Update on Epcoritamab

A quick update on Epcoritamab.

Epcoritamab is a bispecific antibody. I wrote about it less than 2 weeks ago in an ASH preview. I'm predicting that it will be the Follicular Lymphoma presentation that gets the most attention during and after the ASH conference.

Here's some attention before the conference as well:

The makers of Epcoritamab got some good news this week from the U.S. and from Europe.

The European Medicines Agency granted Epcoritamab a validation for a type 2 application for Relapsed/Refractory FL patients with at least two prior treatments.  The EMA is kind of European equivalent of the FDA, approving treatments before they are available to patients outside of clinical trials. A type 2 variance, as I understand it, includes things like expanding the use of an approved treatment. Epcoritamab was approved a few months ago as a treatment for R/R Diffuse Large B Cell Lymphoma.

In addition, the FDA has granted Breakthrough Therapy Designation for  Epcoritamab. This means that it will get a faster review than it would otherwise, because approval would mean a significant improvement in treatment options for patients with FL.

To be clear -- neither one of the agencies has granted a new approval for Epcoritamab for R/R Follicular Lymphoma. These are positive steps in the process. Both agencies will now take a closer look at the data, including the updated data to be presented at ASH, in determining whether or not to approve the treatment. 

That's good news for all of us. 

ASH Preview: Predicting POD24

I'm continuing my look at ASH abstracts, reading the summaries of the research on Follicular Lymphoma that will be presented at the conference in a few weeks. There is some really nice research happening. Nothing that is going to change things in a huge way. But lots of smaller, incremental progress, I think.

Two presentations showed up on my list next to each other. They both deal with predicting POD24. Lots of researchers have made this a priority. As you probably know, POD24 stands for Progression of Disease within 24 months. Research have found that FL patients who have successful immunochemotherapy (like R-CHOP or R-Bendamustine), but whose disease comes back or gets worse within 24 months, have a lower Overall Survival rate than other FL patients. POD24 was first proposed about 6 years ago from data in the GALLIUM study, and it affects about 20% of FL patients. It sometimes goes by other names like EFS24 (Event-Free Survival at 24 months). Slightly different, but essentially the same concept. 

Interestingly, the two ASH presentations that try to predict POD24 both try to build on the FLIPI model. 

I haven't written much about FLIPI lately, but it stands for Follicular Lymphoma International Prognostic Index.  FLIPI uses data like a patient's age, LDH levels, and disease stage to predict survival. It should NOT be used to determine an individual patient's survival, so if you are tempted to take the "quiz" that is linked above, do not panic if it gives you a bad outcome. It means nothing. As an example -- I just took the quiz and it gave me a 50/50 chance of surviving 10 years. I'll celebrate my 16th diagnosiversary in a couple of months.

FLIP is useless in predicting anything about an individual. It's far too general to do that, and it wasn't developed to do that. Instead, it was developed to help analyze clinical trial results, by giving FLIPI scores to participants so they could measure groups, not individuals. Treat FLIPI like a Buzzfeed quiz that predicts which Disney Princess you would be, because it's about as accurate in predicting your future. (That quiz said I was Tiana, when I'm obviously Belle, though Tiana is a pretty good second choice.)

There have been a lot of attempts to build on and refine FLIPI, adding more specific criteria that make more sense as predictors. A biomarker says a whole lot more about an individual's survival than their age. 

The two ASH presentations use refined FLIPI scores to try to predict POD24. They take very different approaches to developing them.

The first is presented in "1657: The FLIPI24 Prognostic Model Identifies Poor Outcomes in Non-Immunochemotherapy Treated Patients with Follicular Lymphoma." As I say above, POD24 involves FL patients who have received Imunochemotherapy.  This group of researchers is interested in FL patients who have progressed within 24 months who did not receive Immunochemotherapy, hoping to find a way to predict progression in that group of patients. They developed the FLIPI24 model to help them do that. The FLIPI24 measures some specific things -- age and LDH levels (both in the old FLIPI model), Hemoglobin (a protein that help carry oxygen in the blood), White Blood Cell counts, and B2M (a biomarker for a gene that is involved in cancer cell growth and survival). Their research looked at 1542 FL patients who had received different treatments like watching and waiting, straight Rituxan, and radiation (and a few more unspecified). 

