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. 

R-Squared: 10 Year Follow-Up

The medical journal Blood published the results of a 10 year follow-up of R-Squared. The results aren't surprising (they are positive), but it's the larger content that it more interesting to me.

The article is called "Lenalidomide plus rituximab for previously untreated advanced follicular lymphoma: the 10-year RELEVANCE trial analysis."  As a reminder: R-squared is the shirt name for the combination of Rituxan and Revlimid (also known as Lenalidomide). R-squared was the first non-chemotherapy treatment that was shown to be as effective as traditional immunochemotherapy (like R-CHOP or R-Bendamustine), though it had a different set of side effects that were just as serious. The AUGMENT trial and the MAGNIFY trial led to R-Squared being approved for FL patients who had already received treatment. 

The RELEVANCE trial involved patients who had yet not received any treatment.  The original trial was large -- 1030 patients. More importantly, it is a two-arm study, so it shows a direct comparison between patient receiving R-Squared and those receiving immunochemotherapy. In 2022, I wrote about a 6 year follow-up study.  As I said then, "The results of the study showed that R-Squared remained just as effective after 6 years as it had been up to that point. The Progression-Free Survival (showing that the disease didn't get worse after 6 years) was 60% for R-Squared and 59% for R-chemo. Overall Survival was 89% for both groups. The transformation rate (the slow-growing FL turned into a fast-growing cancer) per year was 0.68% for R-Squared and 0.45% for R-chemo, and secondary primary malignancies (patients developed a new, different cancer) was 11% for R-Squared and 13% for R-chemo. There are some other statistical comparisons as well, but they all say the same thing -- R-Squared is as effective as R-chemo, and as safe."

So would R-Squared hold up as well after 10 years? Yes it does.

The median Progression Free Survival after 10 years was 110.6 months for the R-Squared group and 102.8 months for the Immunochemotherapy group.  The rate of patients with a 10 year PFS was 46.4% for R-Squared and 46.6% for chemo. Almost identical. The median Overall Survival and the median Time to Next Treatment were not yet reached in either group. (Remember that the "median" means the middle of a group, so if the median wasn't reached, it means that more than half of the group has survived and has not yet needed treatment after 10 years). The 10 year Overall Survival rate was 82.4% for the R-Squared group and 81.1% for the chemo group. The 10 year Time to Next Treatment rates were 62.2% and 66.3%. Only 9 cases of transformation occurred (3 with R-Squared and 6 with chemo). 

Comparing the 6 year follow and the 10 year follow up, it's not surprising that numbers went down after 4 more years, but more importantly, the numbers comparing the two treatments were very similar. As the researchers say, R-Squared continues to be an alternative to immunochemotherapy for untreated FL patients.  

The researchers also said this was 10 year follow-up was always part of the plan for the study, and that it would be their final analysis.

Here's what I mean when I say it's interesting in a larger context.

A few months ago, researchers published a 15 year follow-up of R-CHOP and used some statistical analysis to show that about 40% of patients in the study were probably cured. One of the big outcomes of that article was the idea that we now have a new benchmark -- other long-term studies are going to be challenged to do the same kind of statistical analysis to determine what their cure rate was. In other words, the RELEVANCE study shows that after 10 years, there isn't a whole lot of difference between R-Squared and immunochemotherapy, in terms of effectiveness. But can R-Squared match the 40% cure?

We're not getting that information here (or in the 15 year follow-up of R-Squared in the MDACC trial that was published in February) because that wasn't part of their plan. I don't know enough about statistical analysis of clinical trials to know if a biostatistician can come in later on and look at the data for a trial and make that same kind of call. But it will be really interesting to see if that kind of analysis starts showing up at conferences like ASCO and ASH and in medical journals. I'm certainly all in favor of it. I have a complicated relationship with the word "cure" after 18 years, but more studies that use that analysis and use that word might change my mind.

In the meantime, though, it's great to see long-term data of any kind to show that we have some choices. Given our own individual circumstances, there's more than one treatment available for us that will give us a chance at a good, long Overall Survival. That's some very happy news.

Epcoritamab + R-Squared (+ Pharmacists)

In my quest for some Follicular Lymphoma-related reading material during this slow news time, I found an article in Pharmacy Times called "Epcoritamab Plus Lenalidomide and Rituximab in Practice: A Focus on EPCORE FL-1." 

As you can guess, Pharmacy Times is aimed at pharmacists, the folks who manage and sometimes advise on medications. That's the angle that makes it kind of interesting.

It's mostly a summary of the EPCORE FL-1 clinical trial results. EPCORE is the general name for a series of studies that have looked at the bispecific Epcoritamab. The EPCORE NHL-1 study looked at patients with several types of Non-Hodgkin's Lymphoma who were treated with just Epcoritamab. The EPCORE  FL-1 study is the one described here, and is the one that got people very very excited at last year's ASH conference.  This trial involves only FL patients, and combines Epcoritamab with R-Squared (Rituxan + Revlimid, also known as Lenalidomide).

The article provides a good overview of all of the successful trials for Epcoritamab, and especially for EPCORE FL-1. This was a phase 3 global study, with 488 patients from 30 countries. Patients had refractory or relapsed disease and had previously received a monoclonal antibody + chemotherapy. Patients were divided into two groups: one received R-squared and the other received R-squared plus Epcoritamab. 

Results were very positive. After a median follow-up of 14.8 months, The Epcoritamab group had a 95% Overall Response Rate (versus 79% for the R-squared only group). Most other measures were better in the Epcoritamab group did better than the R-squared only group -- including Progression Free Survival, Duration of Response, and Time to Next Treatment. It's easy to see why people were so excited at ASH.

Safety was also good, with low white blood cells counts (neutropenia) and infections being the most common side effects. Cytokine Release Syndrome, a major concern, occurred in 26% of patients, but all cases were manageable. Other side effects are described in the article. This isn't really providing any new data, just a summary of what was already reported.

What I found so interesting, though, were the "pharmacy" aspects of the article.

For instance, the article goes into some detail about dose escalation, something that gets mentioned in most oncology articles, but not in much detail.

In the EPCORE FL-1 trial, the dosing was changed partway through. At first, patients received a smaller dose first, and then a larger second dose. But in later studies, it was divided into three steps instead of two, so patients received it more gradually. Researchers think this probably helped lessen the severity of some side effects, including CRS. 

It also goes into some detail about "premedications" -- intravenous hydration, an antihistamine, an antipyretic (like acetaminophen), and corticosteroids (preferable dexamethasone) -- as well as "postmedications," including two to three liters of oral fluids within 24 hours after receiving Ecoritamab, plus corticosteroids (dexamethasone again) for 3 days.

I can picture an oncology pharamacist reading the results of the EPCORE FL-1 in an abstract, and thinking "That's nice, but what were the premedications?!" 

And I say that with great admiration, from one amateur Cancer Nerd to a professional one.

I don't really think about the role that pharmacists play in our treatment. 

When I had my Rituxan infusions, I had a blood draw first. Then I met with the oncologist to make sure everything was OK and I was well enough for the day's dose. Then I went to the treatment room, where the excellent Nurse Sue took care of me for a few hours. But somebody had to prepare the Rituxan. Somebody had to worry about my premedication hydration and the antihistamine I needed when I had an allergic reaction. 

