New Combinations for Follicular Lymphoma

Targeted Oncology ran a nice piece last week called "Exploring Novel Combinations in Indolent Lymphomas." It highlights a bunch of studies that are being conducted that involve trying different combinations of treatments to find something that improves outcomes without increasing side effects too much.

A lot of the research being done centers around R-Squared, the combination of Rituxan and Revlimid (also known as Lenalidomide). As you may know, R-Squared was approved with much celebration. It was the first treatment that was shown to be as effective as traditional chemotherapy. As such, it showed that it was possible for treatments that are more targeted to be a viable alternative to chemo. (Traditional chemotherapy likeR-CHOP and Bendamustine is often very effective for Follicular Lymphoma. The problem is, while chemo kills cancer cells, it often kills healthy cells as well.)

So while R-Squared is effective, it's not better. And that's an important distinction. It doesn't have the same side effects as chemo, but it also doesn't have fewer side effects. Just different ones. The official term for this is "non-inferior." That was the outcome of the large clinical trial that led to R-Squared being approved by the FDA -- it's not better than chemo, but it's not worse, either. But if it isn't better (that is, either more effective or safer), then it can't really replace chemo.

That's kind of where this article begins -- R-Squared came close to knocking chemo off the throne, but it didn't quite do it. So the next step is to find some way to make R-Squared more effective. That's what will make it superior to chemo, not just not inferior.

An example of this is the combination Tazemetostat + R-Squared, as I wrote about last month. R-Square is great, but adding a third treatment that goes after cancer cells in a different way just might make it better. Again, the problem is that it can also introduce a third set of side effects that can make things worse (though that doesn't seem to be the issue with Tazemetostat + R-Squared).

The article looks at a few others, though they aren't all being tested for Follicular Lymphoma. (The article is about indolent, slow-growing lymphomas, not just FL). This article is a summary of a presentation from the annual meeting of the Society of Hematologic Oncology (SOHO).

Some of the highlights:

• R-Squared is being combined with Epcoritamab, a bispecific antibody. The research is very early, in stage 1 and 2 trials, involving 66 previously untreated FL patients, but the results are good, with about 80% of patients in the trial getting a response.
• Another bispecific, mosunetuzumab, is also being combined with Lenalidomide (but not Rituxan) in a phase 3 trial with similar results. 
• Some other combinations focus on what are known as protumoral macrophages. Macrophages are another type of immune system cell, like the B cells that turn cancerous in FL. When macrophages become pro-tumorous, they allow cancer cells to grow. Some treatments target this process, including the BTK inhibitor Acalabrutinib. It is being combined with R-Squared in an early trial with 29 patients. It's doing well in the trial, with no new side effects when compared with R-squared, but it's also not much more effective. 
• Another BTK inhibitor called Zanubrutinib is being combined with Obinutuzumab (a monoclonal antibody like Rituxan). In a phase 2 trial, the combination is more effective than just Obinutuzumab.
  

A lot of these combinations are in early trials, as the article points out. But it does show that the approach is still very much on the minds of researchers. As exciting as CAR-T and bispecifics are on their own, there might be even more reasons for excitement if they are combined with other treatments. As long as the side effects remain manageable -- not worse than the side effects of the individual parts of the combination -- then there's some promise. 

All some fun things to keep an eye on.