can watch the videos on your own.

But others are worth mentioning. The most recent video is called "AZD0486 Shows Good Efficacy in Relapsed/Refractory Follicular Lymphoma." It looks at the ASH Presentation #341 "Escalating Doses of AZD0486, a Novel CD19xCD3 T-Cell Engager, Result in High Complete Remissions with Rapid Clearance of Minimal Residual Disease in Patients with Relapsed/Refractory Follicular Lymphoma." It describes data from a phase 1 clinical trial for a new bispecific antbody. The results are good, with 47 patients in the trial, with about 62% of them not having disease progression within 24 months. The Overall Response Rate was 96% and the Complete Response Rate was 86%. The bispecific was designed in a way to attempt to minimize Cytokine Release Syndrome, and there were no serious CRS incidents, though there were other side effects, as expected. This was a small phase 1 trial, so there will need to be larger studies to confirm all of this good stuff.

The video series is heavy on bispecifics and CAR-T, which is not a surprise. As I have said many times before, those two types of treatments seem to create the most excitement among Lymphoma experts these days.

But there are others, including a video called "Pirtobrutinib Shows Potential in Heavily Pretreated Follicular Lymphoma." This looks at the ASH presentation #3026 "Pirtobrutinib, a Highly Selective, Non-Covalent (Reversible) BTK Inhibitor in Relapsed/Refractory Follicular Lymphoma: Results from the Phase 1/2 BRUIN Study."  

Pirtobrutinib is a BTK Inhibitor. Like all inhibitors, its job is to stop (or inhibit) some process that cancer cells need to happen in order for them to grow and stay alive. The best-known BTK inhibitor is Ibrutinib (notice how similar the name is to Pirtobrutinib), which has been very very successful in treating several B cell Lymphomas, but not in Follicular Lymphoma. So another attempt at a BTK inhibitor is welcome. This presentation looked at a phase 2 trial that had some success. The ORR was 50% , 14.6% Complete Responses and  35.4% Partial Responses, plus another 25% with stable disease.The panelists in the video were especially impressed with the safety profile. 

Finally, there is the video called "How Parsaclisib Compares to Other PI3K Inhibitors for Follicular Lymphoma." (This one features different experts that aren't from Ohio State.)  I found this one very interesting because it focuses on a PI3K Inhibitor. If you've been reading for a few years, you know my small obsession with PI3K inhibtiors. There were 4 of them approved by the FDA through accelerated approval, and none of them is available anymore. Two had safety issues and two had trouble getting patients into their phase 3 trials. So it's very interesting that another one is going through the pipeline, and the experts in the video talk about what might make this one different. (There is no link to the ASH presentation on the video age.) They agree that "we haven't moved past them yet," and the trick is to balance their effectiveness with the safety issues that came up. I don't know if this PI3K inhibitor will achieve that balance, but I have to say, I'm a little skeptical. I'd love to be wrong about this one.

So, as I said, this is probably my last ASH review until next December, unless something really interesting comes up. There's plenty more to write about already on my list, and no doubt lots more that I'm not even aware of yet.

Thanks for reading. I hope it's a great year for everyone.

No More Duvelisib for Follicular Lymphoma

Taking a quick break from ASH reports to talk about some news from earlier in the week: The maker of the PI3K Inhibitor Duvelisib has taken it off the market as a Follicular Lymphoma treatment. 

In their statement about the decision, they said this was a business decision, and didn't have anything to do with its safety or effectiveness.

A little background, as a reminder: Duvelisib is a PI3K (Phosphoinositide 3-kinase) Inhibitor. It works by stopping, or inhibiting, some signals that cancer cells receive that allow them to live and grow instead of dying when they are supposed to. 

There are currently four different PI3K inhibitors approved for Follicular Lymphoma. They all work in the same basic way, but there are different variations of PI3K in the body, and they each work on a different variation (or two). They have been fairly effective when given on their own, though they seem to do better in trials when they are combined with another treatment. 

