Follicular Lymphoma Approvals and Trials at ASH

Hello all. 

This is probably my last post for 2022, so I was looking for something appropriately "end of the year"-themed. I couldn't find anything like that, and I don't have time to come up with my own Top 10 list, so I'll offer two things that I think kind of sum up The Year in Follicular Lymphoma.

The first is a quick screenshot from the FDA list of approvals in oncology for the year. There were two FDA approvals in 2022 for Follicular Lymphoma: 

In case that's hard to read, the approvals were for 1) Tisagenlecleucel (also known as Kymriah), a CAR-T treatment approved for patients with Relapsed/Refractory FL who have already had at least two treatments, and 2) Mosunetuzumab (also known as Lunsumio), a bispecific that is also approved for patients with Relapsed/Refractory FL who have already had at least two treatments.

That seems appropriate -- two approvals, one for CAR-T and the other for a bispecific. Those seem to be the two treatment categories that have created the most excitement among Lymphoma experts over the last year. They are both very effective and fairly safe, and move us even further away from traditional chemotherapy (though chemo still has a place for many FL patients, and will for a while). 

So that's a good way to end the year -- looking back at the success that researchers have had in changing the way patients are (and will be) treated.

The second things I want to share is one more look back at ASH. This one is from the website Cancer Therapy Advisor, called "ASH 2022: Trials Show Promising Results in Follicular Lymphoma." It highlights four clinical trials that had results presented at ASH this month. 

Interestingly, the first two trials that I already wrote about: one that showed that Rituxan by itself or with maintenance can give some FL patients a long time until next treatment, and one on the bispecific Odronextamab, which had excellent effectiveness, but raised some questions about safety.

The third one highlighted in the article looks at trial results for Tisagenlecleucel (also known as Kymriah), the CAR-T treatment approved earlier this year. This ASH presentation gave some updated results. The original trial report showed that the overall response rate (ORR) was 86%, and the complete response (CR) rate was 69%. The follow-up showed that it remained effective over a longer-term, with Progression-Free Survival at 67% and Overall Survival at 95% at 12 months, and the PFS rate of 57%, and the OS rate was 88%, after 24 months. 

Interestingly, the article includes an interview with an oncologist who says that we likely won't see CAR-T used in a community setting for 10 more years. In other words, patients will have to go to a hospital for CAR-T treatment, rather than going to an oncologist's office, the way some patients can for chemo, or Rituxan, or even bispecifics. There are still just to many risks involved with things like Cytokine Release Syndrome to administer CAR-T outside of a hospital, where such problems can be handled quickly. 

The fourth presentation is for a "triplet" -- a combination of three treatments. Combinations often have good effectiveness (since they usually come at the cancer in three different ways), but often have safety issues (since the side effects from three treatments can pile up and be three times as bad).

This triplet involves Polatuzumab, Obinutuzumab, and Lenalidomide. Obinutuzumab is a momoclonal antibody, used as an alternatuve to Rtuxan. Lenalidomide is also known as Revlimid, and is part of the R-Squared combination. 

Polatuzumab is less commonly used in Follicular Lymphoma. It's classified as an antibody-drug conjugate. It's like Rituxan, in that it attaches to a protein on the surface of a B cell. But it also has a bit of chemotherapy attached to it as well, so it can deliver the chemo directly to the cancer cell (like the way Zevalin delivers radiation, or a bispecific delivers a T cell). 

This triplet is effective and durable. The PFS rate was 83.3% at 12 months, 67.4% at 24 months, 64.6% at 36 months, and 53.4% at 48 months. The median Overall Survival was not reached. Safety is a concern (as it often is with triple combinations). 86% of patients had a grade 3 or higher Adverse Event (a serious side effect), with 3 fatalities. Most patients (77%) had a side effect serous enough to lead to stop treatment temporarily, and 34% had one that led to stopping permanently.

The researchers seem to think that this combination would do well in a larger study, with one commentator suggesting it could be directly compared to R-Squared in a randomized trial.

So there we are, at the end of 2022: lots of promise from some new treatments, lots of refinements to the treatments we already have, and lots of possibilities for the future.

