FDA Fast Track Designation for EO2463

Last week, the FDA grated Fast Track designation for a new immunotherapy treatment called EO2463. (It will probably get a cooler name soon.)

Some reminders before we go any further: Fast Track designation means that a proposed treatment has the potential to do something new, and so it gets extra help from the FDA to help it through the approval process. Its a way of trying to get treatment to a group that has great need for treatment. In this case, that group is Follicular Lymphoma patients. (The news article about this is not clear about the specific population of FL patients, though the National Cancer Institute page for the clinical trial specifies relapsed/refractory patients with FL and some other indolent blood cancers.)

 Immunotherapy is a group of treatments (like chemotherapy is a group of treatments) that uses the body's immune system to work against the cancer. Our immune systems are usually good at fighting off invaders, like bacteria or viruses). But cancer cells aren't invaders -- they are our own cells, but they refuse to die like they are supposed to. So immunotherapy treatments usually work by either changing our immune cells to find and fight the cancer c ells, or changing the cancer cells so they can be recognized by our immune system as invaders.

EO2463 is a very interesting treatment that takes a unique approach to identifying tumor cells. It's a little complicated, so I've tried to do a bunch of reading and watching to help me understand it. (This video helped.)

The company that makes the treatment focuses on bacteria in our guts. Gut bacteria is kind of big news these days, as researchers are looking into all kinds of ways that our gut biome affects our health. (Though not all of those claims have solid evidence.)

The role of gut bacteria in this treatment is different. The company uses Artificial Intelligence to identify over 20 million different proteins that exist in the gut. Their AI program can help identify proteins that are very similar to those that exist in the body, especially proteins that exist on certain cancer cells.

That distinction between the gut bacteria proteins and the human proteins is important. The bacteria in our gut play important roles, but they aren't meant to leave the gut. If they do leave it, our immune system takes over. Immune cells are meant to recognize and fight off invaders (like bacteria or viruses). When they encounter one, they eliminate it and then remember it, so if they encounter it again, they can eliminate it very quickly. Gut bacteria are included on that list of invaders. As long as they stay in the gut, they are welcome to hang around, and the immune system leaves them alone.

So we have two things happening here. First, you have gut bacteria that are considered invaders if they leave the gut. Second, you have proteins from the bacteria that are very similar to proteins on cancer cells, like the CD20 protein that is on the surface of Follicular Lymphoma B cells. 

When you put those two things together, you can develop a cancer treatment. Create a treatment that targets CD20 (and some other proteins) but create it in such a way that it tells immune cells that the cancer cell is really a bacteria that escaped from the gut and needs to be eliminated. Because the treatment is engaging an immune cell called a Memory T Cell, which remembers invaders, the thinking is that the treatment will be long-lasting.

[A note to you language nerds: I know that "bacteria" is the plural form of "bacterium," but I'm calling a single one a "bacteria" anyway because I think it sounds better. Shakespeare made up words, too, and it's my blog, so I do what I want.] 

The Fast Track designation was earned by the results of the SIDNEY clinical trial. This is a phase 2 trial involving 60 patients split into 4 cohorts. As I said above, there are several different blood cancers being targeted in the trial. Patients are given EO2463 on its own and in combination with R-Squared or one of its components, Rituxan or Lenalidomide/Revlimid. 

The early results are promising. The first 13 patients have an Overall Response rate of 46%, with no severe side effects. The makers of the treatment see this as a possible alternative to watching and waiting (though it's not clear if they are targeting untreated patients.)

I have to say, I'm kind of fascinated by the approach, using AI to identify possible targets based on gut bacteria. But there are also lots of questions to be answered -- as is always the case with a phase 2 study. My guess is that there will be more information at the ASH conference, which is happening in less than 2 months. 

But Fast Track is no guarantee of success. This is definitely one that I will keep an eye on.

 

Stem Cell Transplant vs CAR-T, with a Cannoli

If you read the title of this post and are now very confused, I'll explain below. 

But before I get to that, I want to remind everyone to take the Follicular Lymphoma Foundation's annual survey. The survey will be available until October 19, so you only have a few more days from when I am posting this. It's a chance to have your voice heard - the FLF shares results with oncology researchers and clinicians, so together, we can help them understand the things that think are important for them to know about patients. 