Duvelisib was was approved by the FDA in 2018 for Relapsed or Refractory FL. The approval was based on a phase 2 clinical trial, and the FDA gave Accelerated Approval for the treatment. However, because it was based on a phase 2 trial (which is usually smaller than a phase 3 trial, which typically provides the data for FDA approval), the makers of Duvelisib were required to continue with a larger trial before the FDA would give final, permanent approval. 

And that's where things got a little difficult. The statement said that the "current treatment landscape for FL patients in the U.S. and the logistics, cost and timing of the post-marketing requirements (PMR) for COPIKTRA [another name for Duvelisib] in FL was no longer merited." In other words, the costs of getting the approval probably wouldn't be worth the effort. They will continue to study Duvelisib as a treatment for T-Cell Lymphomas.From what I know, there is a lack of non-chemotherapy treatments for some types of T-Cell Lymphoma, so maybe it will help some folks over there.

It's unfortunate that we're losing a treatment option, but there are plenty still available, and more to come. 

This is a good time to remind everyone that I'm not a doctor or a cancer researcher, just a patient who reads a lot . But in my Cancer Nerd opinion, it seems like we're in a middle place right now. There are still some chemotherapy treatments available, and they're still very commonly used, and lots of doctors are used to them. But there are more and more non-chemo options becoming available -- inhibitors and monoclonal antibodies and bispecifics and CAR-Ts and combinations of all of them. Maybe too many of them to meet the demand that's here now, though there may be more demand in the future if they hang on? That's one possibility, anyway.

As I said, there are more new treatments on the horizon. The ASH Conference ends tomorrow, and we'll start to see commentaries soon about what the experts thought was exciting at ASH. I'll pass that along as I find it.

Copanlisib for Follicular Lymphoma

Last week (yes, I'm still catching up), the manufacturer of Copanlisib announced that it was expanding its clinical trials, with two new phase III trials for indolent lymphoma and one new phase II trial for DLBCL. This is good news (assuming enough people sign up for the trials, of course).

Lots to unpack here.

Copanlisib hasn't been in the news much, at least not the news that I have been reading.  First off, let us note that Copanlisib is a pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor. Kinase inhibitors are a type of treatment that has certainly been in the news lately for Follicular Lymphoma and other lymphomas. These are "pathway treatments" -- they don't attack the cancer cells directly, but block the pathways that help cancer cells develop, grow, and multiply. PI3K inhibitors work by blocking signalling pathways in cells. That is, before a cell can grow, it needs a signal from somewhere else down the pathway. Cancer cells get that signal, but keep on growing.  A PI3K inhibitor keeps that signal from reaching the cell. No signal, no growth. No growth, no cancer.

Now, there is another PI3K inhibitor already approved out there -- Idelalisib. From what I can tell, Idelalisib and Copanlisib will work through slightly different mechanisms, and will target slightly different pathways. Basically, kinases are proteins, and they come in different forms. Idelalisib targets the "delta" form of the protein, while Copanlisib shows activity against both the "delta" and "alpha" forms. So maybe there is a chance that they will work together, or compliment each other in some way.

Copanlisib has already shown some good activity in indolent lymphoma. At the ASH conference a few months ago, results from a phase II study showed that, in 33 patients with different types of NHL (including 16 with Follicular Lymphoma), all of whom had already been given several treatments, almost half had a response. For the Follicular Lymphoma patients, 1 had a Complete Response, 1 had an unconfirmed Complete Response, and 5 had Partial Responses, for an Overall Response of 47%. Not too bad.

Those same patients will be the target group for one of the phase III trials announced last week.

So, this is good news. Another potential arrow for the quiver, as they say -- another possible way of attacking this disease. But in a targeted manner.

