Fraser, Graeme

SummaryIbrutinib, a Bruton tyrosine kinase inhibitor, is approved for treatment of various B‐cell malignancies. In ibrutinib clinical studies, low‐grade haemorrhage was common, whereas major haemorrhage (MH) was infrequent. We analysed the incidence of and risk factors for MH from 15 ibrutinib clinical studies (N = 1768), including 4 randomised controlled trials (RCTs). Rates of any‐grade bleeding were similar for single‐agent ibrutinib and ibrutinib combinations (39% and 40%). Low‐grade bleeding was more common in ibrutinib‐treated than comparator‐treated patients (35% and 15%), and early low‐grade bleeding was not associated with MH. The proportion of MH in RCTs was higher with ibrutinib than comparators (4.4% vs. 2.8%), but after adjusting for longer exposure with ibrutinib (median 13 months vs. 6 months), the incidence of MH was similar (3.2 vs. 3.1 per 1000 person‐months). MH led to treatment discontinuation in 1% of all ibrutinib‐treated patients. Use of anticoagulants and/or antiplatelets (AC/AP) during the study was common (~50% of patients) and had an increased exposure‐adjusted relative risk for MH in both the total ibrutinib‐treated population (1.9; 95% confidence interval, 1.2–3.0) and RCT comparator‐treated patients (2.4; 95% confidence interval, 1.0–5.6), indicating that ibrutinib may not alter the effect of AC/AP on the risk of MH in B‐cell malignancies.

Abstract Background: Patients (pts) with CLL/SLL who use unmutated IGHV (u-CLL) have a less favorable outcome with standard chemotherapy than pts who use mutated IGHV (m-CLL). Ibrutinib (ibr) inhibits B-cell receptor signaling through Bruton’s tyrosine kinase and has robust clinical activity against CLL. This integrated analysis of 3 phase 3 studies examined the impact of IGHV status on ibr- and comparator (comp)-treated pts. Methods: Pooled data from 3 studies of ibr (420 mg/d) in CLL/SLL pts (RESONATE: relapsed/refractory [R/R] pts, ibr vs ≤ 24 weeks ofatumumab; RESONATE-2: treatment-naïve [TN] pts ≥ 65 yrs of age [no del17p], ibr vs ≤ 12 cycles chlorambucil; HELIOS: R/R pts [no del17p], ≤ 6 cycles bendamustine-rituximab with ibr vs placebo) were analyzed by IGHV status. Analyses included Kaplan-Meier method (overall survival [OS]; progression-free survival [PFS]); log-rank test (group comparisons); and Cox multivariate analysis (prognostic factors; Table). Results: For 491 ibr- (366 u-CLL, 125 m-CLL) and 494 comp-treated (351 u-CLL, 143 m-CLL) pts with IGHV data, baseline characteristics were similar for u-CLL vs m-CLL, except for the proportions of pts who were TN (17 vs 31%), had bulky disease (60 vs 37%), or had CLL cells with del11q (32 vs 16%). Median follow up was 21.4 mos for ibr and 20.6 mos for comp. PFS and OS were similar for u-CLL and m-CLL ibr-treated pts; u-CLL had poorer outcomes than m-CLL in comp-treated pts, which remained after adjustment for prognostic factors (Table). Ibr treatment was more effective than comp regardless of IGHV status. Incidence of adverse events (AEs) was similar between groups. For ibr vs comp pts (u-CLL/m-CLL): serious AEs: 49% (50%/47%) vs 36.5% (37%/35%); AEs that led to discontinuation: 12% (11%/15%) vs 13% (13%/14%); death within 30 days of last dose: 5% (6%/3%) vs 5% (6%/2%). Conclusions: U-CLL was an adverse predictor of outcome for comp-treated, but not for ibr-treated pts. Table.Efficacy Outcomes in Ibr- and Comparator-Treated Patients by IGHV Mutation StatusIbrutinib (N=491)Comparator (N =494)u-CLL (n=717)m-CLL (n=268)u-CLL(n=366): m-CLL(n=125)u-CLL(n=351): m-CLL(n=143)Ibr(n=366): Comp(n=351)Ibr (n=125): Comp (n=143)PFS24-month rate HR78%:81%10%:32%78%:10%81%:32%0.93a1.99a0.12b0.21bp = 0.78p < 0.0001p < 0.0001p <0.0001Adjusted HRc1.02a1.94a0.11b0.17bp = 0.93p < 0.0001p < 0.0001p < 0.0001OS24-month rate HR88%:89%78%:87%88%:78%89%:87%0.95a1.96a0.49b0.85b,ep = 0.86p = 0.02p < 0.01p = 0.66Adjusted HRc1.21a2.10a0.49bNAp =0.57p = 0.01p < 0.001Response ratesu-CLLm-CLLu-CLLm-CLLIbrCompIbrCompORR, %d8990475189479051p = 0.96p = 0.36p < 0.0001p < 0.0001CR, %d221546224156p = 0.10p = 0.44p < 0.0001p = 0.01CI, confidence interval; CR, complete response; HR, hazard ratio; ORR, overall response rate; NA, not applicable. aHR < 1 favors unmutated. bHR < 1 favors ibrutinib. cMultivariate Cox model adjusted for age, sex, current Rai stage, baseline ECOG performance status score, del11q, del17p, number of prior therapies, and cytopenias. dp value is from a Cochran-Mantel-Haenszel chi-square test. eInsufficient number of events prevents meaningful analysis, only 13 and 16 events observed in ibr and comp groups, respectively, and 46 (32%) pts in comp arm crossed over to ibr arm; interpret results with caution. Citation Format: Thomas J. Kipps, Graeme Fraser, Steven Coutre, Jennifer R. Brown, Jacqueline C. Barrientos, Paul M. Barr, John C. Byrd, Susan M. O'Brien, Marie-Sarah Dilhuydy, Stephen Devereux, Ulrich Jaeger, Carol Moreno, Paula Cramer, Stephan Stilgenbauer, Asher A. Chanan-Khan, Michelle Mahler, Mariya Salman, Mei Cheng, Anil Londhe, Joi Ninomoto, Angela Howes, Danelle James, Michael Hallek. Unmutated IGHV is not an adverse predictor of outcome to therapy with ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT158. doi:10.1158/1538-7445.AM2017-CT158