Progress seems slow sometimes, but I continue to think that we're in a good place as FL patients, especially compared to where we were just a few years ago.

My plan for 2023 is to continue to do what I've been doing, keeping up with news in the world of Lymphoma and sharing what I learned. My 15th diagnosiversary is coming up just a few weeks. I'll have some things to say on that day.

I hope everyone has a happy and healthy end to 2022, and a good start to 2023.   

FDA Approves Mosunetuzumab for R/R FL

Yesterday, the FDA approved the bispecific treatment Mosunetuzumab for patients with Relapsed/Refractory Follicular Lymphoma who have had at least 2 prior treatments. The treatment will go by the name Lunsumio (but I'll probably keep calling it Mosunetuzumab anyway).

The approval is based on results from a phase 2 clinical trial, so a phase 3 trial will be necessary to confirm that it works on a larger group of patients. But it will be available in a few weeks while that trial is being run.

It's a big deal. It's the first bispecific approved for FL in the United States (the European Commission approved it using pretty much the same data, back in June). As you know if you've been reading the blog, lymphoma experts have been very excited about bispecifics for a few years. Once data from trials started becoming available, it was pretty clear that bispecifics could be a game-changer -- a non-chemotherapy treatment option that uses the immune system to kill cancer cells. I've been very interested in it for a few years, since I asked my oncologist which treatments he would consider if/when I needed treatment again, and he mentioned this trial.

As a reminder, a bispecific works by targeting two proteins, one on a cancer cell, and the other on a T cell, an immune cell. Mosunetuzumab targets CD20 on the B lymphocyte that turns cancerous in patients with FL (it's the same protein that Rituxan targets), and then targets CD3 on the T cells. It brings them together so the T cell can take out the cancer cell. 

It's very effective. The phase 2 trial that led to FDA (and EC) approval showed an 80% Overall Response Rate, including 60% of patients getting a Complete Response. It was also pretty durable, with the time that the treatment lasted being a median of 22.8 months. The most common side effects were Cytokine Release Syndrome (39% of patients), and fatigue, rash, pyrexia and headache (all more that 20% of patients).

Bispecifics are often talked about at the same time as CAR-T (see my last post, for example). They do have some things in common, including that they work by have T cells go after the cancer cells. They're also different in many ways, including cost (because CAR-T needs to be made specifically for each patient, it can be more expensive). A conversation with your oncologist will help sort out which would be most appropriate. 

As I said above, the approval is for FL patients who have had two or more treatments already, so newly diagnosed patients wouldn't be eligible, and neither would I (not having had a second treatment). But it will benefit a whole lot of FL patients out there.

And of course, it's important to remember that this is a provisional approval, and if the results of the next trial show that, for example, there are some dangerous long-term side effects, then approval would be withdrawn. (It happens, unfortunately.)

But for now, there's lots to be excited about.

More ASH commentary soon.

Stay well.

ASH Review: Blood Cancer Progress

There's still a little more to be said about this year's ASH conference, and I will share that soon. 

One of the great things for me about the things that are published after a conference like this is seeing the excitement in experts' writing or hearing it n their voices, as they talk about what they have just seen at the conference. I want to share one of those commentaries. It's by Dr. Vincent Rajmukar, a blood cancer specialist at the Mayo Clinic in Minnesota (you can read his profile here -- he's clearly someone who knows what's happening in the blood cancer world).

 Right after the conference, Dr. Rajmukar wrote a Twitter thread about why he was excited about the progress being made in blood cancer research. There were a whole lot of things that excited him.

You can read the thread here. You don't need to have a Twitter account to read it -- it got collected on a different website so it could be easily read. It's just a series of short statements, but together, they really do present a whole bunch or reasons to be excited about where we are, and where we're going, in blood cancer research.

