ASCO: Two More FL Studies to Look At

The ASCO conference took place a few weeks ago, and I've already written about a bunch of the Follicular Lymphoma presentations from this year. But I also know that, in the weeks after the conference, lots of oncology websites give some analysis, with experts giving their opinion about how important some of the research is. I like these analyses, for two reasons. First, sometimes they talk about presentations that I already wrote about, and it makes me feel smart to know that I kind of guessed right about what's important. 

But I also like it when the articles bring up ASCO presentations that I didn't write about. I'm not an oncologist or a cancer researcher, as I like to remind you all. I like learning more about our disease, and I learn most from the people who are actually experts.

The article that caught my eye is from The ASCO Post, published by ASCO, and is called "Hematology Highlights From ASCO 2022." It looks at a few ASCO presentations that deal with blood cancer, including two that look at Follicular Lymphoma.

The first is a report on the ROSEWOOD trial, which looks at Zanubrutinib added to Obinutuzumab.

Zanubrutinib is a BTK Inhibitor. Like all inhibitors, its job is to inhibit, or stop a process from happening. In the case of BTK Inhibitors, it inhibits Bruton's Tyrosine Kinase, which helps B cells develop. Zanubrutinib is already approved for several other lymphomas.

Obinutuzumab, as you might remember, is a monoclonal antibody like Rituxan.

The ROSEWOOD trial compared Zanubrutinib and Obinutuzumab with Obinutuzumab by itself. The combination improved Overall Response Rate (85.4% versus 72.6%), Progression-Free Survival (27.4 months versus 11.2 months), but could not show a difference in Overall Survival (which is not surprising -- very few new treatments can do that). 

The trial involves FL patients with relapsed or refractory disease (the last treatment didn't work or stopped working). No details on side effects, but the lead researcher was quoted as saying the combination had a"favorable benefit-risk profile," and this could provide another option for R/R FL patients.

The second FL study discussed Epcoritamab added to R-Squared.

Epcoritamab is a bi-specific (I've been writing a lot about them lately). R-Squared is the combination of Rituxan and Revlimid (also known as Lenalidomide). 

The combination resulted in a 100% response rate in 28 R/R FL patients in the EPCORE NHL-2 trial, with all but one patient getting a Complete Response. 93% of the patients maintained their response at 6 weeks.

The side effect that the researchers seemed most concerned about was Cytokine Release Syndrome. There was a "low incidence" that was "predictable" and managed. Other side effects: "injection-site reactions in 53% of patients, cytokine-release syndrome in 50%, constipation in 47%, neutropenia [low white blood cells called netrophils] in 47%, fatigue in 40%, cough in 37%, and rash in 33%. Neutropenia was the most frequent grade 3 or 4 treatment-emergent adverse event."

The potential problem with a "triplet" or combination of three treatments is that there might be three times the side effects. That doesn't seem to be an issue in this combination, at least in this analysis.

More details of both studies are available in the ASCO Post article.

The post is a nice reminder that there are still plenty of trials being run for FL, with lots more potential treatments available for us. It's also a nice reminder that clinical trials can't be run without patients who volunteer for them, so keep talking to your oncologists about potential trials that might be appropriate for you. 

I'll keep an eye out for more ASCO analysis, and share what I learn.

Too Many Possible Treatments for Blood Cancers?

Fierce Pharma had a fascinating article this week called "An abundance of CAR-Ts: $37B cell therapy cancer market can't support 'congested' pipeline, report says." It's actually a commentary on a report from a company called GlobalData. 

The bottom line is this: Because of the success of CAR-T for blood cancers (not just Follicular Lymphoma, but several blood cancers), lots of companies are developing their own versions of CAR-T and other cellular therapies. There's just no way that all of those treatments will be possible.

Right now, according to the report, there are about 800 different cellular therapies in "the pipeline," in different stages of development. These include mostly CAR-T treatments, but also some others, like CAR-NK (which use Natural Killer cells instead of T cells) and TILs (Tumor-Infiltrating Lymphocytes). They all work in the same general way, using immune cells to kill off cancer cells. The report looks at five different blood cancers (not FL specifically, but all B Cell Lymphomas).

