Some Final Thoughts on PI3K Inhibitors (for now)

 One more post about PI3K Inhibitors, and then I'll do my best to stop writing about them for a while. 

(But I make no promises.)

OncLive has a new video series on indolent lymphomas, and it includes a couple of brief episodes on Follicular Lymphoma. One in particular caught my eye -- "PI3K Inhibitors in Relapsed/Refractory Follicular Lymphoma." Conveniently, it includes a transcript in case you want to translate it or you have trouble viewing the video.

The video series features several Lymphoma experts giving their take on recent research on several different types of lymphoma. 

One important detail --  the first video in this series was posted in December, so my guess is that the whole thing was put together during the ASCO conference, and is short pieces are being released every week. That means they discuss PI3K Inhibitors before the various FDA actions had taken place.

The most interesting thing to me is that they focus on Copanlisib. As I have been discussing, there have been four PI3K inhibitors approved by the FDA for Follicular Lymphoma, and three of them have run into problems of different kinds. The fourth one, so far relatively trouble-free, is Copanlisib. As the panelists in the video point out, there are some differences between Copanlisib and the other three. One is the way it is administered. The other three are given in pill form, but Copanlisib is given intravenously, once time per week. Taking a pill at home is a whole lot easier than going for an infusion once a week (Quality of Life matters!), but the pill form might also lead to some gastrointestinal side effects that an infusion doesn't have.

(As always, nothing is easy. Every treatment has side effects, and every treatment is going to affect how we live our lives in some way.)

They also briefly discuss the CHRONOS trial, which looks at the combination of Copanlisib and Rituxan. The results seem very positive, and shows again that there seems to be more success with combinations that with just PI3K inhibitors alone. 

The lesson here, for me, is to remember that problems with some treatments within a group or class does not mean that every treatment in that group or class is in trouble. One of the positive things to come out of the troubles with PI3K inhibitors (and I'm always looking for positives) is that researchers may learn to deal with side effects in the next generation of inhibitors. Ideally that means more demand for them, so "business decisions" don't cause treatments to be removed from the market.

One bit of good news in that regard (which I have been aware of since ASCO) is that there are some potentially "better" PI3K inhibitors coming soon. For example, another PI3K inhibitor called Zandelisib is moving its way through trials and toward FDA application. One of the things that makes Zandelisib different from other inhibitors is its dosing -- how often and how much a patient takes. Like some of the others, it is given in pill form. But instead of being taken every day, patients take it for a number of days and then stop taking it for a number of days. This allows the body to recover, especially the immune system. Numbers are good -- effective, with manageable side effects.

Will Zandelisib (or another PI3K inhibitor under development) be a good replacement for the PI3K inhibitors that are no longer (or may soon no longer) be available? Hard to say. I'm always enthusiastic about having more options available for us, especially when they are more effective and safer than what has come before. So I wish Good Luck to everyone working on an FL treatment.

But the bigger point, as I said, is that problems with some treatments doesn't mean problems with all treatments. 

(I promised last time that I'd be more positive. I think I did OK.)

More Bad News for PI3K Inhibitors

I hate to keep writing with bad news, but this seems too important not to. Another PI3K inhibitor -- this time it's Umbralisib -- has run into problems. Clinical trials for the treatment have been suspended because of an increased risk of death in a phase trial.

Just to remind you of a few things: 

There are currently 4 different PI3K inhibitors approved for Follicular Lymphoma. In the last couple of months, two of them -- Idelalisib and Duvelisib -- have been withdrawn voluntarily because the makers decided it would be too difficult to get final approval by the FDA. Another one -- Parsaclisib -- was withdrawn before it went through the approval process, for similar reasons. All of them were, essentially, business decisions. For whatever reason, it would take more money and/or effort to get final approval and make enough money than was worth it.

The Umbralisib issue is a little different. While it hasn't been taken off the market, clinical trials have been stopped. The trial, called the UNITY-CLL trial, is actually for patients with a different type of blood cancer, Chronic Lymphocytic Leukemia. It's similar to other indolent, slow-growing blood cancers like FL. Similar enough that all FL and Marginal Zone Lymphoma trials for Umbralisib have been stopped, and the FDA is recommending that FL and MZL patients who are currently receiving it should talk to their doctors about risks.

The trial is actually four-armed, meaning patients were given one of four different treatments, including Umbralisib on its own. The results of the trial, in terms of effectiveness, showed some good news. But the increased risk of death was problematic (obviously).

You can look at the links above for some more of my thoughts about this situation and what it means for us as FL patients (keeping in mind that I'm not a cancer researcher or a doctor -- these are just the non-expert opinions of a patient who does a lot of reading. Talk to your own doctor about any concerns you have about any treatments -- that's always the best choice).