It's pretty short and easy to read, but I'll sum it up for you here anyway:

• Immunotherapy is changing everything. Our ability to understand how genes and proteins influence the immune system and its relationship to cancer has completely revolutionized the way researchers approach cancer.
• CAR-T and Bispecifics are the most exciting types of blood cancer treatments happening right now, and they are just beginning. They're already good, and improvements are on the way. They are a direct result of our understanding of genes and proteins and the immune system.
• (When I say "we" and "our," I'm obviously not including myself as part of the research team doing all this. I mean it the same way as someone from Argentina saying "WE won the World Cup!" I let others do the work and then share in the excitement.)
• That understanding of genes and proteins is also creating even more targets for future treatments. (Remember, CAR-T and Bispecifics are general categories, not specific treatments. Future researchers may find different ways to target genes and proteins in ways that improve CAR-T and Bispecifics.)
• That knowledge also allows us to find very small bits of cancer that don't show up on scans -- Minimal Residual Disease -- that could let us find recurring cancer early, making it more treatable.
• mRNA technology, the same approach that created some of the Covid-19 vaccines, is being used as possible cancer treatments as well. We'll be hearing more about that in the near future.
• Technology has allowed researchers to collaborate in ways that weren't possible just a few years ago. Teams from around the world can share data and speak to one another much more easily now.
• Patients can use technology to communicate with doctors much more easily, too. A Zoom meeting can connect a patient with a cancer expert thousands of miles away. We aren't necessarily limited to the doctors that live near us.
• I'll let Dr. Rajmukar's words stand for themselves here: " I am also totally impressed by the talent of the next generation of investigators. These are some brilliant people who are driven to find ways of improving outcomes in cancer."
• Still lots of challenges --  fancy new treatments come with high prices, some of them are/will be complex to administer (like CAR-T), lots of  new treatments means lots of clinical trials, which will require willing participants and high costs, etc. 
• But even with those challenges, there is so much to be hopeful about.
  

I was very happy to have seen that thread on Twitter. There really is so, so much to be hopeful about. And hearing and seeing it directly from a leading lymphoma expert makes it even nicer. 

More ASH information to come soon.

ASH Review: Odronextamab (Bispecific)

 First of all, a couple of photos from the ASH conference (I wasn't there, but there are a whole lot of photos from the conference on Twitter):

 

The first photo is a group of oncologist/hematologists (I blocked out their faces). The second one are the ASH mascots: a white blood cell, a drop of blood, and (I think) a macrophage, another type of immune cell. The blood mascot made an appearance last year, I think, but the other two are new. I'm glad everyone had a good time (that's what conferences are for, in addition to learning about new research). But if I was a platelet, I'd be pretty unhappy that I was left out.

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One the bad things about not being able to go to a conference like ASH in person is that I miss out on things like photo ops and mascots. But ASH happens at the worst time of year for me for my job, and they don't offer discounted registration for independent patient advocates anyway. 

But the other bad thing is that I only get to read the abstracts -- the summaries of the presentations that I always link to. Those presentations are usually presented as posters (with a little more detail than the abstract) or oral presentations (with a lot more detail, plus questions from the audience). For the presentations that seem to make the most impact, there will at least be some discussion on Twitter, or maybe a press release from the researchers, and some discussion online immediately afterwards. 

Today is the last day of ASH, so I'm starting to see some of those press releases and online discussions. And it's clear that bispecifics are the big news for Follicular Lymphoma this year. People seem very pleased with the updated results for Mosunetuzumab, as I discussed in my last post.

But more controversial are the results for Odronextamab, a different bispecific (I gave this a very brief mention in my last post, because the results seemed good, but not overly exciting to me, based on just the abstract.

However, there are two stories being told about Odronextamab today, after the ASH presentation last night. One is very positive, and the other is a lot more cautious. 

The official story from the company that makes Odronextamab is the very positive one, as their press release makes clear. And the results do show some very good effectiveness. Odronextamab is a CD20 x CD3 bispecific -- it attached to the CD20 protein on a lymphoma cell, and then to the CD3 protein on a T cell, an immune cell that can kill the cancer cell. The results from the phase 2 clinical trial show that it had an 82% Overall Response Rate for patients with Relapsed or Refractory Follicular Lymphoma, with a 75% Complete Response Rate. Those are excellent numbers for a phase 2 trial. The company says they are the highest response rates ever for R/R FL patients, and that the trial has set a "new benchmark." And the response was durable, with the Complete Response lasting a median of 20.5 months.

But then there's the other story, which focuses on safety. As several commenters have pointed out, there are some very serious side effects with this trial. In fact, Odronextamab was put on clinical hold two years ago because of serious side effects.

