Cancer, Royalty, and Minding One's Business

I've been thinking about cancer a lot lately.

That's no surprise. There hasn't been a day in 16+ years that I haven't thought about cancer. It's a side effect of being a cancer patient, as well as a blogger who needs content.

But I'm also keeping an eye on a couple of other folks who both have cancer. They are people that I work with. I've known them for years, though I wouldn't say I'm personally close with them. Their diagnoses have an effect on my job, so they told me about it before they told most people. They also know about my own diagnosis from years back, so I think they trust me to be sensitive about theirs.

Both have been in treatment for several months. I try to check in with them every few weeks. Just an email saying "I'm thinking about you. I hope you're doing OK." 

One of them writes me back with updates -- very detailed updates, sometimes as detailed as a medical chart. This colleague also asks lots of questions, about my treatment, my experiences, my feelings. We don't have the same diagnosis, but cancer patients share a lot of things anyway. As you probably know, it's comforting to have someone else who has been through it all say "Yes, I felt that way too." 

The other colleague doesn't usually respond. When I do get a response, it's not really about the details -- more of a general "Had a doctor's appointment last week and things are going OK." For this colleague, it's the second time around. The cancer was first diagnosed a few years ago, and now it has come back. But the funny thing is, I have no idea what kind of cancer this colleague was diagnosed with. They have never shared it. Unlike the first colleague who gives me a full medical chart of detail, this one has always been very private about their personal life, and they give me almost no detail at all. Not even the type of cancer.

And you know what? That's just fine.

That's what I've been telling myself as I see so much news about the British Royal Family. I'm not a "royal watcher," though I did enjoy watching The Crown. Most of what I read about their situation has come from cancer-related websites. 

In case you don't know what I'm talking about, here's a summary: In January, King Charles announced that he was being treated for an enlarged prostate. About the same time, his daughter-in-law, Princess Catherine, announced that she was having abdominal surgery. Eventually, the King announced that he was diagnosed with cancer. And recently, the Princess also announced that her surgery resulted in a cancer diagnosis.

Neither of them has announced the type of cancer they were diagnosed with. The Princess said she has been in treatment with "preventative chemotherapy," but hasn't said what type. 

And you know what? That's just fine.

I've complained elsewhere that I really wish celebrities would give more detail about their diagnoses. I am particularly annoyed when famous people announce "I have been diagnosed with non-Hodgkin's Lymphoma," and leave it at that. Because then I have to see al of the articles that tell me the survival rates for NHL without being clear that NHL isn't really a disease, but a name for about 60 other diseases, ranging from very slow-growing to incredibly aggressive, to the point where anything you say about "NHL" is meaningless. So I wish celebrities would give us some more detail. I feel like if we have to watch them go through the cancer experience, some of us would like to know just how relevant it is to our lives. If someone famous has Follicular Lymphoma, I want to know how much their very visible diagnosis reflects my own.

And then I very quickly push that out of my head.

Because it's their experience, not mine, and it's none of my business. 

As I said, I'm not a "royal watcher," but I do get a sense of how complicated their situation is. As a royal family, they have a different position than most celebrities. And if The Crown is accurate (and I know it's ultimately fiction), they also are very careful in managing their image, for reasons that may or may not be valid. And of course, Princess Catherine is a young mom, and needs to be mindful of her children and how they are experiencing all of this (I've been there, too -- The Princess is two years older than I was when I was diagnosed, and her kids are all within a year of how old my kids were at the time). 

So The King and The Princess are dealing with cancer while they are also dealing with their responsibilities to their families and their country. I don't envy them.

But in the end, whatever their responsibilities, whatever their decisions, the same thing is true for them as it is for all of us:

There's no right or wrong way to experience cancer.

Even for those of us who might be going around for the second or third time with cancer, it's still a new experience. And there's no playbook for this, no instruction manual, no To Do List. We make it all up as we go along.

And that's OK. 

Even if we look back later on and wish we had done things differently, the decisions we make at the time are the ones we are making based on the information we have and our needs at the time. If we decide to share all of the details with the world -- even starting a blog -- that's great. If we decide to keep it all inside and not share any or all of the details? That's OK too.

As for King Charles and Princess Catherine? They can tell us whatever they want, or keep the details to themselves. In the end, they are cancer patients, separate from their lives as Royals, and their only duty is to themselves and their families.

I hope you are all doing well, and feeling like the decisions you have made have been the right ones. 

Because they have been.

FDA Denies Approval for Bispecific (For Now)

The FDA has denied approval for the bispecific Odronextamab -- for now. In giving the denial, the FDA pointed to problems in the trial, rather than concerns about its safety or effectiveness. 

Some background: Odronextamab is a bispecific, meaning that it works in two parts. It is a monoclonal antibody, like Rituxan. (I keep referring back to Rituxan when I talk about monoclonal antibodies, because it's been around for so long and is so widely used in Follicualr Lymphoma that I assume most readers know what it is.) In fact, it attaches to CD20, the same protein on the surface of B cells that Rituxan attaches to. But as a bispecific, Odronextamab also attaches to a T cell, an immune cell that can help kill off the cancer cell when it comes in close contact with it. If you've been reading the blog for the last year or two, you know that bispecifics are one of those treatments that tend to get oncologists very excited.

Odronextamab (which was known as REGN1979 before it got its official name) was granted accelerated review last October by the FDA. As you may know, accelerated review means the FDA will look at a smaller set of data (maybe from a phase 2 trial instead of a larger phase 3 trial) and make a decision in a shorter amount of time (usually about 6 months instead of about 10 months). They usually grant this faster review because the treatment will provide something that is not currently available to patients, and it will help a larger number of people if they can get access to it sooner.

