BRUIN CLL-321: trial | Bending the Curve: Trial by Trial

BRUIN CLL-321

Needs review

Phase III trial of pirtobrutinib versus idelalisib/rituximab or bendamustine/rituximab in covalent BTK inhibitor-pretreated CLL/SLL

Phase 3N = 238NCT04666038

Population

Relapsed or refractory CLL or SLL previously treated with a covalent BTK inhibitor

Design

Open-label randomised phase 3 study exclusively in patients with relapsed or refractory CLL or SLL previously treated with a covalent BTK inhibitor; 1:1 randomisation to pirtobrutinib 200 mg once daily or investigator's choice of idelalisib-rituximab or bendamustine-rituximab, stratified by previous venetoclax and del(17p). Primary endpoint PFS by independent review committee. Primary analysis cut-off 29 August 2023; final OS analysis cut-off 29 August 2024.

Primary endpoint

PFS

Arms

Pirtobrutinib (experimental, n = 119): Pirtobrutinib 200 mg once daily
Investigator's choice (control, n = 119): Idelalisib plus rituximab (n=82) or bendamustine plus rituximab (n=37)

People

Sharman JP, senior author Barr PM

PFSHR 0.58 (95% CI 0.38–0.89)PFSHR 0.54 (95% CI 0.39–0.75)Δ median PFS+5.3 monthsTTNTHR 0.37 (95% CI 0.25–0.52)Δ median TTNT+13.1 monthsOSHR 1.09 (95% CI 0.68–1.75)

Show the numbers

Results reported for BRUIN CLL-321
Endpoint	Analysis	Pirtobrutinib	Investigator's choice	Effect
PFS	primarymedian follow-up 7.5 monthsSharman 2025	—	—	HR 0.58 (95% CI 0.38–0.89)P=0.0105Primary analysis of the primary endpoint (IRC-assessed PFS) at a limited median study follow-up of 7.5 months; the paper gives the hazard ratio and P value but no medians for this cut-off.
PFS	long term-updatemedian follow-up 17.2 monthsSharman 2025	median 14 months (11.2–16.6)	median 8.7 months (8.1–10.4)	HR 0.54 (95% CI 0.39–0.75)P=.0002Updated descriptive analysis at the final-OS cut-off (29 August 2024; median study follow-up 17.2 months), independent review committee. The primary analysis (29 August 2023) is the separate result pfs-primary-analysis.
TTNT	finalSharman 2025	median 24 months (17.8–29.7)	median 10.9 months (8.7–12.5)	HR 0.37 (95% CI 0.25–0.52)Time to next treatment or death; secondary endpoint; updated results from the final OS analysis (cut-off 29 August 2024).
OS	finalSharman 2025	73.4% at 18 mo (63.9–80.7%)	70.8% at 18 mo (60.9–78.7%)	HR 1.09 (95% CI 0.68–1.75)P=.7202Unadjusted OS hazard ratio; OS rate at 18 months.

Results reported for BRUIN CLL-321
Endpoint	Analysis	Pirtobrutinib	Investigator's choice	Effect
PFS	primarymedian follow-up 7.5 monthsSharman 2025	—	—	HR 0.58 (95% CI 0.38–0.89)P=0.0105Primary analysis of the primary endpoint (IRC-assessed PFS) at a limited median study follow-up of 7.5 months; the paper gives the hazard ratio and P value but no medians for this cut-off.
PFS	long term-updatemedian follow-up 17.2 monthsSharman 2025	median 14 months (11.2–16.6)	median 8.7 months (8.1–10.4)	HR 0.54 (95% CI 0.39–0.75)P=.0002Updated descriptive analysis at the final-OS cut-off (29 August 2024; median study follow-up 17.2 months), independent review committee. The primary analysis (29 August 2023) is the separate result pfs-primary-analysis.
TTNT	finalSharman 2025	median 24 months (17.8–29.7)	median 10.9 months (8.7–12.5)	HR 0.37 (95% CI 0.25–0.52)Time to next treatment or death; secondary endpoint; updated results from the final OS analysis (cut-off 29 August 2024).
OS	finalSharman 2025	73.4% at 18 mo (63.9–80.7%)	70.8% at 18 mo (60.9–78.7%)	HR 1.09 (95% CI 0.68–1.75)P=.7202Unadjusted OS hazard ratio; OS rate at 18 months.

Hazard ratio (95% CI) by endpoint. Values below 1 favour the experimental arm.

Data table

Endpoint	HR	95% CI
PFS	0.58	0.38–0.89
PFS	0.54	0.39–0.75
TTNT	0.37	0.25–0.52
OS	1.09	0.68–1.75

Illustrative — modelled from reported values, not trial data. PFS, long term-update.

Show curves

Pirtobrutinib (experimental)
Investigator's choice (control)

Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.

Data table (modelled values)

Months	Pirtobrutinib	Investigator's choice
0	100.0%	100.0%
9	64.0%	48.8%
18	41.0%	23.8%
26	27.6%	12.6%
35	17.7%	6.2%

Illustrative — modelled from reported values, not trial data. TTNT, final.

Show curves

Pirtobrutinib (experimental)
Investigator's choice (control)

Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.

Data table (modelled values)

Months	Pirtobrutinib	Investigator's choice
0	100.0%	100.0%
15	64.8%	38.5%
30	42.0%	14.8%
45	27.3%	5.7%
60	17.7%	2.2%

Appears in

2023 Pirtobrutinib: non-covalent BTK inhibitor after covalent BTK failure

Sources

Sharman JP, Munir T, Grosicki S, Roeker LE, Burke JM, Chen CI, et al. Phase III Trial of Pirtobrutinib Versus Idelalisib/Rituximab or Bendamustine/Rituximab in Covalent Bruton Tyrosine Kinase Inhibitor-Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN CLL-321). J Clin Oncol. 2025;43(22):2538-2549.
PubMed DOI