Contributions
Abstract: S235
Type: Oral Presentation
Session title: Stem cell transplantation - GvHD
Background
Approximately 34% of patients (pts) who develop cGVHD after hematopoietic cell transplant require systemic treatment. Many pts experience recurrent cGVHD or become refractory to standard of care first-line corticosteroids. Ibrutinib (ibr) has demonstrated sustained efficacy and safety in cGVHD and is currently the only therapy approved in the United States for adults with cGVHD after failure of ≥1 line of systemic therapy.
Aims
We present the efficacy and safety results from the randomized, double-blind, placebo-controlled phase 3 iNTEGRATE study (PCYC-1140; NCT02959944) of ibr plus corticosteroids in previously untreated pts with cGVHD.
Methods
Eligible pts (aged ≥12 y) had newly diagnosed moderate/severe cGVHD, required systemic corticosteroid therapy, and had no prior systemic treatment for cGVHD. Pts were randomized 1:1 to receive ibr 420 mg/d or placebo (pbo) in combination with prednisone (pred) starting at 1 mg/kg/d. The primary endpoint was response rate (complete or partial response) at 48 wks per the 2014 NIH Consensus Development Project Criteria. Other endpoints included event-free survival (EFS; ie, survival without cGVHD progression, malignancy relapse, or start of subsequent cGVHD therapy), duration of response (DOR), time to withdrawal of corticosteroids and immunosuppressants (except ibr/pbo), improvement of Lee cGVHD Symptom Scale score, overall survival (OS), and safety.
Results
In total, 95 pts received ibr-pred and 98 received pbo-pred. Baseline pt characteristics were well balanced between treatment arms. Median time on treatment was 5.4 mo and 6.4 mo for ibr-pred and pbo-pred arms, respectively; median follow-up was 25 mo for both arms. At the time of the primary analysis, 41% (39/95) of pts treated with ibr-pred had a response at 48 wk vs 37% (36/98) of pts receiving pbo-pred (p=0.54). Though the primary endpoint of the study was not statistically significant, ibr-pred resulted in clinically meaningful improvements in several other key endpoints, prompting evaluation of these endpoints with a longer follow up (reported p-values are nominal). With extended follow up, median DOR was 16 mo with ibr-pred vs 10 mo with pbo-pred (p=0.12). Median EFS was 15 mo with ibr-pred and 8 mo with pbo-pred (hazard ratio 0.75 [95% CI: 0.53-1.1]; p=0.1; Figure). 48% vs 39% (p=0.15) of pts receiving ibr-pred vs pbo-pred withdrew corticosteroids, and 38% vs 28% (p=0.08) withdrew immunosuppressants. 40% of pts in the ibr-pred arm experienced an improvement in overall Lee cGVHD Symptom Scale score vs 29% in the pbo-pred arm (p=0.09). Median OS was not reached in either arm; 22% (21/95) of pts in the ibr-pred arm and 19% (19/98) in the pbo-pred arm died from any cause. 49% (46/94) of pts in the ibr-pred arm and 46% (44/96) in the pbo-pred arm experienced a grade ≥3 serious adverse event (AE); 22% (21/94) and 25% (24/96), respectively, experienced an AE leading to discontinuation of study drug.
Conclusion
In this randomized, pbo-controlled trial of ibr in combination with corticosteroids for NIH-defined moderate/severe cGVHD, the primary endpoint did not meet statistical significance. However, numerical trends of improved clinical outcomes in the ibr-pred arm were noted, including longer DOR and EFS and improved patient-reported outcomes. Safety was consistent with the known profiles of ibr and pred and was similar between treatment arms. The positive trends observed in other important clinical endpoints along with no additional safety trends and concerns suggest that ibr may have value in some previously untreated pts with cGVHD.
Keyword(s): Chronic graft-versus-host, Ibrutinib, Phase III, Prednisone
Abstract: S235
Type: Oral Presentation
Session title: Stem cell transplantation - GvHD
Background
Approximately 34% of patients (pts) who develop cGVHD after hematopoietic cell transplant require systemic treatment. Many pts experience recurrent cGVHD or become refractory to standard of care first-line corticosteroids. Ibrutinib (ibr) has demonstrated sustained efficacy and safety in cGVHD and is currently the only therapy approved in the United States for adults with cGVHD after failure of ≥1 line of systemic therapy.
Aims
We present the efficacy and safety results from the randomized, double-blind, placebo-controlled phase 3 iNTEGRATE study (PCYC-1140; NCT02959944) of ibr plus corticosteroids in previously untreated pts with cGVHD.
Methods
Eligible pts (aged ≥12 y) had newly diagnosed moderate/severe cGVHD, required systemic corticosteroid therapy, and had no prior systemic treatment for cGVHD. Pts were randomized 1:1 to receive ibr 420 mg/d or placebo (pbo) in combination with prednisone (pred) starting at 1 mg/kg/d. The primary endpoint was response rate (complete or partial response) at 48 wks per the 2014 NIH Consensus Development Project Criteria. Other endpoints included event-free survival (EFS; ie, survival without cGVHD progression, malignancy relapse, or start of subsequent cGVHD therapy), duration of response (DOR), time to withdrawal of corticosteroids and immunosuppressants (except ibr/pbo), improvement of Lee cGVHD Symptom Scale score, overall survival (OS), and safety.
Results
In total, 95 pts received ibr-pred and 98 received pbo-pred. Baseline pt characteristics were well balanced between treatment arms. Median time on treatment was 5.4 mo and 6.4 mo for ibr-pred and pbo-pred arms, respectively; median follow-up was 25 mo for both arms. At the time of the primary analysis, 41% (39/95) of pts treated with ibr-pred had a response at 48 wk vs 37% (36/98) of pts receiving pbo-pred (p=0.54). Though the primary endpoint of the study was not statistically significant, ibr-pred resulted in clinically meaningful improvements in several other key endpoints, prompting evaluation of these endpoints with a longer follow up (reported p-values are nominal). With extended follow up, median DOR was 16 mo with ibr-pred vs 10 mo with pbo-pred (p=0.12). Median EFS was 15 mo with ibr-pred and 8 mo with pbo-pred (hazard ratio 0.75 [95% CI: 0.53-1.1]; p=0.1; Figure). 48% vs 39% (p=0.15) of pts receiving ibr-pred vs pbo-pred withdrew corticosteroids, and 38% vs 28% (p=0.08) withdrew immunosuppressants. 40% of pts in the ibr-pred arm experienced an improvement in overall Lee cGVHD Symptom Scale score vs 29% in the pbo-pred arm (p=0.09). Median OS was not reached in either arm; 22% (21/95) of pts in the ibr-pred arm and 19% (19/98) in the pbo-pred arm died from any cause. 49% (46/94) of pts in the ibr-pred arm and 46% (44/96) in the pbo-pred arm experienced a grade ≥3 serious adverse event (AE); 22% (21/94) and 25% (24/96), respectively, experienced an AE leading to discontinuation of study drug.
Conclusion
In this randomized, pbo-controlled trial of ibr in combination with corticosteroids for NIH-defined moderate/severe cGVHD, the primary endpoint did not meet statistical significance. However, numerical trends of improved clinical outcomes in the ibr-pred arm were noted, including longer DOR and EFS and improved patient-reported outcomes. Safety was consistent with the known profiles of ibr and pred and was similar between treatment arms. The positive trends observed in other important clinical endpoints along with no additional safety trends and concerns suggest that ibr may have value in some previously untreated pts with cGVHD.
Keyword(s): Chronic graft-versus-host, Ibrutinib, Phase III, Prednisone