Final analysis of the iNNOVATE study | Five-year follow-up of ibrutinib plus rituximab versus placebo plus rituximab in WM

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.

Study design

Patients with WM were randomized 1:1 to receive either ibrutinib-RTX (n = 75) or placebo plus rituximab (placebo-RTX; n = 75)

• Arm A: 420 mg oral ibrutinib once daily and 375 mg/m² intravenous (IV) RTX on Day 1 of Weeks 1–4 and 17–20
• Arm B: placebo and 375mg/m² IV RTX on Day 1 of Weeks 1–4 and 17–20
  • Crossover to single-agent ibrutinib allowed after progressive disease (PD)

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.

Patient characteristics and treatment exposure

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)

Key findings

Progression-free survival

• Median PFS was not reached with ibrutinib-RTX vs 20.3 months with placebo-RTX (hazard ratio [HR] 0.25 [95% CI, 0.15–0.42]; p < 0.0001)
• PFS rates were 68% with ibrutinib-RTX vs 25% with placebo-RTX at the 54-month timepoint
• Patients treated with ibrutinib-RTX also had a PFS benefit over those treated with placebo-RTX, regardless of their prior treatment status:
  • Median PFS in previously untreated patients: not reached vs 28 months
  • Median PFS in previously treated patients: not reached vs 15 months
• The PFS benefit of ibrutinib-RTX over placebo-RTX was also independent of genotype and all prespecified subgroups including baseline age, sex, serum immunoglobulin, hemoglobin (Hgb), and International Prognostic Scoring System for Waldenström’s Macroglobulinemia score

Response rates

• The major response rate (≥ partial response) at 60 months was 76% with ibrutinib-RTX vs 31% with placebo‑RTX (p < 0.0001)
• At 60 months, the overall response rates (≥ minimal response) were 92% vs 44% (p < 0.0001) with ibrutinib-RTX and placebo‑RTX, respectively
• Response rates with ibrutinib-RTX increased over time and were sustained (Table 3)
• High response rates were also observed with ibrutinib-RTX regardless of prior treatment and across genotypes

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)

IgM and Hgb

• Sustained improvements in IgM and Hgb were observed with ibrutinib-RTX
  • During the first year of treatment, IgM decreased rapidly
    • Maximum change: −33.5 g/L with ibrutinib-RTX (56 months) and −26.9 g/L with placebo-RTX (57 months)
  • In total, 77% of patients in the ibrutinib-RTX arm had sustained Hgb improvement vs 43% in the placebo-RTX arm (p < 0.0001)

Overall survival

• Median OS was not reached in either treatment arm (HR 0.81 [95% CI, 0.33–1.99]; p = 0.64)

• After adjusting for crossover, OS was consistent with the original analysis but with an improved HR of 0.64 (95% CI 0.26–1.62)
• At 54 months the OS rate was 86% with ibrutinib-RTX and 84% with placebo-RTX arm
• In total, 35 patients (47%) with IRC-confirmed PD crossed over to single-agent ibrutinib

Safety

• The safety profile of ibrutinib-RTX with 63 months of overall follow-up was consistent with previous reports and was considered manageable (Table 4)
• In total, 88% of the adverse events (AEs) that led to a dose reduction in ibrutinib resolved after the dose reduction
• The Grade ≥ 3 AEs of clinical interest with ibrutinib-RTX (infections, anemia, neutropenia, atrial fibrillation, pneumonia hypertension, fatigue, thrombocytopenia, and arthralgia) generally decreased over time.

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)

Conclusions

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.