Protecting the Heart During Chemotherapy

The JAMA Network Open published a research letter last week that I thought was very interesting. It's called "Primary Cardioprotection in Frontline Anthracycline Therapy for Adult Hematologic Cancers," and it brings up some important issues that get at the heart of where we are these days with Follicular Lymphoma treatments.

(There's a really funny pun in there that you'll get if you re-read this post.)

The research letter looks at some research on Anthracyclines, a class of traditional chemotherapy drugs.  They are very powerful. The "H" in "R-CHOP," a common chemotherapy for FL, stands for Hydroxydaunorubicin, which is also known as Doxorubicin or Adriamycin. This is the Anthracycline in the combination. It works by messing with the cancer cell's DNA so it can't grow and divide. 

But the big problem with traditional chemotherapy is that it can often do as much damage to healthy cells as it can to  cancer cells. And in the case of Anthracyclines, one of the places it can do damage is to the heart. This is why FL patients only get R-CHOP once, even if it was very effective. There is too much risk of heart damage over a certain dose, and it can take months or ears to show up.

The research here points out that there are ways to help minimize the heart damage that Anthracyclines can cause. First, patients can be given a drug called Dexrazoxane just before they receive the chemotherapy. This drug latches on to the byproducts of the Anthracycline to keep them from damaging heart cells. The other strategy is to use Liposomal Anthracycline Formulations. For this, the Anthracycline molecules are coated in lipids or fats that keep them from affecting heart tissue and lessening damage.

The researchers found that Anthracyclines are used in chemotherapy treatments for several different blood cancers, including FL. But these two strategies for cardioprotection (protecting the heart) are very rarely used.

They looked at medical records for blood cancer patients over 10 years (from 2014 to 2024) and identified patients who had received Anthracycline-based chemotherapy as a first treatment. They looked particualrl at patients who were diagnosed with Acute Myeloid Leukemia, Diffuse Large B-Cell  Lymphoma, Mantle Cell Lymphoma, and Follicular Lymphoma. They decided to focus their analysis to AML and DLBLC, because there were so few cases of cardioprotection for the MCL and FL patients.

(That's a huge problem that we'll get back to in a second.)

They looked at a total of 13,331 patients, including 3661 with AML, 7241 with DLBCL, 1154 with MCL, and 1275 with FL. There was "infrequent" use of cardioprotection -- only 2.4% of patients with AML and 1.1% of patients with DLBCL received either Liposomal Formulations or Dexrazoxane. As I said, the number of patients with FL who received cardioprotecion was too low to include (obviously, less that 1%).

The researchers are calling for more research into the use of cardioprotective strategies for blood cancer patients who receive Anthracycline-based chemotherapy, hopefully leading to greater use if the research justifies it.

I think there are a couple of important points that this brings up for us as FL patients.

First, this strikes me as a survivorship issue. As I have said many times, the idea of survivorship is becoming more and more important to me -- the idea that there isn't enough attention paid to what happens to patients after the treatment is over and we are told we are OK. I think "side effects" are often studied most intently for a fairly short period right after treatment. It's hard to measure long-term side effects. There are so many other reasons that an FL patient might have heart issues 10 years after treatment. But if Anthracycline-related issues might not show up for years, that doesn't mean there isn't a risk. I am fully in favor of research that tests out strategies for cardioprotection.

This is also an excellent reminder that side effects (long- and short-term) should get a thorough discussion when it comes time to decide on a treatment.As I have said before, even when I'm having a good visit with normal blood test results, I still like to bring up treatment possibilities. I'd rather have those conversations before they become necessary, rather than when I'm in a panic about choosing a treatment that needs to happen soon. It's a lot easier to have a thorough conversation then.

And this specific conversation matters. If you've been reading for a few months, you probably remember the research from last March on 15-year follow-ups of R-CHOP patients, and the possibility that R-CHOP had cured many of them.  I have no idea how this has been accepted by oncologists in the last 6 months -- if they are recommending R-CHOP to more patients. But if that's the case, then we need to do much better than 1% of FL patients receiving cardioprotection. This needs to be a part of the conversation if R-CHOP is back on the scene.

One other important point to remember -- no cancer treatment is without side effects. When R-squared was first declared an alternative to traditional chemotherapy, researchers were very clear that R-squared had side effects, and they weren't better than those from chemo, they were different. It's just not possible to fight something like cancer without causing other issues. The question is, how are those issues dealt with? What can researchers learn from some patients to better protect other patients? 

