Assessing the Impact of FDA Approval of Pirtobrutinib in the R/R Chronic Lymphocytic Leukemia Treatment Landscape

Inhye Ahn, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, shares insight into the background data and real-world practice impact of the FDA approval of non-covalent Bruton tyrosine kinase inhibitor pirtobrutinib for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor, as well as provides information on the current treatment landscape for patients with CLL.

Transcript:

Hi everyone, I'm Inhye Ahn. I'm an assistant professor at Dana-Farber Cancer Institute. My area of research interest is chronic lymphocytic leukemia.

What is pirtobrutinib and what data led to the approval of this drug for this group of patients?

Pirtobutinib is a non-covalent Bruton tyrosine kinase inhibitor. And what the non-covalent means is that it can bind to BTK, the target, in a way that is different from covalent inhibitors, and can actually overcome the mutation that confers the resistance to it. It has been shown in the cell lines and the lab as well as in patients, so a very promising drug with a novel mechanism of binding.

The data that led to the approval of this drug is interesting. It's actually based on the BRUIN phase 1/2 study. They initially submitted a smaller size data to the FDA. It included 110 CLL/SLL [small lymphocytic lymphoma] patients, and 98% of these patients were treated with at least 2 prior lines of therapy, including a conventional covalent BTK inhibitor, as well as a BTK-2 inhibitor, namely, venetoclax. It's a very heavily pretreated, high-risk population that has been exposed to 2 targeted agent classes.

What is the current treatment landscape for patients with CLL. How does pirtobrutinib fit into this treatment paradigm?

The BRUIN population are those who have been exposed to the BTK inhibitor and BCL-2 inhibitor, which are the 2 mainstream treatment options in CLL. We no longer use chemoimmunotherapy a lot in CLL, because of the success we had with these targeted agents. Typically the covalent BTK inhibitors are used as continuous therapy, meaning that patients continue the drug as long as it works, as daily medications, as opposed to BCL-2 inhibitors, such as venetoclax, that are typically given in combination with an antibody, such as obinutuzumab, or rituximab, and in a fixed-duration for 1 year if you give the venetoclax-based regimen up front as a first-line therapy, or for 2 years for relapsed/refractory CLL.

Most patients do well with these therapies and can have durable disease control, but there are subset of patients who progress through each of these therapies or cannot tolerate treatment. After they go through these 2 great targeted agents, and they had very limited options, as of last year. Back then we used to have a targeted class called PI3-kinase inhibitor. This class hasn't been used as much as other targeted agents because of the concerns of toxicities, especially infections, as well as immune-related inflammatory side effects. It has been reserved for third-line relapsed/refractory and CLL patients.

Then there is an allogeneic stem cell transplant. Of course, it can be a very powerful treatment. However, it is intensive and not everyone can tolerate this intensive therapy. And therefore, it has been also reserved for high-risk patients who are fit enough to go through the transplant.

The last option would be chimeric antigen receptor T-cells or CAR T-cell treatment. This has been widely used in other types of lymphomas. And very excitingly, we have the approval for the CAR T-cells in CLL as well, as of this year. But again, it requires a lot of consideration because of the toxicity associated with cytokine relief syndrome.

It has logistical hurdles of setting up for the collection of the T-cells and then engineering, getting it back to the patient. Sometimes it requires hospitalization. It's a lot of consideration for safety. Therefore, it has been really challenging to give these options for everyone who go through BTK inhibitors and BCL-2 inhibitor. And then comes the pirtobrutinb, which can be a very easily accessible treatment options for patients who have failed bio-targeting agents.

How is the safety profile for pirtobrutinib? What is the impact of this approval in real-world practice?

The safety profile of pirtobrutinib has been excellent. Since the initial approval from the FDA, the study has been updated in terms of the number of patients treated from that study, as well as the follow up duration. At last year's ASH meeting, there had been updates for 317 CLL and SLL patients treated under the BRUIN trial, and Dr. Woyach from Ohio State University reported this data.

In that safety analysis, the patients tolerated this drug so well, the dose reduction occurred in about 4% of the patients, and dose discontinuation was less than 3%. It's very exciting, very well-tolerated treatment. I also want to highlight that the rate of cardiac side effects, such as atrial flutter have been not really observed in this trial, less than 5%. This appears to be one of the best tolerated BTK inhibitors currently that we have.

It's immediately impactful for the practice. I think the number 1 reason is that it's safe, and the number 2 it is effective, and also it is very accessible. It's a pill drug given once a day and you don't have to worry about or go through the hurdles of transplanting or collecting for a CAR T-cell, so it’s easier to get this drug.