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Jaypirca ® (pirtobrutinib) tablets
50 mg,100 mg
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What are the efficacy and safety results for the Jaypirca® (pirtobrutinib) in the CLL-321 study?
In a phase 3 CLL-321 study, Jaypirca (pirtobrutinib) showed improved PFS compared with IdelaR/BR and the most common TEAEs for patients who received pirtobrutinib were pneumonia and anemia.
Efficacy Results in the CLL-321 Study
Study CLL-321 is a global, randomized, open-label, multicenter phase 3 trial comparing the safety and efficacy of pirtobrutinib 200 mg daily as continuous monotherapy to investigator’s choice of 2 comparator therapies: either idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) in patients with chronic lymphocytic leukemia (CLL) or small cell lymphoma (SLL) who have been treated with at least a covalent Bruton's tyrosine kinase (BTK) inhibitor (NCT04666038).1 Study CLL-321 Schema provides additional details on the Study CLL-321design.
The primary analysis was conducted on August 29, 2023, upon reaching the predetermined number of events after 238 patients were enrolled. At a limited median study follow-up of 7.5 months, the independent review committee (IRC)-assessed progression-free survival (PFS) primary analysis demonstrated superiority of pirtobrutinib versus IdelaR/BR (HR=0.58; 95% CI: 0.38 to 0.89; p=.0105). As of the data cut-off date on August 29, 2024, 238 patients with CLL or SLL had been enrolled in Study CLL-321 for treatment with either pirtobrutinib monotherapy (n=119) or investigator's choice of either IdelaR (n=82) or BR (n=37) and all of these patients were included in the updated descriptive efficacy analyses.2 Efficacy results are summarized in Efficacy Results Among Patients in the Phase 3 CLL-321 Study and IRC-assessed PFS is displayed in Independent-Review Committee Assessed Progression-Free Survival in CLL-321 Study.
Efficacy Outcomes |
Pirtobrutinib |
IdelaR or BR |
ORR including PR-L, IRC assessed (95% CI) |
65 (55-73) |
53 (44-62) |
Median DOR, including PR-L, IRC assessed, months (95% CI) |
13.8 (11.1-17.2) |
10.9 (7.8-14.8) |
Median PFS, IRC assessed, months (95% CI) |
14.0 (11.2-16.6) |
8.7 (8.1-10.4) |
HR (95% CI) |
0.54 (0.39-0.75); p=.0002b |
|
Median PFS, INV assessed, months (95% CI) |
15.3 (12.8-19.9) |
9.2 (7.3-10.6) |
HR (95% CI) |
0.48 (0.34-0.67); p<.0001b |
|
Median EFSc, months (95% CI) |
14.1 (11.4-17.0) |
7.6 (4.8-8.8) |
HR (95% CI) |
0.39 (0.28-0.53); p<.0001b |
|
Median TTNTd or death, months (95% CI) |
24.0 (17.8-29.7) |
10.9 (8.7-12.5) |
HR (95% CI) |
0.37 (0.25-0.52); p<.0001b |
|
18-month OSe, months (95% CI) |
73.4 (63.9-80.7) |
70.8 (60.9-78.7) |
HR (95% CI) |
1.09 (0.68-1.75); p=.7202 |
|
Median OS, months (95% CI) |
29.7 (27.1-NE) |
NR (28.9-NE) |
HR (95% CI) |
1.09 (0.68-1.75), p=.7202 |
|
Abbreviations: BR = bendamustine + rituximab; CLL = chronic lymphocytic leukemia; DOR = duration of response; EFS = event-free survival; HR = hazard ratio; IdelaR = idelalisib + rituximab; INV = investigator; IRC = independent review committee; iwCLL = International Workshop on Chronic Lymphocytic Leukemia; NE = not estimable; NR = not reached; ORR = overall response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PR-L = partial response with lymphocytosis; SLL = small lymphocytic lymphoma; TTNT = time to next treatment.
aMedian follow-up 17.2 months (95% CI 9.7-23)
bStratified log-rank 2-sided p-value; nominal p-value.
cEFS is defined as the time from randomization to the first occurrence of documented PD per iwCLL 2018 criteria as assessed by Investigator, initiation of subsequent anticancer therapy for CLL/SLL, unacceptable toxicity leading to treatment discontinuation as assessed by the Investigator, or death (due to any cause).
dTTNT is defined as time from the date of randomization to the date of initiation of the subsequent anticancer therapy (including crossover) for CLL/SLL, or death due to any cause, whichever occurs first.
eOverall survival follow-up was limited and confounded by high rate of post-progression crossover (76% [50/66]).