It's kind of cool to think that there's someone else behind the scenes, keeping an eye on things. The size of our care team is really large.

I don't ever remember talking to a pharmacist when I needed treatment, but education is certainly a job for pharmacists, and the article discusses the role that pharmacists can play when a patient needs education about any of the medications that are a part of this treatment process. 

It's just kind of nice to have a broader perspective on things. It's one more person who cares about us, and who is looking out for us. We're lucky to have these hidden angels.  

No More Tazemetostat

The news came out this week that the makers of Tazemetostat will no longer offer this treatment to patients, including patients with Follicular Lymphoma. There are too many concerns about patients developing new, different cancers.

They made an announcement about a month ago that they were stopping a clinical trial that was testing it, and now they have decided to just pull it from the market completely.  

Tazemetostat is an EZH2 inhibitor. It works by inhibiting or stopping an enzyme called EZH2, or Enhancer of Zeste Homolog 2." This enzyme is controlled by the EZH2 gene. EZH2 keeps tumors growing, so when it's not doing its job, it needs to be inhibited -- stopped by Tazemetostat. About 20% of FL patients have an issue with their EZH2, though it can also be effective on patients that don't have that particular mutation.  

Tazemetostat was approved by the FDA in 2020 based on its ability to help that 20% of FL patients -- it was the first treatment that successfully helped that group of patients. The FDA approval was accelerated, meaning it was approved based on a small phase 2 clinical trial, rather than the usual, larger phase 3 trial. The accelerated approval, as always, is based on continuing research. A larger phase 3 confirmatory trial must be run to make sure the treatment is as effective and as safe as the smaller trial suggested.

Accelerated approval can be great. But sometimes the phase 3 trial that comes after approval shows some problems. And in this case, that problem was that the treatment may be causing secondary cancers. I haven't seen anything about how many patients developed the new cancers, or what kind of cancers. 

If you're wondering what happens to the patients in a cancelled trial: in this case, they will continue to receive treatment. The trial (called SYMPHONY-1) involved 2 groups. One received R-Squared (Rituxan and Revlimid) + Tazemetostat, and the other received just R-Squared. So patients who were enrolled in the trial will all continue to receive R-Squared. They won't be left without treatment. 

I have mixed feelings about accelerated approvals. They make new treatments available to patients who might need them. But they also risky in that they haven't gone through the full process that other treatments have gone through. On the other hand, even if there had been a phase 3 trial, the patients who volunteered for it would still be dealing with the same risks. It's all very complicated.  

The unfortunate part for all of us is that we have one less treatment available to us. And for those with the EZH2 mutation, that's even more unfortunate.  

But we can stay hopeful. There are lots of treatments available to us, and many more potential treatments on the way. 

 

 

A Few Approvals

Hello all, and welcome to 2026.

It's been a week since I have posted. I usually try to get something up a little sooner than that. But I started the new year with some computer problems, and it's taken a few days to get things fixed. Thankfully, I'm back to writing. I supposed I could have written a blog post on my phone, but honestly, I'm just too old for that. The buttons are too small, the words are too small, and my patience is too small. I wear progressive lenses for a reason. 

On a related note, Spotify gave me my "Listening Age." If you are unfamiliar, the music steaming service Spotify ends the year by giving you some data about your listening -- the songs or artists you listened to most -- that kind of thing. But they also give you a "Listening Age," a measurement of how old the music is that you listen to. So if you listen to a lot of contemporary music, you'll have a young Listening Age. My Listening Age is 69. I'm not only too old to write with my phone, I'm also too old to listen to anything that wasn't played at my high school prom.

So, just to sum up: 

My biological age is 58.

My Listening Age is 69.

My Lymph Node Age is about 93.

Just so you know what you're dealing with as we enter the new year.

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Unfortunately, I also have a hard time reading on my phone, so I'm behind on Lymphoma news to share with you.

So I'll pass along some of the approval news that has happened in the last few weeks. I haven't been able to share it because I have been focused on ASH.

The big Follicular Lymphoma approval news has been the FDA approval of subcutaneous Mosunetuzumab.  Mosunetuzumab was the first bispecific approved for FL (though Epcoritamab has been in the news a lot more lately). A quick reminder -- bispecifics work by attaching themselves to cancerous B cells, and then also to T cells, which are immune cells that can eliminate the cancer cells. Up until now, Mosunetuzumab has been administered intravenously, through a vein in the arm, over a period of 2 to 4 hours. With the subcutaneous injection, that time is reduced to about 1 minute. A clinical trial showed that the subcutaneous version was as effective and as safe as the IV version. This is, if nothing else, a Quality of Life issue, with less time spent in a hospital or clinic, and more time doing other things. Ideally, this will also bring the cost down. 

In non-USA approval news, the European Union approved Minjuvi (Tafasitamab) plus R-Squared (Revlimid/Lenalidomide and Rituxin) for patients with Relapsed or Refractory Follicular Lymphoma. I wrote about this in November, when it had been given it's almost-approval, but now it's official.

Also, Japan's Japan's Ministry of Health, Labour and Welfare approved the same Tafasitamab for the same population. I briefly mentioned both of these approvals in my "predictions" post, but I thought they deserved a little bit more attention than I gave them then.

There are a few more interesting FL-related articles that I have seen fromm the last few weeks. My old eyes will have an easier time reading them, and my old fingers will have an easier time writing about them, so look for them soon. And of course, look for my diagnosiversary post next week. I'll have some things to say.

 

ASH Review: Epcoritamab

If there was a Big Winner for Follicular Lymphoma at ASH this year, it was without a doubt Epcoritamab.

Epcoritamab is a bispecific antibody, meaning it has two mechanisms working. On one side, it attaches to a protein on the surface of the cancerous B cell, and then also attaches to a protein on a T cell, an immune cell. In this way a bispecific uses the body's immune system to treat the cancer.

The research that has everyone so excited is the results of a phase 3 clinical trial, also published in the prestigious medical journal The Lancet, as "Epcoritamab, lenalidomide, and rituximab versus lenalidomide and rituximab for relapsed or refractory follicular lymphoma (EPCORE FL-1): a global, open-label, randomised, phase 3 trial."

The results really are pretty exciting. This is a phase 3 randomized trial, which means the researchers split a large group of patients into two, so they could directly compare the results of two different  treatments. This kind of trial is considered the most accurate (rather than comparing one group to the results of a trial that happened a few years ago). In this case, one group was given R-squared (Rituxan + Lenalidomide/Revlimid), while the other was given R-Squared plus Epcoritamab. There were 448 patients in the trial (a pretty large number), and all had relapsed or refractory disease (they had already had treatment, and it didn't work or no longer worked).

With a median follow-up of 14.8 months, the Overall Response rate for the Epcoritamab group was 95% (versus 79% for the R-squared group). The Complete Response Rate was 83% for Epcoritamab and 50% for R-squared. 

The Progression-Free Survival for the Epcoritamab group was higher, with estimated PFS of 16 months in 85.5% of that group versus 40.2% in the R-squared group. (They had to use an estimate because some patients hadn't reached the median time yet.)