It's all pretty interesting. As I said in my last post, even though it seems like I've been writing lately about treatments that aren't going to be approved, it's important to remember that fewer than 10% of treatments ever make it to the treatment room. So in some ways it's not surprising that there are so many CAR-T treatments being developed. There's no way they'll all make it.

But it's also a little problematic. 800 treatments means there are a lot of resources being put into something that might be better used somewhere else. Every one of those treatments will need to be at least a little bit different from what is available. And that's certainly possible -- even the CAR-Ts that are available now have improved in the few years since approval. There is always room for improvement. But it seems like too much money, and too many smart people, working on the same problem. 

The report gives an example: most of the CAR-T treatments being developed are autologous. In other words, they use an individual patient's own cells to develop the treatment. There are not nearly as many allogeneic, or "off the shelf" treatments being developed. These are the kind of treatments that use one set of cells that might be given to any patient (or to many patients). The time and expense of developing an individual treatment would be gone. Cheaper and easier. 

Unfortunately, that's not where the resources are going. CAR-T treatments are autologous, and they are very popular, so that's what we'll develop. 

I think the GlobalData report is mostly aimed at those in the pharmaceutical industry, as a warning that this trend could bring problems. 

But that warning is very important for us as patients, too. As I have been saying, resources are probably going in the wrong direction. I think about the problems with PI3K Inhibitors, and so many of them being pulled (or pulling themselves) from the market all at once. Part of the problem was safety issues that came up. But the other part of the problem was the difficulty the companies were having in getting patients into clinical trials so they could provide more data for the FDA. When there are multiple treatments that essentially do the same thing, at some point, there aren't going to be enough patients around to test them. (And I know that the PI3K inhibitors were all slightly different, but obviously not different enough.)

So that's the potential lesson here -- at some point, we're going to have too many choices. I've made this point before: it seems like the treatments that the Lymphoma community are getting most excited about are things like CAR-T and Bi-specifics. One of the things that makes them exciting is that they tend to have long PFS -- Progression Free Survival. They may not necessarily increase Overall Survival, keeping us alive longer. But they do result in longer times between treatments. That means a better Quality of Life. 

It seems to me that the future of FL will mean fewer treatments for us during our lifetimes. That means fewer overall available treatments will be necessary. So the smart move would be for a company to look in new directions, and not offer a slight variation of what's already available. Rituxan was approved in 1997. There have been a whole lot of attempts to improve on it, with darn few successes. Doctors still use it because it's what they are used to. There's a lesson there. 

Of course, this is a good time to remind everyone that I am not an oncologist or a biologist or cancer researcher. Just a patient who reads a whole lot. 

But I also have a heavy interest in seeing new treatments be successful. I hope I'm right about a few things -- that treatments get better, and better treatments become available to us. 

Betalutin (RIT) Trial for FL Has Been Stopped

The company that makes the RadioImmunoTherapy (RIT) treatment called Betalutin has decided to stop its phase 2 trial for third line Follicular Lymphoma treatment. I'm a little sad about it.

Sad, but not really surprised -- I've been saying for a while that I thought Betalutin would face some challenges. RIT treatments just require too much work in the U.S. But what surprised me was that its most recent results showed good safety and decent effectiveness, but "decent" isn't good enough.

A little background, to remind you, since I haven't written about Betalutin in a while:

RadioImmunoTherapy treatments are kind of a combination of monoclonal antibodies (like Rituxan) and radiation therapy. Radiation is not common in Follicular Lymphoma and other blood cancers because it works best when the cancer cells stay still, as they do in solid tumors like lung cancer or colon cancer. Blood cancer cells move around through the blood constantly. A beam of radiation won't work. 

So what if you could take the radition directly to those moving cells? That's what RIT does. It takes something like Rituxan, which seeks out B cells by attaching itself to a protein on their surface, but it adds a little bit of radiation to the Rituxan. So you have a package of radiation delivered right to the cancer cell. 

In theory, it means fewer side effects, since the radiation goes directly to the cancer cell. And it means it's effective, for the same reason -- the treatment has a specific target. 