Figure 1 Description. As of the data cut-off date on August 29, 2024, the independent review committee-assessed median progression-free survival for patients who received pirtobrutinib was 14.0 month compared with 8.7 months for patients who received IdelaR/BR.
Safety Results in the CLL-321 Study
Any grade treatment-emergent adverse events (TEAE) occurred in 108 (93.1%) patients who received pirtobrutinib and 107 (98.2%) patients who received IdelaR/BR, with pneumonia being the most common TEAE in patients who received pirtobrutinib (22.4%) versus IdelaR/BR (11.9%).2
Dose reductions occurred in
- 13 (11.2%) patients who received pirtobrutinib and
- 40 (36.7%) patients who received IdelaR/BR.2
Treatment discontinuation due to adverse event occurred in
- 20 (17.2%) patients who received pirtobrutinib, and
- 38 (34.9%) patients who received IdelaR/BR.2
Grade 5 TEAEs were reported in 12 (10.3%) patients who received pirtobrutinib (none considered related to treatment) and 10 (9.2%) patients who received IdelaR/BR (one considered related to BR).2
Adverse Events of Interest Among Patients in the Phase 3 CLL-321 Study describes the TEAEs reported by patients in the phase 3 CLL-321 study. Adverse Events of Interest Among Patients in the Phase 3 CLL-321 Study provides additional details on the adverse events of interest.
Treatment-Emergent Adverse Event, n (%) |
Pirtobrutinib |
IdelaR or BR |
||
Any grade |
Grade 3/4 |
Any grade |
Grade 3/4 |
|
Subjects with ≥ 1 TEAE |
108 (93.1) |
67 (57.7) |
107 (98.2) |
80 (73.4) |
Pneumonia |
26 (22.4) |
18 (15.5) |
13 (11.9) |
9 (8.3) |
Anemia |
23 (19.8) |
13 (11.2) |
19 (17.4) |
8 (7.3) |
Neutropenia |
21 (18.1) |
17 (14.7) |
17 (15.6) |
13 (11.9) |
Cough |
19 (16.4) |
0 |
19 (17.4) |
0 |
Diarrhea |
19 (16.4) |
0 |
34 (31.2) |
6 (5.5) |
COVID-19 |
15 (12.9) |
0 |
20 (18.3) |
4 (3.7) |
Pyrexia |
15 (12.9) |
1 (0.9) |
29 (26.6) |
1 (0.9) |
Fatigue |
13 (11.2) |
2 (1.7) |
22 (20.2) |
1 (0.9) |
Nausea |
13 (11.2) |
1 (0.9) |
22 (20.2) |
0 |
Vomiting |
8 (6.9) |
1 (0.9) |
19 (17.4) |
0 |
ALT increased |
4 (3.4) |
1 (0.9) |
19 (17.4) |
10 (9.2) |
Weight decreased |
4 (3.4) |
0 |
18 (16.5) |
0 |
Infusion related reaction |
0 |
0 |
19 (17.4) |
3 (2.8) |
Abbreviations: ALT = alanine transaminase; BR = bendamustine + rituximab; IdelaR = idelalisib + rituximab.
Adverse Events of Interest, n (%) |
Pirtobrutinib |
IdelaR or BR |
||
Any grade |
Grade 3/4 |
Any Grade |
Grade 3/4 |
|
Anemiaa |
24 (20.7) |
13 (11.2) |
19 (17.4) |
8 (7.3) |
Atrial fibrillation and atrial flutter |
3 (2.6)b |
2 (1.7) |
1 (0.9) |
0 |
Bleeding |
25 (21.6) |
4 (3.4) |
11 (10.1) |
0 |
Bruisingc |
9 (7.8) |
1 (0.9) |
3 (2.8) |
0 |
Petechiae and purpura |
6 (5.2) |
1 (0.9) |
1 (0.9) |
0 |
Hemorrhaged |
18 (15.5) |
3 (2.6) |
8 (7.3) |
0 |
Hypertension |
8 (6.9) |
3 (2.6) |
4 (3.7) |
1 (0.9) |
Infectione |
74 (63.8) |
34 (29.3) |
54 (49.5) |
21 (19.3) |
Infection without Covid-19 |
67 (57.8) |
30 (25.9) |
47 (43.1) |
19 (17.4) |
Neutropeniaf |
31 (26.7) |
24 (20.7) |
37 (33.9) |
30 (27.5) |
Thrombocytopeniag |
11 (9.5) |
9 (7.8) |
17 (15.6) |
8 (7.3) |
Abbreviations: BR = bendamustine + rituximab; IdelaR = idelalisib + rituximab.
