Pirtobrutinib after a covalent BTK inhibitor in CLL/SLL

Over the past decade, the introduction of highly effective and safe novel therapies such as B-cell lymphoma 2 (venetoclax) and covalent Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib, zanubrutinib, and acalabrutinib) have significantly advanced the treatment landscape of chronic lymphocytic leukemia (CLL). However, while these BTK inhibitors have improved outcomes for patients with CLL/small lymphocytic leukemia (SLL), patients often develop resistance to these treatments and relapse. Emergent resistance against covalent BTK inhibitors is a growing issue in CLL, with 50–75% of patients acquiring a mutation of the target Cys481 residue at the adenosine triphosphate-binding pocket of BTK, rendering covalent BTK inhibitor's binding ineffective.

Pirtobrutinib is a selective, non-covalent BTK inhibitor which inhibits both wild-type and C481 mutated BTK, a common mutation involved in resistance to covalent BTK inhibitors, and is designed to overcome several limitations of covalent BTK inhibitors. It has recently been U.S. Food and Drug Administration (FDA) approved for relapsed/refractory (R/R) mantle cell lymphoma following two lines of systemic therapy including a BTK inhibitor.

The Lymphoma Hub previously reported promising outcomes of pirtobrutinib in relapsed B-cell malignancies and Waldenstrom’s macrobulinemia. Below, we summarize an article by Mato et al., published in New England Journal of Medicine, on the efficacy and safety of pirtobrutinib in R/R CLL/SLL following a BTK inhibitor.

Study design

BRUIN (NCT03740529) is a phase I/II trial of pirtobrutinib in patients with R/R CLL. The study was conducted across ten countries−Australia, France, Italy, Japan, Poland, South Korea, Sweden, Switzerland, United Kingdom, and the United States.

Patients received pirtobrutinib monotherapy in either phase I, at a dose range of 25–300 mg once daily in 28-day cycles, or phase II, at a dose of 200 mg once daily.

The primary endpoint was an overall response (OR), defined as a partial response or better according to the 2018 International Workshop on CLL response criteria. Secondary endpoints were OR including PR with lymphocytosis, progression-free survival, overall survival, and safety.

Results

Baseline characteristics

Of the 317 patients with CLL/SLL, 247 had previously received treatment with at least one BTK; including ibrutinib (n = 216), acalabrutinib (n = 44), zanubrutinib (n = 7), nemtabrutinib (n = 7), vecabrutinib (n = 3), spebrutinib (n = 3), and tirabrutinib (n = 1). Overall, 86 patients were treated in the phase I part, and 161 patients in the phase II portion. The median age was 69 years and median number of prior lines of therapy was three; baseline characteristics are summarized in Table 1.

Table 1. Baseline characteristics*

CAR, chimeric antigen receptor; cBTKi, covalent Bruton’s kinase inhibitor; CLL, chronic lymphocytic leukemia; ECOG, Eastern Cooperative Oncology Group; IQR, interquartile range; SLL, small lymphocytic leukemia *Data from Mato, et al.1 †Ten patients who received previous covalent BTKi’s also received previous non-covalent BTKi’s. ‡In the event that more than one reason for discontinuation was noted, disease progression took priority. §Molecular characteristics were determined centrally and are presented based on data availability, in those patients with a sufficient sample to pass assay quality control. ‖Complex karyotype was defined as the presence of ≥3 chromosomal abnormalities.
Characteristic, % (unless otherwise stated)	Pirtobrutinib after cBTKi (n = 247)
Median age (range), years	69 (36–88)
Sex
Male	68
Female	32
Classification
CLL	99.6
SLL	0.4
Rai stage
0–II	53.0
III or IV	41.3
Bulky disease ≥5 cm	31.6
ECOG Performance Status score
0	53.8
1	39.3
2	6.9
Number of previous lines of systemic therapy
Median (range)	3 (1−11)
1	7.7
2	22.3
3	23.1
≥4	47.0
Previous therapy
BTK inhibitor†	100
Anti-CD20 antibody	87.9
Chemotherapy	78.9
BCL2 inhibitor	40.5
P13K inhibitor	18.2
CAR T-cell therapy	5.7
Allogeneic stem cell transplantation	2.4
Median time from diagnosis to first dose of Pirtobrutinib (IQR)	11 (8–15)
Reason for discontinuation‡
Disease progression	76.9
Toxic effects or other	23.1
Mutation status
BTK C481
mutated	37.8
not mutated	62.2
PLCG2
mutated	8.1
not mutated	91.9
High-risk molecular features§
17p deletion	29.0
TP53 mutation	39.2
17p deletion, TP53 mutation, or both	46.6
Both 17p deletion and TP53 mutation	28.2
Unmutated IGHV	84.8
Complex karyotype‖	42.0
11q deletion	25.0

