RESONATE™-2 (I vs Clb):
Study Design
OS, PFS, & Long-Term Data
CLL17 Study
HR Prognostic Factors
Studies With HR Patients

CLL17 is a Phase 3, noninferiority study comparing fixed-duration combination therapies to continuous IMBRUVICA® monotherapy1-3

Please review RESONATE™-2 data before exploring the CLL17 study.


RESONATE™-2 primary analysis4,5

Study Design: Phase 3, multicenter, open-label trial of 1L CLL/SLL patients (N=269) ≥65 years of age who were randomized 1:1 to IMBRUVICA® 420 mg once daily until disease progression or unacceptable toxicity (n=136) or chlorambucil (n=133) for up to 12 cycles. Patients with del17p were excluded.

Estimated 2-Year OS Rate

  • 95% with IMBRUVICA® (95% CI: 89, 97) vs 84% with chlorambucil (95% CI: 77, 90)
  • HR=0.44 (95% CI: 0.21, 0.92) (secondary endpoint)
  • Median follow-up: 28.1 months
  • 41% of chlorambucil-treated patients crossed over to IMBRUVICA® upon disease progression

Estimated 18-Month PFS Rate

  • 90% with IMBRUVICA® vs 52% with chlorambucil
  • HR=0.16 (95% CI: 0.09, 0.28); P<0.001 (IRC-assessed primary endpoint)
  • Median follow-up: 18.4 months
  • Median PFS with IMBRUVICA® was not estimable vs 18.9 months (95% CI: 14.1, 22.0) with chlorambucil

ARs Reported in ≥15% of IMBRUVICA® Patients (≥4% for ARs Grade 3 or Higher)

  • Diarrhea
  • Musculoskeletal pain*
  • Fatigue
  • Nausea
  • Cough
  • Rash*
  • Peripheral edema
  • Bruising*
  • Upper respiratory tract infection
  • Dry eye
  • Pyrexia
  • Constipation
  • Arthralgia
  • Skin infection*
  • Pneumonia*
  • Hypertension*

Includes multiple ADR terms.

EXPLORING THE CLL17 STUDY

CLL17: Investigator-initiated, international, noninferiority,
randomized phase 3 trial for patients with TN CLL1-3

This is a prespecified interim analysis with still maturing follow up.

The CLL17 study is not included in the Prescribing Information for IMBRUVICA®.

Data are descriptive and provided for informational purposes.

The trial was designed to evaluate for noninferiority (limits claims of superiority/inferiority).

CLL17 study design: key eligibility (age ≥18 years, ECOG PS ≤2, CIRS <4 for every system), stratification according to fitness, del17p/TP53 mutation, IGHV, and N=909 randomization into three arms: (1) Venetoclax-based regimen, (2) IMBRUVICA® 420 mg PO QD until PD or death, (3) Venetoclax 400 mg PO QD C1 D22 – C12 D28 plus Obinutuzumab 1000 mg IV C1 D1(2)/8/15 – C2-6 D1.CLL17 study design: key eligibility (age ≥18 years, ECOG PS ≤2, CIRS <4 for every system), stratification according to fitness, del17p/TP53 mutation, IGHV, and N=909 randomization into three arms: (1) Venetoclax-based regimen, (2) IMBRUVICA® 420 mg PO QD until PD or death, (3) Venetoclax 400 mg PO QD C1 D22 – C12 D28 plus Obinutuzumab 1000 mg IV C1 D1(2)/8/15 – C2-6 D1.

THE PRIMARY ENDPOINT WAS INVESTIGATOR-ASSESSED PFS, WITH AN NI MARGIN FOR HR OF 1.608 (CORRESPONDING TO AN NI MARGIN OF 8% AT 3 YEARS).

KEY SECONDARY ENDPOINTS WERE FINDINGS OF uMRD (<10−4 [<1 CLL CELL PER 10,000 LEUKOCYTES]) IN PERIPHERAL BLOOD AND BONE MARROW, CR, ORR, TTNT, OS, AND SAFETY.

Additional secondary endpoints were DOR, EFS, and PFS after 2L therapy.

CLL17 included stratified randomization and appropriate eligibility criteria.2

A per-protocol population was used as a sensitivity analysis to assess the robustness of the primary endpoint analysis.2

All patients of the ITT population were included and analyzed. Missing data were not replaced or imputed, but may have been censored.2

Fit patients were characterized by CIRS ≤6 points and GFR ≥70 mL/min, while unfit patients by CIRS >6 points and/or GFR <70 mL/min.2

Hypothesis testing for co-primary endpoints was planned to be performed simultaneously with statistical analysis and interpretation independently from each other.