And RIT is indeed effective. In the past, two RIT treatments were approved by the FDA for FL -- Zevalin and Bexxar. However, in the U.S., rules for treating patients with RIT are complicated. Because it is radioactive, it requires special training, so regular oncologists can't give it patients (unlike traditional chemo or immunotherapies). With so many other effective options, most oncologists don't send patients to RIT specialists without some really compelling reason.

So RIT is use much less often than it should be, given how safe and effective it is. Bexxar wasn't used often enough to stay around, and it was discontinued in 2013. Zevalin is still around, and researchers continue to provide data that shows it is an excellent option (most recently in April). But it is still used much less frequently than it should be.

So, as I said, I'm not surprised that Betalutin isn't going to be an option for us (though the manufacturer is looking at other ways to offer it, maybe in combination with other treatments). Only about 33% of the 109 patients in the trial had a response that lasted more than 6 months. That's not great, especially when compared to CAR-T and bi-specifics. 

So why am I a little sad about this? It's personal, I guess. Zevalin was approved in 2009, the year after I was diagnosed. I think it was probably the first FL treatment to get FDA approval during the time I started really paying attention to that kind of thing. I know a couple of people who had Zevalin early on and who had great success -- over 15 years in remission. So I've always hoped that RIT would catch on.  But I can't imagine any one else will make an attempt to bring RIT to the market at this point. The field has moved on.

One last important point. It seems like I've been writing a lot lately about treatments have not been successful . That's true. But I don't think that means that more treatments are failing. If anything, it means that there are more high profile treatments that are being talked about early on in the trial process, and that I am writing about them. Remember, less than 10% of cancer treatments ever make it to a phase 3 trial. The great majority of them don't show enough effectiveness or safety in phase 2, phase 1, or (especially) pre-trial results to move forward.

My point is, there are still lots of treatments available to us, and lots more to come. 

I'll move on from my little bit of sadness. There is so much more to come to be excited about. And I'll keep sharing what I learn.

Priority Review for Mosunetuzumab

Just a quick one today:

The FDA has granted Priority Review for Mosunetuzumab (also known as Lunsumio). As you probably know, Mosunetuzumab is a bi-specific.

You can read a little more about Mosunetuzumab here, when I wrote it about last month. There was an ASCO presentation about it, with some updated numbers from the phase II clinical trial, and some news about the EU approving it for Follicular Lymphoma patients who have already had at least two treatments, and are relapsed or refractory (that is, their last treatment didn't work, or has stopped working).

As I wrote last month, the numbers for Mosunetuzumab are great. The Complete Response Rate was 60% and the Overall Response was 80% after a follow-up of 18 months. The median duration of response was 22.8 months -- very strong numbers when compared to other recently approved treatments.

Priority Review means that Mosunetuzumab kind of skips ahead of the line a little bit. They should have a decision before the end of 2022.

It will be interesting to see how the FDA handles this, in light of all of the problems that happened after the PI3K Inhibitor disaster from earlier this year. All of those inhibitors were approved based on phase 2 clinical trials, which is smaller than the usual phase 3, and come much quicker. The additional time that it takes for a phase 3 trial also means that researchers can see longer term results from the patients in the phase 2 trial -- including longer term side effects that might not have shown up right away. I'm not sure if the FDA is a little more skeptical about all trials, or just those from PI3K Inhibitors. They did grant Priority Review, so they must feel OK about the shorter time. Bi-specifics and Inhibitors are pretty different treatments, so the issues that concerned them might not be as worrisome for Mosunetuzumab.

I'm always a little excited about potential new treatments, and especially this one, because my current oncologist suggested it might be a good one for me if/when I need treatment again, back when it was still in its phase 1 trial. (Remember, it's good to ask your oncologist about nearby trials that might be appropriate for you. It's the only way we'll get newer, better treatments).

But I also know that the approval process can be slow, and slower is better with cancer treatment approvals, no matter how excited we are about them.

I have a few more bits of Follicular Lymphoma news to share. I'll get to them soon.

The Language of Cancer

Hello all. A couple of personal (but cancer-related) items today.

First, an article that I wrote was just published in a medical journal!

