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Randomized comparison of ibrutinib versus ofatumumab in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma: Results from the phase III RESONATE trial.
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
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.
Abstracts by John C. Byrd:
A phase 1b trial of duvelisib, a PI3K-δ,γ inhibitor, in combination with obinutuzumab in patients with CLL/SLL previously treated with a Bruton’s tyrosine kinase inhibitor (BTKi).Meeting: 2015 ASCO Annual Meeting | Abstract No: TPS7100
Dose adherence and baseline exposure analysis of the ibrutinib 420 mg dose administered to patients with previously treated chronic lymphocytic leukemia (CLL).Meeting: 2015 ASCO Annual Meeting | Abstract No: 7012
Early clinical activity and pharmacodynamic effects of duvelisib, a PI3K-δ,γ inhibitor, in patients with treatment-naïve CLL.Meeting: 2015 ASCO Annual Meeting | Abstract No: 7074
Educational Book Articles by John C. Byrd:
Presentations by John C. Byrd:
Meeting: 2012 ASCO Annual Meeting
Session: Toward Successful Targeting of the PI3 Kinase Pathway in Cancer (Education Session)
The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib PCI-32765 (P) is highly active and tolerable in treatment-naive (TN) chronic lymphocytic leukemia (CLL) patients (pts): Interim results of a phase Ib/II study.Meeting: 2012 ASCO Annual Meeting Abstract No: 6507Session: Leukemia, Myelodysplasia, and Transplantation (Oral Abstract Session)
Activity and tolerability of the Bruton's tyrosine kinase (Btk) inhibitor PCI-32765 in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): Interim results of a phase Ib/II study.Meeting: 2011 ASCO Annual Meeting Abstract No: 6508Session: Leukemia, Myelodysplasia, and Transplantation (Oral Abstract Session)