As I said, I think this kind of gets at the heart of where we are with FL treatments. There is, unfortunately, no single best way to treat FL. For all of the excitement about CAR-T and bispecifics and other immunotherapies, traditional chemo still has a place in FL treatment. And there's still lots to know. 

Do your best to keep up -- enough to be able to have a good conversation with your doctor when the time comes.

 

R-Squared: A Systematic Review

The Blood Cancer Journal just published an article called "Lenalidomide and Rituximab for Relapsed/Refractory Follicular Lymphoma: A Systematic Review and Meta-Analysis." 

We're at a point now where R-squared (Lenalidomide/Revlimid + Rituxan) is pretty firmly a part of our lives as Follicular Lymphoma patients. It's a standard treatment, the first option approved that showed to be as effective as traditional chemotherapy (but with a different set of side effects). It has been with us for about 7 years now as an approved treatment.

So this article is a "systemic review" of what we know about R-squared. It looks at all of the research that has been done since 2015, when the first stage 2 clinical trial results were published, on R-squared in Relapsed/Refractory FL. The aim here is to see if all of the results show the same thing, especially when compared to the AUGMENT trial that led to the approval. 

The authors wanted to look at as wide a pool as possible, so in addition to looking at just R-squared, they also looked at Lenalidomide + Obinutuzumab, which like Rituxan is an anti-CD20 monoclonal antibody. They also looked at triplets -- R-squared + some other lymphoma treatment. Finally, they looked at not just published research, but also at research that was presented at ASH, the largest hematology conference in the U.S., and EHA, the largest conference in Europe. 

Looking at so many sources of data is great, in that it gives them much more to work with. But it also complicates things. Each study had its own criteria for inclusion, so the patients across the studies don't match up with each other exactly. Some studies, especially those from the conferences, did not include all of the data that the published studies did. And some studies used slightly different dosing, so patients didn't get the same amount of the treatment across all of the studies.

All that said, they were able to do some analysis that made it possible to compare the different studies.

The results of their analysis aren't surprising -- R-squared works.

The Overall Response Rate for all of the R-squared or Lenalidomide + Obinutuzumab studies was 75.9%, and the Complete Response Rate was 39.6%. For studies involving a triplet (R-squared + another lymphoma treatment), the ORR was 85.1% and the CRR was 53.9%. This makes sense -- a third treatment will, in theory, add another way for the cancer cells to be treated. But something else happened, too, that also makes sense -- the rates of serious side effects went up, too.

In case you are curious about what the third treatment was in those triplets, they were Idelalisib; Polatuzumab; Atezolizumab; Bendamustine; ViPOR [a combination of 5 treatments, not three -- Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid]; Tazemetostat; Acalabrutinib; Epcoritamab; Azacitidine; and Tafasitamab. Some of those names are probably familiar to you, and I have written about a bunch of these trials over the years. You can search for them at the top of the page.

The analysis also broke down the data in a few other ways, including prior lines of therapy. They wanted to see if R-squared was more or less effective if someone had already tried a number of other treatments. If a treatment works when others don't, that's an important piece of data.  In studies where patients had received a median of just one prior treatment, the ORR was 76.7% and the CRR was 41.9%. For patients who had received a median of two or more prior treatments, the ORR was 73.5% and the CRR was 40.5%. There was no significant difference between the two -- R-squared works well no matter how many prior treatments a patient had received. The same was true for the triplets.

As for safety, as mentioned above, there were greater numbers of serious side effects for the triplets. Serious low white blood cell counts occurred in 46.6% of triplet patients, and just 29.1% of R-squared patients. There was a trend toward serious respiratory infections in the triplet patients vs. the R=Squared patients. Low platelet counts were similar in the two groups. Patients who had to leave the study because of serious side effects were also similar -- 23.3% in the triplet group and 16.6% on the R-squared group. 

There are other data breakdowns that you can read about in the article. Click the link. 

Overall, the analysis shows the effectiveness of R-squared and begins to look at some of the effectiveness of triplets, though they are generally more recent and will need more time to see long-term results. If you've been reading for a while, you now I like those "Here's where we are" articles and videos where an expert gives us an update on things that have happened in the past. I see this as one of those articles. It's clear the R-squared is effective and safe for Refractory and Relapsed patients and provides and important option for those of us in that situation. 