†The study did not compare venetoclax-based regimen vs venetoclax + obinutuzumab.

Baseline patient characteristics including high-risk subgroups1

 IMBRUVICA®
n=301		Venetoclax + obinutuzumab
n=303
Characteristic, %  
Median age, yr (IQR)65 (59–72)66 (58–71)
Male sex, n (%)196 (65.1)216 (71.3)
CIRS score, median (IQR)3 (1–6)3 (1–6)
del17p and/or TP53 mutation, n/total n (%)21/300 (7.0)23/303 (7.6)
Unmutated IGHV, n (%)171/297 (57.6)171/300 (57.0)
Complex karyotype (≥3 aberrations), n/total n (%)58/265 (21.9)42/265 (15.8)

PFS outcomes from CLL171

Data Limitations

  • CLL17 efficacy results are not included in the Prescribing Information for IMBRUVICA®2
  • The open-label nature of the study could introduce bias3
  • Racial/ethnic demographics may be skewed by an all-European trial3
  • This is an interim analysis with still maturing follow up (median observation time was 34.2 months)1
  • Median follow-up was 34.2 months for both treatment arms1
  • Median 3-year PFS was 81.0% for IMBRUVICA® vs 81.1% for venetoclax + obinutuzumab1
  • Upper limit of adjusted CI below predefined margin, supporting noninferiority (HR=1.608)1
PFS outcomes from CLL17: line chart of cumulative survival vs months for IMBRUVICA® and venetoclax + obinutuzumab. HR=0.87, 98.3% CI [0.54, 1.41]. Estimated 3-year PFS rate: 81.0% with IMBRUVICA® and 81.1% with venetoclax + obinutuzumab.PFS outcomes from CLL17: line chart of cumulative survival vs months for IMBRUVICA® and venetoclax + obinutuzumab. HR=0.87, 98.3% CI [0.54, 1.41]. Estimated 3-year PFS rate: 81.0% with IMBRUVICA® and 81.1% with venetoclax + obinutuzumab.

PFS outcomes in del17p/TP53 patients1,3,6

Data Limitations

  • CLL17 efficacy results are not included in the Prescribing Information for IMBRUVICA®2
  • The open-label nature of the study could introduce bias3
  • Racial/ethnic demographics may be skewed by an all-European trial3
  • This is an interim analysis with still maturing follow up (median observation time was 34.2 months)1
  • CLL17 was not designed or powered to establish superiority or to provide treatment recommendations for high-risk subgroups. Subgroup analyses are exploratory and should be interpreted with caution1
  • Median follow-up was 34.2 months for all treatment arms1
  • PFS in high-risk subgroups was a prespecified exploratory endpoint2
PFS outcomes in del17p/TP53 patients: line chart of cumulative survival vs months across 4 subgroups — IMBRUVICA® del17p/TP53, IMBRUVICA® none, venetoclax + obinutuzumab del17p/TP53, venetoclax + obinutuzumab none. HR=1.20, 95% CI [0.40-3.59], venetoclax + obinutuzumab vs IMBRUVICA® in del17p/TP53 subgroups. Estimated 3-year PFS rates: 79.4% IMBRUVICA® del17p/TP53, 81.0% IMBRUVICA® none, 62.0% venetoclax + obinutuzumab del17p/TP53, 82.7% venetoclax + obinutuzumab none.PFS outcomes in del17p/TP53 patients: line chart of cumulative survival vs months across 4 subgroups — IMBRUVICA® del17p/TP53, IMBRUVICA® none, venetoclax + obinutuzumab del17p/TP53, venetoclax + obinutuzumab none. HR=1.20, 95% CI [0.40-3.59], venetoclax + obinutuzumab vs IMBRUVICA® in del17p/TP53 subgroups. Estimated 3-year PFS rates: 79.4% IMBRUVICA® del17p/TP53, 81.0% IMBRUVICA® none, 62.0% venetoclax + obinutuzumab del17p/TP53, 82.7% venetoclax + obinutuzumab none.

