Ibrutinib, a once-daily oral inhibitor of Bruton's tyrosine kinase, is approved in the United States and Europe for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study showed improved efficacy of single-agent ibrutinib over ofatumumab in patients with relapsed/refractory CLL/SLL, including those with high-risk features. Here we report the final analysis from RESONATE with median follow-up on study of 65.3 months (range, 0.3-71.6) in the ibrutinib arm. Median progression-free survival (PFS) remained significantly longer for Trial Registration: clinicaltrials.gov identifier: NCT01578707.

clinicaltrials.gov Identifier: NCT02055781.

CTI BioPharma Corp.

Long-term data are critical for physicians and patients to inform treatment decisions. Here we report extended long-term follow-up from the RESONATE-2 phase 3 study of the once-daily Bruton's tyrosine kinase inhibitor ibrutinib, which is the only targeted therapy with significant progression-free survival (PFS) and overall survival (OS) benefit in multiple randomized phase 3 CLL studies. Patients (≥65 years) with previously untreated CLL/SLL, without del(17p), were randomly assigned 1:1 to once-daily ibrutinib 420 mg until disease progression/unacceptable toxicity (n=136) or chlorambucil 0.5-0.8 mg/kg up to 12 cycles (n=133). With up to 8 years of follow-up (range 0.1-96.6; median, 82.7 months), significant PFS benefit was sustained for ibrutinib versus chlorambucil (HR 0.154 [95% CI: 0.108-0.220]). At 7 years, PFS was 59% for ibrutinib versus 9% for chlorambucil. PFS benefit was also observed for ibrutinib- versus chlorambucil-randomized patients with high-risk genomic features: del(11q) (HR 0.033 [95% CI: 0.010-0.107]) or unmutated IGHV (HR 0.112 [95% CI: 0.065-0.192]). OS at 7 years was 78% with ibrutinib. Prevalence of adverse events (AEs) of clinical interest was consistent with previous 5-year follow-up. Ibrutinib dosing was held (≥7 days) for 79 patients and reduced for 30 patients due to AEs. These AEs resolved or improved with dose modifications in 85% (67/79) and 90% (27/30) of patients, respectively. With up to 8 years of follow-up, 42% of patients remain on single-agent ibrutinib. Long-term RESONATE-2 data demonstrate sustained benefit with first-line ibrutinib treatment for CLL, including for patients with high-risk genomic features. These trials are registered at www.clinicaltrials.gov as NCT01722487 and NCT01724346.