The survey is anonymous and shouldn't take more than 10 minutes to complete. Thanks for your help with this.

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Now, about the title of this post:

CancerNetwork is the web site for the medical journal Oncology, and they sponsor a series of recorded debates called CancerNetwork Face-Offs. In these events, cancer experts are divided into two teams. Each team takes one side of a particular controversy in oncology, and makes a presentation about it. The idea is make these events educational, but also "fun" -- as much fun as anyone can have in discussing cancer.

(To be clear, I am all for fun, even in discussing cancer. It's obviously a serious business, but I can appreciate that people who are around cancer patients all day might want to add a little levity to their jobs.)

Part of the fun is in coming up with team names. So, for instance, in one Face-Off, two teams of oncologists from Chicago debate about....well, let me just copy the description at the start of the web page: "Panelists discuss various aspects of lower-risk myelodysplastic syndromes, including trial results on erythropoiesis-stimulating agent timing and novel agents like luspatercept and imetelstat, treatment sequencing and timing debates, personalized approaches based on erythropoietin levels, and complex case management balancing immediate symptom relief with long-term strategies."

The fun part? One team is named after the Chicago Cubs, and the other after the Chicago White Sox, the city's two Major League Baseball teams.  

Now, back once again to the bog post title. Some of these Face-Offs include videos of the debates. But their most recent one included a transcript of the event, with the title "Boston’s Best Did Not 'Leave the Cannoli' in Battle of Lymphoma Top Trials."

This one caught my eye for three reasons. First, it was about Follicualr Lymphoma, at least partially. Second, the oncologists on the panels were all from Dana-Farber Cancer Institute in Boston (the city where I was born and raised). And finally, the teams were named after two well-known pastry shops in Boston, Modern and Mike's. So the "leave the cannoli" is related to the pastry shops, but also is a reference to a famous lime from the movie The Godfather.  It's one of my favorite films. So how could I not write about this?

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That's a long introduction to a post, I know. I suppose you want some details of the actual face-off.

The two teams debated whether or not CAR-T was "better"than Autologous Stem Cell Transplant. It isn't really about these two treatments going head-to-head, but rather about the two teams doing their best to present information in a way that is both fun and informative.

The teams discuss the results of some recent clinical trial updates, look at case studies of patients, and then whether ASCT or CAR-T is better.

First of all, I'm not sure this is a fair fight. The last time I wrote about Stem Cell Transplants in any serious way was almost 10 years ago, and even then, the subject was about whether or not they were still a good option.  And there has been so much progress in FL treatments since then, it's hard to imagine anyone could make a strong case for Auto SCT over CAR-T.

If you're fairly new to all of this, and don't know what a Stem Cell Transplant is, here's a quick description: Patients who receive a Stem Cell Transplant receive very aggressive chemotherapy, aggressive enough that it pretty much destroys their immune system. It can take up to 30 days for the body to recover that system. But that leaves the patients vulnerable to all kinds of problems, since they have no defense against even the weakest virus. So they are given a Stem Cell Transplant, putting immature immune cells into their bodies that can grow into immune cells quickly -- maybe within 7 days -- leaving them much less vulnerable.

There are two types of Stem Cell Transplants. An Autologous STC uses the patients own stem cells. Tey are removed from the body before the patient receives chemo and then put back in after the treatment. An Allogeneic SCT uses immune cells from a donor that are a match. The danger with an Allo STC is that the patient's body can reject someone else's cells. The danger with the Auto STC is that those removed cells might have some cancer in them. Auto STC is considered less aggressive, but Allo STC usually had a greater chance of a cure, when it was successful.

(A Bone Marrow Transplant is very similar to a Stem Cell Transplant. The same dangers apply.) 

You can see how an Auto STC could be compared to CAR-T. They both involve removing immune cells and then putting them back in later. But the CAR-T cells are changed in ways that help them to locate cancer cells and remove them them. The Auto STC cells are just going back to their job of being immune cells - they aren't necessarily targeting cancer cells.

It's an interesting debate overall, even if the Auto STC folks had the harder job.  

