Pooled results from the phase 3 BRUIN CLL-313 and BRUIN CLL-314 trials confirmed the efficacy of pirtobrutinib in treatment-naive CLL.
First-line pirtobrutinib (Jaypirca) delivered durable efficacy and a consistent safety profile in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL), according to pooled data from the phase 3 BRUIN CLL-313 (NCT05023980) and BRUIN CLL-314 (NCT05254743) trials presented at the
Data from the analyses showed that frontline pirtobrutinib monotherapy across all evaluable patients from both trials (n = 253) produced an overall response rate (ORR) of 93.3% (95% CI, 89.5%-96.0%). The ORRs for the pirtobrutinib monotherapy arms in BRUIN CLL-313 (n = 141) and BRUIN CLL-314 (n = 112) were 94.3% (95% CI, 89.13%-97.52%) and 92.0% (95% CI, 85.29%-96.26%), respectively.
At a median follow-up of 27.7 months (range, 27.6-27.7) in the overall population, the 18-month PFS rate was 94.7% (95% CI, 91.0-96.9%) and the 24-month progression-free survival (PFS) rate was 93.2% (95% CI, 89.1%-95.8%), with the median PFS being not reached (NR; 95% CI, 35.19 months-not estimable [NE]). Additionally, at a median follow-up of 29.5 months (range, 28.9-30.7), the 24-month overall survival (OS) rate was 97.5% (95% CI, 94.6%-98.9%), and the median OS was also NR (95% CI, NE-NE).
“In this pooled analysis, the ORR was 93.3%, and at 2 years, which is the longest follow-up data we have so far, the PFS rate was 93.2%. Patients are doing very well, and we look forward to being able to provide additional data in the future,” said Jennifer Woyach, MD, about the analysis in an exclusive interview with OncLive®.
Woyach is a physician and professor of hematology, director of the Division of Hematology, and co-leader of the Leukemia and Hematologic Malignancies Program at The Ohio State University Comprehensive Cancer Center in Columbus.
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“The purpose of the analysis was to get additional data on patients who were receiving pirtobrutinib as their frontline treatment regimen and to look at the populations on the 2 different trials to see whether the data and the patients were similar,” Woyach explained.
BRUIN CLL-313 enrolled patients with confirmed CLL/SLL requiring therapy per 2018 International Workshop on CLL (iwCLL) criteria, with no evidence of 17p deletions and an ECOG performance status of 2 or less.1 Patients in BRUIN CLL-313 were randomly assigned to receive pirtobrutinib at 200 mg orally once daily (n = 141) or bendamustine plus rituximab (Rituxan; n = 141).
The BRUIN CLL-314 trial enrolled patients who were BTK inhibitor naive and had 17p deletions, confirmed CLL/SLL requiring therapy per 2018 iwCLL criteria, and an ECOG performance status of 2 or less. Patients in BRUIN CLL-314 were randomly assigned to receive pirtobrutinib at the same dose as in BRUIN CLL-313 (n = 331) or ibrutinib (Imbruvica) at 420 mg once daily (n = 331).
The primary end points for both studies were investigator-assessed ORR, PFS, and OS. The pooled analysis included all patients who were treatment naive and had received pirtobrutinib.
“There have been a lot of studies that have looked at pirtobrutinib in the relapsed/refractory setting in CLL. It’s exciting to see this drug being tested in the frontline setting, primarily because it is such a potent and selective inhibitor of BTK,” Woyach added. “We expect that the efficacy is going to be even better when used in the frontline setting, and it is a well-tolerated medication, which makes it particularly appealing for use earlier in therapy, especially for patients who may not tolerate other treatments well.”
Baseline characteristics revealed that across the pooled population in the analysis, the median age was 66 years (range, 29-90), 59.7% of patients were male, and 60.1% of patients were enrolled in Europe. Most patients had CLL (90.5%), an ECOG performance status of 0 or 1 (95.3%), and Rai stage 0 to II disease (60.3%). High-risk molecular features included unmutated IGHV in 57.5% of patients, complex karyotype in 24.2% of patients, TP53 mutations in 9.5% of patients, and 17p deletions in 6.7% of patients.
Any-grade treatment-emergent adverse effects (TEAEs) occurred in 95.6% of patients, and grade 3 or higher TEAEs occurred in 45.6% of patients. The most frequently reported any-grade TEAEs included COVID-19 (20.6%), upper respiratory tract infection (17.1%), neutropenia (14.3%), anemia (12.7%), diarrhea (11.5%), back pain (10.7%), hypertension (10.7%), and arthralgia (10.3%). Common grade 3 or higher TEAEs were neutropenia (9.9%), anemia (4.8%), and hypertension (4.0%).
Any-grade AEs of special interest occurred in 78.6% of patients; those that occurred most frequently were infection (59.9%) and bleeding (32.9%), including hemorrhage (20.2%) and bruising (13.1%). Grade 3 or higher AEs of special interest occurred in 27.4% of patients, including infection (13.9%), neutropenia (13.5%), anemia (4.8%), and thrombocytopenia (2.0%). Atrial fibrillation or flutter of any grade occurred in 2.8% of patients, with 1.2% of patients experiencing these AEs at grade 3 or higher, including 3 events among patients 75 years or older. Treatment discontinuation due to TEAEs occurred in 4.8% of patients.
“[No] new safety signals have been observed [with] frontline treatment with pirtobrutinib in either of these studies. The rates of cardiac toxicity, like atrial fibrillation, are extremely low. The rates of hypertension are extremely low. There is a signal of neutropenia, which has been seen in other trials of pirtobrutinib as well. That’s probably one AE that occurs early on in therapy. The bruising [and] bleeding rates were low as well. It was an extremely well-tolerated drug,” Woyach added.
“These [study data] are looking similar [to each other]. They’re going to be generalizable to the [real-world] CLL patient population, and it’s going to be important to see follow-up from both these trials and hopefully integrated analyses like this in the future, so we can decide which patients are best suited to be given or even offered pirtobrutinib in the frontline setting,” said Woyach.
“The goal is that our patients with CLL live the same time of their lifespan and the same quality of their lifespan as if they didn’t have the disease,” she emphasized. “Adding better and better-tolerated drugs like pirtobrutinib that are also effective helps us achieve those goals. Whether the utility for pirtobrutinib is in the frontline setting for some patients or in the relapsed setting for some patients, either alone or in combination with other active agents, these data are helpful to get more experience using this drug. Pirtobrutinib doesn’t currently have a label for use in frontline CLL; it probably will be some time before this is extremely applicable to most patients with CLL. However, there are probably still patients [in whom] this drug is going to be appealing to use, like those who might be older, more frail, or who think they may not tolerate the other covalent BTK inhibitors or venetoclax [Venclexta] plus obinutuzumab [Gazyva].”