Photographs and Memories

I have an old phone. It doesn't have a huge amount of storage on it, so it fills up fast, to the point where I can't do any updates because there isn't any space.

I know the reason. I run my dog's Instagram page (oh yes -- that guy named Lympho Bob is not my only online persona).  I take several pictures of the dog every day. "For online content," I say to my wife and kids who roll their eyes at me when I tell them to keep still so the dog will stay in whatever cute position she is in. I end up with way more photos and videos on my phone than I actually need. And then I forget to go back and erase them and they pile up.

So over the last few weeks, I've been going through the photos on my phone, erasing anything that I don't really need, like duplicate photos of the dog or old memes that I though were funny and may r may not think the same now. Last week, my wife and youngest kid and I took a train ride into New York City to go to the Metropolitan Museum of Art. It's an amazing place. I spent the 2 hour train ride going through all of my photos for 2023. I had a ridiculous number of photos of my dog sleeping while she's lying on her back. Maybe two of them ended up on Instagram. It was very therapeutic to erase so many of them and create some space.

As you might imagine, going through thousands of photos brings back some memories. And some of those memories are directly related to being a cancer patient.

I found several photos that I had saved over several months, all variations of the same meme: "My Lymph Nodes are Assholes." I liked that one a lot, enough to save it whenever it came up. I don't think I ever re-posted it anywhere, including in this blog. But I enjoyed the fact that it kept coming back to me, and I kept enjoying it. And it's true -- if my Lymph Nodes were people, I probably wouldn't want to spend much time with them. They're much too negative. I'm getting to an age where I'm more selective about who I spend time with. I'd rather not have what they are offering.

I found another meme, a list written by a cervical cancer patient: "You Know You Have Cancer If...." and then there were 10 items like "You can pronounce difficult drug names correctly" and "You speak very freely about your own body." They were all very true. But my favorite was "You have a favorite vein." Because I do have a favorite vein -- left arm, along the inside of the elbow. It's a beautiful one -- I have been told so by many phlebotomists. In fact, when I get blood taken and the phlebotomist doesn't comment on how nice it is, I get a little insulted. "Pretty privilege," I think it's called. Those of us with beautiful veins can get a little bit obnoxious about it. 

I found a bunch of vacation photos of people I have met who are cancer survivors. My wife and I are doing our best to travel now, when we can, when we are healthy enough to enjoy it. We don't want to look back 10 years from now, wishing we had taken the trips we used to dream about. We're living the dreams now, as much as we can.

There were some photos of a group we had met on a river cruise, and one of the women in the group was a two-time breast cancer survivor. One night, when the wine was flowing at dinner, we started talking about how ridiculous it was to be diagnosed with cancer at a relatively young age -- me at 40, she in her late 30s. We were laughing in a way that cancer patients do sometime. But it wasn't a happy conversation for her husband. He said to me, stone-faced, "But it wasn't funny when it happened, was it?" No, it wasn't. I told him about watching moving with my young kids and turning out the lights in the room so they wouldn't see me crying. 

It's funny how shared sadness can make someone feel happier. 

A few years before that, we traveled to Italy, something we'd talked about for 30 years. While we were there, we met someone who was in active treatment for lung cancer. She and her husband were great travel companions, and we spent a wonderful afternoon with them in Venice -- one of our favorite travel memories in many years of traveling. Of course, it came out that both of us were in different stages of our dealing with cancer. She was a cancer blogger and writing teacher, like me. We had lots to talk about.

I kept up with her blog for a long time. As I said, she was in active treatment when we met. She is a long-distance bike rider, and enjoyed good days when she could get out and ride. She hasn't written anything on her blog since April. It was good news at that point -- she was able to see her oncologist three times a year instead of four. So I'm going to assume she's doing well and spending her time riding instead of writing. Writing about cancer is hard to keep up sometimes, I know. We all need a break. 