Of course, we are still early in the process. As Karl from Lymphomation.org has pointed out before, we have lots of potential new treatments out there in various stages of the pipeline, and that is certainly something to cheer. But unless we get enough people who are willing to be a part of the clinical trials for those treatments, we won't really know just how effective they might be.

The Problems with Accelerated Approvals

I've been doing a lot of reading lately about the FDA approval process and some of the things that make it problematic. There have been a couple of really interesting books published in the last year that look at this process from a couple of different angles. I may try to write about them soon. But the big theme that I find in all of my reading is that the when new treatments are up for approval, there is a delicate balance that needs to be achieved -- the safety of the treatment and its effectiveness for patients, the desire for doctors to help their patients but also to keep them safe, the need for drug companies to make a profit to justify doing research, etc. It's a very complex process.

So it was interesting to see an article in JAMA Internal Medicine a couple of weeks ago that highlighted some of these issues in ways that are similar to the books I have been reading. 

The article is called "Clinical Trials Portfolio and Regulatory History of Idelalisib in Indolent Non-Hodgkin Lymphoma."

Now, I will admit to a small obsession with Idelalisib and other PI3K inhibitors. It was about a year ago that they were pulled from the market, or voluntarily withdrawn. I wrote about this a few weeks ago. The problems came because of safety issues (more serious side effects, including patient deaths, than were expected). There were also problems with recruiting enough patients into the trials, probably because of the Covid pandemic (but also, I think, because there were at least 4 PI3K inhibitors competing for the same patients).

PI3K inhibitors fascinate me because they held so much promise (and maybe still do?), and got oncologists very excited about their possibilities. Their trial results were very good, and they worked against cancer in new ways that targeted the cancer cells while sparing many healthy cells (unlike the way chemotherapy works). 

As I've written before, several PI3K inhibitors (including Idelalisib) were given accelerated approval by the FDA. This meant that the companies could start selling the treatments, and doctors could start prescribing it, based on the results of small phase 2 clinical trials. The stipulation was that a larger phase 3 trial would be conducted to confirm the small phase 2 trial. The term "accelerated approval" is probably not completely accurate. It's more like "temporary approval." It allows the manufacturer to start earning some money on the treatment earlier than usual.

Here's the problem, as the JAMA article points out -- the issues with serious side effects were already clear, up to 6 years before the withdrawal from the market. The researchers who wrote the article looked the clinical trials involving Idelalisib. There were 31 of them. 20 of those involved indolent lymphoma (including Follicular Lymphoma). During the period after the accelerated approval, the results of 6 of those trials were available. These 6 trials were Randomized Clinical Trials, meaning they allowed a direct comparison between Idelalisib and another treatment. And in those trials, it was clear that Idelalisib had higher rates of serious side effects and patient deaths than the treatment it was being compared to.

The big problem here? It was six years later that Idealisib was withdrawn from the market, and in those 6 years, the manufacturer had $842 million in sales (though they declined over time, as problems became evident).

It's a tricky thing. Patients need new and better treatments, and businesses need incentive to spend money to develop them. Accelerated Approval from the FDA seemed to solve both problems -- promising treatments get to patients sooner, and businesses begin to make money sooner.

But, as the article's authors point out, there needs to be greater oversight during the process. It's not enough to complete the phase 3 trial and then ask for approval; there need to be steps along to way to make sure things are doing well, particularly in terms of patient safety. There isn't much incentive for a company to make trial results public after Accelerated Approval. That needs to change.

I hear lots of patient opinions about drug companies, and the kind of gray area we are all in. We need them, but we don't trust them -- I think that sums up a lot of our attitudes. Problems like this doesn't make us trust them any more, but it certainly makes us need them more.

My biggest fear with a situation like this is that it damages patient trust in other ways -- in the clinical trial process itself. If we are being asked to be a part of a trial, but problems are being "hidden," will that make fewer people want to be a part of them?