The researchers found that their model did a good job of predicting EFS24 (Event Free Survival within 24 months). By grouping patients by risk, they were able to identify high risk patients, and this group had a median Event Free Survival of 1.8 years and a 5 year Overall Survival of just 65.1% (the whole group had a 5 year OS of about 90%). These smaller numbers held whether the patient had high or low tumor burden at diagnosis, and even if they were watching and waiting. In other words, clinical signs at diagnosis might have looked like the disease wasn't too aggressive, but the predictor model suggested otherwise. 

The second presentation took a very different approach. This one is called "3048: Development and Validation of a Machine-Learning Model to Predict POD24 Risk of Follicular Lymphoma."As the title suggests, this group of researchers used Artificial Intelligence (machine-learning) to develop their FLIPI variation, which they call FLIPI-C.  As I have written about before, I am very interested in AI and how it can help cancer patients. Still skeptical, but hopeful.

This group of researchers sued machine learning, a type of AI that can learn to develop algorithms, or ways of making decisions based on statistical patterns. One of the potential good things about AI is that it can look at things in ways that humans can't, because of our own biases, or because looking at the data would be expensive and time-consuming. That's what this group is doing with AI. (I'm being very generous here with AI's capabilities. As I said, I'm still skeptical.)

The researchers looked at 1938 patients with grade 3a Follicular Lymphoma. There are lots of statistics involved here, which is not my strength. But essentially, the researchers looked back at the FL patients and used the AI program to identify features that were common to the POD24 patients and then developed a new FLIPI model from there. They compared their model to other FLIPI variations. 

Interestingly, there is some overlap with the FLIPI24 model above, like measuring LDH, Hemoglobin, and B2M, but also includes things like comparing some white blood cell levels and several more involving lymph nodes (not much detail in a summary of just a few hundred words -- it will be interesting to see all of it laid out in a journal article some day).

What I find most interesting about the two studies is the overlap. They came at them from different directions, and came to some of the same conclusions. That gives me some hope that an improved FLIPI model could help. I'll be very interested to see if anyone does a more thorough job of comparing these two presentations in one of the many commentaries that will come out in the next few months.

Whatever the case, I'm pleased that there is continued effort to figure out early on which FL patients are likely to be POD24. That might mean more aggressive treatment early, or more careful observation, or ideally, the development of new treatments based on newly discovered biomarkers. Some kind if help for this vulnerable group would be wonderful.

I'll keep reading and sharing. Stay tuned.

ASH Preview: Epcoritamab (Bispecific)

OK, enough about skin cancer. This is supposed to be a blog about Follicular Lymphoma. 

So let's get back to the ASH convention and what is coming up there.

It's always interesting to guess which FL presentations at conferences (if any) are going to get lots of attention by the oncology community. Occasionally, there are some blockbusters that change the way FL patients are treated (like when R-Squared trial results were announced). Most years, there isn't much that generates a lot of excitement on sites like OncLive that cover cancer news.

If I had to guess which presentation will get some attention this year, it will be this one: 1655 Epcoritamab SC Monotherapy Leads to Deep and Durable Responses in Patients with Relapsed or Refractory Follicular Lymphoma: First Data Disclosure from the Epcore NHL-1 Follicular Lymphoma Dose-Expansion Cohort. 

Epcoritamab is a bispecific antibody. To remind you of what that means -- a bispecific antibody works sort of like a monoclonal antibody like Rituxan. It targets a protein on the surface of the cancer cell. In fact, Epcoritamab targets the same prtein that Rituxan targets -- CD20. But a bispecific has a second part to it ("bi" in "bispecific" means "two," so two parts to it). The second part targets the protein CD3 on T cells, a kind of immune cell. So by bringing the cancer cell in close contact with an immune cell, the bispecific helps to eliminate the cancer cell. 

There is already a bispecific approved by the FDA for FL -- Mosunetuzumab (for patients with relapsed/refractory disease who have had at least 2 treatments). Another (Odronextromab) has received priority review from the FDA. And Epcoritamab has been pretty successful, too. It has been approved in the US and UK for r/r Diffuse Large B Cell Lymphoma. And at the ASCO conference last June, some results were shared that showed a successful pairing of Epcoritamab and R-Squared. 