But I'll add one more thought to all of this. The three inhibitors that have already been approved went through some form of an accelerated approval by the FDA. The FDA began using accelerated approval a few years ago, in response to many in the cancer community (and other health communities) being frustrated with how long it was taking for new treatments to be approved. The program allows a treatment to be approved based on the results of a small phase 2 trial. But the understanding is that a larger phase 3 trial would need to be conducted and finished, and if the results hold up, then final, permanent approval would be granted. 

But there are also many in various healthcare communities who don't like the accelerated approval process. Sometimes the process relies on what are called "surrogate endpoints." This means that, instead of looking at something like Overall Survival after 5 years, the developers of the treatment can use a different statistic, like maybe 2 year Progression Free Survival, as a substitute. This is done when another study has shown that enough patients who made it to that 5 year OS (maybe the first ones enrolled in the trial) also made it to 2 year PFS. So the assumption is that the approval can be given based on that 2 year statistic, and then things will be checked again at 5 years to make sure that 5 year statistic really did match up. 

My guess is that there might be more attention paid to accelerated approvals. That might end up being an issue with Umbralisib, if it's shown that the increased risk of death came later on. But it could also end up being an issue with the other inhibitors. Idelalisib was withdrawn because there weren't enough people who signed up for the phase 3 trial. that doesn't necessarily mean anything related to how effective or safe the treatment is. But it does say something about how resources are used. Researchers might think more carefully about how much effort, time, and money to put into a treatment if there's little chance it will be used by doctors.

The whole treatment development process is huge, takes many years, and lots of money, and its far more complicated than I can fully understand. But it seems to me that having 3 of 4 approved treatment options run into big problems says something about the process, even more than it does about the treatments themselves.

And what's especially frustrating is that I really haven't seen a lot of discussion about all of this online. Maybe that will come soon. I'll keep an eye out for those kinds of commentaries (maybe one of those video series that I come across pretty frequently), and if any of you see a Lymphoma expert with an opinion on all of this, please let me know.

I'll try to find something more positive to say next time. But, gosh, they're making it hard.

World Cancer Day

Happy World Cancer Day!

Today is considered World Cancer Day by the Union for International Cancer Control. As the name of the Day of the Organization suggest, World Cancer Day is a day to raise awareness all around the world about cancer, to increase education, and to work together to reduce the incidences of cancer everywhere.

This year's theme is "Close the Care Gap," and is meant to highlight the differences in cancer care aware the world. I'm especially sensitive to this issue. I am very aware of how lucky I have been to have the care that I have had, and I think it's a big reason why I have been able to go 12 years since my treatment. I'm also aware that not everyone is so lucky. I have had readers from over 80 countries (so my Google data tells me), and many of you have written to me with your stories. Not everyone gets the same care. I hope this campaign works -- even just a little bit -- to change that.

With that in mind, is it a little strange to wish everyone a "happy" World Cancer Day?

No, it's not strange. I've been highlighting some potentially bad news over the last few weeks -- three treatments no longer available to us. But there's plenty of good news for Follicular Lymphoma patients, too, even in just the last few days.

For example, the "Cancer Moonshot" initiative that was first created in 2016 was relaunched this week, with the aim to cut cancer deaths in the United States by half in the next 25 years. While there won't be any new money right away (which some see as a big weakness), there will be a greater priority on things like testing and prevention and early detection, and perhaps down the road, providing more funding. I'm choosing to see this as a positive development, despite some things I'd do differently (like involving patients more directly). And, thinking about "closing the care gap," I hope some of the initiatives bring prevention and care to those who haven't gotten it as easily, in the U.S. and around the world.

The other bit of big news this week has to do with CAR-T. The first CAR-T patients, who received the treatment 10 years ago, are still cancer-free. That 10 year time period has some cancer experts saying we can consider the cured. The patients had CLL, a slow-growing blood cancer that is similar in many ways to FL. That has some great implications for us. It's also more complicated than being able to say everyone who has CAR-T will be cured. That's all I'll say about it for now because I plan to write more about it in a few days.

So, yes, I think this is a happy World Cancer Day. If nothing else, it reminds us that there are things to be hopeful about, even if there is always some less happy news whenever we receive good news. 

But we're used to that, aren't we? Personally, I'll hang on to the happy news and keep my focus there.

Enjoy the day, everyone. World Cancer Day is a good excuse to treat yourself to something fun. 

Stay well. 

ASH Review

The ASH conference took place almost two months ago, but Cancer Therapy Advisor has a nice interview with Dr. Connie Lee Batlevi, a Lymphoma expert from Memorial Sloan Kettering Cancer Center. Dr. Batlevi talks about some of the most important research on Follicular Lymphoma from the conference.

