Acalabrutinib + R-Squared for FL

The journal Nature Communications published an article a couple of months ago (I know, I'm behind on things) called "Frontline acalabrutinib, lenalidomide and rituximab for advanced stage follicular lymphoma with high tumor burden: phase II trial." 

It's a follow-up on some research that was presented at the ASH conference in 2023.  

In this study, researchers added Alcalabrutinib (also known as Calquence) to R-Squared. Alcalabrutinib is a BTK inhibitor. Just like other inhibitors, its job is to inhibit, or stop, something from happening -- in this case, Bruton's Tyrosine Kinase, an enzyme that is necessary for B cells to develop. B cells are, of course, the type of immune cell that includes the cells that can lead to Follicular Lymphoma. And that's what happens with a BTK inhibitor. The BTK enzyme does its job too well and won't die off, meaning the B cell won't die, leading to cancer. A BTK inhibitor stops that process and lets the cell die the way it is supposed to. 

Alcalabrutinib is already approved for some other blood cancers -- Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), and Waldenström's macroglobulinaemia.  So it makes sense that researchers are trying it with FL. However, there have also been several other BTK inhibitors that are effective with other blood cancers, but not FL.

The presentation at ASH in 2023 showed that this combination of Alcalabrutinib was very promising. The research is from a phase 2 clinical trial with 24 patients (a pretty small number). The patients had not received any treatment yet. The Overall Response Rate was 100%, and the Complete Response was 92%. After 26 months, 6 patients had their disease progress. The most common serious side effects (grade 3-4) were low neutraphils, a type of white blood cell, 58%, liver function test elevation (17%), infection (12.5%; 2 out of 3 related to COVID19), anemia (8%) and skin rash (8%). 

The Nature article was meant as a follow-up, looking at some longer-term data. The researchers were especially interested in what they call CR30 -- how many patients were able to maintain their Complete Response after 30 months. For them the CR30 rate was 65%. I'm not sure how that compares to some other treatments, but it seems positive. (This is a single-arm study, meaning they didn't split the patients into two groups so they could compare two treatments directly).   

After a median follow-up of 43 months, the median PFS (Progression-Free  Survival) was not reached, meaning more than half of the patients had not progressed. The PFS rate after 2 years was 79%, and for 3 years it was 62%. The POD24 rate was 17%, meaning 17% of patients who had a response had their disease return within 24 months. About 20% of FL patients are POD24, so this seems roughly in line with that number. 

Overall, the numbers look very promising. It will be interesting to see how this goes in a larger phase 3 trial.

I think what's really interesting, though, is the number of articles I've seen recently that look at R-squared triplets -- combinations if Rituxan, Revlimid (Lenalidomide), and something else. It makes sense. R-Squared has been shown to be as effective as traditional chemotherapy, but with a different set of side effects. SO instead of combining a single agent with chemo, researchers are hoping a combination with R-squared will increase effectiveness, hopefully without increasing side effects. That seems to be the case with this triplet, making a BTK inhibitor more effective than it has been on its own.

 Time will tell.