I hope that's not the case. I hope that anyone interested in a trial places their trust in the oncologist who they are working with -- someone who can explain the potential risks as well as the benefits, and pay close attention to each individual patient to make sure they are staying safe. (In the books I read about this process, that was very clear -- the oncologists working directly with patients made it a priority to protect those patients. They were kind of the heroes of the stories, even if they were in the background sometimes.)

And I hope none of you are turned off from being a part of a trial. They're the only way we find new treatments, as risky as they are, by their nature. 

Cancer is a complex thing -- within our bodies and outside of them. But like knowing all I can about my disease, I'd still rather learn about the process and know what I'm dealing with than be in the dark.

A Third Inhibitor is Withdrawn

Well, this is getting silly now.

The maker of the PI3K inhibitor Parsaclisib has withdrawn its New Drug Application with the FDA. This comes a little more than a week after Idilalisib was withdrawn from the market for Follicular Lymphoma, and about six weeks after Duvelisib was withdrawn.  

Unlike the other two PI3K inhibitors, Parsaclisib was not yet approved by the FDA. It had applied for accelerated approval, but after discussions with the FDA, it decided not to go through with the application. They were not confident that they would be able to meet the requirements. Like the other two, this was called a "business decision." The application would have covered relapsed/refractort Follicular Lymphoma, and MZL and MCL, two other lymphomas.

I haven't seen a whole lot of analysis or commentary about any of these withdrawals. On Twitter this morning, I saw someone comment that there would probably be more of this happening with NHL treatments, as the large number of treatments (especially PI3K treatments) would mean more competition, and so more data to show that this version of the treatment would be better than others -- either more effective or safer. Another commentor said everyone is afraid of bi-specifics.

As I said in my post about Idelalisib, it does seem we've reached a point where we (patients, doctors, the FDA) will need to start focusing on quality over quantity. It's great to have so many options for treatment, but if the differences between those treatments are minimal, then someone is going to win that competition. 

And as good as PI3K inhibitors seem to be (they seem especially popular as a third-line treatment, after two other treatments have failed), the treatments that have gotten the Lymphoma community so excited in the last few years have been R-Squared (Rituxan + Revlimid), CAR-T treatments, and more recently, bi-specifics. What do they al have in common? They are as good as, or better than, traditional chemotherapy. And by "better than," I mean they are either more effective (they work on as many patients as chemo does, for as long) or they are safer (with fewer or less severe side effects).

But really, the biggest thing that the "exciting" treatments has going for them is durability. They have shown that they can work for a long time before a patient needs another treatment. And that matters. 

When I was first diagnosed in 2008, the assumption about Follicular Lymphoma was that patients could expect a lifetime of treatment. The disease would become more aggressive over time, and treatments would need to become more aggressive as well, with less and less time between them. Maybe the first treatment would last 5 years, and then the next 2 years, etc.

That's certainly still the case for some patients. But if newer treatments are also providing durable responses, then we would have less need for a wide range of choices. In other words, there's less need (and maybe desire) for 10 treatments that will each last 2 years when we could have 4 treatments that each last 5 years. Fewer treatments means fewer side effects to deal with, and better quality of life.

At least that's what seems to be happening. Remember, I'm not a doctor or a cancer researcher. Just a Cancer Nerd -- a patient who reads a lot.

Whatever the case, I think we don't need to be worried about treatments being withdrawn from use or from the approval process. There are lots of options still available and lots more being developed. We can afford to be picky (and patient). 

I hope to give you some good news next time.

Clinical Trial: Keto Diet and Copanlisib

Someone on the Follicular Lymphoma Facebook group posted a bunch of FL links this morning, and this one caught my eye:  Some very prestigious cancer centers in New York are conducting a clinical trial involving Follicular Lymphoma patients and ketogenic diets. 

Lots to comment on here.

Let me begin (since it seems appropriate here) by reminding you that I am not an oncologist, or a cancer scientist, or a medical or science professional of any kind. I'm a Follicular Lymphoma patient who had been reading about FL for over 13 years. My opinions are just opinions, though I like to think that they are informed by science.

