First-line ibrutinib plus prednisone missed the primary endpoint in the phase 3 iNTEGRATE trial by not improving the response rate in patients with chronic graft-versus-host-disease compared with placebo plus prednisone.
In the frontline setting of chronic graft-vs-host disease (cGVHD), ibrutinib (Imbruvica) plus prednisone did not elicit better response rates than placebo plus prednisone, thus missing the primary end point of the phase 3 iNTEGRATE trial (NCT02959944), according to primary and final analyses of the study that were published in the Journal of Clinical Oncology.1
Patients treated with the combination (n = 95) experienced a 48-week response rate of 41% compared with 37% in the placebo plus prednisone arm (n = 98; P = .54). Among the responders, 9% (n = 9) and 6% (n = 6) of patients in the ibrutinib and placebo arms, respectively, achieved a complete response (CR).
“The iNTEGRATE study represents the first phase 3 therapeutics trial in previously untreated cGVHD using objective response criteria,” lead study author David Bernard Miklos, MD, PhD, of Stanford University School of Medicine in California, said. “This was a negative study, yet positive trends in other cGVHD end points like withdrawal of immunosuppression and patient-reported outcomes concern me.”
Patients ages 12 years and older were eligible for this trial if they had newly diagnosed, previously untreated moderate or severe cGVHD requiring systemic corticosteroid therapy. Patients were excluded if they had received prior systemic treatment for cGVHD, however, patients who had received other prophylaxis immunosuppressants or treatment for acute graft-vs-host disease were eligible.
A total of 193 patients were randomized 1:1 to receive ibrutinib 420 mg once daily plus prednisone starting at 1 mg/kg once daily or placebo plus prednisone. Ibrutinib or placebo was given until cGVHD progression, initiation of another systemic cGVHD treatment, relapse of an underlying malignancy, or unacceptable toxicity.
Patients received prednisone until unacceptable toxicity. Prednisone could also be tapered using a 6-month taper schedule. Patients in the ibrutinib arm received a mean of 4.9 g of prednisone while in the study (median, 4.2 g; range, 0-18), and patients in the placebo arm received a mean of 5.4 g of prednisone (median, 4.1 g; range, 0-22). Patients received a median total dose of 4 g of prednisone in both arms.
The primary end point of iNTEGRATE was 48-week response rate, defined as CR or partial response (PR) in at least 1 organ or site without progression in any other organ or site. Secondary end points included event-free survival (EFS), failure-free survival (FFS), duration of response (DOR), time to withdrawal of immunosuppressants including and excluding ibrutinib, time to corticosteroids withdrawal, Lee cGVHD Symptom Scale score improvement, overall survival (OS), and safety.
At data cutoff, the median treatment duration in the ibrutinib arm was 5 months (range, 0-44) for ibrutinib and 5 months (range, 0-34) for prednisone. The median treatment duration in the placebo arm was 6 months (range, 0-36) for placebo and 6 months (range, 0-44) for prednisone. The median relative ibrutinib dose intensity was 100%.
At a median follow-up of 33 months (range, 0.03-47.20), all patients had discontinued ibrutinib or placebo. The most common reasons for treatment discontinuation were progressive cGVHD (ibrutinib, 23%; placebo, 31%), adverse effects (AEs) unrelated to cGVHD (ibrutinib, 20%; placebo, 16%), and investigator decision (ibrutinib, 23%; placebo, 27%). In addition, 8% of patients (n = 15) discontinued ibrutinib (n = 13) or placebo (n = 2) because of study closure, and 3% of patients on ibrutinib (n = 3) discontinued study ibrutinib and continued with other ibrutinib treatment as part of a long-term access study.
At 48 weeks, 4% (n = 4) and 2% (n = 2) of patients had stable disease, 24% (n = 23) and 35% (n = 34) had progressive disease, and 1% (n = 1) and 3% (n = 3) had a cGVHD flare in the ibrutinib and placebo arms, respectively.
At an additional 96-week follow-up, ibrutinib plus prednisone demonstrated a response rate of 27% compared with 22% with placebo plus prednisone (P = .43). At this follow-up, 14% (n = 13) and 9% (n = 9) of patients had a CR in the ibrutinib and placebo arms, respectively. Treatment with ibrutinib plus prednisone resulted in a reduced best overall response in the liver and lower gastrointestinal tract.
In patients who had a CR or PR at any time during the study, the median DOR was 19.09 months (95% CI, 7-not evaluable) in the ibrutinib arm and 10.22 months (95% CI, 6.5-17) in the placebo arm (HR, 0.717; 95% CI, 0.482-1.068; P = .10). The 24-month DOR estimates were 45% (95% CI, 33%-56%) and 32% (95% CI, 22%-42%) in the ibrutinib and placebo arms, respectively.