I've published a bunch of articles on some patient websites, but this one is in JCO Oncology Practice, a journal aimed at clinical oncologists. The article is called "We Need to Talk About War Metaphors in Oncology." It's based on some research that I have been doing for the last couple of years on the language that oncologists use when they write personal stories about cancer. Very often, people (patients and oncologists) use "war" language -- we say we are "warriors" who are "fighting" or "battling" cancer. Sometimes we use "journey" language, saying we are on a "cancer journey," or that we "didn't chose to walk this path." There has been a lot of research on how and why patients use this kind of language -- for some of us, it can be really helpful, while others really dislike that language. But there hasn't been much research on how oncologists use that language.

So my article (which is really an editorial, giving my opinion) shares some of what I found about how oncologists use "war" language when they tell stories about their experience. And what I found is that that some kinds of language can be really unhelpful, and oncologists can really dislike it sometimes (just like patients), but also that they it can be really helpful to them at other times (just like patients!). In the end, I argue that we need to spend more time thinking and talking about the language we use to talk about cancer, and figure out how and when certain words are helpful or hurtful. Words matter.

The article created quite a bit of discussion on Twitter over the weekend, when one of the editors from the journal tweeted about it. (When I say "quite a bit," I mean it's one of the most talked-about articles from the journal ever.)

I'm so pleased with the response. Not everyone agreed with my opinion, which is fine -- people are talking about the issue, and that's exactly what I wanted to happen.

All of this is leading to the next stage of my project -- finding a way to continue this conversation. My plan is to create a website, hopefully ready in the fall, where patients and oncologists can write short articles about the language of cancer, and what they find helpful and not helpful. I'll also use it to share more of my own research into what kind of language oncologists use. (It's a pretty big project, and I have lots to share.) 

My aim is to create a place that will help us all find words to describe our experience, and for patients and doctors to better understand one another. I'll be looking for writers. If you have something you want to share about the way we talk about cancer, I'd love to have you be a part of it (and I'm happy to help you say what you want to say, if that's a concern.) I'll share more on this project very soon!

*********************

The second item is my annual request to support my brother Mike in his Pan Mass Challenge bike ride. 

The PMC is a ride across Massachusetts over two days (August 6 and 7) that raises money for cancer research at Dana-Farber Cancer Institute in Boston. My brother has been riding since 2008 (the year I was diagnosed), and he's personally raised almost $80,000 in that time. 

Here's his fundraising letter for this year:

In just over one month, I'll be participating for the 15th year in the Pan Mass Challenge. The PMC is one of the largest cancer fundraising events in the country, consisting of a number of one or two day bike rides across the state of Massachusetts with proceeds used to benefit cancer research at the Dana-Farber Cancer Institute in Boston.

As many of you know, cancer has impacted many members of my family, including both of my parents and my two siblings. My Mom and Dad were patients at the Dana-Farber Institute, and had I've seen the direct impact of the care and research by the doctors and researchers at DFCI.

My goal this year is to raise $6,000 in donations, to help reach the overall goal of $66 million. If you would like to donate , please click on this link: https://profile.pmc.org/MM0386

Thanks for considering a contribution to this year's goal.

 

I know some of you have donated in the past. If you're able to, that's wonderful. If not, that's OK. But thanks for considering it.

No More Bone Marrow Biopsies?

Interesting research from the Journal of Clinical Oncology about Bone Marrow Biopsies (BMB). Some strong evidence that maybe we don't need them anymore (at least not as often).

I probably don't need to explain Bone Marrow Biopsies to any of you, but just as a reminder, when a patient is diagnosed with Follicular Lymphoma, they are put through a bunch of tests to determine the disease stage (how widespread the disease is) and grade (how aggressive it is). One of the tests is a Bone Marrow Biopsy.  It's different from a lymph node biopsy. With a BMB, a sample of bone marrow is taken from the bone. If there is FL present, it's likely a sign of advanced stage disease -- stage 4. The bone marrow is where immune cells are created, so cancer cells in the marrow means things have progressed pretty far.

(Though, as another reminder, stage 4 FL is different from stage 4 for other cancers. Still serious and advanced, but easier for treatment to get to the cancer cells and do its job than it is for many other stage 4 cancers.)

I won't get into the details of how BMB works. Most of you have been there, and the rest of you don't want to hear about it. It's not a fun procedure (and it's still pretty fresh in my memory, many years later).