I know some of you are interested in Keto diets, and in general in how the things we eat can affect our cancer. (I'm not on a ketogenic diet, but I think this is a decent introduction -- gets at the basics and points out the potential bad parts, too. So let me say here that I don't know of any study that shows that FL patients can definitively help themselves by eating certain foods, at least in terms of keeping our cancer in check or making it go away after we've been diagnosed. There are plenty of theories about why certain foods might help (turmeric, broccoli, blueberries, whatever), but no large, controlled studies that show benefits. There are lots of individual patients who say they have eaten certain foods, and remained cancer-free, but one person's experience doesn't mean much, because there are too many other factors that might have been contributing. 

(If you want to look at one person's experience, look at mine -- every week or two, I go to a hot dog stand in my town, eat a hot dog and french fries and a large diet soda, and sometime I dip my fries in fake cheese sauce. It's all delicious and it makes me happy and the owner sits with me sometimes and tells me funny stories. If you want your FL to stay away for 13 years, eat hot dogs and fries and fake cheese every two weeks. You're welcome.)

But really, what I would love to see is some kind of controlled study that does just that. And unfortunately, there aren't many out there. In 2007, there was a really cool-sounding study where they asked FL patients to take a bunch of different supplements, but I never saw anything about the outcomes, so I assume there were no results worth reporting. I think that happens a lot. Researchers aren't interested in publicizing the stuff that didn't work -- which is too bad, because there's a lot to learn from failure, too. 

Anyway, back to this trial. As far as I can tell, the trial is based on an old idea about cancer and sugar. As I'm sure you've heard, cancer cells feast on sugar. This is the basis of PET scans -- you are given a sugary drink, and the scan shows which cells are eating the sugar most quickly. Cancer cells like to eat sugar.

Now, some folks have turned that around incorrectly, and say that eating sugar is the way to feed cancer cells, and the way to kill cancer cells is to starve them of any sugar. The problem with this is, that's not how the body works. Our bodies are amazing machines, and they find ways to create sugar out of other materials, if there is no easy sugar supply available. Cancer cells operate the same way. They'll find a way to get sugar, even if you've given up cookies and ice cream.  That's what they do. They always seem to find a new way to survive, even when we cut off their usual way of surviving. 

(By the way, that Hot Dog place I love so much? The owner's sister opened an ice cream shop next door. After my hot dog, I usually get some ice cream.)

So cutting off sugar won't kill off cancer cells. They'll find a way to survive.

However -- limiting sugar while taking a PI3K inhibitor? That's a slightly different thing.

There has been research that shows that PI3K inhibitors increase blood sugar, causing an increase in insulin, which decreases the effectiveness of the inhibitor. (Remember that PI3K is an enzyme that is part of a long chain of events that keep a lymphoma cell alive.)  If there was a way to decrease blood sugar, and thus decrease insulin, in patients receiving a PI3K inhibitor, then maybe the treatment will work better. All of this was discovered in a study involving mice. The next step is to try it in humans.

And that's where this trial comes in. Patients receiving Copanlisib will also be put on a ketogenic diet, which is higher in fat and lower in carbohydrates that the typical diet. Fewer carbs means lower blood sugar and less insulin produced. 

To be clear about a couple of things:

This trial is not testing whether limiting sugar will stop cancer. It's about a specific treatment and how a specific diet can help make it more effective.

I'm also not suggesting that anyone eat bad food all the time. We should all eat healthily -- lots of fruits and vegetables, whole grains, limit meat and sugar and alcohol. That's good for our general health. But I also think a hot dog and ice cream every now and then in not a bad thing. Every now and then.

I think the trial is great, and if anyone is in a position to join, I hope you'll consider it. And if it were possible to construct a decent trial involving diet and FL, I hope someone gives it a try. There are some challenges to a trial like that, but I think we'd all be better off knowing how much (and in what ways) the food we eat affects our lives as cancer patients.

