Clow, Fong

Abstract Introduction In 2 large phase 3 trials of patients (pts) with relapsed or refractory (R/R) CLL/SLL, single-agent ibrutinib (ibr) was superior to ofatumumab (ofa) (RESONATE; Byrd. NEJM 2013) and ibr + BR was superior to placebo + BR (HELIOS; Chanan-Khan. ASCO 2015). Both studies evaluated ibr in different pt populations with different relevant comparators (eg, ofa in pts who had relapsed following prior anti-CD20-based chemoimmunotherapy [CIT] and/or with del17p, and BR in pts eligible for CIT). In the absence of head-to-head evaluations of single-agent ibr vs BR or single-agent ibr vs ibr + BR, indirect comparisons can be used for hypothesis testing by potentially providing insights on the relative efficacy of treatments. As such, an indirect comparative analysis of data from RESONATE and HELIOS was performed. Recognizing biases inherent in cross-trial comparisons, including lack of randomization across trials and consequent differences in distributions of important confounding variables (eg, pt characteristics, prognostic factors), we used pt-level data from both studies to risk adjust for confounders using accepted multivariate statistical approaches. Methods In RESONATE, pts received 420 mg oral ibr daily until disease progression or unacceptable toxicity or intravenous ofa for up to 24 weeks. The primary end point was IRC-assessed PFS, with secondary end points of OS and ORR. In HELIOS, pts received BR (≤ 6 cycles) with either 420 mg oral ibr daily or placebo until disease progression or unacceptable toxicity. Pts with del17p were excluded. The primary end point was IRC-assessed PFS, with secondary end points of ORR and OS. Per protocol amendment in both studies, pts in comparator arms could switch to ibr upon IRC-confirmed progression. The current exploratory analysis was based on the latest available data from each trial (median time on study: RESONATE, 19 months; HELIOS, 17 months) using investigator assessments, but excluding del17p pts from RESONATE. Analyses were performed using data from both the overall CLL/SLL population and only the CLL pts. Separate multivariate Cox proportional hazards models were constructed for PFS and OS, including treatment and clinically relevant prognostic variables as covariates (age, gender, Rai staging, ECOG score, del11q status, refractory status, number of prior lines of therapy, bulky disease, IgVH status). Adjusted HRs and 95% CIs are presented vs single-agent ibr, along with predicted survival curves derived from the multivariate Cox regressions. Results RESONATE and HELIOS enrolled populations with notable differences making naïve comparison flawed. Because HELIOS enrolled only CIT-eligible pts, the trial included younger pts who had received fewer lines of therapy, as well as lower proportions of pts with purine analog refractory disease, del11q, or Rai stage 4 disease. These factors have been previously reported to influence outcomes in pts with R/R CLL/SLL and thus were included as covariates in the statistical models. Other baseline factors (gender, ECOG score, bulky disease, and IgVH status) were not notably different between the trials, but were found to impact PFS and OS and thus were included as additional covariates. In the overall CLL/SLL population, PFS and OS were comparable for single-agent ibr vs ibr + BR, and were significantly improved for single-agent ibr vs BR (Figure 1). Results for only the CLL pts were similar to those shown in Figure 1 for both PFS (ibr + BR vs single-agent ibr: 1.03 [0.61-1.75], p = 0.9042; BR vs single-agent ibr: 7.52 [4.72-11.99], p < 0.0001; single-agent ibr reduced the risk of progression/death by 87% vs BR) and OS (ibr + BR vs single-agent ibr: 1.20 [0.59-2.43], p = 0.6197; BR vs single-agent ibr: 2.24 [1.14-4.40], p = 0.0197; single-agent ibr reduced the risk of death by 55% vs BR). Conclusions The adjusted indirect comparisons reported here suggest superiority of single-agent ibr over BR for PFS and OS in patients with R/R CLL/SLL. The comparisons also suggest that the addition of BR to ibr did not improve PFS or OS compared with single-agent ibr. However, as median PFS has not been reached for either ibr arm, it is too early to draw firm conclusions. Longer follow-up in the ibr arms of these studies will be required to give an indication of whether CIT adds any benefit to ibrutinib for PFS and OS. Overall, these findings provide support for single-agent ibr as an appropriate choice for all pts with previously treated CLL/SLL. Disclosures Hillmen: Roche Pharmaceuticals: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding. Fraser:Janssen: Honoraria, Research Funding, Speakers Bureau; Hoffman LaRoche: Consultancy, Honoraria; Celgene: Honoraria, Research Funding. Jones:Acerta Pharma BV: Research Funding. Rule:Roche: Consultancy, Other: Travel reimbursement; J&J: Consultancy, Other: Travel reimbursement, Research Funding; Celgene: Consultancy, Other: Travel reimbursement; Gilead: Research Funding. Dilhuydy:Roche: Honoraria, Other: Travel reimbursement; Janssen: Honoraria, Other: Travel reimbursement; Mundipharma: Honoraria. Jaeger:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cymbalista:Karyopharm: Honoraria; Roche: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Research Funding. Sun:Janssen/J&J: Employment, Equity Ownership. Ninomoto:Pharmacyclics LLC, an AbbVie Company: Employment. Mahler:Janssen: Employment, Other: Travel reimbursement. Cheng:Pharmacyclics LLC, an AbbVie Company: Employment. Diels:Janssen: Employment. Clow:Pharmacyclics LLC, an AbbVie Company: Employment. Salman:Janssen/J&J: Employment, Equity Ownership. James:Pharmacyclics LLC, an AbbVie Company: Employment. Howes:Janssen/J&J: Employment, Equity Ownership.