(I linked to a video series featuring Dr. Batlevi last September. She is both an MD and a PhD, going to medical school and then getting another doctorate, which is pretty amazing to me. Some weeks I can barely find the energy to write a blog post.)

Much of the interview focuses on bi-specifics, which seems like the choice of most experts for the biggest news out of the conference. Dr. Batlevi focuses on two different bi-specifics -- Glofitimab and Mosunetuzumab. I wrote about Mosunetuzumab, but not Glofitimab. Glofitimab was in a small study, with some patients receiving only the bi-specific and some also receiving Obinutuzumab. Patients who only received the Glofitimab had an 81% response rate, and those who received the combination had a 100% response rate.

That's a very good response rate, obviously. Better than the results from the Mosunetuzumab study, though those patients did better with side effects -- especially with Cytokine Release Syndrome, which can be very dangerous. 

As Dr. Batlevi notes, both bi-specifics also have good durations -- they work for a long time. As I said in my last post, it seems to me (and this is just my non-expert opinion) that duration of response is becoming more of a priority in the Lymphoma community.  With treatments like CAR-T (which Dr. Batlevi also discusses) potentially giving us longer and longer times in between treatments, and therefore fewer different treatments over our lifetime, and therefore fewer side effects building up, bi-specifics' duration is going to be just as important as its effectiveness and safety.

Thinking about my last post, where I wrote about the inhibitor Parsaclisib being withdrawn from the FDA approval process, it's ironic that the last treatment that Dr. Batlevi talks about is Parsaclisib. The results of a study of this treatment were presented at ASH, and obviously the interview with Dr. Batlevi was conducted before the FDA news. 

Still, her reaction to Parsaclisib was mixed, especially when compared to her enthusiasm for bi-specifics and CAR-T. She points out that when inhibitors are used on their own, they do have a response, but usually a Partial Response rather than a Complete Response. She thinks maybe they'll do better in combination with other agents.

Overall, it's a good interview. It confirms for me what I have been saying for the last few weeks about where the Lymphoma community seems to be heading. That might change, of course.  It will be interesting to see what the trends are in a few short months when the ASCO conference happens.

I'll let you know what I hear in the meantime.

A Third Inhibitor is Withdrawn

Well, this is getting silly now.

The maker of the PI3K inhibitor Parsaclisib has withdrawn its New Drug Application with the FDA. This comes a little more than a week after Idilalisib was withdrawn from the market for Follicular Lymphoma, and about six weeks after Duvelisib was withdrawn.  

Unlike the other two PI3K inhibitors, Parsaclisib was not yet approved by the FDA. It had applied for accelerated approval, but after discussions with the FDA, it decided not to go through with the application. They were not confident that they would be able to meet the requirements. Like the other two, this was called a "business decision." The application would have covered relapsed/refractort Follicular Lymphoma, and MZL and MCL, two other lymphomas.

I haven't seen a whole lot of analysis or commentary about any of these withdrawals. On Twitter this morning, I saw someone comment that there would probably be more of this happening with NHL treatments, as the large number of treatments (especially PI3K treatments) would mean more competition, and so more data to show that this version of the treatment would be better than others -- either more effective or safer. Another commentor said everyone is afraid of bi-specifics.

As I said in my post about Idelalisib, it does seem we've reached a point where we (patients, doctors, the FDA) will need to start focusing on quality over quantity. It's great to have so many options for treatment, but if the differences between those treatments are minimal, then someone is going to win that competition. 

And as good as PI3K inhibitors seem to be (they seem especially popular as a third-line treatment, after two other treatments have failed), the treatments that have gotten the Lymphoma community so excited in the last few years have been R-Squared (Rituxan + Revlimid), CAR-T treatments, and more recently, bi-specifics. What do they al have in common? They are as good as, or better than, traditional chemotherapy. And by "better than," I mean they are either more effective (they work on as many patients as chemo does, for as long) or they are safer (with fewer or less severe side effects).

But really, the biggest thing that the "exciting" treatments has going for them is durability. They have shown that they can work for a long time before a patient needs another treatment. And that matters. 

When I was first diagnosed in 2008, the assumption about Follicular Lymphoma was that patients could expect a lifetime of treatment. The disease would become more aggressive over time, and treatments would need to become more aggressive as well, with less and less time between them. Maybe the first treatment would last 5 years, and then the next 2 years, etc.

That's certainly still the case for some patients. But if newer treatments are also providing durable responses, then we would have less need for a wide range of choices. In other words, there's less need (and maybe desire) for 10 treatments that will each last 2 years when we could have 4 treatments that each last 5 years. Fewer treatments means fewer side effects to deal with, and better quality of life.

At least that's what seems to be happening. Remember, I'm not a doctor or a cancer researcher. Just a Cancer Nerd -- a patient who reads a lot.

