CLL/SLL

RESONATE final analysis confirms efficacy of ibrutinib in patients with R/R CLL

Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase and is widely used for the treatment of various lymphomas, including chronic lymphocytic leukemia (CLL), Waldenström's macroglobulinemia (WM), and mantle cell lymphoma (MCL).1,2

RESONATE (NCT01578707) was the first randomized, multicenter, open-label trial to compare ibrutinib with ofatumumab in patients with relapsed or refractory (R/R) CLL or small lymphocytic lymphoma (SLL).3 The trial design and results have been reported previously; ibrutinib significantly improved progression-free survival (PFS), overall survival (OS) and overall response rates (ORR) in comparison with ofatumumab.3 The final analysis from the RESONATE trial, with up to 6 years follow-up, was recently published by Talha Munir, St. James's University Hospital, Leeds, UK, and colleagues and is summarized below.4

 

Study design summary

Patients with R/R CLL or SLL who failed ≥ 1 prior line of therapy were enrolled from June 2012 to April 2013. Patients were randomly assigned 1:1 to receive either oral ibrutinib (n= 195) 420mg once daily (until disease progression or unacceptable toxicity) or intravenous ofatumumab (n= 196) for up to 24 weeks at an initial dose of 300mg at week 1, followed by a dose of 2000mg weekly for 7 weeks and then every 4 weeks for 16 weeks. Patients were stratified according to whether they had resistance to purine analogue chemoimmunotherapy and whether they had a chromosome 17p deletion. Approximately 4 months after the last patient was randomized, a protocol amendment allowed patients in the ofatumumab arm who had disease progression, to crossover to receive ibrutinib.

The primary end point was PFS. Secondary endpoints included OS, ORR, safety and the patient-reported outcome: Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F).

 

Patient summary

The majority of patients in both arms (86% ibrutinib and 79% ofatumumab) comprised the high-risk population, defined as having any of the following: del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status.

The median follow-up of patients initially assigned to ibrutinib was 65.3 (range: 0.3–71.6) months with 41% of patients receiving more than 4 years of therapy (see Table 1). Among patients initially assigned to ibrutinib, 43/195 (22%) remained on therapy until study closure.

The median follow-up of the 196 patients initially assigned to the ofatumumab arm was 65.6 months (range: 0.1–73.9). There were 133/196 patients (68%) who crossed over to receive ibrutinib; 36% of whom had received > 4 years of next-line ibrutinib therapy and 35% were still receiving ibrutinib at the time of study closure.

Table 1: Patient disposition and treatment exposure

Parameter, n (%)

Ibrutinib

(n= 195)

Ofatumumab

(n= 196)

Duration of treatment, months, median (range)

41.0 (0.2–71.1)

5.3 (0.0–9.0)

Disposition of study treatment

Did not receive study drug

Completed treatment (ofatumumab arm only)

Discontinued

Progressive disease

Study terminated by sponsor

Adverse event

Patient withdrawal

Death*

Investigator decision

 

0

N/A

195 (100.0)

72 (36.9)

43 (22.1)

32 (16.4)

15 (7.7)

13 (6.7)

20 (10.3)

 

5 (2.6)

120 (61.2)

71 (36.2)

36 (18.4)

0

7 (3.6)

6 (3.1)

9 (4.6)

13 (6.6)

Duration of treatment, years (randomized therapy)†

˃ 0 to 1

> 1 to 2

> 2 to 3

> 3 to 4

> 4 to 5

> 5 to 6

 

36 (18.5)

25 (12.8)

31 (15.9)

24 (12.3)

22 (11.3)

57 (29.2)

 

191 (97.4)

0

0

0

0

0

*These cases of death included the following: ibrutinib arm, pneumonia (n= 3), sepsis (n= 2), unknown cause (sudden death, n= 2), neutropenic sepsis, terminal bowel cancer, lung infection, cardiac arrest, subdural hematoma, and burns and ensuing complications in 1 patient each; ofatumumab arm, pneumonia (n= 2), upper respiratory tract infection, squamous cell carcinoma of the neck, influenza A, aggressive squamous cell carcinoma of the scalp, nocardiosis, fever of unknown origin, and bacteremia in 1 patient each

†Planned duration of treatment with ofatumumab was up to 24 weeks

Progression-free survival

  • With an overall follow-up of 74 months, the median PFS (investigator-assessed) was 44.1 months (95% confidence interval [CI], 38.5–56.2) in the ibrutinib arm and 8.1 months (95% CI, 7.8–8.3) in the ofatumumab arm
  • PFS was significantly longer for patients assigned to ibrutinib than ofatumumab (HR= 0.148; 95% CI, 0.113–0.196; p˂0.0001)
  • At 60 months, the estimated PFS rates were 40% in the ibrutinib arm and 3% in the ofatumumab arm
  • PFS benefit with ibrutinib versus ofatumumab was preserved in the genomic high-risk population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs 8.0 months; HR= 0.110; 95% CI, 0.080–0.152)
    • See Table 2 for PFS analysis by genomic subgroups
  • The PFS benefit with ibrutinib versus ofatumumab was consistent across all subgroups defined by patient baseline clinical and genomic risk factors
  • Purine analog refractoriness had no impact on PFS (HR= 0.983; 95% CI, 0.685–1.413)

Table 2. PFS by lines of therapy and genomic subgroups in the ibrutinib arm

 

Median PFS, months, (95% CI)

 

Number of prior lines of therapy

One (n= 35)