Selected ARs ≥10% reported in CLL171

Scroll right to see full chart
Safety populationIMBRUVICA®
(N=298)		Venetoclax + obinutuzumab
(N=295)
All Grades, n (%)Grade 3 or higher, n (%)All Grades, n (%)Grade 3 or higher, n (%)
Blood or lymphatic system disorder85 (28.5)49 (16.4)174 (58.9)135 (45.8)
Anemia35 (11.7)13 (4.4)‡47 (15.9)18 (6.1)‡
Neutropenia35 (11.8)25 (8.4)‡131 (44.4)108 (36.6)
Thrombocytopenia12 (4.0)‡2 (0.6)‡54 (18.3)27 (9.2)‡
Cardiac disorder103 (34.6)34 (11.4)41 (13.9)13 (4.4)‡
Atrial fibrillation50 (16.8)12 (4.0)‡11 (3.7)‡2 (0.7)‡
Cardiac failure‡11 (3.7)9 (3.0)1 (0.3)1 (0.3)
Gastrointestinal disorder189 (63.4)23 (7.7)‡176 (59.6)16 (5.4)‡
Diarrhea104 (34.9)7 (2.3)‡80 (27.1)5 (1.7)‡
Infection or infestation238 (79.9)74 (24.8)225 (76.3)103 (34.9)
COVID-19117 (39.3)20 (6.7)‡113 (38.3)47 (15.9)
Pneumonia40 (13.4)22 (7.4)‡41 (13.9)29 (9.8)‡
Laboratory investigation81 (27.2)30 (10.1)117 (39.7)54 (18.3)
Neutrophil count decreased‡19 (6.4)16 (5.4)29 (9.8)25 (8.5)
Metabolism or nutrition disorder72 (24.2)10 (3.4)‡90 (30.5)25 (8.5)‡
Tumor lysis syndrome‡1 (0.3)1 (0.3)12 (4.1)12 (4.1)
Musculoskeletal or connective tissue disorder169 (56.7)21 (7.0)‡111 (37.6)12 (4.1)‡
Neoplasms benign, malignant, and unspecified55 (18.5)26 (8.7)‡34 (11.5)19 (6.4)‡
Nervous system disorder103 (34.6)10 (3.4)‡103 (34.9)12 (4.1)‡
Skin or subcutaneous tissue disorder166 (55.7)10 (3.4)‡87 (29.5)2 (0.7)‡
Vascular disorder124 (41.6)31 (10.4)60 (20.3)14 (4.7)‡
Hypertension72 (24.2)28 (9.4)‡34 (11.5)10 (3.4)‡

‡AR <10%.

Causes of death reported in CLL171

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IMBRUVICA®Venetoclax + obinutuzumab
Infection312 (7 COVID-19)
Cardiovascular55
Progression of disease/
Richter’s transformation		01
Second primary malignancy24
Other40
Total1422

Overall survival is an exploratory endpoint which is descriptive in nature.2

Abbreviations

1L=first-line, 2L=second-line, ADR=adverse drug reaction, AR=adverse reaction, C=cycle, CIRS=chronic inflammatory response syndrome, Clb=chlorambucil, CLL=chronic lymphocytic leukemia, COVID‑19=coronavirus disease 2019, CR=complete response, D=day, del=deletion, DOR=duration of response, ECOG PS=Eastern Cooperative Oncology Group Performance Status, EFS=event-free survival, FD=fixed duration, f/u=follow-up, GFR=glomerular filtration rate, HR=hazard ratio, IGHV=immunoglobulin heavy-chain variable region gene, IV=intravenous, IRC=independent review committee, ITT=intention-to-treat, iwCLL=International Workshop on Chronic Lymphocytic Leukemia, NCI=National Cancer Institute, NI=noninferiority, ORR=overall response rate, OS=overall survival, PD=progression of disease, PFS=progression-free survival, PO=orally, QD=once daily, SLL=small lymphocytic lymphoma, TN=treatment-naïve; TP53=tumor protein p53, TTNT=time to next treatment, uMRD=undetectable minimal residual disease.

References

1. Al-Sawaf O, Stumpf J, Zhang C, et al. Fixed-duration versus continuous treatment for chronic lymphocytic leukemia. N Engl J Med. Published online December 6, 2025. doi:10.1056/NEJMoa2515458 2. Protocol for: Al-Sawaf O, Stumpf J, Zhang C, et al. Fixed-duration versus continuous treatment for chronic lymphocytic leukemia. N Engl J Med. doi:10.1056/NEJMoa2515458 3. Supplement to: Al-Sawaf O, Stumpf J, Zhang C, et al. Fixed-duration versus continuous treatment for chronic lymphocytic leukemia. N Engl J Med. doi:10.1056/NEJMoa2515458 4. IMBRUVICA® (ibrutinib) Prescribing Information. 5. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437. 6. Al-Sawaf O. Fixed-duration versus continuous targeted treatment for previously untreated chronic lymphocytic leukemia: Results from the randomized CLL17 trial. Paper presented at the 67th ASH® Annual Meeting and Exposition; December 7, 2025; Orlando, FL.