LBA7005 Background: The phase III HELIOS study evaluated the first-in-class, oral covalent BTK inhibitor ibrutinib in combination with BR (BR+ibr) vs BR plus placebo (BR+plb) in patients (pts) with previously treated CLL/SLL. The preplanned interim analysis reported here showed that the primary end point was met, upon which the IDMC recommended unblinding the study. Methods: Pts received BR ( ≤ 6 cycles) and were randomized 1:1 to ibr (420 mg daily) or plb. Purine analog refractoriness was a stratification factor. Pts with del17p ( > 20% of cells) were excluded. Primary end point was independent review committee (IRC)-assessed progression-free survival (PFS). Secondary end points included overall survival (OS) and overall response rate (ORR) per IRC. Results: 578 pts were randomized (289 per arm); median age 64 yrs; 38% Rai Stage III/IV; median 2 prior therapies. 6 cycles of BR were completed in 83% and 78% of pts in the ibr and plb arms, respectively. At a median follow-up of 17.2 months, IRC-assessed PFS was significantly longer with BR+ibr vs BR+plb (median not reached vs 13.3 months; HR: 0.203, 95% CI: 0.150-0.276, P< 0.0001); PFS results were consistent across high-risk subgroups. ORR and CR/CRi rates were 82.7% vs 67.8% (P< 0.0001) and 10.4% vs 2.8%. Median OS was not reached. 90 pts (31%) in the BR+plb arm with confirmed PD crossed over to receive ibr, as permitted per the protocol. Incidence of most AEs was similar between arms. The most common all-grade AEs with BR+ibr and BR+plb were neutropenia (58.2% vs 54.7%) and nausea (36.9% vs 35.2%); most common grade 3/4 AEs were neutropenia (53.7% vs 50.5%) and thrombocytopenia (15.0% each arm). Rates of grade 3/4 atrial fibrillation were 2.8% and 0.7%, and major hemorrhage were 2.1% and 1.7%. Fatigue (FACIT-Fatigue) was improved with BR+ibr vs BR+plb. Conclusions: The addition of ibr to BR reduced the risk of progression or death by 80% compared with BR+plb. ORR was also significantly improved. Safety of BR+ibr was consistent with the known profiles for BR and ibr. The data further support ibr as an important treatment option for pts with previously treated CLL/SLL. Clinical trial information: EudraCT No. 2012-000600-15; UTN No. U1111-1135-3745.