With a "triplet" -- a combination of three different treatments -- like this one, safety is always an issue. Three treatments might mean three times the effectiveness, but can also mean three times the side effects or adverse events. Grade 3 (serious) adverse events were higher for the Epcoritamab group (219 of 243, or 90% of that group, versus 161 of 238, or 68% of the R-squared group), which was to be expected. Cytokine Release Syndrome, which can be very dangerous, was low grade for the Epcoritamab group, and was managed by the doctors.

I was going to link to a few videos of Lymphoma experts talking about the results, but they're kind of all the same thing, with the expert repeating the numbers and talking about how exciting this could be (like this one from OncLive). And I do think it's exciting, having finally seen all of the data.

Any skepticism I have comes from whether or not patients will have access to it. It does seem to me that bispecifics are probably more accessible than CAR-T (the two are often talked about together, including by me). CAR-T is great, but more expensive (as one recent bit of research pointed out), which is going to make bispecifics a more popular choice for those who make those decisions about cost. But there are going to be still less expensive options for R/R patients, probably. I hope FL patients can get the best treatment available, no matter the cost.

This isn't the last we're going to hear about Epcoritamab. There were many ASH presentations on this treatment, for many different types of Lymphoma. Two that I thought were interesting were the results of a phase 2 trial of Epcoritamab and Rituxan for untreated FL patients (97% Complete Response Rate in a small trial), and Epcoritamab and R-squared in untreated FL patients (95% Overall Response Rate). 

But it's that randomized, phase 3 trial that really makes me think that Epcoritamab will be around for a while. A large number of patients over a long period of time. It seems pretty likely that it will be a regular part of treatment programs. It might take a while to get to that point, but it probably will.

I'm still looking at ASH abstracts and watching and reading commentaries. I'll have more soon. 

ASH Review from the Follicular Lymphoma Foundaton

The ASH meeting ended yesterday, so no more previews. Now we're into reviews. Over the next few weeks, there will be lots of Lymphoma experts writing articles and making videos that talk about what they found most exciting at ASH. They're helpful. They often provide more detail and analysis than I could get from the abstracts, and it's usually easy to see patterns when they all talk about the same thing.

For this first review, we'll look at a video sponsored by the Follicular Lymphoma Foundation. It features Dr. Jessica Okosun, a Lymphoma specialist and professor at Bart's Cancer Institute in London. (Prof. Okosun was one of the panelists for the FLF's webinar, "Charting Our Progress Toward a Cure" last summer.) 

You can watch Dr, Okosun's video here on YouTube, or go to the FLF's website and see it there with some additional commentary. 

The thing that excited Dr. Okosun the most was the research on Epcoritamab and R-Squared (Rituxan + Revlimid or Lenilidomide). If there was a standout for FL reseach at ASH this year, it was this one. Since it was presented a few days ago, I've seen about 20-30 articles about it, with phrases like "game changer" and "new standard." (I'm always a little skeptical about new treatments being talked about so excitedly. I'll get more into that at some point.) The results were also published in the prestigious medical journal The Lancet a couple of days ago, which is a bigger deal, since it means the data has been peer-reviewed by other experts. 

As Dr. Okosun says in the video, the research was a randomized trial with about 400 patients, half of them getting R-squared and the other half getting R-squared + Epcoritamab. The R-Squared group had a Progression Free Survival of about 11 months, with the Epcoritamab group had not reached its median after almost 15 months (meaning fewer than half of the patients had their Lymphoma return). 

She was excited about bispecifics in general -- there was additional research at ASH on Mosunetuzumab as well -- but she also pointed out some safety concerns. Bispecifics tend to increase the risk of infection in some patients, so as with any treatment, there needs to be some caution when giving it. 

Dr. Okosun was also excited about the research on the biology of FL that was presented at ASH. We still have some basic questions that we don't have answers to, like why FL comes back after it seems to have been treated successfully. She was excited especially about research by Dr. Karen Tarte, who presented data that looked at differences between FL cells at diagnosis and then at relapse. You can see that abstract here; I'll try to look at it and comment on it soon. 

As I said, there will be more commentary from Lymphoma experts in the next few weeks about what they found exciting at ASH. And I'm sure a lot of it will be about Epcoritamab. I have no doubt that it has the potential to make things better for Relapsed and Refractory FL patients. It will be a matter of getting it to them. 

More ASH reviews to come.  

 

Two Approvals and a Story

My email notifications have been very busy over the last few days, with news of treatment approvals in the US and in Europe. If I get that many notices, it must be a big deal. I'll tell you about them, but first, a story.

A couple of days ago, I went for my first CT scan in many years. It wasn't for cancer, but for a heart-related issue. (Everything is fine -- just needed to check on something to make sure it really is fine.)  I haven't had a cancer-related scan in a while because I haven't needed one, and my oncologist is pretty firm in his belief that if there isn't a reason to do a scan, we shouldn't do one. "Surveillance" scans, just looking to see if there are any problems, don't usually work that way. Something else happens that calls for a scan, and the scan confirms the problem. 

So that's what happened with my heart-related issue -- something else showed a problem that CT scan could confirm. It was different than any of my cancer-related scans. It was just a CT scan, not a PET scan, so there was no nasty liquid to drink, no IV with a contrast in my arm, no getting undressed. Just me on a table, gliding into a big donut. It took about 5 minutes. 

I've been so busy lately that I really hadn't had time to even think about getting this scan. So it wasn't until I was on the moving table that I even thought "Wow -- it's been a long time since I had a scan. I really don't like scans. There is way too big a chance that a scan is going to bring bad news." That little bit of scanxiety didn't kick in until I was in the middle of it.

And then the voice came on, the one that gives you instructions. So a male voice started speaking to me: "Take a deep breath....now let it all the way out.....take another breath.....now let it all the way out......Now breath in deeply and hold," but his voice went way up when he said "hold," like he was asking a question. Then he continued, "Now you may release your breath." This happened three times.

I almost messed up the scan because I started laughing a little.

The whole "hold" like it was a question was kind of funny. But then I started thinking about the last scan I had, several years ago, at my cancer center. The voice that spoke to me there had a British accent. So instead of saying "Now you may release your breath, " the British voice said "Carry on breathing."

"Carry on breathing" is not a phrase that we use in the US. I remember telling my kids about it, years ago, and them thinking it was very funny. 

So there I was in the CT machine, already smiling at the guy say "hold" like it was question, and now I'm also thinking about the British guy saying "Carry on breathing," and I know I'm about to laugh out loud and ruin this whole scan. 

Thankfully, I was able to hold in my laughter until I was done (thank goodness it was a short scan). But I did tell the technician about it, since she was looking at me funny when I was chuckling a little bit when she came back into the room. She thought it was amusing.

So it's nice to be in a place where I can laugh during a CT scan. I hope that's someplace we can all be someday, with no worries about anything. 

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Now, on to those approvals.

The first is from the US. The FDA approved Epcoritamab for two different situations involving Follicular Lymphoma.  

Epcoritamab is a bispecific, attaching itself to B cells with the CD20 protein, ans then to a T cell (an immune cell) with the CD3 protein. In this way, it brings the immune cell close to cancer cell, so the immune cell can take out the cancer cell. Epcoritamab was accelerated approved by the FDA for relapsed/refractory FL in 2024. Accelerated approval is kind of temporary, allowing the treatment to be used on patients while additional data is collected. So the first of the two new approvals is making the accelrated approval into a permanent approval. Epcoritamab can be given as a single agent for patients with Relapsed/Refractory FL who have had at least two treatments already.