This research at ASH focuses on single use Epcoritamab, tested in a phase 1/2 clinical trial. It's a fairly large trial for one that is early -- 128 patients with r/r FL who have had at least 2 prior treatments. The ASH abstract makes clear that the hope is to show that Epcoritamab can work for as many patients as possible. They point out all of the different prior treatment types that patients had received -- 77% had anthracyclines (like R-CHOP), 31% had Lenalidomide, 19% had a stem cell transplant. 

Most patients (54%) were primary refractory (they never had a Complete Response to a treatment), 70% were double refractory (two treatments didn't work), and 69% were refractory to their last treatment. In addition, 42% were POD24 (their disease returned within 24 months of receiving immuno-chemotherapy). So, in short, this is a group of patients that could really use a good option.

Results were very good.  The Overall Response Rate was 82%, with a Complete Response Rate of 63%. (For the sake of comparison, the phase 2 trial that led to Mosunetuzumab's approval showed an 80% ORR and a 60% CR). More importantly, the response rates were pretty consistent across high-risk subgroups -- double refractory patients had an ORR of 76% and a CR of 56%, POD24 were 80% and 60%, etc. Patients who had 2 prior treatments had response rates of 89% and 72%; 3 prior treatments were 88% and 68%; 4 or more prior treatments were 68% and 45%.

As for safety (the most important thing being considered in a phase 1 trial), the most common side effects were Cytokine Release Syndrome (66%), injection-site reaction (57%), COVID-19 (40%), fatigue (30%), low white blood cell counts (28%), diarrhea (27%), and fever (25%). Side effects leading to stopping treatment happened to 19% of patients, the most commonly because of COVID-19. Side effects were mostly low grade.

(It's worth noting that the data here is from patients treated from  2020 to 2022, at the height of Covid. It makes sense that a treatment that compromises the immune system would result in such a high number of people stopping treatment. This is the first time I've seen Covid mentioned this way in a trial write-up.)

So overall, this is very good news. It's still a very early trial. I don't imagine an application for approval will come until there is more data (the FDA is being more careful about these things lately), but it's good news. And since bispecifics are one of the treatment types that gets oncologists most excited these days (along with CAR-T), I'm guessing it will be included in news stories and summaries about the best things that happened at the conference.

I'll try to pick out a few more gems from the abstract list. The conference is coming up pretty soon -- just a few more weeks. I'll see how much reading I can do before then.

Skin Cancer Surgery

 A quick update -- I had my skin cancer surgery yesterday. It all went fine.

As you might remember, I was diagnosed a few weeks ago with Basal Cell Carcinoma on the top of my head. Basal Cell Carcinoma is the most frequently diagnosed cancer in the United States. It is generally not very aggressive, though if it goes untreated, it can cause problems. Mine was caught pretty quickly (I see my dermatologist every 6 months for this exact reason).

I've written about this before, but my skin cancer likely came because of a combination of things -- my own carelessness when I was young, leading to multiple bad sunburns, plus having a cancer of the immune system, plus getting a treatment that messes with my immune system. That perfect storm of factors probably all contributed to the cancer. It happens to about 1 in 10 FL patients, roughly.

So, as far as the surgery goes, it was both fast and slow. The fast part was the actual surgery. I had the basal cell carcinoma removed with Mohs Surgery, which is common for skin cancers. Basically, the surgeon removes a thin layer of skin, and then checks it for cancer cells. If there are cells present, then they remove another layer and check that. And they keep going until there are no more cancer cells present. It's an effective and less-invasive surgery than some others, since they are able to work on only the areas that have cancer cells present.

So the incising part was fast -- maybe 5 minutes. But then came the slow part -- bring the sample to an in-house lab and going through the process of finding the cancer cells. That took about 90 minutes. They told me to bring a lunch and something to keep me occupied, since it could take a while if I had multiple layers to remove. I brought some work with me, thinking I'd be productive. But I ended up in the regular waiting room, which wasn't too conducive to the work I had brought. So I did some reading instead. The time passed OK.

After the first round, the surgeon said there was one more area with cancer cells, but he was confident that he could get them all on one shot. So he did some more work, then stitched me up and sent me home. He said if he found more cancer (which he didn't think was likely), he'd let me know. I didn't get a call within a couple of hours, so I'm clear.