Two (n= 57)

Three (n= 32)

Four (n= 27)

Five (n= 44)

 

 

NR (44.4–NE)

67.3 (36.0–NE)

44.1 (25.4–NE)

33.0 (13.6–NE)

27.3 (22.0–40.8)

Analysis by del(17p) and del(11q)

del(17p) subgroup (n= 63)

del(11q) subgroup (n= 50)

Neither del(11q) nor del(17p) (n= 81)

 

 

40.6 (25.4–44.6)

60.7 (36.4–NE)

42.5 (31.7–56.2)

Analysis by complex karyotype

Complex karyotype (n= 39)

Without complex karyotype (n= 114)

 

40.8 (24.4–67.7)

44.6 (37.9-61.0)

 

Analysis by IGHV mutation status

Mutated IGHV (n= 36)

Unmutated IGHV (n= 98)

 

 

48.4 (35.6–60.8)

49.7 (40.2–NE)

Analysis by TP53 mutation status

Without TP53 mutation (n= 75)

With TP53 mutation (n= 79)

 

 

56.9 (36.4–NE)

40.7 (25.4–44.6)

Analysis by del(17p) and/or TP53 mutation status

Both del(17p) and TP53 mutation (n= 38)

Either del(17p) or TP53 mutation (n= 48)

Neither del(17p) nor TP53 mutation (n= 68)

 

40.6 (17.6–56.2)

40.7 (25.4–57.3)

56.9 (36.4–NE)

 

*Genomic abnormalities by FISH cytogenetics were categorized according to Döhner hierarchical classification.

NE, not estimable; NR, not reached

Overall response

  • At extended follow-up, the ORR with ibrutinib was 91%
  • The proportion of patients with a best response of complete response/complete response with incomplete bone marrow recovery (CR/CRi) increased over time to 11% at the current follow up

Overall survival

  • With up to 6 years of post-randomization follow-up, median OS was 67.7 months (95% CI, 61.0–NE) in the ibrutinib arm and 65.1 months (95% CI, 50.6–NE) in the ofatumumab arm irrespective of the crossover (68%) to ibrutinib (HR= 0.810; 95% CI, 0.602–1.091)
  • OS censored for crossover, was better with ibrutinib than ofatumumab (HR= 0.639; 95% CI, 0.418–0.975)

Patient-reported outcomes

  • Mean FACIT-F score at baseline was 36.2 for the ibrutinib arm and 35.6 for the ofatumumab arm
  • A greater proportion of patients achieved clinically meaningful improvements in FACIT-F score with ibrutinib (65%) than with ofatumumab (49%)

Adverse events

  • Commonly reported grade ≥ 3 hematologic adverse events (AEs) included neutropenia (25%), thrombocytopenia (10%), and anemia (9%)
  • Commonly reported grade ≥ 3 non-hematologic AEs included pneumonia (21%), hypertension (9%), urinary tract infection (7%), diarrhea (7%), and atrial fibrillation (6%)
  • Up to the six-year follow-up, grade ≥ 3 infections occurred in 87 patients (45%) in the ibrutinib arm, occurring at a median time of onset of 7.0 months
  • Overall, 19 patients (10%) in the ibrutinib arm experienced major hemorrhage
  • The prevalence of any grade ≥ 3 AEs with ibrutinib decreased after the first year and remained stable thereafter, with rates of 62%, 48%, 46%, 46%, 48%, and 32% during years 0–1, 1–2, 2–3, 3–4, 4–5, and 5–6, respectively
  • All-grade (grade ≥ 3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of patients, respectively
    • Most of the patients who developed atrial fibrillation (92%) or hypertension (68%) had relevant risk factors for developing these complications
    • The prevalence of grade ≥ 3 atrial fibrillation was 4%, 0%, 2%, 2%,1%, and 0% over years 0–1, 1–2, 2–3, 3–4, 4–5, and 5–6, respectively
    • The prevalence of grade ≥ 3 hypertension was 4%, 8%, 7%, 7%, 8%, and 11% over years 0–1, 1–2, 2–3, 3–4, 4–5, and 5–6, respectively
  • In the ibrutinib arm, 17% (34/195) and 65% (126/195) of patients required dose reductions and dose holds, respectively, to manage AEs
    • Among the 34 patients with dose reductions due to AEs, 8 (24%) ultimately discontinued because of an AE, of which 4 discontinuations (12%) were due to the same AE that led to dose reduction
    • Of the 126 patients with a dose hold due to AEs, 20 patients (16%) ultimately discontinued ibrutinib because of an AE, of which 13 discontinuations (10%) were due to the same AE that led to the dose hold

Conclusions

  • The 6-year update of the RESONATE study confirmed the efficacy of ibrutinib in patients with R/R CLL, including in patients with high-risk clinical and genomic features
  • The safety profile of ibrutinib was consistent with previous reports
References
  1. IMBRUVICA Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/imbruvica-epar-product-information_en.pdf. Accessed October 14, 2019
  2. IMBRUVICA Prescribing Information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210563s000lbl.pdf. Accessed October 14, 2019
  3. Byrd J, Brown J, O'Brien S, et al. Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia. N Engl J Med. 2014;371:213–223. DOI: 10.1056/NEJMoa1400376
  4. Munir T, Brown J, O’Brian S. et al. Final analysis from RESONATE: up to 6 years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma.  Am J Hematol. 2019 Sep 11. DOI: 10.1002/ajh.25638. [Epub ahead of print]
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