Whatever the case, I think we don't need to be worried about treatments being withdrawn from use or from the approval process. There are lots of options still available and lots more being developed. We can afford to be picky (and patient). 

I hope to give you some good news next time.

Bi-Specifics: The Basics

Well, this was one of those tough blogging weeks. I started three different posts, and then abandoned them for different reasons. That happens fairly frequently. Maybe I start a post, and then realize I don't fully understand the science behind it, so I don't want to post it because I might be giving incorrect information. Or maybe I decide that the information isn't as significant for Follicular Lymphoma as I had first thought. It happens. 

It's kind of rare that it happens three times in one week, though. Frustrating.

So I'm giving up on writing something significant for now.

Instead, I'm linking to a piece from Cancer Therapy Advisor called "Development and Clinical Application of CD19xCD3 and CD20xCD3 Bispecific Antibodies." It's an interview with Dr. Andreas Klein from Tufts Medical Center. He discusses the two main types of bi-specifics that are in development. Remember, a bi-specific is a treatment that connects to a protein on the surface of a cancer cell (the way Rituxan does), but also connects to a protein on a T cell, a powerful immune cell. By bringing the immune cell close to the cancer cell, the T cell can work on the cancer cell the way it would work on a virus or bacteria. 

CD19 bi-specifics are currently used on Leukemias, and CD20 bi-specifics are used on Lymphomas, like FL. I found it interesting that Dr. Klein sees bi-specifics as kind of in competition with CAR-T treatments. That makes sense -- the commentaries I saw after ASH this year did seem to try to compare those two types of treatments -- cost, effectiveness, safety. 

It's an interesting interview that gives some nice background on bi-specifics. 

I'll get back to writing soon. Wish me luck.

Idelalisib No Longer Available for Follicular Lymphoma (in the U.S.)

The maker of Idelalisib (also known as Zydelig) has announced that it will no longer offer the treatment in the U.S. for Follicular Lymphoma (and for Small Lymphocytic Leukemia).

According to the press release, the FDA's approval had been based on a phase 2 clinical trial. It was expected that a phase 3 trial (with a larger number of patients) would be conducted, and if the trial showed similar results (a 54% response for FL), then final approval would be given. Partly because of Covid, the company had problems recruiting patients for the trial. They decided that it was better to withdraw the treatment from the market for FL and SLL. 

Idelalisib has also been approved for Chronic Lymphocytic Leukemia (CLL) in the U.S, and it will remain available for patients with CLL. It will also remain available for FL patients in the E.U, the U.K., Canada, Australia, New Zealand, and Switzerland.

I say Covid is "partly" to blame because, from what I could tell, Idelalisib wasn't a very popular treatment. The sales for the first quarter of 2021 (January to March) was about $16 million. That's a lot of money, but not compared to Yescarta, the CAR-T treatment made by the same company, which had 1st quarter sales of $160 million. 

I don't think that's a coincidence. Certain treatments seem more and more to be the future of Follicular Lymphoma, and based on the excitement that I hear when I listen to Lymphoma experts, CAR-T (and lately, bi-specifics) are going to be the choice of doctors, especially for relapsed/refractory FL.

If all of this sounds familiar, it's because just over a month ago, the maker of Duvelisib also announced that it would be pulling its treatment from the U.S. market. Duvelisib and Idelalisib are both PI3K inhibitors. There were 4 available, and now there are two.

I have to say, I'm not entirely surprised. Last June, I wrote a post where I asked, are there too many inhibitors available for FL patients? All four (and another being featured at ASCO) did slightly different things. But it seems like there wasn't going to be room for all of them.

And that seems to be the case. Losing two options like this doesn't mean that they are bad treatments. If anything, it might mean that they are good treatments -- good enough that 5 different companies want to get in on the action. If an oncologist suggests one, either alone or in combination, it's probably still worth having that conversation.

It probably says more about the state of treatments overall for Follicular Lymphoma, rather than any one individual treatment.

I know I always get excited about approvals for new treatments -- or even about applications for new treatments. When one gets approved, I usually say it's "another arrow in our quiver" -- another option for treating our disease. (That's the phrase that the Lymphoma specialist used when I saw him about a week after I was diagnosed. It's stuck with me for 14 years.)

And I'll continue to get excited about new treatments being approved. But maybe we're at a point in Follicular Lymphoma research where the bar is being raised -- where the newer options (R-Squared, CAR-T, bi-specifics) are going to be so good that we'll see fewer new treatments being approved. Instead, we'll see better treatments being approved -- treatments with greater effectiveness, or fewer side effects, than what we have available now. 

If that's the case, then you won't hear me complain. I'll gladly write less if it means we have better options available to us. 

(I'll probably still write just as much.)

Something tells me this is going to be a very interesting year for FL patients.