ASH: Acalabrutinib and R-Squared

Many thanks to longtime reader William, who learned about a promising Follicular Lymphoma treatment from an email from MD Anderson. This one was discussed at ASH, and it's worth highlighting. 

The ASH presentation is "#983: Addition of Acalabrutinib to Lenalidomide and Rituximab Induces High Complete Response Rates in Patients with Previously Untreated Follicular Lymphoma: Results of a Phase II Study." 

To break down the title a little bit -- if you've been reading for a while, you are familiar with R-Squared, or the combination of Rituxan and Revlimid (or Lenalidomide). It was shown to be a viable alternative to traditional chemotherapy. It's very good, but could be better (like every other FL treatment). This research looks at adding Acalabrutinib.

The logic makes sense. Alcalabrutinib (also known as Calquence) is a BTK inhibitor. Like all inhibitors, its job is to inhibit, or stop, something from happening. In this case, the target is Bruton's Tyrosine Kinase, an enzyme that is necessary for B cells to develop. As you probably know, B cells are immune cells that can cause a number of B cell lymphomas (including Follicular Lymphoma) when things go wrong. Alcalabrutinib stops one of the processes that allows B cells to grow unchecked. 

BTK inhibitors should make sense for B cell lymphomas like FL. Indeed, Alcalabrutinib has been approved in the USA and in Europe for other B cell lymphomas like CLL and Mantle Cell, both indolent like FL. But for some reason, BTK inhibitors just haven't been as effective on FL as it has with those other lymphomas. (Ibrutinib, also known as Imbruvica, was the first major BTK inhibitor, and has also been very successful for some other lymphomas, but not for FL.)

So maybe the trick is to use it in combination with another successful treatment?

This ASH presentation does present some good evidence for that. 

As the researchers point out in the abstract, they have already had some success with this combination with FL patients with Relapsed/Refractory disease. For this research, they tried the combination on untreated FL patients. It's a phase 2 trial, so there is a relatively small group of patients involved (just 24 of them).  As the researchers explain, one possible reason that R-squared might not be effective is because of "pro-tumoral macrophages." A macrophage is a kind of heavy-duty immune cell -- when B cells and T cells don't work, macrophages take over. But cancer is all about things not working the way they are supposed to, and macrophages can become "pro-tumoral" -- working to protect cancer cells, not eliminate them. BTK inhibitors like Alcalabrutinib can help keep macrophages from protecting tumors.

The small phase 2 study was pretty successful. The Overall Response Rate was 100%, and the Complete Response was 92%, with a median time of 3 months to the CR. As for durability, after a median follow-up of 26.8 months, 6 patients had their disease progress, including two whose disease transformed. After 2 years, Progression Free Survival was 79.2%, and Overall Survival was 91.7% (two patients dies, one from Covid).  The most common serious side effects (grade 3-4) were neutropenia (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 researchers also point out that some blood cells had changed in ways that indicate that BTK was being inhibited.

So overall, it seems like a promising treatment. The researchers think so, too -- they are expanding the trial from 24 patients to 50. I hope we'll see updated results next year.

Thank you again to William for pointing this one out. We're getting to the point where people will be looking back at the conference and writing and talking about what excited them. I'll keep sharing.