Ibrutinib for First-Line Treatment of Chronic Graft-Versus-Host Disease: Results From the Randomized Phase III iNTEGRATE Study

Abstract

Purpose: To present primary and final analyses from the randomized, double-blind, placebo-controlled, phase III iNTEGRATE study, which evaluated the safety and efficacy of ibrutinib with prednisone in previously untreated patients with chronic graft-versus-host disease (cGVHD).

Methods: Patients (age ≥ 12 years) with newly diagnosed moderate or severe cGVHD, requiring systemic corticosteroid therapy, and with no prior systemic treatment for cGVHD were randomly assigned 1:1 to receive ibrutinib 420 mg once daily plus prednisone, starting at 1 mg/kg once daily or placebo plus prednisone. The primary end point was response rate at 48 weeks according to 2014 National Institutes of Health Consensus Development Project Criteria. Other end points included event-free survival, duration of response, time to withdrawal of immunosuppressants, improvement in Lee cGVHD Symptom Scale score, overall survival (OS), and safety.

Results: Ninety-five and 98 patients enrolled in the ibrutinib-prednisone and placebo-prednisone arms, respectively. At 48 weeks, response rates were 41% (ibrutinib-prednisone) and 37% (placebo-prednisone; P = .54). At 33 months of follow-up, median duration of response was 19 months (ibrutinib-prednisone) and 10 months (placebo-prednisone; P = .10). Median event-free survival was 15 months (ibrutinib-prednisone) and 8 months (placebo-prednisone; hazard ratio, 0.76; 95% CI, 0.54 to 1.1; P = .11). Improvement in overall Lee cGVHD Symptom Scale was 43% (ibrutinib-prednisone) and 31% (placebo-ibrutinib; P = .07). Median OS was not reached in either arm. The 24-month Kaplan-Meier OS estimates were 80% for both arms (hazard ratio, 1.06; 95% CI, 0.59 to 1.90). Grade ≥ 3 serious adverse events occurred in 49% (ibrutinib-prednisone) and 47% (placebo-prednisone) of patients.

Conclusion: There was no statistical difference observed in the primary and secondary end points with ibrutinib-prednisone treatment. No new safety signals were observed with ibrutinib treatment in previously untreated patients with cGVHD. The primary end point of iNTEGRATE was not met.

Trial registration: ClinicalTrials.gov NCT02959944.

FIG 1.

CONSORT diagram of ibrutinib disposition. ^aReasons for not receiving the study drug were hyperbilirubinemia, relapse of malignant disease, and withdrawal of consent. ^bDeaths are listed as reasons for discontinuation of study drug. AE, adverse event; cGVHD, chronic graft-versus-host disease; ibr, ibrutinib; NIH, National Institutes of Health; PD, progressive disease.

FIG 2.

(A) EFS for all patients, (B) EFS and cumulative incidence of competing events in the ibrutinib-prednisone arm, (C) EFS and cumulative incidence of competing events in the placebo-prednisone arm, and (D) FFS, (E) DOR, and (F) OS in the two treatment arms. End points evaluated with 6 months of additional follow-up after primary analysis (median follow-up, 33 months [range, 0.03-47.20]). ^aA total of 18 fatal AE events were reported, and 11 total deaths (including AEs and non-AEs) were events for the EFS analysis. Nine of the 18 fatal AE events (ibrutinib-prednisone n = 4; placebo-prednisone n = 5) were not captured as death events in the EFS analysis because they occurred after other preceding events (such as relapse, initiation of subsequent cGVHD treatment, or cGVHD progression). Conversely, of the 11 total EFS death events, two (in the ibrutinib-prednisone arm) were not considered fatal AE events because they occurred after the prespecified AE treatment-emergent period but were not preceded by any other EFS event. AE, adverse event; cGVHD, chronic graft-versus-host disease; DOR, duration of response; EFS, event-free survival; FFS, failure-free survival; HR, hazard ratio; K-M, Kaplan-Meier; NE, not estimable; OS, overall survival; PD, progressive disease.

FIG 3.

Time to withdrawal of (A) all immunosuppressants, excluding ibrutinib, (B) all corticosteroids, and (C) all immunosuppressants. End point evaluated with 6 months of additional follow-up after primary analysis (median follow-up, 33 months [range, 0.03-47.20]). CIF, cumulative incidence function.

FIG 4.

Most common any-grade treatment-emergent adverse events (occurring in ≥ 15% of patients in the ibrutinib-prednisone or placebo-prednisone arm).