ROBUST: First report of phase III randomized study of lenalidomide/R‐CHOP (R²‐CHOP) vs placebo/R‐CHOP in previously untreated ABC‐type diffuse large B‐cell lymphoma

Introduction: The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) continues to convey inferior survival despite efforts to enhance outcomes with novel R-CHOP combinations. Phase II studies have suggested that the addition of the immunomodulatory agent lenalidomide to R-CHOP could ameliorate the poor prognostic effect of the ABC phenotype and improve treatment outcome in this subgroup of patients. Methods: The global phase III ROBUST trial (NCT02285062) is the first to compare lenalidomide/R-CHOP (R2-CHOP) vs placebo/R-CHOP in previously untreated, prospectively selected, CD20+ ABC-type DLBCL. Patients included adults with Ann Arbor stage II-IV disease, IPI score ≥ 2, and ECOG PS ≤ 2. Confirmation of histology and cell-of-origin type were prospectively analyzed from formalin-fixed, paraffin-embedded excisional/surgical or core needle biopsy samples by central pathology using the NanoString Lymphoma Subtyping Test (LST), based on the Lymph2Cx GEP assay (Scott, Blood 2014). ABC-DLBCL patients were stratified by IPI score (2 vs ≥ 3), bulky disease (< 7 vs ≥ 7 cm) and age (< 65 vs ≥ 65 y), and randomized 1:1 to lenalidomide PO 15 mg/d, d1-14/21 + standard R-CHOP21 vs placebo/R-CHOP21 for 6 cycles, with 2 additional, optional doses of rituximab per local practice. The primary endpoint was progression-free survival (PFS) assessed by independent central radiology per 2014 NHL IWG criteria, and defined as time from randomization to PD or death from any cause. Results: A total of 570 ABC-DLBCL patients met eligibility criteria and were enrolled in ROBUST (n = 285 per arm). Baseline demographics were similar between arms, with a median age for all patients of 65 y (52% ≥ 65 y), 42% IPI 2 score/58% IPI ≥ 3 score, 88% stage III/IV disease, and 34% bulky disease. The primary endpoint of PFS was not met with an HR = 0.85 (95% CI, 0.63-1.14) and P = 0.29; median PFS was not reached for either arm (Figure). Positive PFS trends favoring R2-CHOP over placebo/R-CHOP were observed with disease stage III/IV (HR = 0.81 [95% CI, 0.60-1.10]) and IPI score ≥ 3 (HR = 0.74 [95% CI, 0.53-1.05]). Median EFS was not reached for either arm (HR = 1.04; 95% CI, 0.80-1.34; P = 0.73). At a median follow-up of 27.1 mo (range, 0-47) for survivors, 2-y OS was 79% for R2-CHOP and 80% for placebo/R-CHOP (medians not reached). ORR was 91% for both arms, with 69% vs 65% CR for R2-CHOP vs placebo/R-CHOP, respectively. 74% R2-CHOP and 84% placebo/R-CHOP patients completed 6 cycles of treatment; AEs (mainly neutropenia) were the most common reason for treatment discontinuation. The most common grade 3/4 AEs (≥ 10%) for R2-CHOP vs placebo/R-CHOP were neutropenia (60% vs 48%), anemia (22% vs 14%), thrombocytopenia (17% vs 11%), leukopenia (14% vs 15%), febrile neutropenia (14% vs 9%), and lymphopenia (11% vs 8%).

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