BTK Inhibitors: In-Focus - Episode 4

Envisioning the Role of Combination Therapy in the Treatment of CLL: A Q&A With Philip Thompson, MB, BS

Targeting different pathways may dramatically reduce the risk of resistance emergence and improve outcomes.

Bruton’s tyrosine kinase [BTK] inhibitors have demonstrated great versatility in the treatment of patients with chronic lymphocytic leukemia [CLL]. In addition to mounting data showing their benefits in various CLL subpopulations, BTK inhibitors may also have utility when used in combination with other mechanisms. Various ongoing studies are assessing different potential BTK-based combination regimens for the treatment of CLL. Ahead, Philip Thompson, MB, BS,assistant professor at the University of Texas MD Anderson Cancer Center in Houston, Texas, discusses how these regimens may affect the current treatment spectrum.

Targeted Oncology:There are trials underway investigating BTK inhibitors in combination with other agents such as ibrutinib with venetoclax and acalabrutinib with obinutuzumab. What are your expectations for these combination therapies?

Philip Thompson: There’s a dizzying array of studies going on. Basically, they’re all testing permutations: doublets with a BTK inhibitor and a BTK inhibitor plusvenetoclax plus or minus [anti-]CD20 [monoclonal] antibodies. I think it’s going to be really interesting.

It’s not going to be surprising to know that, if you use a BTK inhibitor plus venetoclax, [then] you’re going to do much better than [you would] with chemoimmunotherapy. There will be a higher rate of undetectable minimal residual disease [MRD]. Patients with high-risk genetics will do much better with targeted agents. What I think we don’t know here is, when you use ibrutinib plus venetoclax or acalabrutinib plus venetoclax, do you need a CD20 antibody on top of that? My suspicion is that a CD20 antibody is going to add very little to that combination. I don’t know for sure, but when you look at some of the triplet regimens from phase 2 studies, the undetectable MRD rates seem fairly similar to what you get with ibrutinib plus venetoclax or acalabrutinib plus venetoclax. But there are ongoing randomized studies that are going to properly answer that question. There are some that are going to directly compare BTK monotherapy versus BTK inhibitor plus venetoclax.

Targeted Oncology: For BTK inhibitor combination therapies, what would you like to see in clinical trials to determine the number of cycles and length of maintenance therapy?

Thompson: There were several phase 2 studies—1 at [The University of Texas] MD Anderson [Cancer Center] and 1 in the United Kingdom with ibrutinib and venetoclax—where there was an MRD-directed approach to treatment duration. In the CAPTIVATE trial, patients received ibrutinib for 3 cycles then ibrutinib plus venetoclax for 12 cycles, [which was] 12 months or 48 weeks of combination therapy. If they had confirmed undetectable MRD, they [received] randomized to ibrutinib maintenance vs. no maintenance at that point. If they had detectable MRD, they [received] randomized to discontinuing ibrutinib monotherapy or continuing combination therapy with ibrutinib and venetoclax. That’s an attempt to use MRD analysis to guide duration of therapy.

The U.K. study used a similar approach where they treated to undetectable MRD targets. If patients [did] not achieve early undetectable MRD, they continued the combination therapy with ibrutinib/venetoclax for longer. If they still had MRD at the end of 3 years, they continued ibrutinib monotherapy.

My colleague Dr Nitin Jain, MD, [from the] University of Texas MD Anderson Cancer Center in Houston, Texas had a similar study to that [with] patients in the frontline and relapsed [settings] where they were treated for 2 years. If they had MRD at the end of treatment they continued ibrutinib maintenance, and if they had undetectable MRD they stopped. This is an example of an MRD-directed approach, which I think some people are going to do as part of their routine practice.

Targeted Oncology: Looking specifically at ibrutinib plus venetoclax, what is your perspective regarding the implications and potential benefits of 2 oral oncolytic treatments coming together?

Thompson: Each drug makes the other drug work better. They target completely different pathways in the cell so that should—theoretically and in practice—dramatically reduce the risk of resistance emergence during therapy, particularly at point mutations in BTK or BCL2 emerging during therapy. We’ve seen very few patients develop on-treatment resistance in our ibrutinib [plus] venetoclax studies. The drugs have nonoverlapping toxicity profiles, which is hugely useful. Really, the [main adverse] effect that we see that is worse with combination [therapy than it is] with either drug alone is diarrhea. There’s more diarrhea on that combination [regimen] than with either drug alone because both of those drugs usually cause relatively minor diarrhea. Most patients [can] tolerate that combination very well.

Targeted Oncology: There are studies underway evaluating BTK inhibition with chemoimmunotherapy for treatment naïve CLL/SLL [small lymphocytic leukemia]. Are there data that you find compelling? How could this impact the treatment landscape?

Thompson: Yes, there are 3 studies in particular. There’s 1 led by Matthew S. Davids, MD, MMSC, at [the] Dana-Farber Cancer Institute [in] Boston, Massachusetts with ibrutinib and FCR [fludarabine, cyclophosphamide, rituximab]. That study included all patients, regardless of genomic risk, so they had patients with 17p deletion on that study, for example. They had extremely high response rate[s] and rate[s] of undetectable minimal residual disease. I think around 80% [of patients had] undetectable MRD on that study. [There was also] a very high rate of progression-free survival. Overall, it was an extremely potent regimen. It’s a time-limited regimen, [and] they didn’t select patients according to genomics.

But the challenge is[that] you’re still giving [the patient] chemoimmunotherapy. You’re still exposing the patient to the risks associated with chemoimmunotherapy; in particular, the risk of secondary myeloid neoplasms like MDS [myelodysplastic syndromes] and AML [acute myeloid leukemia], which occur in 2% to 5% of patients [who] receive FCR. [These are] devastating, usually fatal complications. I think most people are leaning away from chemoimmunotherapy for that reason given that we can get such high rates of undetectable MRD with venetoclax-based therapy.

If you’re hoping to achieve undetectable MRD with time-limited treatment, most people are going to say, “well, OK, I’ll use a venetoclax-based treatment rather than adding a BTK inhibitor to chemotherapy.” I think that’s probably the way the field is headed. It’s hard for me to see a path forward to widespread use of chemoimmunotherapy plus a BTK inhibitor.