Background: PAC is an oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CSF1R that has demonstrated significant and sustained spleen volume reduction (SVR) and symptom control vs BAT (excluding JAK2 inhibitors) in MF pts regardless of platelet count (PERSIST-1). The PERSIST-2 study was a randomized, controlled, open-label, phase 3 trial of PAC 200 mg BID and PAC 400 mg QD vs BAT (including JAK1/JAK2 inhibitor ruxolitinib [RUX]) in pts with 10 or 20 MF whose platelet counts were ≤100,000/µL, a recognized adverse prognostic variable. Prior JAK2 inhibitor use was allowed. Methods: Pts were randomized 1:1:1 to PAC BID, PAC QD, or BAT. The co-primary efficacy endpoints were the percentages of pts achieving ≥35% SVR (MRI or CT) and ≥50% reduction in total symptom score (TSS; MPN-SAF TSS 2.0), both from baseline to Week 24. The primary objective was to compare the efficacy of pooled PAC (BID+QD) to BAT and the secondary objectives were to compare PAC BID and PAC QD individually to BAT. PK samples were collected and analyzed for PAC. Safety analyses were based on all pts exposed to study treatment of any duration (safety population); efficacy analyses were based on ITT pts with a randomization date allowing Week 24 endpoint evaluations prior to the full clinical hold* (ITT efficacy population). Results: 311 pts were randomized (107 PAC BID, 104 PAC QD, 100 BAT), 308 received study drug, and 221 were included in the ITT efficacy population (74 PAC BID, 75 PAC QD, 72 BAT). Demographics and baseline disease characteristics were generally balanced among the treatment arms (Table) and analysis populations. A total of 32 (44%) BAT pts in the ITT efficacy population received RUX as treatment at some point on study. Population PK analyses showed that the steady-state plasma levels achieved with BID were higher than with QD, however the Cmax levels were lower. A significantly higher percentage of pts in the pooled PAC arm achieved SVR ≥35% (18% [27/149]) vs the BAT arm (3% [2/72]; p=0.001; Figure 1A). 25% of PAC pts (37/149) had ≥50% reduction in TSS vs 14% of BAT pts (p=0.079; Figure 1B). In secondary analyses vs BAT, PAC BID demonstrated significant improvement over BAT for both efficacy endpoints with 22% achieving SVR ≥35% (BAT=3%; p=0.001) and 32% achieving ≥50% reduction in TSS (BAT=14%; p=0.011). The PAC QD arm had a significant SVR ≥35% (15% v 3%, respectively; p=0.017), but a similar proportion with ≥50% reduction in TSS (17% v 14%, respectively; p=0.652). More PAC pts reduced their red blood cell transfusion dependence at Week 24 (defined as a ≥50% reduction in average transfusions/month for 3 months relative to baseline) with 19% (7/37) in the PAC QD arm, 22% (8/36) in PAC BID, and 9% (3/35) in BAT. There was no significant difference observed in OS across the treatment arms (Figure 2). Hazard ratios for OS (95% confidence intervals) were 0.68 (0.30, 1.53) for PAC BID v BAT, 1.18 (0.57, 2.44) for PAC QD v BAT, and 0.61 (0.27, 1.35) for PAC BID v QD. PAC BID maintained this survival advantage vs BAT across nearly all demographic and MF-associated risk factors. During the course of the study, 10 (9%), 15 (14%), and 15 (14%) died on PAC BID, PAC QD, and BAT, respectively. The most common treatment-emergent adverse events (AEs) associated with PAC were gastrointestinal (diarrhea, nausea, vomiting) and hematologic (anemia and thrombocytopenia), and were generally less frequent for BID vs QD administration. Grade 3/4 cardiac AEs occurred in 7%, 13% and 9% of PAC BID, PAC QD, and BAT pts, respectively, and grade 3/4 bleeding AEs occurred in 14%, 7%, and 7%, respectively. Grade 3/4 bleeding AEs were associated with grade 3/4 thrombocytopenia, which was also more common in the PAC BID group. Nine pts had cardiac failure (2% PAC QD, 4% PAC BID, 3% BAT) and 1 (1%, PAC QD) had intracranial hemorrhage.* Conclusions: The PERSIST-2 study is the only randomized, controlled trial to date in pts with MF and thrombocytopenia (platelets ≤100,000/µL), allowed prior JAK2 inhibitor treatment exposure (including RUX), and allowed RUX as BAT comparator. Irrespective of prior JAK2 inhibitor treatment, both PAC arms were more effective at SVR than BAT; however, PAC BID appeared more active than QD dosing and achieved significance versus BAT for both SVR and TSS. The most frequent AEs with PAC were gastrointestinal and hematologic toxicities. *PAC on full clinical hold by the FDA on 2/8/2016 based on concerns around excess deaths and cardiac and hemorrhagic events in PERSIST-1. Disclosures Mascarenhas: Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; CTI BioPharma: Research Funding; Janssen: Research Funding; Roche: Research Funding; Promedior: Research Funding. Talpaz:CTI BioPharma: Research Funding; Pfizer: Research Funding; Incyte Corporation: Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Gilead: Other: Travel, Accommodations, Expenses, Research Funding; BMS - Canada: Consultancy. Gerds:CTI BioPharma: Research Funding; Astra-Zeneca: Research Funding; Roche: Research Funding; Incyte: Research Funding. Stein:Incyte Corporation: Consultancy. Gupta:Incyte Corporation: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Drummond:CTI BioPharma: Honoraria; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Roche: Speakers Bureau. Granston:CTI BioPharma Corp.: Employment. Daly:CTI BioPharma Corp.: Employment. Dean:CTI BioPharma Corp.: Employment, Equity Ownership. Al-Fayoumi:CTI BioPharma Corp.: Employment, Equity Ownership. Callahan:CTI BioPharma: Employment. Singer:CTI BioPharma Corp.: Employment, Equity Ownership, Other: Leadership . Gotlib:Novartis: Other: Travel, Accommodations, Expenses; Steering Committee Chairman, Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding; Gilead: Research Funding; Incyte: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Jamieson:GSK: Research Funding; Johnson & Johnson: Research Funding; CTI BioPharma: Research Funding. Harrison:Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria, Speakers Bureau; Baxter: Consultancy, Honoraria; Shire: Speakers Bureau; Gilead: Speakers Bureau; Incyte: Speakers Bureau. Mesa:Novartis: Consultancy, Honoraria; Incyte: Research Funding; Gilead: Research Funding; CTI BioPharma: Research Funding; Celgene: Research Funding; Genetech: Research Funding; Promedior: Research Funding. Verstovsek:CTI BioPharma Corp: Research Funding.