And to be clear, Stem Cell Transplants are still used. There's no definitive answer when it comes to Lymphoma treatment. Every patient's needs (including their financial situation) has to play a part in the individual decisions about treatment. CAR-T is great, but it's not the best choice for everyone.

Cancer Nerds will enjoy reading this transcript. And whether or not this is your idea of "fun," it is always interesting to me to see experts delve deeply into a topic, present some interesting data, show how it applies to real people, and help us stay informed.

 

Mental Health Awareness Day

Today is World Mental Health Day. 

I found out about it because a notice popped up on my computer. The notice featured a green ribbon, which is the color for mental health awareness.

Of course, Lymphoma awareness uses a lime green ribbon. But the mental health ribbon looked kind of lime-like on my computer, so I had to look it up and make sure we weren't sharing the same ribbon color. These things are important. (Not really.) 

But when I saw that the two ribbons might be the same color, it seemed very appropriate to me, particularly for Follicular Lymphoma. As I have said for a long time, for many FL patients, the symptoms and side effects of the disease are not physical, but emotional, mental, and spiritual. Lots of us were asymptomatic at diagnosis, and maybe stayed that way for a long time. For me, it was two years of watching and waiting.

But even with no or few physical symptoms, there are plenty of mental ones during that watch and wait period.  (The Follicular Lymphoma Foundation just did a webinar on Watching and Waiting, and of course, issues related to mental health were a major part of of the discussion.) 

And there are plenty of other times during our lives as FL patients when mental health issues are important. Certainly at diagnosis. It's such a surprise for many of us, especially when we're asymptomatic. I've spoken with so many FL patients who say they were in the best shape of their lives when they were diagnosed -- again, myself included. That shock takes some time and effort to deal with. Even those of us who suspected that there was an issue still have the shock of having it conformed. "You have cancer" might be the scariest words in the world, despite all of the advances in cancer research in the last 20 years. 

And then comes treatment, and all of the mental health issues that come with it. Uncertainty over whether it will work, or whether there might have been a better choice. Fear of physical side effects -- still a huge concern for so many patients. And the mental health issues that come with being physically weakened by treatment, and having to worry about finances and every day life.

And then, post-treatment. the fear of recurrence. Even that one is different for us as FL patients. We've been told since diagnosis that the disease is incurable, and chances are good that it will return even after successful treatment. Dealing with that possible return has its own special mental health challenges.

And then, there's the mental health challenge that I think doesn't get talked about enough -- guilt. There's the survivor's guilt of going through treatment. There's the guilt that comes from being in an online group and realizing that others have had it much rougher than you have, and wondering if yu have anything to tell them that's helpful.

I'm not listing all of these mental health challenges because it's in any way fun. 

I'm listing them because I've been through each of them myself.I think there is something very special about reading or hearing about someone else's problems and realizing that you are not alone in having that problem. If, for example, you feel some kind of guilt related to your FL, know that you're not the only one. There's some comfort in that.

Which is ultimately what "awareness" days are about. They're about a collective understanding of something, and hopefully, a collective resolve to do something about it.

The FL Community Podcast's most recent episode is on mental health issues. It's worth listening to; you'll get an even greater sense that you're not alone in feeling what you're feeling.

And remember that if having Follicular Lymphoma gets a little overwhelming sometimes, that's OK. There are places online to have conversations with other FL patients and to get some reassurance. (And I'm always happy to listen, and to offer advice if I'm asked for it. I respond to every email that I receive.) And if talking it through isn't working, talk to your oncologist's office for advice on mental health professionals that might be affiliated with your cancer center. It's ok to seek professional help if that's what you need. 

I hope everyone has a great day today. Do something nice for yourself. 

 

Acalabrutinib + R-Squared for FL

The journal Nature Communications published an article a couple of months ago (I know, I'm behind on things) called "Frontline acalabrutinib, lenalidomide and rituximab for advanced stage follicular lymphoma with high tumor burden: phase II trial." 

It's a follow-up on some research that was presented at the ASH conference in 2023.  