I've had a little bit of pain, but nothing that some Tylenol hasn't taken care of. So it hasn't been too horrible an experience. Cancer is always serious, and surgery is never fun. But I'm doing OK. I did that work I had hoped to do when I got home.

It was, in the end, a fairly small incision, covered by a fairly big bandage:

So, as always, the lesson here is -- take care of yourself. Go to your doctor appointments. Do whatever tests and preventative and diagnostic procedures that you are supposed to. I know those of you reading are cancer patients and caregivers -- you take this stuff seriously. Remind the people that you love and make sure they take it seriously, too.

Take care, everyone. More soon on that other cancer that we are all so interested in.

Goodbye to the Last PI3K Inhibitor

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

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

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

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

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

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

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

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

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

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

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

ASH Abstracts (and Watching and Waiting)

 ASH Abstracts are here!

For those of you who are newer to this, ASH is the American Society of Hematology, a large group of blood disease specialists (including blood cancers like Follicular Lymphoma). Every year, they have a big meeting, usually in early December. This year it will be held December 9-12.

And about a month or so before the meeting, they release their abstracts -- the summaries of the presentations that researchers will make at the meeting. (The abstracts are available to view online.) The presentation might be about new research or clinical trial results (my favorite), or research that looks more closely at already available treatments (also very interesting), or research done on topics like survivorship, diet and exercise, or other topics related to blood cancers. 

I read as many of them as I can, and try to talk about some of the interesting ones here. 

I'm already getting emails about the research that will be presented. The makers of Yescarta (or Axi-cel), a CAR-T treatment, are planning to present a whole bunch of updated research results at ASH, according to a press release I got today.

My quick look at the abstracts tells me that there should be a whole lot of good things to share this year. I haven't looked deeply enough to know if there will be a game-changer for FL, but I'll keep my eyes open.

I'll share a quick one, though, that I found interesting -- abstract #4417: Time to Lymphoma Treatment within 24 Months in Watchful Waiting Follicular Lymphoma Defines Patients at High Risk for Progression: A Multicenter Analysis.

As someone who watched and waited (for 2 years, to the day!) before getting treatment, any research on W & W always catches my eye. This presentation looks at 411 FL patients diagnosed between 2008 and 2022, who watched and waited until they needed treatment. the researchers are interested in whether TLT (Time to Lymphoma Treatment -- the amount of time between diagnosis and treatment) affected survival outcomes.

They found that patients who needed treatment within 24 months of beginning watch and wait had lower 5 year Progression Free Survival. The 5 year PFS for the TLT24 group (as they are calling it) was 62.3%, while the 5 year PFS for those who didn't need treatment within 24 months was 89.5%. The researchers developed a model that uses clinical and laboratory factors to identify patients at high risk for TLT24, and recommend that those patients get early treatment instead of continuing to watch and wait.

This is one of those presentations that make we wish I had more information. My ears kind of perk up a little at this, given that the time period covered begins right when I was diagnosed (in January 2008) and includes information that involves me (I was TLT24 myself, apparently). Looking back, i am firmly in the 62.3% that had a good 5 year PFS. It makes me a little defensive.

But then I step back and put on scientist hat (remember, I'm not an actual scientist, so I have dress up like one). And I remember that statistics look at a large group of people reduced to numbers, not at individual patients. 

I'd still like to know more about the patients in the study, and how many of them had factors that put them at greater risk already. And I have to remind myself that this research is not a criticism of watching and waiting -- no one is saying that the W and W caused the problem (I do see research that seems to imply that every now and then).

No, it's a good thing -- an attempt to find out early on whether watching and waiting is a good option for people. If we knew that, it might help with the emotional decision that a lot of people have to make. I know very well what a weird thing it is to have a doctor say "You have cancer, but we're not actually going to treat it." Being able to say "Based o these factors, you're at a lower risk, so we can wait" might be a great thing. And so might, "Based on these factors, even though you're asymptomatic, we think you should get treatment now and potentially avoid problems later." It's one more factor to help patients make a decision.

So that was a good one right off the bat. I'm sure there will be some more interesting research to come.

Stay tuned.