One of the big side effects was Cytokine Release Syndrome (CRS), which seems common in bispecifics, and definitely in CAR-T. And there were others --- all 131 FL patients had side effects, with 118 of them related to the treatment. There were 81 serious events. There were also 17 deaths recorded during the study, with 6 of them related to the treatment (the others were for things like Covid), with causes such as pneumonia, a brain infection and a fungal infection. Another 15 patients had to leave the trial because of problems like CRS, tremor, epilepsy, high liver enzyme s, etc. The company points out that it did take steps during the trial to cut down on some of these side effects like CRS.

 

The company that makes Odronextamab is planning a phase 3 trial immediately, but is also going to apply to the FDA for accelerated approval. It has already been given Orphan Drug Designation was for FL by the European Medicines Agency (which means it will get some special help during the approval process). It will be very interesting to see what regulators have to say about the side effects. As one lymphoma expert pointed out on Twitter, Mosunetuzumab doesn't seem to have these same safety issues, despite using a similar mechanism.

So far, this has been the most-talked-about presentation from ASH this year. It officially ends today, so there will probably be more experts weighing in the days and weeks to come.

I think the big lesson here is a reminder that, for now, cancer treatments are always about the balance between effectiveness and safety. Treatments that are very good at killing cancer cells are also more likely to cause problems. It's pretty hard to avoid. Maybe someone will figure out how to do that in the future, but for now, it's about recognizing them early and managing them well. 

I'll continue to look out for expert commentary from ASH, and share what I find out. 

In the meantime, may your days be filled with large, cuddly pathogen-killing immune cells like the ones in the pictures.

ASH Preview: Bispecifics for Follicular Lymphoma

More on what's happening at ASH this weekend. 

William asked in a comment what I found interesting with bispecifics. There's actually a lot of bispecifics research being presented, some on new treatments, some on treatments that have been in trials for a while. But it's safe to say that bispecifics and CAR-T are still the treatments that get lymphoma experts the most excited these days.

As a quick reminder: bispecifics act sort of like monoclonal antibodies, in that they find a protein on a cancer cell (like CD20) and attach to it. But unlike a monoclonal antibody, they have two sides (that's the "bi" in the name), and the other side attaches to a protein on a T cell (an immune cell), allowing the T cell to eliminate it.  Very effective, and pretty safe.

Right now, there are not any bispecifics approved for use with Follicular Lymphoma in the U.S. The closest we have is Mosunetuzumab, which is currently under review by the FDA, though it has been approved by the EU. The FDA set a target date of December 29 for a decision, so we may hear something soon.

In the meantime, there are a few interesting presentations on Mosunetuzumab at ASH. For example, "610 Mosunetuzumab Monotherapy Demonstrates Durable Efficacy with a Manageable Safety Profile in Patients with Relapsed/Refractory Follicular Lymphoma Who Received ≥2 Prior Therapies: Updated Results from a Pivotal Phase II Study." The phase II clinical trial results are what the FDA will base its decision on, so this update is important. And the results are very good -- the Overall Response Rate was 77.8%, and Complete Response was 60%. And 79.5% of those with a CR remained in remission for 24 months. This treatment was given to patients with 2 or more previous treatments. When the researchers compared the results to the patients' previous treatments (chemo, PI3K inhibitors, CAR-T, or R-squared), the bispecific treatment had a better response rate, Progression-Free Survival, and time to next treatment. And in this update, there were no new major safety issues. It's easy to see why people are excited about it.

There will also be a description of a trial using Mosunetuzumab and Lenalidomide (no results yet). And in another presentation, a subcutaneous version of Mosunetuzumab is shown to be effective and safe. (Subcutaneous means it can be given under the skin, as a "shot," rather than as an IV.)

There are other bispecifics for FL that are getting attention at ASH. 

Plamotamab, for example, showed good effectiveness and safety in a phase 1 trial.

Epcoritamab is being tested on R/R Follicular Lymphoma in a phase II trial. (This is a subcutaneous bispecific.) It is also being tested in combination with R-squared.

Odronextamab is another bispecific with high response rates for FL in a phase II trial.