The median EFS was 14.98 months (95% CI, 6-27) in the ibrutinib arm and 8.31 months (95% CI, 6-13) in the placebo arm (HR, 0.756; 95% CI, 0.535-1.066; P = .11). The earliest events for each patient included cGVHD progression (ibrutinib, 27%; placebo, 44%), initiation of subsequent cGVHD treatment (ibrutinib, 19%; placebo, 21%), death (ibrutinib, 11%; placebo, 1%), and underlying malignancy relapse (ibrutinib, 5%; placebo, 8%). The 24-month EFS estimates were 43% (95% CI, 32%-53%) and 28% (95% CI, 19%-37%) in the ibrutinib and placebo arms, respectively.
The median FFS was 16.43 months (95% CI, 8-29) in the ibrutinib arm and 9.10 months (95% CI, 7-18) in the placebo arm (HR, 0.806; 95% CI, 0.566-1.149). The 12-month FFS estimates for the ibrutinib and placebo arms were 56% (95% CI, 45%-66%) and 47% (95% CI, 37%-57%), respectively. The 24-month FFS estimates were 45% (95% CI, 35%-55%) and 33% (95% CI, 23%-42%) in the ibrutinib and placebo arms, respectively.
The median OS was not reached in either arm (HR, 1.061; 95% CI, 0.591-1.904). The 24-month OS estimates were 80% in both arms. At the time of final analysis, 24% (n = 23) of patients in the ibrutinib arm and 22% (n = 22) of patients in the placebo arm had died.
The proportion of patients with at least a 7-point Lee cGVHD Symptom Scale score improvement on at least 2 consecutive visits was 43% (n = 41) and 31% (n = 30) in the ibrutinib and placebo arms, respectively (P = .07).
Corticosteroid withdrawal occurred in 47% and 39% of patients in the ibrutinib and placebo arms, respectively (P = .28). Additionally, at 24 weeks, 41% and 46% of patients in the ibrutinib and placebo arms, respectively, had received a reduced prednisone dose of less than 0.15 mg/kg/d for at least 30 days.
A total of 39% and 31% of patients in the ibrutinib and placebo arms, respectively, withdrew from all immunosuppressants, excluding ibrutinib or placebo (P = .22). In total, 18% (n = 17) and 8% (n = 8) of patients withdrew from all immunosuppressants, including ibrutinib and placebo, in the ibrutinib and placebo arms, respectively (P = .03). The 24-month cumulative incidence rates of immunosuppressant withdrawal, including ibrutinib, were 0.17% (95% CI, 0.10%-0.26%) and 0.08% (95% CI, 0.03%-0.14%) in the ibrutinib and placebo arms, respectively.
In the safety population, which included all patients who received at least 1 dose of study drug, 99% of patients in each arm experienced any-grade treatment-emergent AEs (TEAEs; ibrutinib, n = 93/94; placebo, n = 95/96). The most common any-grade TEAEs in the ibrutinib and placebo arms, respectively, were insomnia (28% vs 19%), peripheral edema (27% vs 15%), and cough (21% vs 30%). The most common grade 3 or higher TEAEs of clinical interest in the ibrutinib and placebo arms, respectively, were opportunistic infections (6% vs 2%), hyperglycemia (4% vs 7%), hypertension (5% vs 5%), major hemorrhage (3% vs 4%), atrial fibrillation (2% vs 2%), and cardiac arrest (1% vs 1%).
In total, 52% (n = 49) and 49% (n = 47) of patients in the ibrutinib and placebo arms, respectively, experienced serious AEs of any grade, and 28% (n = 26) and 27% (n = 26) of patients in the ibrutinib and placebo arms, respectively, experienced serious corticosteroid-related AEs. A total of 49% and 47% of patients in the ibrutinib and placebo arms, respectively, experienced grade 3 or higher serious AEs.
AEs leading to dose reduction occurred in 10% (n = 9) of patients in the ibrutinib arm and 11% (n = 11) of patients in the placebo arm. Additionally, 23% (n = 22) and 28% (n = 27) of patients experienced AEs leading to study drug discontinuation in the ibrutinib and placebo arms, respectively. A total of 13% (n = 12) and 6% (n = 6) of patients in the ibrutinib and placebo arms, respectively, experienced fatal AEs.
“This trial proved that it is feasible to conduct multi-institutional trials using the National Institutes of Health [NIH] consensus criteria for cGVHD, a disease that has many different presentations and in which severity and response to therapy isn’t easy to objectively measure. There are many lessons to be learned and used in the design of future trials and further refinements of NIH consensus criteria,” study author Mohammad Abu Zaid, MD, of the Melvin and Bren Simon Cancer Center at Indiana University in Indianapolis, concluded.
Miklos DB, Abu Zaid M, Cooney JP, et al. Ibrutinib for first-line treatment of chronic graft-versus-host disease: results from the randomized phase III iNTEGRATE study. J Clin Oncol. Published online January 6, 2023. doi:10.1200/JCO.22.00509