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Ibrutinib is an oral first-in-class Bruton’s tyrosine kinase inhibitor and is approved for the treatment of Waldenström’s macroglobulinemia (WM), either as a single-agent therapy or in combination with rituximab.1,2 The Lymphoma Hub previously reported the outcomes of the phase III iNNOVATE trial (NCT02165397) after a median follow-up of 26.5 months, where the combination of ibrutinib plus rituximab (ibrutinib-RTX) demonstrated a significantly prolonged progression-free survival (PFS) compared with rituximab alone in patients with WM.
During the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, Christian Buske from the Comprehensive Cancer Center Ulm, Germany, presented the results of the final analysis of the randomized arms of iNNOVATE, with an overall follow-up of 63 months.3 This article is based on data presented at the ASH Annual Meeting and Exposition and may supersede the data in the published abstract.
Patients with WM were randomized 1:1 to receive either ibrutinib-RTX (n = 75) or placebo plus rituximab (placebo-RTX; n = 75)
The primary endpoint was PFS assessed by an independent review committee (IRC). The secondary endpoints included response rates, overall survival (OS), hematologic improvement, time-to-next-treatment, and safety.
The median follow-up was 50 months (0.5–63). Patient disposition and treatment exposure can be seen in Table 1. In the placebo-RTX arm, 47% of patients crossed over to single-agent ibrutinib after experiencing PD. At study closure, 45% of patients remained on ibrutinib.
Table 1. Patient disposition and treatment exposure3
CI, confidence interval; N/A, not applicable; NE, not evaluable; NR, not reached; PD, progressive disease; RTX, rituximab; TTNT, time-to-next-treatment. |
||
|
Ibrutinib-RTX (n = 75) |
Placebo-RTX (n = 75) |
---|---|---|
Median duration of ibrutinib, months (range) |
48 (1–59) |
N/A |
Discontinued treatment, n (%) PD AE Patient withdrawal Investigator decision |
7 (9) 8 (11) 10 (13) 3 (4) |
34 (45) 5 (7) 7 (9) 29 (39) |
Patients receiving subsequent treatment, n (%) Median TTNT, months (95% CI) |
9 (12) NR (NE–NE) |
47 (63) 18 (11–33) |
Baseline and clinical characteristics were well balanced between arms, see Table 2.
Table 2. Baseline and clinical characteristics3
BM, bone marrow; Hgb, hemaglobin; IPSSWM, International Prognostic Scoring System for Waldenström’s Macroglobulinemia; RTX, rituximab; WHIM, Warts, Hypogammaglobulinemia, Infections and Myelokathexis; WT, wild type. |
||
Characteristic at randomization |
Ibrutinib-RTX (n = 75) |
Placebo-RTX (n = 75) |
---|---|---|
Median age, years (range) |
70 (36–89) |
68 (39–85) |
Male, n (%) |
45 (60) |
54 (72) |
IPSSWM, n (%) Low Intermediate High |
15 (20) 33 (44) 27 (36) |
17 (23) 28 (37) 30 (40) |
Median Hgb, g/L (range) Baseline Hgb ≤ 110 g/L, n (%) |
105 (69–155) 44 (59) |
100 (66–161) 50 (67) |
Median serum IgM, g/L (range) |
33 (6–78) |
32 (6–83) |
Prior systemic therapies, n (%) 0 1–2 3 |
34 (45) 34 (45) 7 (9) |
34 (45) 36 (48) 5 (7) |
Genotype, n (%) MYD88(L265P)/CXCR4(WT) MYD88(L265P)/CXCR4(WHIM) MYD88(WT)/CXCR4(WT) Unknown |
32 (43) 26 (35) 11 (15) 6 (8) |
35 (47) 23 (31) 9 (12) 8 (11) |
BM infiltration: % cellularity, mean (range) |
73 (25–100) |
75 (2–100) |
Table 3. Response rates3
ORR, overall response rate; RTX, rituximab. Major response rate: ≥ partial response. |
||
Response rate |
Ibrutinib-RTX (n = 75) |
Placebo-RTX (n = 75) |
---|---|---|
ORR (months), % 6 12 18 24 36 48 60 |
84 88 89 92 92 92 92 |
32 40 41 43 44 44 44 |
Median time to ORR, months (range) |
1 (1–21) |
3 (1–22) |
Major response rate (months), % 6 12 18 24 36 48 60 |
52 65 68 72 72 76 76 |
12 21 27 29 29 31 31 |
Median time to major response, months (range) |
3 (1–46) |
6 (2–41) |
Table 4. Safety summary3
AE, adverse event; TEAEs, treatment-emergent adverse events. *One patient in the ibrutinib-RTX arm died due to pneumonia which was not considered to be related to the study drug. |
||
Prevalence |
Ibrutinib-RTX |
|
---|---|---|
Year 3–4 (n = 54) |
Year 4–5 (n = 40) |
|
AE leading to ibrutinib dose reduction, n (%) |
6 (11) |
2 (5) |
AE leading to ibrutinib discontinuation, n (%) |
2 (4) |
2 (5) |
Death due to TEAE, n (%) |
0 |
1 (3)* |
Major hemorrhage, n (%) |
0 |
0 |
Most common TEAEs, n (%) Diarrhea Arthralgia Hypertension |
6 (11) 8 (15) 9 (17) |
1 (3) 5 (13) 4 (10) |
With 63 months of overall follow-up in the iNNOVATE study, treatment with ibrutinib-RTX continued to demonstrate superiority over RTX in clinical outcomes in patients with WM. Responses deepened over time and median PFS was not reached with ibrutinib-RTX. The safety profile remained manageable with no new safety signals identified with long-term ibrutinib treatment.
Pharmacyclics, Sunnyvale, US. IMBRUVICA® prescribing information. https://imbruvica.com/files/prescribing-information.pdf. Revised Dec, 2020; Accessed Dec 22, 2020.
Janssen-Cilag International NV, Belgium. IMBRUVICA® summary of product characteristics. https://ec.europa.eu/health/documents/community-register/2014/20141021129815/anx_129815_en.pdf. Revised 2019; Accessed Dec 22, 2020.
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