Thursday, March 14, 2024

A Follow-Up on Secondary Cancers and CAR-T

 A follow-up to the news from a few months ago that the FDA was issuing a warning about CAR-T causing secondary cancers. After reports of patients who had received CAR-T developing T cell cancers, the warning was issued in January

The concern was that the patients were developing T cell cancers specifically. CAR-T, of course, currently made for each individual patient who receives the treatment. T cells are removed from the patient, manipulated to recognize cancer cells, and put back into the patient. Because the T cells are manipulated, the concern is that the process might go wrong in some way and make the cells cancerous. There are several varieties of CAR-T (it's a general category, not a specific treatment, though I know I often write about it as if it is one thing and not many). Each one has a slightly different way of manipulating the cells. But they do have the same general process.

Since then, there has been some research on just how common secondary cancers are among CAR-T patients. This morning, the journal Blood published "Second Primary Malignancies After Commercial CAR T Cell Therapy: Analysis of FDA Adverse Events Reporting System (FAERS)." I can't see the article, or even a summary, but ASH, which publishes Blood, put out a press release about it, which is very helpful.

The researchers who wrote the article looked at the FDA's Adverse Events Reporting System, or FAERS, and catalogued the number of times CAR-T patients reported developing a new cancer. The FAERS system is voluntary -- an adverse event, or side effect, can be reported by a doctor, or a patient, or by someone else. So it's possible that some of the adverse events were reported more than once, by both a  doctor and a patient. And it's very possible that an adverse event wasn't reported at all.  So it's important to keep in mind that these numbers are not comprehensive.

That said, they do offer at least a small picture of how common secondary cancers are in CAR-T patients.

The researchers looked at a total of 12,394 adverse events that were reported about CAR-T patients. They found that 536, or about 4.3% of the adverse events reported were secondary cancers. So, to be clear about this -- of all of the adverse events (or side effects) reported voluntarily, 4.3% were new cancers. And to be even more clear -- there isn't necessarily a clear connection between the treatment and the new cancer. It's certainly possible, but not definite.

I'll give you an example of how this works. I received Rituxan 14 years ago. I was diagnosed with a secondary cancer (a skin cancer) a few months ago. Did the Rituxan cause the cancer? Maybe. Did my immune system cancer cause it? Maybe. Did my never wearing sunscreen as a kid cause it? Maybe. Was it a combination of al three? Maybe.

It's really difficult to connect a secondary cancer to a previous cancer treatment. But there can be a comparison to other populations who didn't get cancer treatment, and compare how common the cancers were.

So which cancers were most common among CAR-T patients? Leukemia was most common -- 2.7% of all of those 12,394 adverse events were leukemia. Skin cancers (the most common secondary cancers among all cancer patients) were 0.4% of the adverse events.

And T cell cancers, the type that are most concerning? They amounted to just 0.1% of all of the adverse events reported. 

I want to be clear here -- I'm not saying here's no danger of getting a T cell cancer. The fact is, I don't know. And I can't say for sure what the odds are of getting any secondary cancer. The FAERS system only gives a partial picture of things. 

I'm not an oncologist or a cancer researcher. If you're concerned about secondary cancers -- if you're concerned about any adverse events or side effects -- the best person to talk to about it is your own oncologist. They'll have a much better idea of what the risks and rewards are for any treatment you might have.

And that should be a part of any conversation you have about treatment, anyway, whether you are in need of one immediately, or you're thinking about the future and what might happen when you do need treatment. It's easy to trust your doctor when they have a suggestion for treatment (and I hope you have a relationship with your oncologist that does allow you to trust them). But make sure you know everything you can before you make that decision together.


Friday, March 8, 2024

New FDA Approval for R/R Follicular Lymphoma

Yesterday, the FDA granted accelerated approval for the combination of Zanubrutinib and Obinutuzumab for Relaped/Refractory Follicular Lymphoma patients who have had at least two previous treatments. this is good news -- we have another option.