The second approval is for Epcoritamab to be used with R-Squared -- Rituxan and Revlimid/Lenalidomode. R-Squared is being used more and more as a substitute for traditional chemotherapy, so just as there are combinations of chemo with new agents, there are also combinations with R-Squared. The potential problem with that kind of combination is that with three treatments, you have the potential for triple the side effects. In fact, safety was a concern when research on Epcoritamab was presented at the ASCO conference in 2024. But apparently there was enough data to lessen those concerns.

So we have a couple of more treatment possibilities in the US. (It has already been approved in Europe and Japan.)

The second approval is for Tafasitamab in Europe. This isn't a full approval just yet, but it's very close. This approval is the last step before it becomes official. It was recommended by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP), which approved it for use with (again) R-Squared for Relapsed/Refractory FL who have had at least one other treatment. It needs to get its final approval from the European Commission.

Tafasitamab (also known as Monjuvi) is a monoclonal antibody, like Rituxan. But unlike Rituxan, which binds to the CD20 protein, Tafasitamab binds to the CD19 protein. So in theory, it should work well with R-Squared, since it works in a slightly different way. The same potential problems with safety can happen with this combination, but the clinical trial data seems to show that it was OK. Given how many notices I received about this, it seems like there won't be any major issues with it getting approval from the European Commission. 

I know that there is going to be some new data for Epcoritamab at ASH in a couple of weeks. I haven't looked to see if there will be anything new for Tafasitamab. I know I need to get moving on ASH previews. I hope to have some for you soon.

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.

 

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. 

Three Factors to Consider in Choosing R/R Treatment

The website Oncology News Central posted an interview a few days ago with Dr. Ahmit Mehta, a Lymphoma specialist at the University of Alabama at Birmingham. It's called "Three Factors to Consider in Relapsed/Refractory Follicular Lymphoma Care." It runs a s a video, but there is also a transcript if you'd rather read, or you need to translate. The website is mostly aimed at oncologists and other health professionals, but I have to say, Dr. Mehta does a fantastic job of explaining things very clearly. I don't know if anyone out there is a patient of his, but I'd bet he's just as good at explaining things in person. 

I thought it was an interesting interview for two reasons. 

First, it focuses a lot on Tafasitamab, which I talked about in my last post. So it's kind of a timely video that way.

Second, he discusses the factors that he considers when he needs to help a patient make a decision about treating Relapsed or Refractory Follicular Lymphoma. Let's look at that first, since it's the title of the video.

When he was asked how he makes decisions about treating R/R FL, he said, "When the patient relapses, at that time, there are multiple factors we consider for second-line treatment. Usually, the way I think in my mind, is: Patient-related factors are number one, disease-related factors are number two, and number three (that I’ve added recently) is center-related factors."

I find this really interesting. I've seen lots of general descriptions about the kinds of factors that go into those decisions, but never in quite this way.   

First, the patient-related factors. (It's nice that he puts patients first, and not surprising if you watch the whole video). These factors include things like comorbidities -- the other health problems that a patient might have. Certain problems will mean that particular treatments are not a good idea, since their side effects can be aggressive and create even more new health problems. Second are the disease-related factors. Is the patient POD24 or showing B symptoms? An aggressive relapse might mean a more aggressive treatment recommendation.

And third is "center-related" factors. I thought it was really interesting that he added this consideration recently. Not all treatment centers offer every treatment, and something like a bispecific or CAR-T are only offered at a limited number of centers. If a patient will have a hard time getting to a treatment center, or staying at the center for a couple of weeks to be evaluated, then a different treatment might be considered instead.

Now, any decent doctor would consider all of those factors as well, and I don't think Dr. Mehta came up with all of that on his own. But I do appreciate the way he breaks it down, and how he shows the things that he prioritizes. As we consider our own treatment choices, those same factors are what we should be thinking about, or at least be prepared to ask questions about. 

The second interesting thing that Dr. Mehta talked about was Tafasitamab. As I wrote about in my last post, there are lots of Lymphoma specialists who are very excited about the newly-approved combination of Tafasitamab and R-Squared (Rituxan + Revlimid). Dr. Mehta is one of those specialists. He sees very real possibilities for Tafa-R-squared, as he calls it, becoming a very popular choice for R/R FL.

One thing I thought was interesting was that he said R-Squared was currently the most popular second-line treatment for FL. I haven't seen evidence of that, though I'm also not someone whose job it is to know such a thing. But anecdotally, it seems to me that lots of FL patients are receiving R-CHOP or B-R, especially if they didn't receive chemo as a first line treatment, as well as CAR-T or bispecifics. I wonder sometimes if doctors who work in academic medical centers, where cutting-edge treatments are developed and tested, have a different perspective on things than doctors in community clinics, where old habits tend to rule. 

Or maybe Dr. Mehta is correct, and more and more doctors are using R-squared as a second treatment for R/R FL. And if that's true, then the jump to Tafasitamab shouldn't be hard. (But, as I said last time, I have my doubts, still.) 

Overall, it's a very good video, and those of us who have already had treatment would find it very interesting. The video is about 15 minutes long, and as I said, there's a transcript available as well.

I hope you get a chance to watch or read.

Tafasitamab: New Standard for R/R FL?

I've been seeing some discussion online lately about Tafasitamab, and its promise for treating Follicular Lymphoma. There are a few people who think it could become the standard treatment for Relapsed/Refractory FL, given the success of the clinical trial that led to is approval a couple of months ago.

But all of the positive talk got me thinking more about how certain treatments get to be so popular, and why others never really seem to catch on.

Part of my thinking this ways comes from a conversation I had recently with someone about RIT (RadioImmunoTherapy). This type of treatment involves taking a monoclonal antibody (something like Rituxan) and adding a tiny amount of radiation to it. Because the antibody seeks out a protein on the lymphoma cell, the radiation gets delivered right where it is needed, so there is less damage to cells that don't need the treatment. It was all the rage when I was first diagnosed, and I know a few people who received it many years ago and who a very long remission because of it.

However, it never really caught on the United States. The rules for a treatment like this required that an expert in nuclear medicine administer it, rather than a regular clinical oncologist. To be able administer it, the doctor would need 400 hours of training (if I am remembering this correctly). So very few people received RIT, even though trials showed it was very effective and there were a few different options available.

It's an example of a good treatment not getting to patients who would benefit from it.

So when I see the headlines about Tafasitamab -- that it might be a "game changer," or a "new horizon," or a "new standard," I have to wonder if it's really going to happen. (The "game changer" headline comes from a website that uses that phrase once a week about some new cancer treatment. The articles are generated by Artificial Intelligence. That's a whole different blog post.)

The reasons for excitement over Tafasitamab are pretty clear. In the InMIND trial, the phase 3 trial that led to its approval, 548 patients were either given R-Squared (Rituxan + Revlimid/Lenolidomide) or R-Squared plus Tafasitamab. The results were great. The Tafasitamab group had an 83.5% Overall Response Rate (versus 72.4% for the R-squared group) including a 49.4% Complete Response (versus 39.8%) and a median Progression Free Survival of 22.4 months (versus 13.9 months for R-Squared). Safety was comparable to R-Squared alone. You can find a good summary of all of the side effects here.