Priority Review for Duvelisib

The FDA has granted Priority Review for Duvelisib for Relapsed or Refractory Follicular Lymphoma (and for another blood cancer, CLL).

Duvelisib is a PI3K inhibitor (Phosphoinositide 3-kinase inhibitor). It works (as all inhibitors work) by stopping something from happening, in this case, some signals that cancer cells receive that allow them to live and grow and not die.

Duvelisib is different from other PI3K inhibitors in that it works on two different isoforms of PI3K, the delta and gamma isoforms. (An isoform is a different type of a protein -- the different isoforms do the same job, but they might be controlled by different genes. So an inhibitor that works on more than one isoform should, at least in theory, do a better job than one that works on just one isoform.) It is taken by mouth twice a day -- no ports, no infusions, no visits to the treatment room.

FDA Priority Review basically means the application will be looked at faster -- usually within 6 months. Regular Review usually takes about 10 months. Priority Review is given to treatments that seem to show an improvement in effectiveness or safety over other available treatments.

The FDA decision is based on results from the phase 2 DYNAMO clinical trial. In the trial, there was a 46% Overall Response Rate for indolent NHL patients, inlcuding a 41% ORR for Follicular Lymphoma patients.

OncLive has a nice, brief video from Dr. Lori A. Leslie that discusses some of the good and bad of Duvelisib and other kinase inhibitors. They are effective, though they have side effects that need to be considered. And while they are effective on their own, a better strategy might be to combine them with other agents, which seems to increase overall effectiveness.

As a patient, I am always happy to see another treatment move up the pipeline. Dr. Leslie discusses these in terms of eventually replacing traditional chemotherapy, which is also a great thing -- targeting lymphoma cells and keeping them in check.

As always, we'll keep an eye for the news of this the FDA's decision.

Duvelisib Approved for R/R Follicular Lymphoma

Good news for us -- the FDA has approved Duvelisib for Relapsed/Refractory Follicular Lymphoma.

Duvelisib, which is also known as Copiktra, was given Priority review by the FDA in April. The review looked at two clinical trials (the other one was for CLL/SLL, another type of slow-growing blood cancer).

Duvelisib is a PI3K inhibitor (Phosphoinositide 3-kinase inhibitor). It works (as all inhibitors work) by stopping something from happening, in this case, some signals that cancer cells receive that allow them to live and grow and not die.

There are a few PI3K inhibitors out there. Duvelisib is different because it works on two different isoforms of PI3K, the delta and gamma isoforms. (An isoform is a different type of a protein -- the different isoforms do the same job, but they might be controlled by different genes. So an inhibitor that works on more than one isoform should, at least in theory, do a better job than one that works on just one isoform.) It is taken by mouth twice a day, which should make it easier to administer.

The trial that the FDA looked at was called the DYNAMO study. It involved 83 FL patients weho were refractory to Rituxan and then either chemotherapy or RadioImmunoTherapy (RIT). In other words, they had to have had at least two treatments that stopped working. (The approval is for these patients -- it's not approved as a first treatment.)

42% of the patients in the trial had a response (1 Complete Response and 34 Partial Responses). Of those patients who responded, 43% were still responding at 6 months and 17% were still responding at 12 months.

Like all treatments, Duvelisib has side effects. They include things like diarrhea or colitis, nausea, increased risk of respiratory infections or pneumonia, and problems with blood cell counts (among others).

Duvelisib is one of those treatments that a lot of Lymphoma experts have been excited about (see this interview with Dr. Lori Leslie, for example). It's another option, and I think that's always a good thing.

The numbers aren't spectacular (42% is very good, but it's not a cure by any means). It will be interesting to see where it goes from here. My guess is that we'll see it in combination with other treatments (that seems to be where things are going these days).

Overall, though, it's good news. Another arrow for the quiver.