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7523 Background: Ibrutinib, a once-daily Bruton’s tyrosine kinase inhibitor, is the only targeted therapy with significant progression-free survival (PFS) and overall survival (OS) benefit in multiple randomized phase 3 studies versus established therapies in patients (pts) with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Extended long-term follow-up data for the RESONATE-2 study of first-line ibrutinib vs chlorambucil in older pts with CLL/SLL are reported. Methods: In the phase 3 RESONATE-2 study, older pts (≥65 years [y]) with previously untreated CLL/SLL and without del(17p) (N=269) were randomly assigned 1:1 to once-daily single-agent ibrutinib 420 mg until disease progression (PD) or unacceptable toxicity (n=136) or chlorambucil 0.5–0.8 mg/kg up to 12 cycles (n=133). Outcomes included PFS, OS, overall response rate (ORR), and safety. Long-term responses were investigator-assessed per 2008 iwCLL criteria. Results: With up to 7y of follow-up (median, 74.9 months; range, 0.1–86.8), significant PFS benefit was sustained for pts treated with ibrutinib vs chlorambucil (hazard ratio [HR] 0.160 [95% confidence interval (CI): 0.111–0.230]). At 6.5y, PFS was 61% in pts treated with ibrutinib vs 9% in pts treated with chlorambucil. This PFS benefit was observed across all subgroups, including in ibrutinib-treated pts with high-risk genomic features of unmutated IGHV (HR 0.109 [95% CI: 0.063–0.189]) or del(11q) (HR 0.033 [95% CI: 0.010–0.107]). OS at 6.5y was 78% with ibrutinib treatment. ORR was 92% for ibrutinib-treated pts with complete response (CR/CRi) rate increasing to 34% with this follow-up. Ongoing rates of grade ≥3 adverse events (AEs) of interest remained low for hypertension (5–6y interval: 5%, n=4; 6–7y: 4%, n=3) and atrial fibrillation (5–6y: 1%, n=1; 6–7y: 1%, n=1); no grade ≥3 major hemorrhage occurred in 5–7y. Dose reductions due to grade ≥3 AEs occurred in 1% (n=1) of pts during the 5–6y and 6–7y intervals. Across full follow-up, 31 pts had dose reductions due to any-grade AEs of whom 22/31 (71%) had resolution or improvement the AE. Primary reason for discontinuations in 5–7y was PD (5–6y: 5%, n=4; 6–7y: 6%, n=4). Any-grade AEs leading to discontinuations were seen in 3% (n=2) of pts from 5–6y and none in 6–7y. With over 7y of follow-up, 47% of pts remain on single-agent ibrutinib. Conclusions: Extended long-term data from RESONATE-2 demonstrate the sustained PFS and OS benefit of first-line ibrutinib treatment for pts with CLL, including for pts with high-risk genomic features. Responses continue to deepen over time. Rates of grade ≥3 AEs of interest continued to be low at up to 7y follow-up and further discontinuations and dose reductions due to AEs were rare; most AEs leading to dose reduction resolved or improved. Ibrutinib remains well tolerated with no new safety signals observed. Clinical trial information: NCT01722487, NCT01724346.

LBA7006 Background: PAC is a potent JAK2 inhibitor without significant JAK1 inhibition with minimal myelosuppression in early-phase studies in MF. Methods: The efficacy and safety of daily oral PAC was compared to BAT (2:1 randomization stratified for risk and platelet count). The 10 endpoint was the proportion of ITT patients (pts) achieving ≥ 35% spleen volume reduction (SVR) at week (wk) 24 by centrally reviewed MRI or CT. Secondary endpoints included the proportion achieving ≥ 50% reduction in total symptom score (TSS) at wk 24 using the MPN Symptom Assessment Form. Results: Patients:327 were enrolled (PAC:220, BAT:107), 62% with 10 MF. Median time from diagnosis was 1.12 years (PAC 0.99, BAT 1.60): 32% and 15% had a platelet counts < 100,000/µL or <50,000/ µL; 75% were JAK2V617F positive. Efficacy: The median duration of treatment was 16.2 months PAC and 5.9 months BAT. Sixty-two percent of BAT patients received active disease directed therapy. The SVR rates at week 24 were 19.1% for PAC vs. 4.7% for BAT (p=0.0003) in ITT and 25% vs. 5.9% (p=0.0001) in the evaluable population. 79% of BAT patients crossed over to PAC; 21% had achieved a >35% reduction in spleen volume at data cutoff. TSS composite V1 + V2 response rates were 24.5%for PAC vs. 6.5% for BAT (p<0.0001) by ITT, and were 40.9% vs. 9.9% in evaluable pts (p<0.0001). Efficacy with baseline cytopenias: In pts with <100,000 and <50,000 platelets/μ/L, the SVR rates were 16.7% for PAC vs. 0% for BAT (p=0.009), and 22.9% vs. 0% (p=0.045) by ITT and 23.5% vs. 0% (p=0.007) and 33.3% vs. 0% (p=0.037) in evaluable pts. In RBC transfusion dependent pts, 25.7% of PAC pts became RBC independent vs. 0% of BAT pts (p=0.043). Safety: The most common adverse events (AE) for PAC were diarrhea, nausea, and vomiting; (grade 3 were <5%, <1%, <1% respectively). Hematologic AEs were similar between PAC and BAT. Conclusions: This study demonstrated PAC was well tolerated and induced significant and sustained SVR and symptom control even in patients with severe thrombocytopenia. PAC therapy resulted in RBC transfusion independence in a significant proportion of pts. Clinical trial information: NCT01773187.