We had corresponded by email for a while, and that made me think of all of the emails I have received over the years from readers. I think about you all a lot. It's true. I'll read or something that will make one of you pop into my head. The filmmaker from the Netherlands. The doctor who retired and moved to Portugal. The marathoner from Ireland. The second amendment advocate who was finding out information for her brother. The guy who just wanted to stop thinking about cancer and get back to riding his motorcycle with his wife. I am honored that you reached out to me and trusted me with your stories. I save all of those emails, and every now and then I think about writing to you to ask how you are doing. But I don't, because maybe you're in a place where you don't want to think about all of this anymore. And I respect that. 

But I'd also love to hear from you if you're still reading. I'd love to now that you're doing OK. 

Cancer is such a long, strange trip if we're lucky. I hope all of you are able to make happy memories and have some time to reflect on them. And maybe smile a little.

 

Epcoritamab + B-R

The journal HemaSphere published new research last week on another Epcoritamab combo. It's an early trial, but it could be an effective treatment for some patients.

Epcoritamab has been getting a lot of attention lately. If you've been a regular reader, you know I've been saying for a few years that that the treatments that seem to get oncologists most excited these days are CAR-T and Bispecifics. And he bispecific that gets them most excited is Epcoritamab.

A quick reminder: a bispecific works by targeting two different proteins. One of them is on the surface of the cancer cell. So it works a lot like Rituximab, which also targets a protein on the cancer cell. But a bispecific also targets a different protein on a different cell -- a T cell, which is an immune cell. So bringing a cancer cell close to an immune cell, the bispecific helps the immune system work against the cancer. 

Epcoritamab works by targeting the CD20 protein on the cancer cell (just like Rituxan does) but also the CD3 protein on the T cell. It works very well, and there are more and more reports of it being used successfully in various combinations (like the recent presentation on Epcoritamab + R-Squared).   

In this research, the combination is Epcoritamab + Bendamustine + Rituxan. As many of you now, Bendamustine is a traditional chemotherapy. The article from HemaSphere is called "First-line treatment with epcoritamab in combination with bendamustine plus rituximab induces sustained remissions beyond 3 years in patients with follicular lymphoma." 

It's a pretty straightforward title. The article describes a phase 1b/2 clinical trial (meaning it looks at safety, like a phase 1 trial, but also effectiveness, like a phase 2 trial). The study involves 25 patients from the trial who have been diagnosed with Follicular Lymphoma but had not yet received any treatment. The patients received Epcoritamab + BR and thenwere given additional Epcoritamab for up to 2 years. 

At a median follow-up of 41.3 months, the Overall Response Rate and the Complete Response Rate were both 96%. In other words, 24 of 25 patients had a Complete Response. That's very high, and I can't remember any trial where the OR was the same as the CR. And at a median of 36 months, 87% of patients had kept that Complete Response. The 3 year Progression Free Survival was 83%, and the 3 year Overall Survival was 96%.

As for safety, the combination did not produce any new side effects, just the ones that were expected with either Epcoritamab or BR. However, those expected side effects were not minor. There was no high-grade Cytokine Release Syndrome (CRS) or ICANS (Immune Effector Cell Neurotoxicity Syndrome), which are perhaps the most serious possible side effects, though lower-grade CRS occurred in 68%. But there were other side effects. 92% of participants reported infections (a sign of a weakened immune system),   with COVID-19 being the most common (patients were enrolled in 2021). Injection site reactions in 56%. Fatigue in 52%. The most common grade 3side (more serious) side effects were infection (44%), and low white blood cell counts. In all, 72% of patients experienced a grade 3 or higher side effect of some kind.

The researchers point to the high CR rates and long duration as very positive things. But they also point out that a combination like this can potentially bring about serious side effects, and caution doctors to think very carefully about which patients would benefit from it instead of a different treatment with less serious side effects.

It's a small study, very early in the process, but probably justifies moving on to a larger study. It will be very interesting to see if the side effects become an issue. Epcoritamab is part of our future, no question. But how it ends up in our future -- as a single agent or in some combination -- will be worked out over the next few years.

 

Vitamin D and Cancer: No Easy Answers

The Journal of the American Medical Association published an article that this week that disappointed a lot of people. It's called "Addition of High-Dose Vitamin D₃ to Standard Treatment in Patients With Metastatic Colorectal Cancer: The SOLARIS Randomized Clinical Trial (Alliance A021703)." The hope was that taking high-dose vitamin D along with standard chemotherapy would improve outcomes in this specific group of colorectal cancer patients. Unfortunately, it did not improve Progression-Free Survival. 