The JCO article is called "Relevance of Bone Marrow Biopsies for Response Assessment in US National Cancer Institute National Clinical Trials Network Follicular Lymphoma Clinical Trials." 

It looks at a very particular use of BMBs, but it has some bigger implications.

Specifically, it looks at the use of BMBs in clinical trials. For many trials, a Bone Marrow Biopsy is a requirement. At the beginning of the trial, before the treatment is given, patients have a BMB to see if they have any FL cells in their bone marrow. That's common for many of us -- to get a BMB at diagnosis. However, many trial participants also get a BMB at the end of the trial, to make sure the treatment worked all the way into the bone. And some will even have one or more in the middle of the trial to kind of see how it's going.

It's a lot like getting a PET scan at the beginning, middle, and end of treatment. It's a way to check on things. But, as unpleasant as a PET scan is, a BMB is even more invasive and unpleasant. If there is a way to get rid of them, I'm all for it. 

The research in the article provide some evidence that maybe we can indeed get rid of BMBs.

The researchers looked back at two clinical trials that took place from 2008 to 2016. The first one looked at 580 FL patients, and found that only 5 of them had a positive BMB at the beginning of the trial. That's less than 1%. In the second trial, 5 out of 385 patients had a positive BMB (1.3%). The researchers conclusion was obvious -- if less than 1% of patients even need a BMB, why are they putting the other 99% through it -- multiple times? 

When they dug a little deeper, they found that the BMBs really didn't add anything to the analysis. Not every patient in the trial had multiple BMBs, so they could compare patient outcomes. They found that there was not any difference -- patients who had multiple BMBs didn't have a longer Progression Free Survival or Overall Survival. In other words, the BMB did catch anything early, or find cancer cells that weren't found by some other means.

Even though the focus of the research was on BMBs in clinical trials, the researchers are making bigger recommendations. First, they think BMBs should be eliminated from clinical trials. They don't add anything, and they put patients through unnecessary pain and cost. But they go further -- they think BMBs should stop being part of standard diagnostic testing for Follicular Lymphoma, except in special circumstances, like confirming limited stage disease (stage 1 or 2), or assessing cytopenias (low blood cell counts). 

For many (maybe most) of us, those things don't matter, or there are other ways to find them out. Liquid Biopsies, for example -- as I discussed in my last post -- might do a better job of all of this. Better in that (maybe soon) they will be just as accurate, but will not affect quality of life the way an invasive test like a BMB does.

This is all part of a larger trend in Follicular Lymphoma research, and in cancer research in general. Examine the way we do things, and don't just say "that's the way we've always done it." If we can't find a cure, then we can at least find ways to make the experience less unpleasant, whether it's treatment side effects or tools for diagnosis.

It's a small study, but an important one, with some potential implications for making our lives just a little bit easier.

Circulating Tumor DNA for Lymphoma

Well, I'm finished writing about Follicular Lymphoma presentations at ASCO. (You can read the posts from the last month, but here's my quick review: not a whole lot of exciting new stuff to report, but lots of small bits of progress, which is usually how cancer research goes.)

So now I'm going through all of the links that I've been saving for the last month to find all of the really interesting Follicualr Lymphoma research that wasn't reported at ASCO. There are a few very cool articles from medical journals that I want to share over the next few weeks. 

The first is from the journal Leukemia, and the article is called "Circulating tumor DNA in B-cell lymphoma: technical advances, clinical applications, and perspectives for translational research." 

This is a review article, so it's more of a "here's everything we know about a topic" piece than one that's reporting on original research. But it's fascinating, and could have some very important information for lymphoma patients, with stuff that could happen very soon (unlike lots of the research we see).

The article is about Circulating Tumor DNA, how to find it, and how to use it. It describes "liquid biopsies," which have been around for a while, but are finally getting accurate enough to be helpful.

So here's how they work:

All of us had a biopsy to help in our diagnosis. It was most likely a lymph node biopsy. For me, that meant a surgeon cut out one of the many swollen lymph nodes near my hip (the surgeon told my wife, "There were about 15 of them in there, I just picked the biggest one.") That tissue sample went to a lab, where a diagnosis specialist looked at it under a microscope. He saw the pattern and shape of the cells and knew right away it was Follicular Lymphoma. (When I say "he," I'm not making assumptions about the doctor being male -- it turns out the Diagnosis specialist at the hospital I was at is the father of a kid who was in the school band with my son. Small world.)