So, to sum things up, there might not be anything that is really game-changing about bispecifics at ASH this year. But instead of one big impressive presentation, there are a whole lot of very good presentations about bispecifics that show that it is a treatment that will probably be with us for a very long time. That's certainly the story that many are telling -- the future of FL will revolve around CAR-T and bispecifics, and since bispecifics are probably going to be less expensive, and thus maybe more popular.

Of course, we still don't have an approved bispecific in the U.S., and no real long-term data for effectiveness and safety. I'm kind of seeing shadows of PI3K inhibitors -- lots of excitement, priority review and approval, and lots of variations. And we know how that worked out. 

But I'm more optimistic about bispecifics. As a reminder, I'm no expert -- I'm not a medical doctor or  a cancer researcher. But it seems like 25 years of monoclonal antibody research might matter, since bispecifics work by a similar mechanism.

Lots to be hopeful about.

More ASH previews soon.

 

ASH Preview: The Costs of CAR-T

I saw my first television commercial for a CAR-T treatment recently. It kind of confused me a little bit, but then, most ads for cancer treatments have that affect on me. It's customary in the U.S. to include an "ask your doctor about...." statement in those ads, as if most of the population just casually brings those things up during doctor appointments ("My elbow hurts when I raise my coffee mug. Hey, what's this CAR-T stuff I saw an ad for when I was watching that rerun of Modern Family?")

But that's the way it is with our healthcare system. I have no idea if other countries, who have single-payer healthcare systems, even have such things as television ads for pharmaceutical treatments. I'm guessing you do not.

But I was thinking of that when I read an abstract for an ASH presentation called "4859 Total Costs of Care during Chimeric Antigen Receptor T-Cell Therapy in Patients with Relapsed/Refractory B Cell Non-Hodgkin Lymphoma: A Large Private Insurance Claim-Based Analysis."

CAR-T has been probably the most talked about, and most promising, blood cancer treatment in the nearly 15 years since I was diagnosed. It gets people very excited. At this year's ASH conference, there will be about 350 presentations related to CAR-T in some way. It's a big deal, as I'm sure you all know.

But one of the big criticisms of CAR-T has been the price. The treatment is developed by removing some T cells from a patient, changing them in a lab so they'll recognize cancer cells as something to be eliminated, and then put back into the patient. So each patient has their very own, personalized treatment made specially for them. So it's an expensive process, much more expensive than a treatment that can be made for thousands of people.

This ASH presentation looked at the private insurance records of patients who had received CAR-T and added up the costs. When CAR-T treatments were first approved, the manufacturers estimated that the treatment would cost roughly $450,000. (If you're not in the U.S., you can use this currency converter so you get a sense of the cost. Hint: it will be a lot.) But that $450,000 is just the price for the treatment itself. The researchers for this study also looked at all of the other costs related to the treatment, all of which were paid for by the private insurance: inpatient, outpatient, professional and associated drug costs. In other words, the costs for the doctor appointments before treatment, the costs of the drugs that help with side effects, separate fees for specialists that need to be consulted, etc. 

What they found was that the mean total cost was $618,100, and the median was $573,300. Nearly 6% of patients had a total cost of over $1,000,000. There weren't many FL patients in the study (only 6, compared to 269 with DLBCL), and their costs were higher ($611,900 for DLBCL, and $743,100 for FL).

And while the numbers are high, and awful, for patients in the U.S., this is a problem for all of us, no matter where we live: even single-payer systems will have to prioritize treatments, and make sure the effectiveness is worth the cost, or if some other treatment will a better, more cost-effective choice. 

So what's the alternative? Well, possibly an "off-the-shelf" or Allogeneic CAR-T. In other words, instead of making a personalized treatment for each patient, there could possibly be one CAR-T that could be effective for all patients. There are a number of Allo CAR-T treatments in development, including one called CB-010, which is getting an update at ASH.

One of the exciting things about ASH (and ASCO in the spring) is getting to see the small improvements that are made in treatments that have been around for a while. As great as CAR-T is, there's still lots of room for improvement, so hopefully we'll see more ways of getting this treatment to people soon.

I'm still reading. I'll post more interesting ASH presentations soon.