The study looked at high-dose (8000 IU for two weeks, followed by 4000 IU daily) versus standard-dose (400 IU daily). There was a small PFS benefit for the high-dose group, but it wasn't statistically significant.

This isn't a study about Follicular Lymphoma, or any other kind of blood cancer, so it doesn't say anything directly about how vitamin D would affect those of us with FL. But studies of cancer and vitamin D always catch my eye because it's one of those interventions that people have asked me about fairly frequently over the years. There have been some tantalizing studies that get our hopes up. For example, in 2022, a study of Diffuse Large B Cell Lymphoma patients found that those with low Vitamin D levels had a lower response rate to CAR-T and a lower Overall Survival after 2 years than patients with normal vitamin D levels.  But that's not the same thing as saying vitamin D will improve outcomes if you already ave normal levels. Another study from 2019 found that Lymphoma patients who had higher sun exposure (and thus more opportunity for the body to naturally develop vitamin D) had a smaller risk of developing some kinds of Lymphoma, including FL. But they also found that getting vitamin D through food or supplements didn't have any effect. And then in 2018, there was a presentation at ASCO on a phase 3 clinical trial comparing FL patients who received Rituxan + vitamin D versus just Rituxan. I never saw results from the trial, which typically means it wasn't successful.

There are more. You can put "vitamin D" in the search box at the top of the blog to see more. But it's more of the same -- studies that show there might be some benefit maybe to some small population in some particular circumstance. I get these reminders every now and then that I need to step back and ask why I'm doing things and consider what I believe.

To be very clear -- I'm not saying you shouldn't take vitamin D. It has all kinds of health benefits. The National Institutes of Health have a nice comprehensive sheet that describes some of those benefits. 

But keep reading -- it also describes some of the problems that come from excessive vitamin D intake.

The point here is that it's worth knowing what your vitamin D levels are, and working with a doctor to figure out what that means for your own overall health. But I wouldn't expect it to cure your cancer. 

This is also a good time to remind you that I am not a medical doctor or a cancer biologist, and you shouldn't take medical advice from me. The best person to take medical advice from is your own doctor. They know you best, and they have the expertise to help you.

All of that said, I do take vitamin D every day. I tested low a few years ago, and my doctor recommended supplements. My vitamin D levels are normal now. I still take a fairly high dose every day, and that keeps me within normal range. In fact, it's at kind of the lower end of normal range, which suggests that my high dose is what I need. There's something happening in my body that keeps my levels low without the supplement. 

What is that thing that keeps my levels low? I have no idea, and I'm not going to worry about it. The very easy and fairly inexpensive intervention that my doctor recommended is doing its job. 

As I said, I like to have a reminder every now and then -- even a negative one -- that there are no easy answers, as much as we'd like there to be. The best we can do is stay informed, work with our doctors, and trust the excellent research that is being done.

 

Cancer Medicine Approvals in the US

The medical journal JAMA Oncology published a research letter a couple of days ago that I found really interesting. A "research letter" is a kind of informal discussion of research results, very different from the long articles that report of clinical trial results. But it provides some historical content for cancer research as a whole that should be very encouraging for all of us.

The article is called "Cancer Medicine Approvals in the US," and it looks at the circumstances surrounding the approvals of cancer treatments by the FDA for the last 20 years (from January 1, 2006 to December 31, 2025). The research focused on treatments for solid tumors, so there were no blood cancer treatments involved. There are also no pediatric treatments or generic drugs or biosimilars.

But even without the blood cancer treatments that would be most relevant to us, it still gives us a picture of the kinds of trends that have happened in the last 20 years. I think those same trends are probably true for those other treatments that aren't included in the data.

The researchers found that from 2006 to 2025, the FDA approved 385 different cancer treatments for solid tumors. Of those, 154 (40.0%) were for brand new treatments, and 231 (60.0%) were for new indications for approved treatments. For example, a treatment might have been approved for a first-line breast cancer treatment that was already approved for relapsed breast cancer. 

Another breakdown: of the 385 approvals, 105 (27.3%) were approved through the Accelerated Approval process. This means they were approved using data from a smaller phase 2 clinical trial, rather than a larger phase 3 trial. Accelerated Approvals are granted when a treatment meets a particular need that isn't being met by any other available treatment. That number is lower than I would have expected. It seems like there are lots of Accelerated Approvals these days for blood cancers, and they don't always work out well. So I feel a little better knowing that about three quarters of approvals are from the regular process. Accelerated Approvals often work out great, but they concern me sometimes. 

