BRUIN Trial Establishes Efficacy of Noncovalent BTK in Pretreated CLL
During a live event, Shuo Ma, MD, PhD, discussed the outcomes of the BRUIN trial of pirtobrutinib in BTK inhibitor–pretreated chronic lymphocytic leukemia.
Shuo Ma, MD, PhD
Many patients with chronic lymphocytic leukemia (CLL) continue to face disease progression after the use of Bruton tyrosine kinase (BTK) inhibitor and BCL2 inhibitors. In a recent virtual Case-Based Roundtable meeting, Shuo Ma, MD, PhD, professor of medicine in hematology and oncology at Northwestern University Feinberg School of Medicine in Chicago, discussed the newer approved options for these patients. Considerations such as high-risk molecular factors and BTK resistance mutations were addressed during discussions between Ma and the participating oncologists. Feedback and perspectives from participants during the event showed how oncologists are dealing with the challenge of refractory CLL and adapting to the use of new regimens.
Targeted OncologyTM: What treatment options are available for patients with CLL who are refractory to BTK inhibitors?
Shuo Ma, MD, PhD: In the National Comprehensive Cancer Network guidelines, for patients who have already [not seen a response with] covalent BTK inhibitors and have already been exposed to venetoclax [Venclexta], the 2 new FDA approved agents are pirtobrutinib [Jaypirca] or the CAR T-cell therapy [lisocabtagene maraleucel (Breyanzi)]. Pirtobrutinib is a noncovalent BTK inhibitor. The 3 BTK inhibitors [ibrutinib (Imbruvica), acalabrutinib (Calquence)] and zanubrutinib [Brukinsa] are covalent BTK inhibitors because they all bind to the BTK protein through a covalent chemical bond to the C481 amino acid. Often when patients develop resistance, they're developing resistance in the C481 site, and so the covalent BTK inhibitors are no longer able to bind, and that's why they become refractory to those inhibitors. Noncovalent BTK inhibitors, such as pirtobrutinib, bind to the BTK protein not through 1 amino acid, but are binding with multiple different amino acids in the pocket, and that's why they're less impacted by the single point mutation in 1 amino acid. Pirtobrutinib is the first noncovalent BTK inhibitor that received FDA approval, and there are also a number of others that are currently in clinical trials.
Could you describe the study that led to the use of pirtobrutinib?
The BRUIN study [NCT03740529] is the first-in-human phase 1/2 study of pirtobrutinib in patients with B-cell malignancies, which included CLL or small lymphocytic lymphoma [SLL] cohorts, mantle cell lymphoma cohorts, as well as several other non–Hodgkin B-cell lymphomas. Here we're focusing on the CLL/SLL cohorts, where 296 patients were included. For the efficacy analysis population, 252 patients were included, and these patients received dose escalation in the phase 1 part testing doses from 25 mg daily all the way to 300 mg daily. There were no dose-limiting toxicities identified, so 200 mg once daily was selected as the recommended phase 2 dose. Then there's a dose expansion phase for the study. Eligibility was for patients with CLL or lymphoma who had been previously treated. The key end points are safety and preliminary efficacy.1
Focusing on the CLL patient population, the median age was 69 years and the median number of lines of prior therapy was 3, with a range of 1 to 11. There were a lot of patients who [underwent numerous] prior lines of treatment. [Some] of those prior lines of treatment include 100% with prior BTK inhibitor exposure. This was required for inclusion in the study. Most patients also had prior exposure to chemoimmunotherapy. Approximately 40% of patients also had prior BCL2 inhibitor treatment with venetoclax, 6% of patients had prior CAR T-cell therapy, and 2% had prior allogenic stem cell transplant. The reason for discontinuation of any prior BTK inhibitors for 76% of patients was due to disease progression. That means the majority of the patients discontinued prior BTK inhibitor due to refractory disease, so they were refractory to covalent BTK inhibitors. Only 23% of patients discontinued due to intolerance.
[Looking at] the baseline molecular characteristics, I want to focus on the BTK C481 mutation status. As I mentioned, mutation in the C481 amino acid site in BTK is one of the most common mechanisms of resistance to covalent BTK inhibitors; 38% of patients had a confirmed C481 mutation. Another common mechanism of resistance is the PLCG2 mutation, which was found in about 8% of patients. [Nearly] 30% of patients had 17p deletion, 40% had TP53 mutation, and [nearly] half of the patients had either one of those 2 high-risk features. [Additionally,] 85% of patients had unmutated IGHV, which is another high-risk feature, and 40% had complex karyotype. So this is a group of patients who were heavily pretreated with a lot of very high-risk features, and many of them had refractory disease.
What efficacy outcomes were reported with pirtobrutinib in this patient population?
The overall response rate [ORR] in the patients who had been previously exposed to BTK inhibitor was 73%. For patients who have been exposed to both BTK and BCL2 inhibitors, the ORR is very similar at 70%. The median progression-free survival [PFS] for the overall population was 19.6 months [95% CI, 16.9-22.1]. Those who are BCL2 naive tended to have longer median PFS of 22.1 months compared with 16.8 months for double refractory patients.2
The vast majority of patients had significant reduction in their lymph node burden with pirtobrutinib treatment, even though these are very heavily pretreated patients and many of them had been refractory to prior covalent BTK inhibitors.
Comparing patients who had or did not have prior BCL2 inhibitor treatments, the waterfall plots are showing that the vast majority of patients are responding beautifully with reduction in their lymph node burden, whether or not they had prior BCL2 inhibitor.
What was the safety profile for pirtobrutinib in this trial?
Pirtobrutinib appears to be fairly well tolerated.1 One thing to highlight is that grade 3 or higher adverse events [AEs] are fairly uncommon in the pirtobrutinib-treated patients. For [most common] treatment-related AEs, all grade 3 or higher AEs are less than 3%. [For] adverse events of special interest, we know that BTK inhibitors in general have several well-known AEs, such as cardiac risk, especially with atrial fibrillation or flutter, bleeding risk, hypertension, infection risk, and cytopenia risk. If you look at each of them, they're mostly low grade, and grade 3 or higher AEs is uncommon. [The grade 3 or higher AEs] are mostly neutropenia at 26%, infection at 28%, and the rate of atrial fibrillation or flutter is fairly uncommon: any-grade is only 3.8% and grade 3 or higher is only 1.3%. The treatment-related bleeding risk is 23% and treatment-related hypertension risk is 3.8%, so the impression is that it appears to be well tolerated.
DISCLOSURES: Ma previously reported receiving research funding from Abbvie, AstraZeneca, Beigene, Loxo, and Juno, and is a consultant for Eli Lilly and Janssen.