Zanubrutinib is an inhibitor. It's different from the PI3K inhibitors that have been approved (and then pulled) in the last few years. But it works on the same very general principle of inhibiting (or stopping) a process from happening that cancer cells need to grow and live. 

Zanubrutinib is a Bruton tyrosine kinase (BTK) inhibitor. BTK is an enzyme that plays an important role in B cells developing. B cells are of course the cells that turn cancerous in Follicualr Lymphoma and a bunch of other blood cancers. So stopping their development is a way of holding off the cancer  from growing.

Obinutuzumab is a monoclonal antibody, like Rituxan, but with some differences. It's the "O" in a treatment like B-O or O-CHOP, and probably the most successful attempt at an alternative to Rituxan. 

The accelerated approval is based on the results of a phase 2 trial known as the ROSEWOOD trial. In this trial, patients were given the Zanubrutinib-Obinutuzumab combination and the results were compared to patients who were given just Obinutuzumab. The comparison involved looking at two statistics -- Overall Response Rate and Duration of Response. 

The researchers found that 69% of the Z-O patients had a response (whether it was Complete or Partial), compared to just 46% of patients who had just O. As for Duration of Response (DOR), after a median 19 months, the median DOR was not yet reached for the Z-O combination. In other words, more than half of the patients in the trial were still getting a response after that time. For the O patients, the median DOR was just 14 months. 

As for side effects, there were no surprises. Zanubrutinib had already been approved for other blood cancers, and the Z-O combination didn't result in any new or worse side effects than have already been reported. These include diarrhea (18.2% in the Z-O patients and 16.9% in the O patients), fatigue (15.4% and 14.1%), and fever (13.3% and 19.7%).

As I have said before, there are several BTK inhibitors already approved for other blood cancers, but this is the first for Follicular Lymphoma. It's interesting -- it would make sense that a BTK inhibitor would work on FL, but so far, none have been successful, including Ibrutinib, which was a game-changer for CLL patients. Not sure why. But this combination seems to be working for some patients.

And it needs to be noted that this comes form an accelerated approval. Obviously, OS was not even considered as a primary endpoint or way of measuring success. That's likely because this is an approval for R/R FL, and finding a treatment that keeps patients from needing further treatment is the priority. But as an accelerated approval, the combination will still need further clinical trial testing to get permanent approval. We'll keep an eye on that.

No one is really talking about it much online just yet, maybe because Zanubrutinib is already pretty well known, so there's less excitement. But it will be interesting to see how often this gets prescribed from here. If any of you have a conversation with your oncologist about this, please let me know. I'd love to hear what an expert thinks.

Stay well.


Sunday, March 3, 2024

Will the FDA Change the Way They Approve Treatments?

The website BioSpace posted a really interesting article a coupe of weeks ago called "How Will FDA’s Pivot to Overall Survival Affect Cancer Drug Development?

In my last post, I mentioned that I was a little surprised that the FDA was considering accelerated approval for the bispecific Epcoritamab, and that I had been doing some reading lately about the FDA potentialy changing the way they approve cancer treatments. The BioSpace article is a nice summary of the kind of things I have been reading.

As the article points out, over the summer, there was a workshop at the American Association for Cancer Research conference, co-sponsored by the FDA, that looked at the issue of Overall Survival (OS) in cancer clinical trials. OS is the gold standard in clinical trials -- if the developer of a new treatment can show that it keeps patients alive longer than currently available treatments, it has an excellent chance of being approved (assuming the side effects are not awful). As patients, this is what we want, too -- a treatment that will keep us alive longer.

The problem is, OS is hard to measure in a reasonable time. As cancer treatments have improved over the years, OS has gotten larger. That means newer treatments have more work to do. In other words, if a new FL treatment was going to be approved, it would need to show a better OS than what we have now -- maybe 15 or 20 years. But in order to do that, a trial would have to last at least that long. How else can you show that patients will survive for 20 years without following them for 20 years? 