But here's why I'm a little skeptical about Tafasitamab becoming a new standard. One of the very enthusiastic pieces I saw about this said that this new combo would be a potential replacement for patients who would be eligible for R-Squared. This makes sense, given that it was shown to be more effective than R-squared. But how many patients would be given R-Squared in the first place?

About a year ago, the Follicular Lymphoma Foundation conducted a survey of FL patients from 49 different countries. One question asked which treatments the patient had received. In that survey, only 6.2% of respondents had received R-Squared. That's not a huge number. But if that's the ceiling -- if the Tafasitamab combination is going to replace it for some patients -- I'm not sure how much of a "game changer" it's going to be for patients in general.

I want to be clear about a couple of things. 

First, and most importantly, I'm not a doctor. I remind you all of that every now and then because it's really important for you to remember. I have not formal medical training. I'm not an oncologist or a cancer biologist (or a scientist of any kind). I'm a Cancer Nerd -- a patient who reads a lot, and then thinks and rights about what I read. So why listen to me? Good question. The most important person to listen to is your own doctor. 

Second, I want to be clear that I'm not anti-Tafasitamab in any way. Just the opposite. I hope it gets to the patients who would benefit from it. I still have a lot of frustration over RIT. I think it could have helped a lot of people 15 years ago, and it was frustrating t see it not being used. (Search for "RadioImmunoTherapy" on this blog and you can see my long history of frustrated posts.)

But take another look at the FLF survey. The treatment type that most patients have had? Chemotherapy, with 60%.  

And that's not necessarily bad (it can be very effective) and it's also explainable in some ways (FL patients can live for a very long time and treatment types were limited 15-20 years ago).

But I also think it's true that FL patients can be over-treated, given more aggressive treatments than necessary. (I'm getting this from a couple of conversations with oncologists.) People get chemo who don't need chemo, and maybe could do just as well with something like Rituxan.

So why so much chemo? I  read a comment from an oncologist once that doctors are creatures of habit. If they have always recommended chemotherapy, and it has worked well, there's not much reason to change to something else. It's hard to argue with that logic. As a patient, if my doctor said "My previous patients have done really well with Bendamustine," I probably wouldn't argue.

But I think that's ultimately what this is all about. Very few of us patients argue.

And I don't really mean "argue," as in getting mad at the doctor. I mean, few of us know enough to have a conversation with a doctor that might lead to a different option. Why chemo? What are the other alternatives? Why not them? Can you recommend someone else I can talk to for a second opinion? 

It's not really about arguing so much as asking questions. And that can be hard to do when you've just been told you have cancer. 

But it's what I hope you will do, especially with Relapsed/Refractory FL, when we've had some time to think and learn and perhaps plan. We don't all have the opportunity to get a second opinion, or to question the decisions that a doctor or a health plan make for us. But if we can? That's how change comes, and how good treatments get to people who need them.

Stay informed, and stay well.

 

Some Analysis on Tafasitamab (Monjuvi)

CURE magazine has a nice interview with Dr. Christina Poh of the Fred Hutch Cancer Center about Tafasitamab. 

As you might remember, Tafasitamab was recently approved by the FDA, in combination with R-Squared (Rituxan and Revlimid/Lenalidomide), for Follicular Lymphoma. I wrote about this recently, looking at the the announcement from the FDA. 

But Dr. Poh offers some more insight into why this approval is so significant. Some of it came out in the FDA announcement, but hearing it from a hematologist/oncologist at a prestigious cancer center is even better.

For example, Dr. Poh points out how great the design of the clinical trial was. It's a double-blind study, meaning half of the patients in the trial receive one treatment, and the other half receives a different treatment. This allows for a direct comparison between the two. But more importantly, as a "double blind" study, it means that neither group knew for sure which of the treatments they were receiving. Knowing the treatment (which happens in lots of trials) can influence how a participant feels. If they know a treatment may cause a certain side effect, the patient may "feel" that symptom and ask to pull out of the trial. That's not a criticism of the patient -- any trial participant has the right to pull out of the trial for any reason at any time. But it's one example of how a double-blind study can be more significant. 

Another element that Dr. Poh points out is that the population more accurately mirrored a "real world" population. Many trials for newer treatments have strict limitation on who can participate in the trial. It's for a good reason. If a new treatment might affect a patient's heart, for example, then patients with heart issues are kept out of the trial. If they did participate and then had heart issues, it would be hard to know if the new treatment caused the issue or if it was a pre-existing heart issue. Once a treatment is approved, researchers might do a "real world" study without those restrictions, to get a better idea of how the treatment will really affect all patients. Because all of the elements in this trial (Tafasitamab, Rituxan, and Revlimid) had already been approved, there was already plenty of "real world" data on side effects. So the trial could include a wide range of FL patients -- those who were asymptomatic, those with POD24, etc. So there is more certainty that the combination will be helpful for many patients.

Finally, Dr. Poh talks about the significance of this being a non-chemotherapy treatment. When R-squared was approved, it was a very big deal.  It was the first time a non-chemotherapy treatment was shown to be as effective as traditional chemo like R-CHOP or B-R. And now, this combination is perhaps even more effective than R-Squared. Because treatments like this are more targeted, affecting fewer non-cancer cells than chemotherapy, they have a different set of side effects. (One of the big takeaways from R-Squared being approved was just that -- different side effects, not necessarily fewer or less harsh side effects.) But the feeling is, according to Dr. Poh, that it will not result in long-term side effects like bone marrow damage that can come from chemo. So it may result in greater use by oncologists.

It will be interesting to see if that is true -- that this non-chemo treatment becomes a replacement for chemo, or if it becomes just another option for second and third line situations. I haven't seen too much of this kind of analysis, but it's speculation, anyway. "Real world" data will tell us for sure in the years to come.

Dr. Poh was on the team that conducted the trial, so she has seen the effects of the treatment in patients. If any of you has a conversation with your oncologist about this as a treatment option, please do share what you learned.

 

FDA approval for Tafasitamab-cxix for R/R FL

The FDA has approved Tafasitamab-cxix (also known as Monjuvi) in combination with Lenalidomide (also known as Revlimid) and Rituxan for Relapsed/Refractory Follicular Lymphoma.

I wrote about this combination in November, just before the ASH conference. The results of a phase III clinical trial were being presented at ASH, and the website Fierce Pharma called the early results a "triumph." The makers of Tafasitamab had said immediately afterwards that they were going to seek FDA approval. And it came.

Tafasitamab had already been approved by both the FDA and the EU for use on R/R Diffuse Large B Cell Lymphoma, in combination with Lenalidomide.

Tafasitamab is a monoclonal antibody, like Rituxan. But Tafasitamab targets a different protein, CD19, on the surface of B cells (Rituxan targets CD20). The idea was that combining the two (along with Lenalidomide) would increase the chances that the treatment could find the cancer cells. That seems to have been the case.

The trial involved a direct comparison between Tafasitamab + Lenalidomide + Rituxan and a placebo + Lenalidomide + Rituxan. In other words, patients in the trial were going to receive either this new combination or just R-squared (Lenalidomide/Revlimid + Rituxan). Patients in the trial had already received at least one treatment for their FL already.