Abstract Background: Patients with chronic lymphocytic leukemia (CLL) with deletion of the short arm of chromosome 17 (del 17p) follow an aggressive clinical course and demonstrate a median survival of less than 2 years in the relapsed/refractory (R/R) setting. Ibrutinib (ImbruvicaTM), a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, has been approved for previously treated patients with CLL and for patients with del 17p CLL. We report results from the primary analysis of the Phase II RESONATETM-17 (PCYC-1117-CA) study, designed to evaluate the efficacy and safety of single-agent ibrutinib for treatment of patients with R/R del 17p CLL or small lymphocytic leukemia (SLL). Methods: Patients with del 17p CLL or SLL who failed at least one therapy were enrolled to receive 420 mg oral ibrutinib once daily until progression. All patients receiving at least one dose of ibrutinib were included in the analysis. The primary endpoint was overall response rate (ORR) per an independent review committee (IRC). Other endpoints included duration of response (DOR), progression-free survival (PFS), and safety of ibrutinib. Results: Among 144 treated patients (137 with CLL, 7 with SLL), the median age was 64 (48% 65 years or older) and all had del 17p. Baseline characteristics included 63% of patients with Rai Stage III or IV disease, 49% with bulky lymphadenopathy of at least 5 cm, and 10% with lymphadenopathy of least 10 cm. The median baseline absolute lymphocyte count (ALC) was 32.9 x 109/L with 57% of patients with a baseline ALC at least 25.0 x 109/L. Baseline beta-2 microglobulin levels were at least 3.5 mg/L in 78% of patients (range 1.8-19.8 mg/L), and lactate dehydrogenase levels were at least 350 U/L in 24% of patients (range 127-1979 U/L). A median of 2 prior therapies (range 1-7) was reported. Investigator-assessed ORR was 82.6% including 17.4% partial response with lymphocytosis (PR-L). Complete response (CR)/complete response with incomplete bone marrow recovery (CRi) were reported in 3 patients. IRC-assessed ORR is pending. At a median follow up of 13.0 months (range 0.5-16.7 months), the median PFS (Figure 1) and DOR by investigator determination had not been reached. At 12 months, 79.3% were alive and progression-free, and 88.3% of responders were progression-free. Progressive disease was reported in 20 patients (13.9%). Richter transformation was reported in 11 of these patients (7.6%), 7 of the cases occurring within the first 24 weeks of treatment. Prolymphocytic leukemia was reported in 1 patient. The most frequently reported adverse events (AE) of any grade were diarrhea (36%; 2% Grade 3-4), fatigue (30%; 1% Grade 3-4), cough (24%; 1% Grade 3-4), and arthralgia (22%; 1% Grade 3-4). Atrial fibrillation of any grade was reported in 11 patients (7.6%; 3.5% Grade 3-4). Seven patients reported basal or squamous cell skin cancer and 1 patient had plasma cell myeloma. Most frequently reported Grade 3-4 AEs were neutropenia (14%), anemia (8%), pneumonia (8%), and hypertension (8%). Major hemorrhage was reported in 7 patients (4.9%, all Grade 2 or 3). Study treatment was discontinued in 16 patients (11.1%) due to AEs with 8 eventually having fatal events (pneumonia, sepsis, myocardial or renal infarction, health deterioration). At the time of data cut, the median treatment duration was 11.1 months, and 101 of 144 patients (70%) continued treatment with ibrutinib. Conclusions: In the largest prospective trial dedicated to the study of del 17p CLL/SLL, ibrutinib demonstrated marked efficacy in terms of ORR, DOR, and PFS, with a favorable risk-benefit profile. At a median follow up of 13 months, the median DOR had not yet been reached; 