The answer is to use a "surrogate endpoint." That means finding a different measurement that would signal that OS will be long. For most trials, that surrogate endpoint is Progression Free Survival (PFS). This is a measure of how long a patient goes before the cancer comes back or gets worse. The idea is, if a new treatment can show a longer PFS than current treatments, that's good enough to approve it. 

And that's where there are problems. PFS is often measured in just a few years, maybe even in months -- certainly fewer than the 8 or 10 years that we might get for an OS in Follicular Lymphoma. For some cancers, PFS can be measured in months. But the makers of new treatments don't want to wait that long. They want their treatments to be available as soon as possible, so they can begin making back the money they put into the development of the treatment, plus a big profit.

To be fair, it's not just the drug makers who want the treatment available quickly -- patients want that, too. And that's why the FDA developed accelerated approval procedures. If a new treatment can show an improvement in PFS, it can potentially get approved based on the results of a phase 2 trial (it usually takes a phase 3 trial for approval),with the understanding that a phase 3 trial will come later. Final approval will depend on the phase 3 trial results.

But, again, the problem is that approving a treatment too soon can create some problems. The biggest one is, there may be side effects that come out years after approval. And this happens, unfortunately. In Multiple Myeloma, a treatment was withdrawn a few years ago by the FDA after accelerated approval because over time, it was found that the treatment had a significant increase in the chance of death. And of course, if you've been reading the blog for a while, you know that a similar (though not so drastic) issue came up with PI3K Inhibitors for FL. Problems come out over time.

Some FDA officials (according to the article) have signaled that they would like OS to be more commonly used, with less of a reliance on PFS.  Ideally, a treatment would be approved after there was an Overall Survival benefit, with no safety issues, based on a randomized clinical trial. That is, there would be a fairly large trial with two groups of patients. One group would get the currently used treatment (called the "Standard of Care") and the other would get the new treatment. They would be followed for potentially many years, until an OS was determined. And then the data would be submitted to the FDA for approval.

Will that happen? It's hard to say. The FDA has a tough job. They have to make decisions based on the best interests of patients. But the question is -- is the best interest of patients to have a treatment become available as soon as possible? Or is it to make absolutely sure that it increases survival?

It will be very interesting to see which direction the FDA goes in. Certainly, based on the Epcoritamab decision last week, they are still considering accelerated approval and not relying on OS completely. And in my opinion (for what it's worth -- I'm not a doctor or a cancer researcher), it will probably be something they consider for each individual application. Some cancers are so rare and have so few treatment options that it will be worth the risk to approve something based on PFS and get it into doctors' hands as soon as possible. And for others, maybe less rare and with other options already available, maybe they will be more cautious and want to see the full trial results. 

The question for us is, where does Follicular Lymphoma fall on that scale?

 

Tuesday, February 27, 2024

Epcoritamab Gets FDA Priority Review

A quick bit of news: The FDA granted Priority Review status to Epcoritamab for Relapsed/Refractory Follicular Lymphoma.

Epcoritamab is a bispecific antibody. As a bispecific, Epcoritamab acts like a monoclonal antibody like Rituxan, by seeking out and attaching to a protein on the cancer cell (in this case, it attaches to the CD20 protein, just as Rituxan does). But then it dos something else -- it attaches to a protein (CD3) on a T cell, a kind of immune cell. By bringing the T cell close to the cancer cell, it helps the immune system work on the cancer.

The Priority Review means that the FDA thinks Epcoritamab will offer significant improvements in either safety or effectiveness over what is now available for R/R FL patients. It will make a decision in 6 months, rather than the usual 10 months, so it is likely to decide whether or not approve by June 28. 

The Priority Review is based on the phase1/phase 2 EPCORE trial. These results were presented at the ASH convention a couple of months ago. The results of that trial were very good; the Overall Response Rate was 82%, with a Complete Response Rate of 63%, comparable to Mosunetuzumab, the bispecific that is currently approved for FL patients. 