As Fierce Pharma said, the results were triumphant. After a median follow up of 14.1 months, the Progression Free Survival for the Tafasitamab combination was 22.4 months and 13.9 months in the other group. The Complete Response Rate was 49.9% for Tafasitamab and 39.8% for the other group, and the Overall Response Rate was 83.5% vs 72.4%.

The question with the combination was going to be about safety. Monoclonal antibodies like Tafasitamab and Rituxan work by eliminating B Lymphocytes, a kind of immune cell. They target both healthy B cells and cancerous B cells. So while having two antibodies targeting the same cells might mean it's more effective, it also means you're running the risk f having too many immune cells being disabled all at once, opening up the possibility of greater risk of infections.

And that did happen. In their announcement, the FDA points out that "serious adverse reactions occurred in 33% of patients" in the Tafasitamab group, including serious infections in 24% of participants.The announcement doesn't give a direct comparison to the other group in the trial, though the ASH presentation did -- 36% of the Tafasitamab group vs 32% for the other group (the FDA numbers are a little different because they were updated 6 months later). Also in the ASH presentation, it was noted that during the study, 15 patients in the Tafasitamab group died, 5 because of disease progression and 6 because of side effects, versus 23 in the other group (17 due to disease progression and 6 from side effects). 

It will be interesting to see how popular this combination becomes with oncologists. Will this become a substitute for R-Squared? Similar way of working, but more effective? Or will some patients still be given R-squared instead because it seems slightly less aggressive on the immune system? (Remember, I'm not a medical doctor -- these are just questions that are coming to me immediately after reading this). I look forward to reading more commentaries in the coming weeks and months.

ASCO: Amulirafusp alfa

 As I have been saying, there really weren't a lot of presentations on Follicular Lymphoma at ASCO this year, and most of them have been focused on treatments that are already established.

But there is at least one presentation on a newer treatment. It's one that I haven't written about before. (To be clear, I'm not saying that I manage to write about everything FL-related. But this is definitely one that I haven't mentioned before.)

The presentation is Abstract #7051: "Phase II safety and preliminary efficacy of amulirafusp alfa (IMM0306) in combination with lenalidomide in patients with relapsed or refractory CD20-positive follicular lymphoma." I actually remember reading about this when I looked at abstracts from ASH in November and December, but for whatever reason, I decided not to write about it. The ASH presentation looked at phase 1 trial results. This one looks at phase 2 results.

In this research, a treatment called Amulirafusp Alfa is given in combination with Lenalidomide (also known as Revlimid, one of the Rs in R-Squared). Amulirafusp Alfa is a very interesting treatment. It worls in ways that are similar to a bispecific, but it isn't a bispecific (which attaches to a protein on a lymphoma cell, and to a protein on a T cell, a kind of immune cell, bringing them together so the T cell can elimiate the cancer cell).

Amulirafusp Alfa works by targeting two proteins on the lymphoma cell. One of them is CD20, the same protein that is targeted by Rituxan and by some bispecifics. But it also targets CD47, another protein on the cell. By attaching to CD47, it blocks something called SIRPα (Signal Regulatory Protein a). When CD47 and SIRPα interact, they send a "Don't Eat Me" signal to the immune system. When that interaction is blocked, the immune system can eliminate the lymphoma cell.

And just as a bispecific is an immunotherapy -- it allows the body's T cells to work against cancer cells -- Amulirafusp Alfa allows other (even more powerful) immune cells to work against the cancer cells, in this case Macrophages and NK/Natural Killer cells.

This phase 2 trial involves 34 patients with Relapsed/Refractory FL. All of them had a previous treatment with anti-CD20. In the study, 22 patients were evaluated; 10 of them had a Complete Response (45%), 8 had a Partial Response, making the Overall Response Rate 82%; 2 more had Stable Disease. As for safety, the side effects were considered "well-tolerated," with most pateints having descreased blood cell counts of different types, another 35% having an infusion-related reaction. About 65% of patients had a more serious (grade 3 or higher) side effect. 

It certainly seems like a promising treatment, one that works in ways that are different from what we have seen so far.  It will be interesting to see updated figures (only 22 of the 34 patients in the phase 2 trial were evaluated), and to see how this treatment goes in a larger phase 3 trial.

Definitely one to keep an eye on.

Two Quick Videos

As I said in my last post, I'm going to be away from the blog for a little while, but I'll be back before the end of the month. In the meantime, I'm planning to post a couple of things that will automatically be available, so you'll stay in the habit of reading.

This is the first one. 

The website OncLive posted a couple of video commentaries last week. They are short videos discussing some recent research on Follicular Lymphoma.

The first is a video featuring Dr. Vivek Patel of Vanderbilt University Medical Center, who discusses some of the issues with side effects from bispecifics.  He points out that recent clinical trials haven't shown any major (grade 3 or higher) side effects, which would be the most dangerous. There is still an issue with Cytokine Release Syndrome for some patients, but there are protocols in place to recognize and deal with CNS quickly before it becomes a problem. He believes bispecifics are safe and effective and are a good choice for a community-based setting, that is, a regular oncologist's office and treatment room, as opposed to a large hospital.

The second video features Dr. Lorenzo Falchi of Memorial Sloan Kettering in New York, who talks about the findings of the phase 1/2 EPCORE NHL-2 trial, which looks at Epcoritamab in combination with R-Squared (Lenalidomide /Revlimid and Rituxan) in patients with Relapsed/Refractory FL. As Dr. Falchi points out, with 111 patients in the study, there was an Overall Response Rate of 96%, including a Complete Response of 87%. He emphasizes the impressive Minimal Residual Disease rate of 88%, and those patients had a 21 month Progression Free Survival rate of 86%. He says the study says good things about the treatment combination, but also about the ability to use MRD monitoring to help guide decisions about treatment.

They are quick videos, but interesting subject matter. 

I'll set up another post to be published next week, so check back in a bit.

R-Squared: 10 Year Follow-Up

The journal Blood Advances just published an article called "Six-month rituximab-lenalidomide regimen in advanced untreated follicular lymphoma: SAKK 35/10 trial 10-year update." It says some excellent things about R-Squared, as well as about Rituxan.

The article reports on a phase 2 clinical trial conducted by researchers in Switzerland. It compares R-Squared (Rituxan plus Revlimid, also known as Lenalidomide) to straight Rituxan as a first treatment for Follicular Lymphoma patients. There were 154 patients in the trial, with grade 1 to grade 3A FL. Half were given Rituxan and half were give R-Squared.The data looks at results of the trial 10 years after it started -- a very long time for cancer research.

The study found that overall, the R-Squared combination worked better than the Rituxan.  The primary endpoint (the most important outcome being measured) was Complete Response at 6 months and then at 30 months. By comparing the two time intervals, researchers can get a sense of Duration of Response -- how long the response lasted.

The R-Squared combination had a longer duration of response. The median was not yet reached after 9.5 years (meaning more than half of the patients continued to have a response), while the duration of the Rituxan group was 3.2 years (still very good).  The median Progression Free Survival was also very good for the R-Squared (9.3 years versus 3.2). 

As far as efficiency goes, the R-Squared clearly won that comparison.