However, accelerated review is also provisional review. Approval will allow the maker of the treatment to make it available, but they also have to keep up their clinical trials and submit data to show that it really is as safe and effective as it seems in that shorter amount of time. 

For Odronextamab, the original application was based on data from phase 1 and phase 2 trials. The results from those trials were strong. In phase 2 trial, patients with Follicular Lymphoma had an Overall Response of 82% and a Complete Response of 75%. The treatment was durable, with a median duration of response of 20.5 months and median Progression Free Survival was 20 months. Safety was decent, though 100% of the 131 patients with FL experienced side effects, with 78% of them experiencing grade 3 (serious) side effects, including Cytokine Release Syndrome (in over 50% of patients in the trial), low blood cell counts, diarrhea, fever, and joint pain. 

Importantly, the denial of the application is based on numbers of patients, not on concerns about safety or effectiveness. Basically, the FDA wants to see how the treatment works in more patients. They aren't denying the application forever, just until more data can be collected.

Of course, that's not what the maker of Odronextamab wanted to hear. There are actually two types of trials required, one focused on dosing (making sure the optimal amount of the treatment is given) and the other focusing on confirming the results f the earlier trials. The company behind Odronextamab says it is actively recruiting patients for these trials and is working with the FDA to have a new schedule later this year.

A couple of things seem significant to me.

First, this seems like a clear signal that the FDA really is getting more serious about accelerated approvals. With problems coming up after a quick approval, the agency wants to make sure treatments are safe and effective. In this case, they don't seem to be switching to an emphasis on Overall Survival, with all of the complications that would come with it (as William and Peter pointed out in their comments to my post earlier this month). They don't necessarily want new or different data here, just more of it. That seems like a reasonable approach.

Second, this confirms the importance of clinical trials, and patient participation in them. New treatments can't be approved without large trials, and large trials need willing patients. As you meet with your oncologist, add that question to your conversation -- are there clinical trials that would be appropriate for me, if and when I need treatment again? It's important to know what might come next for you, and important to all of us that new treatments have the data that they need to be approved (or not approved, which is just as important).

I'm sure there will be updates about Odronextamab in the very near future -- maybe as soon as a couple of months from now at the ASCO conference. But we'll definitely hear something by the end of the year about what the plans are for trying to get permanent approval.

Drug Name Tournament

Here's a kind of fun item for you Cancer Nerds: the website Fierce Pharma is holding a "drug name tournament" for the next few weeks.

Some background for you first. In the U.S., we are just beginning the period known as "March Madness." College basketball is a big deal to many people in this country, and this week, the NCAA tournament begins. This involves 64 basketball teams that will play each other to determine who the national champion is. (I know it's actually 68 teams, but we're not going to complicate this any more than necessary.) And there are actually two tournaments, one for men's teams and one for women's teams. You can find a decent explanation of it all here.

There are lots of opportunities to get into a "tournament pool" where you have to guess which teams will win in each round of the tournament, all the way to the national champion. There are "office pools" set up among people who work together, and lots of chances to play against strangers online. Participating involves "filling out a bracket," guessing the winner of every game before the first game has even started. Sometimes there is light gambling involved, with the participants putting up a little money and the winner getting all of it. 

It is notoriously difficult to guess every winner of every game in the tournament. This is because of the way the tournament is set up. It doesn't involve the best 64 teams in the country. Instead, some teams get in because they have won their conference or group, and so a few teams are very small and not well known, and no one expects them to win against bigger, better-known teams. But these small teams do occasionally win, bringing up lots of David vs Goliath comparisons. It can be fun to get into a pool, unless your teams lose early.

Because not everyone is basketball fan, there are also lots of alternate "March Madness" tournaments around at this time of year. Everything from best Beyonce songs to best characters from Pride and Prejudice. You're not guessing the winners of games; instead, you're guessing which choices you think will be the more popular in the bracket.

So back to Fierce Pharma. They are holding a "drug name tournament." Last year, they had a tournament where readers picked the best advertising campaigns from pharmaceutical companies. this year, they're going with drug names. They have chosen 64 drugs out of the 92 that were approved by the FDA in 2022 and 2023, and put them into a bracket, NCAA tournament-style.

Their goal isn't to have people choose the "best" drug, but rather to choose the best name. It's more about marketing than effectiveness (since that is Fierce Pharma's focus). In making choices, they'd also like participants to add what they think the drug name sounds like. Fierce Pharma has given their own example for each of the 64 names. (For instance, one of the drugs is Jesduvroq, which is meant to help with low red blood cell counts due to chronic kidney disease. They think Jesduvroq sounds like something you would say "when you hit your finger with a hammer, but it’s in front of your children so you’re trying not to swear.")

For me, as a Cancer Nerd, it all sounds kind of fun. Drug names are always a little strange, though with some very serious work behind them, and this tournament pokes some gentle fun at them. I like that.

And if you're wondering if any Follicular Lymphoma treatments made the cut -- YES! There are two of them.

The first is Lunsumio, the bispecific that is also known as Mosunetuzumab. Fierce Pharma says the name Lunsumio sounds like a Japanese wrestler.

The second is another bispecific, Columvi, also known as Glofitamab. This was approved by the FDA for Diffuse Large B-cell Lymphoma, though it includes DLBCL arising from transformed FL. (There are some additional clinical trials for FL going on as well.) Fierce Pharma says Columvi sounds like an ancient Roman detective. Slightly more creative than their Lunsumio comment.

So good luck to all of you participating in March Madness tournaments, whether it's for basketball or something else.  Let me know if you do well in the Fierce Pharma competition.

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.

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.

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?