One thing that I find especially interesting is that they are considering approval based on a phase1/2 trial. Though it's fairly large for an early trial (128 patients), the FDA has also been sending signals that they want to slow down on accelerated approvals. They'd rather see full, phase 3 randomized trials instead, which are more reliable and give more time for potential side effects to come to light. I've actually been working on a post on that very subject; I may have to speed it up and get it on the blog soon.

Regardless, this is good news, assuming that everything goes well with the review. As I have said several times before, bispecifics are one of the treatment types that seem to get Lymphoma specialists most excited (and I include my own oncologist in that group). So another bispecific option would be great for all of us. 

More to come, I'm sure -- I'll keep an eye out for news and commentary about Epcoritamab, and share any good stuff I see. 


Thursday, February 22, 2024

Survivorship Research

I've been thinking a lot about the idea of "survivorship" lately. 

In cancer terms, survivorship is what happens after treatment is finished, particularly after treatment has been successful. I've known lots of cancer patients who were just kind of on their own at that point (or maybe who felt like they were on their own).  Once the treatment is done, there's no need for a doctor anymore, right? Except for a couple of visits to make sure everything is still OK?

That was certainly the attitude for a long time. But more and more, cancer centers are creating and promoting "survivorship centers," with specialists who focus on helping out patients after they are "done." As many of us know, after a successful round of treatment, there is still a whole lot to deal with -- the many, complex emotions that come with cancer; physical changes, big and small; financial difficulties with lingering bills. There's a lot to deal with, even after the cancer cells are gone. It's great that more and more cancer centers are recognizing that, and equipping them with social workers, psychologists, nutritionists, pain specialists, and others who can provide some help. 

So how do all of these folks know what to do for cancer patients to help them? That's where survivorship research comes in. The ASCO Post has a nice piece about this subject from two people who know a lot about it -- the lead of evidence-based survivorship supportive care and the director of cancer survivorship and supportive care programs at the University of Miami Sylvester Comprehensive Cancer Center.

They  point out the many, many issues that Survivorship Clinics help patients with -- physical, emotional, and financial -- that I mention above. Add to that short list a few more -- issues with pain, fatigue, sleep, attention and memory, sexual function anxiety, depression. All of those things are very common problems for cancer survivors. It's good to know how common they are. I think a lot of cancer patients have difficulties and think "It's all over now. The cancer is gone. Is all of this in my head?" Probably not. It's good to know that there are places to go to get help.

And here's the good part. Survivorship research sometimes gets its data from clinical trials. Just like developing treatments, survivorship benefits from patients who are willing to be a part of a study. And just like trials for new treatments, survivorship trials often have trouble recruiting.

The ASCO Post article doesn't recommend any specific survivorship trials, but they do recommend a couple of places to look if you're interested in participating. The first is by looking at the National Cancer Institute's database of clinical trials and/or at the U.S. government's clinicaltrials.org site. Both are fairly easy to use. (And they're great for seeing all of the Follicular Lymphoma trials near you, not just the survivorship ones.)

The second is by looking at the websites for different patient support organizations. I've done the NHL search for you, so you can find a list of lymphoma organizations here. Some of them may be participating in, or helping to recruit for, survivorship trials. 

Now, I've talked about the importance of clinical trials many times on the blog, and I always try to find out what my oncologist is excited about in research, and whether my cancer center is doing any trials on it. But also know that cancer patients can be very hesitant about participating in a trial, since the treatments are unproven (that's the whole point f a clinical trial).  One of the great things about survivorship trials is that, in some ways, the stakes are lower. If a patient is worried about side effects of a new drug, the interventions for many survivorship trials do not involve physical side effects. Here's an example from the Mayo Clinic in Minnesota (which has an excellent survivorship program) -- breast cancer survivors who are taking endocrine therapy are in a trial to see if motivational interviews and text messages will help them to remember to continue their therapy. There may be some emotional side effects to a study like that, but not the physical ones that scare off lots of cancer patients from participating in a trial. (And just to be clear, it's worth talking to your oncologist about those fears. They may be fears about nothing, and a good talk with lots of honest questions might calm a lot of those fears.) 