As for safety, things were a little bit different. There has been much research on the two types of treatment already, so the side effects are well-known. As expected, R-Squared tends to have more side effects than Rituxan (since there are two treatments being combined, each with its own set of side effects). No new side effects were noticed, and the R-Squared side effects were "manageable." Each of the groups reported a similar number of deaths after 9.5 years, with 15 in the R-Squared group and 14 in the Rituxan group, though one of the R-Squared deaths came from sever side effects. 

It's important to note here that deaths are from any cause, not necessarily from the disease or the treatment, with the exception of the one that was mentioned.

Along those same line, the Overall Survival of both groups about the same after 9.5 years: 77% for the R-Squared group and 78% for Rituxan. That's also not a surprise. The Overall Survival of most treatments for FL is about the same. It's very hard to show a survival benefit among treatments. If there was a big difference, we'd probably all be gravitating toward that treatment instead of arguing over which one was the right one.

And that's important to note, too. If the goal is to live as long as statistically possible, then there are lots of choices. So other factors have to be considered when choosing a treatment. If the goal is to avoid side effects right now and sacrifice a long PFS (meaning you'd need to get a second treatment sooner), that's different from tolerating harsher side effects now for the chance at a longer time until another treatment. that's why it's important to talk things out thoroughly with your oncologist before choosing a treatment. We all have different goals.

It's important, too, to remember that all of these numbers are medians. That means whatever they are measuring, the median is the exact middle. So if the median PFS for Rituxan is 3.2 years, then half of the patients had their disease progress before 3.2 years, and half went longer than 3.2 years. I've known people who didn't respond at all to Ritixan. And then there's me -- I had Rituxan 15 years ago and I haven't needed treatment since.

It's all very complicated, isn't it? 

I wish that wasn't how it is, but that's what we're dealing with. As I said, the best thing to do is keep up-to-date, including regular conversations with your oncologist. You have choices. It's best of they are informed choices. 

R-Squared in the Real World

As I mentioned in my last post, the medical journal Haematalogica recently published results of a real-world study of R-Squared. The quick summary: R-Squared still works well for Relapsed/Refractory Follicular Lymphoma. The article is called "Rituximab and Lenalidomide for the Treatment of Relapsed or Refractory Indolent Non-Hodgkin Lymphoma: Real-Life Experience."

First some background on this (or a couple of reminders for those of you who have been following for a while). R-Squared is short for the tretament combination of Rituximab and Revlimid (also known as Lenalidomide). Those two R words are usually shortened to R-Squared. (Interestingly, this article uses R-Len to describe the combination, which I have seen elsewhere, too. Revlimid is the brand name for Lenalidomide, so they're trying to avoid using the brand, I guess. I'm sticking with R-Squared because that's what I have been using since I first wrote about it in 2012, and I'm getting too old to change now.)

This is what is known as a "real word" study. That's an actual medical term. Many articles in medical journals that describe the results of research are describing the results of clinical trials. Trials are necessary for a treatment to get approved, and the patients in the trials are restricted in many ways. For example, patients with previous heart problems might be excluded from a trial because the researchers need to know if the treatment will cause heart problems. So only patients with healthy hearts are allowed in the trial.

But those restrictions can also make it hard to know if a treatment is appropriate for people who have lots of comorbidities (that is, other health problems). So after trials are over and a treatment has been approved, and after the treatment has been given to many patients, with no restrictions, some researchers will conduct "real world" studies. These are studies of how a treatment affects all patients, not just the small group that was allowed into the trial. They can confirm that a treatment is as safe and effective as it first seemed to be. 

R-Squared is an important treatment for R/R FL because it was the first non-chemotherapy that proved to be just as effective as traditional chemotherapy. So getting real-world results is important.

The researchers did a fairly small (84 patients) retrospective study, meaning they looked back at the medical records of the patients who had received R-Squared between 2013 and 2023. About 82% of those patients had been diagnosed with Follicular Lymphoma, so those are the ones we'll focus on (the rest had Marginal Zone Lymphoma, another indolent, slow-growing blood cancer). The median age for the patients in the study was 65, with the range being 39 to 94. (I find that highest age kind of fascinating, and I think it says something about how much easier on the body R-Squared must be compared to traditional chemotherapy.) 

The results were in line with what the clinical trials from several years ago had suggested. The Overall Response Rate was 82%, with a 52% Complete Response Rate. (The CRR for FL patients was 55%, and 40% for the MZL patients.) The median follow-up for the patients was 22 months, and the median Progression-Free Survival was also 22 months (the disease hadn't gotten worse in that time). The Overall Survival at two years was 83%, and the median duration of that Complete Response was almost 4 years. Patients in the study who had bulky disease (larger lymph nodes) or who were refractory to Rituxan (that is, that treatment had stopped working for them) were more likely to have a shorter Progression-Free Survival. 

As for safety issues, the side effects were also in line with the earlier clinical trial results. The most common side effects were low blood  ell counts, fatigue and gastrointestinal problems like diarrhea and constipation. As for severe side effects, the most common were low white blood cell counts (making patients more susceptible to infection) and low platelet counts (making them more susceptible to risk of bleeding). There were no new side effects reported. 

The researchers in the study see all of this as very positive, and their main take away is that R-Squared should continue to be used as a comparison in clinical trials. That is, if a new treatment shows it is just as effective and safe as R-Squared, then it should be approved.

I see another important take away from this, for what it's worth. I think R-Squared isn't used as much as it should be. This isn't the first research that shows "real world" success for R-Squared. And yet, according to a survey from the Follicular Lymphoma Foundation from last year, only about 6% of respondents had been given Lenalidomide as a treatment. (About 10 times as many had been given traditional chemotherapy.)

A big reason for that is probably just habit. For Relapsed/Refractory disease, chemotherapy has always been the go-to option. It seems like a whole lot of treatment recommendations boil down to "that's how we've always done it," especially in a community clinical (rather than a research hospital). That's not to say chemo is a bad choice, and is probably an excellent choice for aggressive FL. But it doesn't necessarily have to be the first and only choice.

I wonder how much newer treatments like CAR-T and Bispecifics will cut further in the use of R-Squared. It could end up being one of those treatments like RadioImmunoTherapy that had great results but just kind of went away because of under-use. (Though RIT had its own set of problems that made it under-used.)  

The big lesson here? Understand all of your options, and make sure your oncologist is considering them all. Best to keep up with these things and have be able to have a conversation when the time comes, rather than having to make a decision under pressure.

Of course, that's why you're here, isn't it?

More soon. Take care. 

Year-End Predictions

This is the last time I'll be posting in 2024. It's been an interesting year, for me personally and for the world of Follicular Lymphoma.

I had considered using this last post of the year to come up with a top 10 (or more likely a top 5) list of things that happened in 2024 related to FL. But honestly, I'm too busy and too tired, and even when I get a small break, something seems to fill my time. (Yesterday, it was our dog, who had to go to the hospital with an infection. She's doing fine. But my wife and I spent way more time than we wanted to trying to figure out how to get her to swallow her antibiotic pill. Our final solution involved American cheese, coconut milk-based yogurt, and cheese popcorn. But we got the job done.)

So instead of my going back and re-reading all of those posts and journal articles and figuring out how to rank them, I'm going to do something slightly different. I'm going to make three predictions about the long-term prospects of some of the FL-related things that happened this year. Maybe I'll remember to check in next year and see if I was right (though I think these might take more than a year to really work themselves out.