aIncludes anemia and iron deficiency.
b2 out of the 3 patients had a medical history of atrial fibrillation.
cIncludes contusion and ecchymosis.
dIncludes hemorrhage and hematoma.
eIncludes all infection events reported including COVID-19.
fIncludes neutropenia, neutrophil count decreased, febrile neutropenia, and neutropenic sepsis.
gIncludes thrombocytopenia and platelet count decreased.
Baseline Patient Characteristics in the CLL-321 Study
Baseline Patient Characteristics Among Patients in the Phase 3 CLL-321 Study and Prior Treatments Among Patients in the Phase 3 CLL-321 Studydescribe the baseline patient characteristics and prior treatments for the patients included in the phase 3 CLL-321 study. The population was heavily pre-treated population with 33% of patients having received ≥4 prior lines of therapy.2,3
Baseline Patient Characteristicsa |
Pirtobrutinib |
IdelaR/BR |
Median age, years (range) |
66 (42-90) |
68 (42-85) |
Male |
83 (70) |
83 (70) |
Region |
||
North America |
24 (20) |
39 (33) |
Europe |
76 (64) |
63 (53) |
Asia |
14 (12) |
15 (13) |
Australia |
5 (4) |
2 (2) |
Histology |
||
CLL |
109 (92) |
108 (91) |
SLL |
10 (8) |
11 (9) |
ECOG PS |
||
0 |
51 (43) |
50 (42) |
1 |
56 (47) |
64 (54) |
2 |
12 (10) |
5 (4) |
Rai stageb |
||
0-II |
58 (49) |
62 (52) |
III-IV |
56 (47) |
54 (45) |
Bulky disease (lymph node) |
||
<5 cm |
67 (56) |
53 (45) |
≥5 cm |
48 (40) |
59 (50) |
≥10 cm |
14 (12) |
18 (15) |
No measurable target lesion at baseline |
4 (3) |
7 (6) |
β2 microglobulin |
||
≤3.5 mg/L |
27 (23) |
39 (33) |
>3.5 mg/L |
89 (75) |
77 (65) |
High-risk molecular features (central lab), n/n available (%) |
||
TP53 mutation |
36/97 (37) |
30/94 (32) |
17p deletion |
39/111 (35) |
43/112 (38) |
17p deletion and/or TP53 mutation |
51/94 (54) |
53/98 (54) |
IGHV unmutated |
90/97 (93) |
74/93 (80) |
Complex karyotypec |
53/74 (72) |
44/75 (59) |
11q deletion |
19/101 (19) |
25/99 (25) |
Molecular characteristics, n/n available (%) |
||
BTK C481S |
37/99 (37) |
36/94 (38) |
PLCγ2 |
15/99 (15) |
11/94 (12) |
Reason for any prior cBTKi discontinuationd |
||
Disease progression |
85 (71) |
87 (73) |
Toxicity |
20 (17) |
22 (18) |
Other |
14 (12) |
8 (7) |
Abbreviations: BR = bendamustine + rituximab; BTK = Bruton's tyrosine kinase; cBKTi = covalent Bruton tyrosine kinase inhibitor; CLL = chronic lymphocytic leukemia; ECOG = Eastern Cooperative Oncology Group; IdelaR = idelalisib + rituximab; IGHV = immunoglobulin heavy chain gene; SLL = small lymphocytic lymphoma.
aProvided as n (%) unless otherwise noted.
bRai stage at study entry, excludes patients with missing stage.
cDefined as ≥3 abnormalities in same clonal population.
dIn the event more than one reason was noted for discontinuation, disease progression was prioritized, then toxicity, then other reasons.