In this study, researchers added Alcalabrutinib (also known as Calquence) to R-Squared. Alcalabrutinib is a BTK inhibitor. Just like other inhibitors, its job is to inhibit, or stop, something from happening -- in this case, Bruton's Tyrosine Kinase, an enzyme that is necessary for B cells to develop. B cells are, of course, the type of immune cell that includes the cells that can lead to Follicular Lymphoma. And that's what happens with a BTK inhibitor. The BTK enzyme does its job too well and won't die off, meaning the B cell won't die, leading to cancer. A BTK inhibitor stops that process and lets the cell die the way it is supposed to. 

Alcalabrutinib is already approved for some other blood cancers -- Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), and Waldenström's macroglobulinaemia.  So it makes sense that researchers are trying it with FL. However, there have also been several other BTK inhibitors that are effective with other blood cancers, but not FL.

The presentation at ASH in 2023 showed that this combination of Alcalabrutinib was very promising. The research is from a phase 2 clinical trial with 24 patients (a pretty small number). The patients had not received any treatment yet. The Overall Response Rate was 100%, and the Complete Response was 92%. After 26 months, 6 patients had their disease progress. The most common serious side effects (grade 3-4) were low neutraphils, a type of white blood cell, 58%, liver function test elevation (17%), infection (12.5%; 2 out of 3 related to COVID19), anemia (8%) and skin rash (8%). 

The Nature article was meant as a follow-up, looking at some longer-term data. The researchers were especially interested in what they call CR30 -- how many patients were able to maintain their Complete Response after 30 months. For them the CR30 rate was 65%. I'm not sure how that compares to some other treatments, but it seems positive. (This is a single-arm study, meaning they didn't split the patients into two groups so they could compare two treatments directly).   

After a median follow-up of 43 months, the median PFS (Progression-Free  Survival) was not reached, meaning more than half of the patients had not progressed. The PFS rate after 2 years was 79%, and for 3 years it was 62%. The POD24 rate was 17%, meaning 17% of patients who had a response had their disease return within 24 months. About 20% of FL patients are POD24, so this seems roughly in line with that number. 

Overall, the numbers look very promising. It will be interesting to see how this goes in a larger phase 3 trial.

I think what's really interesting, though, is the number of articles I've seen recently that look at R-squared triplets -- combinations if Rituxan, Revlimid (Lenalidomide), and something else. It makes sense. R-Squared has been shown to be as effective as traditional chemotherapy, but with a different set of side effects. SO instead of combining a single agent with chemo, researchers are hoping a combination with R-squared will increase effectiveness, hopefully without increasing side effects. That seems to be the case with this triplet, making a BTK inhibitor more effective than it has been on its own.

 Time will tell. 

Take This Survey about Follicular Lymphoma!

The Follicular Lymphoma Foundation is conducting its annual global patient survey, and I strongly encourage you to take a few minutes to respond.

The survey is anonymous, and takes about 5-10 minutes to complete.

The FLF conducts a survey every year to get input from FL patients from around the world about their experiences. They share the results on their website for patients to look at, but they also share the results with oncologists and other medical professions at medical conferences. A few months ago, they shared results from one of their surveys at ASCO, one of the largest gatherings of oncologists in the world. By telling oncologists about how patients and caregivers prioritize treatment decisions, they were able to show that doctors and patients think differently. It's a great way to have the voice of patients heard, and potentially change the way oncologists do their jobs. 

This survey asks questions about experiences with treatment, and about the kinds of emotional issues that FL patients have to deal with. It's very valuable information -- the kinds of information that don't usually show up on surveys.

(Which reminds me -- the latest edition of The FL Community Podcast is out now, and it's on "Mental Health and FL: Coping with the Psychological Impact of Cancer." I haven't had  chance to watch/listen yet, but I'm guessing Dr. Paul, one of the hosts, will have lots of good things to say, since he's a mental health professional, and Nicky and Nicola have had plenty of experiences to share as well.)

You can click here to find out a little more about the survey and click on the link to begin.

A couple of things to help you get oriented (I already took the survey, so I know these things):

You can take it in English or Spanish.

Some questions ask you to choose one item, and when you choose it, it will automatically move to the next question. 

If you need to go back and change an answer, there are two small arrow in the lower right corner that will let you do that. Don't feel like you can't go back and forth just because the survey moved forward on its own. 

I hope you will take a few minutes and complete the survey before it closes on October 19. A large response will benefit all of us.