Table 3.
Major clinical trials of ibrutinib in CLL/SLL.
| Trial (reference) | Population studied (n) | Phase and design | Response rates | Survival |
|---|---|---|---|---|
| [8] | Relapsed or refractory (n=85) with a median of 4 prior therapies | Ib/II, two doses: 420 mg (n=51) and 840 mg (n=34) | ORR 71% with both doses; another 20% and 15% had PRL, respectively; 2 CRs at 420 mg/d | At 26 months, estimated PFS 75% and OS 83%, median PFS not reached |
| [100] | Frontline, elderly (≥65, n=31) | Ib/II, initially two doses, later 840 mg dose discontinued | ORR 71% after median f/u of 22.1 months (13% CRs, 3% nPRs, 55% PRs) | At 24 months, estimated PFS 96.3% and OS 96.6%, median PFS not reached |
| RESONATE [9] | Relapsed or refractory (n=391); median 3 prior therapies in ibrutinib group and 2 in ofatumumab group; crossover allowed | III, RCT (1:1) of ibrutinib 420 mg/d vs. ofatumumab (300 mg in week 1, followed by 2000 mg weekly x 7, then every 4 weeks x 16) | ORR 42.6% vs. 4.1% favoring ibrutinib; another 20% in ibrutinib group had PRL | At median f/u of 9.4 months, median PFS not reached vs. 8.1 months; PFS at 6 months 88% vs. 65%; OS 90% vs. 81% at 12 months |
| RESONATE-17 [11] | Relapsed or refractory with deletion 17p (n=144); median 2 prior therapies | II; single arm (420 mg/d) | ORR 82.6% (including 17.4% PRL, 3 patients with CR/CRi) | At median f/u of 13 months, median PFS not reached; 79.3% PFS at 12 months |
| [10] | Treatment-naïve (n=35) or relapsed or refractory (n=16) with TP53 aberrations (47 had deletion 17p) | II, single arm (420 mg/d) | ORR 97% (55% PR + 42% PRL) among previously untreated; 80% (40% PR + 40% PRL) among R/R | At 24 months, estimated PFS for all patients 82% and OS 80% (ITT); 24-month OS 84% in previously untreated and 74% in R/R pts |
| RESONATE-2 [6] | Previously untreated, elderly (≥65, n=269); crossover allowed | III, RCT (1:1) of ibrutinib 420 mg/d vs. chlorambucil (up to 12 28-day cycles; 0.5 mg/kg (could be ↑ to 0.8 mg/kg) on days 1 and 15 | ORR 86% with ibrutinib vs. 35% with chlorambucil (CRs 4% vs. 2%); 4% in ibrutinib group had PRL | At median f/u of 18.4 months, estimated PFS not reached vs. 18.9 months; estimated OS at 24 months 98% vs. 85%; 84% reduction in risk of progression or death with ibrutinib |
| [66] | High risk (del17p, TP53 mutation, del11q, PFS < 36 months after CIT, n=40); median 2 prior therapies | II, single arm, ibrutinib 420 mg/d plus rituximab (375 mg/m2, weekly in cycle 1, then once per cycle till cycle 6) | ORR 95% (87% PR + 8% CR); 1 patient achieved MRD-negative CR; 2 CRs occurred in patients with deletion 17p | At 18 months, PFS in all patients 78%; 72.4% in patients with deletion 17p or TP53 mutation (n=20) |
| [67] | Patients who had failed ≥2 prior therapies; PLL (n=2) and RT also included (n=3); median 3 prior therapies | Ib/II, ibrutinib 420 mg/d plus ofatumumab x 12 (ibrutinib lead-in, n=27; concurrent start, n=20; ofatumumab lead-in, n=24) | ORRs in CLL/SLL pts (n=66) 100%, 79% and 71% in the 3 groups, respectively (overall 83.3%); 1 CR and 54 PRs | Estimated 12-month PFSs for all patients 89%, 85% and 75% in the 3 groups, respectively |
| HELIOS [101] | Relapsed or refractory (n=578) without deletion 17p; crossover allowed | III, RCT (1:1) of bendamustine (70 mg/m2/dose x 2) plus rituximab x 6 cycles plus ibrutinib 420 mg/d or placebo | ORR 83% in IBR group vs. 68% in BR group; CR/CRi rate 10% vs. 3%; MRD-negativity rates 13% vs. 5% | At median f/u of 17 months, estimated PFS not reached in IBR group vs. 13.3 months in BR group; at 18 months, PFS 79% vs. 24% |
Abbreviations: CLL, chronic lymphocytic leukemia; SLL, small lymphocytic lymphoma; ORR, overall response rate; CR, complete remission; CRi, complete response with incomplete count recovery; PR, partial response; PRL, partial response with lymphocytosis; nPR, nodular partial response; MRD, minimal residual disease; RCT, randomized controlled trial; PFS, progression-free survival; OS, overall survival; R/R, relapsed/refractory; IBR, ibrutinib, bendamustine and rituximab; BR, bendamustine and rituximab; f/u, follow-up.