I also know that, for many Follicular Lymphoma patients, the whole idea of "survivorship" can be a tricky thing. The idea that FL is incurable is always in our minds. What does it mean to be a "survivor" if there's a chance that it might come back soon? Is it worth going through the things that "survivors" go through?

I would say yes, absolutely. The National Cancer Survivors Day folks tell us that anyone who has ever been diagnosed and is still alive is a survivor. There's no 5 year waiting period or anything like that. Different survivorship trials might have certain criteria to participate, which is understandable. But being finished with active treatment, no matter what the status, should be enough to make it worth looking into some trials. (Here's another example -- Sloan Kettering in New York has one comparing Music Therapy and Cognitive Behavioral Therapy to treat anxiety in cancer survivors.)

And your status as a survivor certainly opens the door to whatever survivorship benefits are available to you at your cancer center. And if your cancer center doesn't have a survivorship clinic, or you go to a community oncologist in a smaller office, then ask if there are any services for survivors. I'm guessing they're have some suggestions.

Most importantly, be sure to continue to take care of yourselves, physically and emotionally, long after you are finished with any treatment. There's help for you if you need it. 


Friday, February 16, 2024

Upcoming LRF Event

As you may know, I like to promote some of the webinars and workshops the the LRF (the Lymphoma Research Foundation). I've been able to attend them in person and online, and I think they're great. They usually involve one or more oncologists giving a presentation, and then time for questions and answers. Sometimes the topics are very general, and sometimes they are very specific. But the LRF usually does a great job of finding speakers who know the latest research on Lymphoma, and who can explain things clearly. 

There is a big  LRF event coming up that is worth attending -- the "National Lymphoma Workshop: Understanding Lymphoma Basics and Current Treatment Options."

This a virtual workshop, so everything is online. The date is Saturday, March 16, and it runs from 9:30am to 1:30pm. The first part of the webinar is a general overview of Lymphoma. After there, there are individual sessions for different types of lymphoma, including one for Follicular Lymphoma, led by Dr. Laurie Sehn of the British Columbia Cancer Agency. (Dr. Sehn was one of the panelists from the video series that I linked to a couple of weeks ago. She knows her stuff.)

After a break, there are two more general sessions -- one on Nutrition with Peter Adintori of Memorial Sloan Kettering Cancer Center, and one on Integrative Medicine with Dr. Santhosshi Narayanan of MD Anderson Cancer Center. These should be very good. I'm especially interested in the Integrative Medicine session, which will look at the ways traditional cancer treatment can be supplemented with other practices. Always a fascinating topic.

You can use the link above to see the full agenda and to register for the workshop. As I said, the LRF does a good job of finding speakers who can explain things well. This workshop should be the same way.

I hope some of you can find time to attend, and get something out of it.


Sunday, February 11, 2024

How to Read Survival Statistics

A couple of weeks ago, a reader made a comment about Overall Survival, and I gave a brief response. But I know there are some new readers here who were diagnosed fairly recently, so I think it's a good time for a reminder about "Overall Survival" and what it means.

It's especially important for folks who are newly diagnosed. For most of us, when we heard those words -- "You have cancer" -- our minds immediately went to some variation of "How long do I have?" Survival statistics serve as a kind of easy way to figure out how worried we should be. 

But survival statistics don't tell us anything about our own situations. It's easy to read a statistic that says the survival rate for a cancer is X years, and say "Well, I only have X years left." That's just not true. That's not how statistics work.

I'll use myself as a quick example. When I was diagnosed in 2008, the Median Overall Survival for Follicular Lymphoma was thought to be 8-10 years. Here I am, 16 years later. 