Prior therapya |
Pirtobrutinib |
IdelaR/BR |
Median lines of prior systemic therapy, n (range) |
3 (1-13) |
3 (1-11) |
cBTKib |
119 (100) |
119 (100) |
Ibrutinib |
100 (84) |
106 (89) |
Acalabrutinib |
17 (14) |
20 (17) |
Zanubrutinib |
10 (8) |
7 (6) |
Otherc |
5 (4) |
3 (3) |
BCL2 inhibitord |
60 (50) |
62 (52) |
Chemotherapy |
81 (68) |
83 (70) |
Anti-CD20 Antibody |
86 (72) |
83 (70) |
PI3K inhibitor |
11 (9) |
11 (9) |
Immunomodulator |
2 (2) |
3 (3) |
Autologous Stem Cell Transplant |
1 (1) |
0 |
Allogeneic Stem Cell Transplant |
2 (2) |
1 (1) |
Abbreviations: BCL-2 = B-cell lymphoma 2; BR = bendamustine + rituximab; cBTKi = covalent Bruton tyrosine kinase inhibitor; CD20 = B-lymphocyte antigen CD20; IdelaR = idelalisib + rituximab; PI3K = phosphoinositide 3-kinase.
aProvided as n (%) unless otherwise noted.
b35 patients received more than one prior BTKi (17 patients in the pirtobrutinib arm, and 18 patients in the IdelaR/BR arm).
cOther includes: orelabrutinib, tirabrutinib, zebutinib, and AVL-292-003.
d2 patients in the IdelaR/BR arm received an investigational BCL2i, all other patients received venetoclax.
CLL-321 Clinical Study
The primary endpoint is progression free survival assessed using International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018.1 Key secondary endpoints of the study are
- overall response rate (ORR)
- overall survival (OS)
- time to next treatment (TTNT)
- event free survival (EFS)
- time to worsening of CLL/SLL symptoms, and
- time to worsening of physical function.2
Study CLL-321 Schema describes the design of Study CLL-321.
Figure 1 description: Study CLL-321 is a global, randomized, open-label, multicenter phase 3 trial comparing the safety and efficacy of pirtobrutinib 200 mg daily as continuous monotherapy (Arm A) to investigator’s choice (Arm B) of 2 comparator therapies: either idelalisib plus rituximab or bendamustine plus rituximab in patients with chronic lymphocytic leukemia or small cell lymphoma who have been treated with at least a covalent BTKi. Patients were randomized 1:1 to either Arm A or Arm B and were stratified according to p17 deletion status and prior venetoclax treatment.
Abbreviations: BID = twice daily; BTKi = Bruton's tyrosine kinase inhibitor; CLL = chronic lymphocytic leukemia; IRC = independent review committee; IV = intravenous; PD = progressive disease; SLL = small lymphocytic lymphoma.
*Idelalisib is administered 150 mg orally BID. Rituximab is administered IV as 8 total infusions. Bendamustine is administered 70 mg/m2 IV on days 1 and 2 of cycles 1-6. Rituximab is administered IV as 6 total infusions.
**Patients in Arm B who have PD, as assessed by IRC, are allowed to
crossover to Arm A.
Enclosed Prescribing Information
References
The published reference below is available by contacting 1-800-LillyRx (1-800-545-5979).
1Study of LOXO-305 versus investigator's choice (IdelaR or BR) in patients with previously treated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) (BRUIN CLL-321). Clinicaltrials.gov identifier: NCT04666038. Updated April 20, 2025. Accessed May 12, 2025. https://clinicaltrials.gov/ct2/show/NCT04666038
2Sharman JP, Munir T, Grosicki S, et al. Phase III trial of pirtobrutinib vs. idelalisib/rituximab or bendamustine/rituximab in cBTKi pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma (BRUIN CLL-321). J Clin Oncol. Published online June 6, 2025. https://doi.org/10.1200/JCO-25-00166
3Sharman JP, Munir T, Grosicki S, et al. BRUIN CLL-321: Randomized phase III trial of pirtobrutinib versus idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) in BTK inhibitor pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma. Oral presentation presented at: 66th Annual Meeting of the American Society of Hematology (ASH); December 6-9, 2024; San Diego, California. Accessed December 9, 2024.
Supplementary Material
An infographic summary of the data presented at American Society of Hematology (ASH) 2024 is also available here.
Date of Last Review: June 06, 2025