Efficacy

The OR for patients who previously received a BTKi or BTKi plus BCL2 inhibitor are reported in Figure 1. The OR rate remained consistent across most subgroups by patient demographic characteristics, molecular features, or the extent of additional previous therapy. The majority of patients showed a decrease in the size of target lesions, regardless of the reason for discontinuation or previous BTKi/BCL2 inhibitor treatment.

CR, complete response; PR, partial response.
*Data from Mato, et al.¹

At a median follow-up of 19.4 months, the median progression-free survival across different therapies and subgroups are reported in Figure 2. At a median follow-up of 22.6 months, the 12-month and 18-month overall survival among patients who previously received a BTK inhibitor was 86.0% and 80.5%, respectively.

BCL2, B-cell lymphoma-2; BTKi, Bruton’s tyrosine kinase inhibitor; IGHV, immunoglobulin heavy chain; PFS, progression-free survival.
*Data from Mato, et al.^1
†Therapies include BTKi, BCL2, and PI3K inhibitors as well as chemoimmunotherapy (chemotherapy and an anti-CD20 antibody).

Safety

Among the safety population (n = 317), the most common adverse events of special interest were infections, bleeding, and neutropenia (Table 2).

• No sudden cardiac deaths were reported.
• A total of 16 deaths were reported due to coronavirus disease-related pneumonia (n = 8), fungal pneumonia (n = 2), septic shock (n = 2), and other causes (n = 4).
• Treatment-related adverse events led to pirtobrutinib dose reductions in 35 patients and permanent discontinuations in 20 patients.

Table 2. AEs of special interest*^†

AE, adverse event *Data from Mato, et al.1 †Adverse events of special interest are those that were previously associated with covalent BTK inhibitors. ‡ Bruising included contusion, petechiae, ecchymosis, and increased tendency to bruise. §Of the 12 cases of atrial fibrillation or flutter in the overall safety population, three occurred in patients with a medical history of atrial fibrillation.
AE, %	Any grade	Grade ≥3
Infections	71.0	28.1
Bleeding	42.6	2.2
Neutropenia	32.5	26.8
Bruising‡	30.3	0
Hemorrhage	21.1	2.2
Hypertension	14.2	3.5
Atrial fibrillation or flutter§	3.8	1.3

Conclusion

Despite the lack of an active control group in this trial, pirtobrutinib proved effective and safe in patients with heavily pretreated CLL/SLL who experienced disease progression with a prior covalent BTK inhibitor; this demonstrates its potential as a therapeutic option, regardless of discontinuation due to disease progression, toxic effects, or other reasons.

There are several ongoing randomized phase III trials investigating pirtobrutinib in patients with CLL/SLL, including the BRUIN CLL-313 study (NCT05023980) evaluating pirtobrutinib versus bendamustine plus rituximab in untreated patients; the BRUIN-CLL-314 trial (NCT05254743) on pirtobrutinib versus ibrutinib; the BRUIN CLL-321 trial (NCT04666038) on pirtobrutinib versus either idelalisib plus rituximab or bendamustine plus rituximab; and the BRUIN CLL-322 study (NCT04965493) on pirtobrutinib plus venetoclax and rituximab versus venetoclax plus rituximab.