A phase 3 randomized study (HOMER) of ofatumumab vs rituximab in iNHL relapsed after rituximab-containing therapy

Abstract

Because of high relapse rates with rituximab combinations, there is an unmet need for new therapeutic agents for treatment of indolent B-cell non-Hodgkin lymphoma (iNHL) or follicular lymphoma (FL). In previous trials, ofatumumab in combination with chemotherapy showed good results in relapsed/refractory FL pretreated with rituximab. This phase 3 trial evaluated the efficacy and safety of single-agent ofatumumab vs single-agent rituximab in rituximab-sensitive relapsed FL that relapsed at least 6 months after completing the last prior treatment with single-agent rituximab or a rituximab-containing regimen. Patients were randomized 1:1 to receive either ofatumumab (1000 mg) or rituximab (375 mg/m2) every week for 4 weeks for the induction phase, followed by once every 2 months for 4 additional doses. The primary endpoint, progression-free survival (PFS) and secondary endpoints, overall response rate (ORR) and overall survival (OS), were evaluated. Overall, 438 patients were assigned to receive ofatumumab (n = 219) and rituximab (n = 219). Baseline characteristics were similar in both arms. The independent review committee assessed whether median PFS was shorter in the ofatumumab arm than in the rituximab arm (16.33 vs 21.29 months), with no significant difference (hazard ratio, 1.15; 95% confidence interval, 0.89-1.49; P = .29) and also showed a lower ORR (50%) compared with the rituximab arm (66%). At the time of analysis, data were not matured for OS results. The number of grade >3 adverse events was higher in the ofatumumab arm (37%) than the rituximab arm (28%). Ofatumumab showed no superiority over rituximab in patients with FL who had relapsed after a rituximab-containing therapy. This study was registered at www.clinicaltrials.gov as #NCT01200589.

Chemotherapy-Free Management of Follicular and Marginal Zone Lymphoma

“…42 Of note, another anti-CD20 antibody ofatumumab failed to show improvement in outcomes over rituximab. 43,44 Obinutuzumab is a type II glycoengineered anti-CD20 IgG monoclonal antibody with increased direct cytotoxic effect as well as antibody-dependent cellular cytotoxicity. 45 It has shown efficacy for iBCL in both relapsed/refractory and first-line settings, extends PFS when combined with chemotherapy instead of rituximab, and has gained FDA approval in combination with chemotherapy for treatment of FL.…”

“… 42 Of note, another anti-CD20 antibody ofatumumab failed to show improvement in outcomes over rituximab. 43 , 44 …”

“… 84 Using an alternative antibody (ofatumumab or obinutuzumab) does not appear to meaningfully improve outcomes ( Table 2 ). 43 , 47 However, for patients who experience a rituximab-refractory FL/MZL or a symptomatic relapse within 2 years of prior therapy, we favor an alternative approach when life expectancy exceeds 2 more years because a second remission with rituximab alone is likely to be brief.…”

Role of antibody-based therapy in indolent non-Hodgkin's lymphoma

“…NA = not available, NR = not reached. Target Study (Phase) Population Sample ORR (%) CR (%) PFS CD20 PRIMA: R-chemo +/- maintenance 10-yr follow up (III) [6] FL 309 (R) vs 298 (Observation) ( N = 607) – – Median: 10.5 vs 4.1 yr ( P < 0.001) RELEVANCE: R-Lenalidomide vs -chemo (III) [9] Advanced FL 513 vs 517 ( N = 1030) 61 vs 65 48 vs 53 Rate: 77 vs 78 at 3 yr ( p = 0.48) AUGMENT: R- Lenalidomide vs –placebo (III) [10] R/R indolent FL and MZL 178 vs 180 ( N = 358) 78 vs 53 34 vs 18 Median: 39.4 vs 14.1 mo ( P < 0.001) BRISMA/IELSG36: R-Benda in splenic MZL(II) [12] Splenic MZL N = 45 82 73 Rate: 90% at 3 yr GALLIUM: O-chemo vs R-chemo(III) [14] FL 601 vs 601 ( N = 1202) 88 vs 86 19 vs 23 Rate: 80 vs 73 at 3 yr ( P = 0.001) GADOLIN : O-Benda vs Benda(III) [13] R/R iNHL (FL, MZL, SLL, WM) 204 vs 209 ( N = 413) 79 vs 77 17 vs 17 Median: 25.8 vs 14.1 mo ( P < 0.001) HOMER : Ofatumumab vs Rituximab(III) [15] R/R iNHL (FL, SLL, MZL, LPL) 219 vs 219 ( N = 438) 50 vs 66 16 vs 20 Median: 16.3 vs 21.3 mo ( P = ...…”

Prognostic significance of FCGR2B expression for the response of DLBCL patients to rituximab or obinutuzumab treatment

“…16 In part, these hypotheses regarding critical effector mechanisms have been informed by clinical experience with second generation anti-CD20 mAbs, such as ofatumumab and obinutuzumab (GA101 [G]). Ofatumumab is a fully human mAb with enhanced CDC activity, but has not demonstrated clinical improvement over R. [17][18][19] In contrast, the humanized mAb, G, has shown improved activity over R in CLL 20 and FL, 21,22 but not DLBCL. 23,24 The augmented activity of G has several possible explanations.…”