Another interesting bit of data: Traditional chemotherapy accounted for 40% of all approvals from 2006 to 2010. However, for the last 5 years, they have accounted for only 3.9% of approvals. This is not at all surprising. We can see it in blood cancers -- R-squared, CAR-T, bispecifics, monoclonal antibodies. All of them are proving to be good alternatives to traditional chemotherapy. They are more targeted, so they do less damage to non-cancer cells and have a different set of side effects. And even though the word "cure" was recently applied to R-CHOP, an immunochemotherapy combination, the excitement lately comes from those non-chemo options. 

Another interesting bit of information from the research is about endpoint markers. These are the data that ultimately proves whether a trial is a success or not. The best endpoint should be Overall Survival -- how many patients were still alive after 5 years or 10 years or whatever length of time they need to compare to. If a treatment keeps more people alive, that should be the measure of success, right?

It's more complicated than that. Only 102 of the 385 trials (26.5%) had Overall Survival as an endpoint. And that number is declining -- it went from 40% of trials from 2006 to 2010 to 18.7% from 2021 to 2025. Instead of Overall Survival, most trials used a "surrogate endpoint" -- a different statistic that shows "success." In blood cancers, especially in Follicular Lymphoma, the surrogate endpoint is often PFS -- Progression Free Survival, or the number of patients whose disease did not get worse over a period of time. This makes sense for FL -- if the Median Overall Survival is now 18-20 years for FL patients, it could take much too long for a treatment to be approved. No drug company is going to wait 20 years for the data they need to get approval. So while PFS isn't a perfect surrogate, it's good enough for FL.

For this research on solid tumor treatment approvals, PFS was the most common surrogate from 2006 to 2015 (60% of all trials). But from 2016 to 2025, the most common was Response Rate (46.7%). This strikes me as more problematic. A response to a treatment is great. But some responses last only for months. At least PFS typically goes on for a couple of years. Of course, I understand that not all PFS measures are long, and not all Response measures are short, and some for some cancers with few treatments available, any response is a big success. It's all more complex than these numbers suggest. But in my observation, it seems like PFS, and not Response Rate, is the primary endpoint for most new treatments, which is good.

One final bit of data comes from the way trials are constructed. Many consider the "gold standard" for clinical trials to be a randomized, two-arm controlled trial. This type of trial involves randomly splitting patients into two groups. One group gets the "standard of care" -- the treatment that is accepted as the best available at the time. This is the "control" group. The other group gets whatever new treatment is being tested. In this way, the researchers can guarantee that the two groups are the same and that a fair comparison is being made between the old and the new. The alternative is a "single arm" study. There is no direct comparison because there is only one group. The data from the trial is compared to another trial that took place in the past. There is no guarantee that the old and the new are the same. It's much easier to run a single-arm study like this, and they are more common in phase 2 trials than phase 3 trials.

This research found an increase in approvals based on single-arm trials -- 12.9% from 2006 to 2010, up to 40% from 2021 to 2025. 

The researchers conclusion says "Continued decline in the proportion of approvals based on overall survival, increase in response rate–based approvals, and underutilization of the accelerated approval pathway all reveal concerning trends." Interesting that they want to see more Accelerated Approvals. 

As I said, this research doesn't include blood cancers, but the trends that they see are pretty close to what I have observed over 18 years of paying attention to the research on FL. I'll admit that I have become kind of a Clinical Trial Nerd over that time, and I have some definite opinions about some things. But I will also remind you that I'm not a doctor or a cancer researcher, so keep that in mind.

The big lesson for me in all of this is that FL has a number of treatment options available to us. The whole reason I've become such a nerd is that there is so much research for me to read. So even when a treatment doesn't get approved, or gets pulled after approval, we still have other options. Don't ever lose sight of that. 

Stay well. More soon. 

EHA: Surovatamig + Rituxan

 I'm still sifting through some of the abstracts from ASCO and EHA from last week, and I found another one from EHA (the European Hematology Association's annual meeting): "SUROVATAMIG (AZD0486) PLUS RITUXIMAB IN PREVIOUSLY UNTREATED FOLLICULAR LYMPHOMA (FL): INITIAL SAFETY DATA FROM THE PHASE 3 SOUNDTRACK-F1 TRIAL."