79.3% of patients remained progression-free at 12 months, consistent with efficacy observed in earlier studies (Byrd, NEJM 2013;369:32-42). The PFS in this previously treated population compares favorably to that of treatment-naïve del 17p CLL patients receiving fludarabine, cyclophosphamide, and rituximab (FCR) (Hallek, Lancet 2010;376:1164-74) or alemtuzumab (Hillmen, J Clin Oncol 2007;10:5616-23) with median PFS of 11 months. The AEs are consistent with those previously reported for ibrutinib (Byrd, NEJM 2014;371:213-23). These results support ibrutinib as an effective therapy for patients with del 17p CLL/SLL. Figure 1 Figure 1. Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Jones:Pharmacyclics: Consultancy, Research Funding. Coutre:Janssen, Pharmacyclics: Honoraria, Research Funding. Mato:Pharamcyclics, Genentech, Celegene, Millennium : Speakers Bureau. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding. Tam:Pharmacyclics and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siddiqi:Janssen: Speakers Bureau. Furman:Pharmacyclics: Consultancy, Speakers Bureau. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Stevens-Brogan:Pharmacyclics: Employment. Li:Pharmacyclics: Employment. Fardis:Pharmacyclics: Employment. Clow:Pharmacyclics: Employment. James:Pharmacyclics: Employment. Chu:Pharmacyclics: Employment, Equity Ownership. Hallek:Janssen, Pharmacyclics: Consultancy, Research Funding. Stilgenbauer:Pharmacyclics, Janssen Cilag: Consultancy, Honoraria, Research Funding.

LBA7008 Background: Treatment options for CLL/ SLL patients (pts) who fail chemoimmunotherapy are limited. We report interim results from a phase III randomized study of ibrutinib (ibr), a first in class covalent BTK inhibitor, vs ofatumumab (ofa) in R/R CLL/SLL. The Data Monitoring Committee recommended this analysis be considered final, based on meeting the primary and a key secondary endpoint. Methods: R/R CLL/SLL pts who failed ≥1 therapy received 420 mg oral ibr daily until progression or IV ofa 300/2000mg for 12 doses. Primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). Secondary endpoints included overall survival (OS), IRC assessed overall response rate (ORR) and safety. Results: Of 391 pts enrolled (median age 67 years; 40% ≥70 years; 57% Rai stage III/IV disease; 30% del 17p), 195 were randomized to ibr and 196 to ofa. Ibr pts had median 3 prior therapies vs 2 for ofa. Median follow-up was 9.4 months (m). Ibr significantly lengthened PFS (median not reached vs 8.1 m; HR 0.215, CI 0.146–0.317, p<0.0001; 78.5% risk reduction), and significantly improved OS (median not reached; HR 0.434, CI 0.238–0.789, p=0.0049) compared with ofa. ORR was 42.6 vs 4.1% (p<0.0001) and ORR+PR with lymphocytosis was 62.6 vs 4.1% for ibr vs ofa. Similar effects were seen in del17p and purine analog refractory subsets. In each arm 2 pts had confirmed Richter’s transformation. Most frequent adverse events (AE) for ibr vs ofa were diarrhea (47.7 vs 17.8%) fatigue (27.7 vs 29.8%), and nausea (26.2 vs 18.3%). Atrial fibrillation was more frequent with ibr (5.1 vs 0.5%). Major hemorrhages were reported in 1.0 vs 1.6% for ibr vs ofa. Drug discontinuation due to AE was 4.1 vs 3.6% for ibr vs ofa. 86% of ibr pts were continuing treatment. 57 pts randomized to ofa with confirmed PD had initiated ibr at cross-over. Conclusions: Compared with ofa, ibr significantly improved PFS, OS and ORR in pts with R/R CLL/SLL. The safety profile was comparable with that previously reported (Byrd NEJM 2013). These results support ibr as a beneficial therapy for R/R CLL patients irrespective of del 17p or purine analog refractory disease. Clinical trial information: NCT01578707.