One of the problems with that 8-10 year statistic is that it was probably already outdated when I saw it. At that point, Rituxan had been in use widespread for FL for about 10 years (it was approved by the FDA in 1997). Rituxan is generally credited with increasing the Median Overall Survival, which had probably already done by the time I was diagnosed. But that 8-10 year figure was from the last large study of  FL survival, done before Rituxan, and looking backwards anyway, measuring the survival rate of people who were diagnosed in the 1980s. 

So that's the first danger with looking at survival statistics and thinking they are a measure of your fate -- they're probably outdated, maybe very outdated, and don't take into account any newer treatments.

As for the other problems, let's look at the term "Median Overall Survival," which is the official term for survival statistics. 

First of all, it's important to remember what "Overall Survival" is measuring. This statistic looks at death from any cause, not from the disease being considered. A statistician looks at a bunch of records of cancer patients, marks which have died, and notes when it happened. Those deaths aren't distinguished by cause. So it includes people who died from their cancer. And people who died from complications of their treatment. But it also includes people who died from heart disease, car accidents, getting too close to wildlife at national parks -- any cause of death. "Overall Survival" simply looks at how many people died, and how long they lived after they were diagnosed.

That's especially important for Follicular Lymphoma patients. We are generally diagnosed with FL sometime in our 60's (I haven't seen a solid statistic for this anytime recently). So for a group of people who are diagnosed fairly late in life, we can probably expect a lifespan of 15-20 years. That just makes sense -- anyone at the age of 65 (whether they have FL or not) probably has a life expectancy of about 15-20 years. 

And that is indeed about what researchers put as Median Overall Survival -- about 15-20 years. In other words, as a group, we're pretty much in line with the general population.

The other important word in this formulation is "Median." That's a term from statistics. It's different from "average," because one big number can throw off an average. "Median" means the exact middle. So if you had 999 Follicular Lymphoma patients, and you lined them up based on how long they survived after diagnosis, then number 500 in that line up would be the median. (There would 499 on either side of that patient.)

Since the "median" is the exact middle, that means 499 of those patients would have a shorter survival than #500. But it also means that 499 would have a longer survival.

Think about that. If #500 has a survival rate of 20 years, that means half of us will have a survival rate of greater than 20 years. How much greater? Maybe 20 years and 1 day. Maybe 25 years. Maybe 50. 

That's especially important for us who were diagnosed on the young side. Like me -- I was diagnosed at 40 years old. That doesn't mean I can expect to only live a few more years. The patients on the right side of #500 don't have an upper limit. Statistically, I could live until I'm 90 -- a 50 year survival rate. 

(By the way, that's how long I expect to live -- at least.)

But what about those folks who were to the left of #500? That still doesn't mean anything. It includes people who didn't know they had FL until very late in their lives, maybe in their late 70s, and then had a normal life expectancy. It includes people who didn't get a diagnosis until their disease was very far along. It includes people who walked out of the doctor's office after getting a diagnosis and had a piano fall on them 5 minutes later. 

The point is this -- statistics are not destiny. The numbers that describe a group of thousands of people, especially because they are collected by looking at the past, don't tell us anything about us as individuals. Our lives are all different, and our diseases are different.

I personally stopped looking at statistics a long time ago. When I was first diagnosed, the things that threw me into a depression were almost always statistics.  Numbers seem so definite, so correct, so real. And it's very easy to get sucked up into them and take them as the truth about ourselves. But that;s just not how it works. 

So if you want some numbers, here is a good one. 

A long time ago, a reader told me that her doctor was discussing treatments with her, and how excited he was about there being so many new options in the pipeline. The doctor told her "If we can keep a Follicular Lymphoma patient alive for 5 years, we can keep them alive for 50 years."

And that conversation happened before CAR-T, before bispecifics, before R-squared. And who knows what other treatments that might be coming soon.  

If you feel yourself getting pulled down by numbers, keep that one in mind.

I hope this helps some newer folks to better understand what survival statistics actually mean, and how little significance you should give to them. And I hope those of you who have been around for a while appreciate the reminder. Numbers are not destiny.

Take care.