Prediction #1: Tafasitamab won't be the "game-changer" that the headlines predict it will. I've mentioned this a few times in the last month or so. The Big News fro the ASH meeting was the results of the stage 3 trial for Tafasitamab + Rituxan + Revlimd. Even before the ASH meeting, there were articles about how great the results were. And they were great. This is a non-chemo treatment with manageable side effects. It's been called a "game-changer." But to me, it's not going to change a lot of the ways that oncologists treat FL. As excited as many Lymphoma experts are about this, it matches the excitement that they had about R-Squared (Rituxan + Revlimid) a few years ago. But that doesn't mean that oncologists are recommending it. A survey by the Follicular Lymphoma Foundation found that only 6.2% of FL patients had received Revlimid (Lenalidomide), with or without Rituxan. I can't imagine that number is going to get bigger when a third agent is added to the mix. To be clear -- this combination is probably going to be approved by the end of 2025, and it's going to help a lot of people. But I predict that it won't be a game-changer. It won't become the default treatment for FL any time soon. Oncologists are creatures of habit. If you're seeing a generalist oncologist, get a second opinion from a Follicular Lymphoma expert if you can. See what other options are out there.

Prediction #2: Epcoritamab will have cause some concerns.  The ASH presentations for Epcoritamab, which was approved by the FDA this year, were very positive. It's the second bispecific approved by the FDA for FL. But the presentations also mentioned some safety issues. The same safety issues were voiced just after Epcoritamab data was presented at ASCO this year. The issues can be explained -- the clinical trial ran during the Covid pandemic, and like most FL treatments, Epcoritamab causes some immune system issues, which were especially important during Covid. Clearly, those issues were not enough to keep the FDA (or the EU) from approving it. But I have a feeling that there will be enough lingering concerns from oncologists that Epcoritamab won't be as widely used as it could be. I certainly hope that this isn't true, but my gut tells me those concerns haven't been completely answered. 

Prediction #3: There Won't Be Any Major Changes to the FDA Approval Process. This one is tricky. Back in March, I wrote about a movement to make the FDA cut back on surrogate endpoints and focus on Overall Survival. This would mean a longer, more rigorous approval process. However, in the second part of the year, political changes in the U.S. could potentially make it more likely that the FDA will loosen up regulations and be more friendly toward pharmaceutical companies, which  might make the process easier. Or maybe the opposite -- an FDA that does not have close relationships to people in the pharma industry. Honestly, I can't predict that, and we won't know what exactly will happen for another month at the earliest. But there is lots of speculation about potential good and bad changes at the agency and potential harm or help for cancer patients. My prediction? There will ultimately be little change. There might be a lot of big talk about change, but there will be very little actual change. Cancer treatments will remain safe and effective and will get approved only when they're ready. All of th talk won't match the reality.

So there you have it. My three FL predictions for 2025.

I want to remind you all that I am not an oncologist, or a cancer biologist, or a pharma insider, or anyone else that has any kind of information that would help with these predictions. Just a cancer patient who reads a lot. 

I hope you all have a Happy New Year. Eat your grapes, your black eyed peas, your soba noodles, your black bun, your crepes, and whatever else you eat to bring you good luck for the year. 

I'll be back soon with more. And you can all look forward to my diagnosiversary post in a coupe of weeks. I'll have some things to say.

 

ASH Review: Epcoritimab + R-Squared

 OK, SH is over, and it's time to continue to look at some of the presentations that made some noise. We already looked at some of the FL presentations that got some attention (those presentations on diet and blood cancer had some people talking on Twitter/X). 

So now it's time to look at the presentations that are getting attention after the meeting is over. 

Let me first respond to a comment from a reader named Peter, who wrote about my post on the "triumph" of Tasafitamab. He wrote "I’m always a bit skeptical of headlines that use superlatives (like “triumph”), especially when they’re from less scientifically rigorous sources (like fiercepharma)....A good mantra I learned to repeat to myself, back when I was first getting diagnosed and learning about lymphoma, is “if something sounds too good to be true, it probably is”. I found it the best way to try to control my own confirmation bias."

Amen to that. And it is with Peter's words echoing that I present to you "342 Fixed-Duration Epcoritamab + R² Drives Deep and Durable Responses in Patients with Relapsed or Refractory Follicular Lymphoma: 2-Year Follow-up from Arm 2 of the Epcore NHL-2 Trial." 

This presentation looks at data from a phase 1b/2 clinical trial. (This means they have combined the phase 1 study, which focuses on safety, and the phase 2 study, which focuses on effectiveness -- they use many of the same patients rather than having to start a whole new trial). There were 111 patients in the trial, and they received the bispecific antibody Epcoritamab as well as the combination R-Squared (Rituxan + Revlimid, also known as Ledalidomide). The patients all had relapsed or refractory disease (their last treatment didn't work or had stopped working). 

The results were very good -- the patients had an Overall Response Rate of 96%, and a Complete Response Rate of 87%. That's pretty great. The treatment worked well no matter what the patients' treatment history was. Patients with POD24 had a CRR of 79%, for example. After a median follow up of 24 months, an estimated 69% of patients were still responding to the treatment, and 75% of those with a Complete Response had maintained their Complete Response.

The researchers note that the study took place during the Covid pandemic, and 57% of patients reported getting Covid at some point, resulting in a number of health problems, though there were no Covid-related decisions to stop Epcoritamab.  The most common side effects were were neutropenia (62%) and Cytokine Release Syndrome (51%). At a median of 25.3 months, 17 patients (15%) were still on the treatment; 41 patients (37%) had completed treatment as it was described in the study description; and 53 (48%) had stopped treatment for several reasons: 18 of them had their disease progress, 22 had severe side effects, 7 withdrew from the study on their own, 1 died, one left because of Covid, and 4 left becuase of a doctor's decision.

So why the "If it's too good to be true, it probably is" attitude? 

A lot of the post-meeting analysis will come in the next few weeks or months, at least from oncologists and oncology-focused web sites. The more immediate analysis come from other web sites, and that's where almost all of the news that I got about this presentation came from, namely, finance and investment web sites.

In other words, at least immediately after the ASH meeting, the folks who are most excited about this are the ones who will make some money off of it. 

I've struggled with this for years, and in the United States, we're in the middle of a very controversial situation that is related to it. I won't get into that, because I don't think I can describe my feelings about it very well. 

But I also have to have a little skepticism about the excitement that a new treatment regiment is generating based mostly on a press release from the company that has developed it. It might very well be one of the ASH presentations that oncologists are excited about, and that they'll discuss elsewhere. But I'm going to hold off on my excitement until then, especially given that almost half of the trial participants dropped out before they finished. In their abstract conclusion, the researchers point out that there are no new side effects, compared to the Epcoritamab trial that resulted in its being approved for FL by the FDA and the EU. (And despite there being some safety concerns about Epcoritamab, too.) A few people are talking about it online, but no one is really bursting with excitement.

The clinical trial had a few arms, so there were patients who received Epcoritamab and B-R, for example. It will be interesting to see what oncologists have to say about all of it in the next few weeks and months. I'll keep you posted.

In the meantime, be the good critical thinkers that you are. Stay hopeful, but realistic.