This is how most biopsies have happened for a long time. A doctor looks under a microscope and makes a diagnosis based on what he (or she) sees.

The problem is, there is a lot happening in that cell that can't be seen with the eye, even with a very powerful microscope. Two cancer cells can look the same on the surface, but there are enough genetic differences between them -- mutations in their DNA -- that they are really two different types of cancer. This is why I hate it when someone says they have Non-Hodgkin's Lymphoma. Which type? Because there are as many as 80 different kinds of NHL, and lots of them look similar under a microscope but behave very differently because of differences in their DNA.

That's where a "liquid biopsy" comes in. After a traditional biopsy is done (a "solid biopsy"), a liquid biopsy can use a blood sample to determine if there are any of those DNA mutations floating around a patient's body.

Much of the article looks at different methods for collecting, storing, and analyzing blood samples to test for circulating tumor DNA. It's not worth getting into all of that -- none of us is going to say to a doctor, "Hey, if you're going to do a liquid biopsy, can we talk about advantages and disadvantages of llele-specific oligonucleotide PCR and digital droplet PCR and NGS-based approaches?" (Even I don't have an opinion of those things, and I'm pretty sure I'm a bigger Cancer Nerd than any of you.)

More importantly, the article talks about why a liquid biopsy could be helpful for a patient with a B Cell Lymphoma like Follicular Lymphoma.

First, at diagnosis, a liquid biopsy can identify if the patient has a specific subtype of Lymphoma. Follicular Lymphoma doesn't have a lot of subtypes -- at least not really any that can be identified with a genetic analysis. But it's possible that, in the near future, enough genetic analysis is done that we can start to see some of those subtypes. Right now, patients don't really know if, for example, they are POD24 (their FL is aggressive enough to come back within 24 months after immuno-chemotherapy) until the lymphoma comes back. It's possible that a liquid biopsy could identify POD24 patients right at diagnosis so a more aggressive and appropriate treatment can start immediately. (I say "possible" because researchers still haven't identified a biomarker that can do that.)

Second, a liquid biopsy could be helpful during surveillance, such as during watch and wait, or in the years after treatment. For example, a liquid biopsy could help confirm transformation. As most of you know, Follicular Lymphoma can sometimes transform from a slow-growing cancer into a different, more aggressive one. A solid biopsy can confirm this -- pick a node and remove it through surgery and biopsy it. A microscope can show that the cells are different. Two problems with this, though. The first is, transformation doesn't happen all at once, so there are both Follicular Lymphoma cells and more aggressive transformed cells in the body at the same time. It's possible to get a solid biopsy sample that doesn't have any transformed cells -- the wrong node got picked -- so it doesn't look like there has been a transformation. Also, the biopsy will probably require surgery. Not fun. A liquid biopsy won't require surgery (good for the patient), and can measure DNA circulating in the blood, not hanging around in one spot in a node. Potential for greater accuracy.

Finally, a liquid biopsy can be very helpful after treatment. Right now, a PET scan is used to measure how successful a treatment was. If the scan doesn't light up, the cancer must be all gone. However, small bits of cancer cells might remain -- so small that they don't light up on a scan. But a liquid biopsy may be able to detect some remaining cancer by finding it in the DNA of cells that are moving around in the blood. If that's the case, then salvage treatment (maybe something like Rituxan Maintenance) can be used to clean up anything that's still left over. 

As the article points out, this technology has been around for a little while. Like lots of new medical innovations, at first, they are either too expensive or not accurate enough to be useful. But that has changed with liquid biopsies -- they are becoming more refined and accurate (that's another big part of the article that isn't worth getting into).

Liquid biopsies for Lymphoma aren't perfect, and there are a few different ways of doing them that make it hard to have a standard approach. But the authors of the article think these problems will be overcome "in the near future," and we will see a greater use of them soon.

I think this is something worth asking your oncologist about. There may be trials or testing being done at your cancer center, and it probably wouldn't require more than a blood sample to be involved. And it might get us all closer to having fewer scans and fewer biopsies.

[More interesting non-ASCO research coming soon.]