(The EHA puts its titles in ALL CAPS.)

I don't know much about Surovatamig, which was previously known as AZD0486. I written about it only once before in the blog -- a description of a phase 1 trial that was reported on at the 2024 ASH conference.  Surovatamig is a bispecific, like Epcoritamab and Mosunetuzumab. It works by attaching itself to a cancerous B cell by grabbing on to the CD19 protein on the surface, and then also grabbing on to a T cell by the CD3 protein. In this way, it brings together the cancer cell and the immune cell that can eliminate it. 

The EHA presentation reports on results of a phase 3 trial called Soundtrack-F1. Let me say first of all that "Soundtrack" is a very cool name for a clinical trial. Maybe that's just because I love music so much.

Anyway, the study is looking at Surovatamig combined with Rituxan. It is a phase 3 study, with the goal of recruiting over 1000 Follicular Lymphoma patients who have not yet received teatment, though this presentation looks only at 43 of them. According to the U.S. government's clinical trials website, it has not begun recruiting trial participants in the U.S., which might be why I haven't heard much about it. Once this smaller trial is finished, the larger phase 3 trial will begin.

Still, even with only 43 patients, the researchers had some good things to present at EHA. The focus here is on safety rather than effectiveness -- reporting on the side effects experienced by the participants. The combination is interesting --  Surovatamig targets CD19, while Rituxan targets CD20. So there seems to be, at least in theory, that the two treatments would compliment each other well when used together. But any combination of treatments also means there is the possibility of doubling up the side effects.

For this study, the researchers looked at two different dose levels of Surovatamig, and divided the patients into two groups. It's very early in the trial, so median follow-up was about 6.3 months. The first group, which had a lower dose of Surovatamig, had a 95% response rate. The second group, with the higher dose, had a 100% response rate. At the time that they cut off the data to analyze it, 75% of patients in the lower dose group and 100% of patients in the higher dose group had no Minimal Residual Disease.

As for safety, 100% of patients had Treatment-Emergent Adverse Events (TEAEs), meaning side effects that develop after the treatment has been given. The most common were infusion-related reactions (36% in group 1 and 52% in group 2), mostly due to the Rituxan (not surprising to any of us who have had Rituxan). Other common side effects were fatigue (36% and 43%), muscle aches (36% and 38%) and low white blood cell counts (36% and 38%).

More serious side effects occurred in 18% of the lower dose group and 29% of the higher dose group. Cytokine release syndrome (CRS) occurred in 36% and 38% of patients and one instance of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) occurred in each of the groups. 

The study was specifically designed as a "safety run-in," a smaller study to test for side effects before the larger study happens. It's interesting to me that this is happening in a phase 3 study; that kind of dose escalation (testing different doses to find the best combination of safety and effectiveness) usually happens much earlier. In this case, there wasn't much difference between the two doses in terms of safety, but there was a slightly better effectiveness with the higher dose, so that will be the recommended dose for the larger phase 3 trial.

The larger phase 3 trial will be a randomized two arm study. Half of the patients will receive the Surovatamig + Rituxan combination, and the other half will receive Immunochemotherapy (R-CVP + Rituxan maintenance, R-CHOP + Rituxan maintenance, or Bendamustine + R + Rituxan maintenance). 

There are a couple of takeaways for me. The first is that Bispecifics are clearly going to be in our future as FL patients. This kind of large study isn't messing around -- they're looking for full FDA approval. Lots of newer treatments try to get accelerated approval, and they do that with smaller phase 2 trials and aiming at Refractory/Relapsed disease. This trial has neither. That tells me that Bispecifics are fully mature.    Epcoritamab and Mosunetuzumab are pretty well accepted at this point.

The other thing that strikes me is the care that is being taken to focus on safety. As far as I can tell, there has not been a phase 1 or 2 trial for this combination, but that's probably because there are already known side effects for both of the treatments involved. Still, with so much already known about other Bispecifics, it's a help the the researchers to know what to look for in this type of treatment.

As always, looking at this kind of research being presented at medical conferences tells me that we have lots to look forward to. Not every treatment in a trial will ultimately be approved. In fact, less tan 10% will likely be. But there is still lots being tested, and lots of good stuff coming.