Abstract
Identify subgroups of patients with relapsed/refractory follicular lymphoma deriving substantial progression-free survival (PFS) benefit with bortezomib-rituximab versus rituximab in the phase III LYM-3001 study. A total of 676 patients were randomized to five 5-week cycles of bortezomib-rituximab or rituximab. The primary end point was PFS; this prespecified analysis of candidate protein biomarkers and genes was an exploratory objective. Archived tumor tissue and whole blood samples were collected at baseline. Immunohistochemistry and genetic analyses were completed for 4 proteins and 8 genes. In initial pairwise analyses, using individual single-nucleotide polymorphism genotypes, one biomarker pair (PSMB1 P11A C/G heterozygote, low CD68 expression) was associated with a significant PFS benefit with bortezomib-rituximab versus rituximab, controlling for multiple comparison corrections. The pair was analyzed under dominant, recessive, and additive genetic models, with significant association with PFS seen under the dominant model (G/G+C/G). In patients carrying this biomarker pair [PSMB1 P11A G allele, low CD68 expression (≤50 CD68-positive cells), population frequency: 43.6%], median PFS was 14.2 months with bortezomib-rituximab versus 9.1 months with rituximab (HR 0.47, P < 0.0001), and there was a significant overall survival benefit (HR 0.49, P = 0.0461). Response rates were higher and time to next antilymphoma therapy was longer in the bortezomib-rituximab group. In biomarker-negative patients, no significant efficacy differences were seen between treatment groups. Similar proportions of patients had high-risk features in the biomarker-positive and biomarker-negative subsets. Patients with PSMB1 P11A (G allele) and low CD68 expression seemed to have significantly longer PFS and greater clinical benefit with bortezomib-rituximab versus rituximab.
Highlights
Significant (P < 0.05) differences in progression-free survival (PFS) in patients treated with bortezomib–rituximab versus rituximab were seen in patient subgroups defined by biomarkers including www.aacrjournals.org
CD68 positivity, NF-kB p65 cytoplasmic signal, and PSMB1 P11A, FCGR2A/H166R, and FCGR3A/V212F genotypes; the PFS benefit in these patient subgroups was generally less than 5 months or population frequencies were low (Supplementary Fig. S2)
In pairwise analyses (1,140 comparisons), in which genotypes of single-nucleotide polymorphism (SNP) markers were used individually in combination with other biomarkers, 102 biomarker pairs were identified as defining a patient subgroup in which there was a significant (P < 0.05) difference in PFS in patients treated with bortezomib–rituximab versus rituximab
Summary
1, 2), is to prolong progression-free survival (PFS) and improve overall survival (OS). Given the heterogeneity of follicular lymphoma and range of possible therapeutic options for patients with relapsed/refractory disease, the use of selected biomarkers based on mechanistic rationales to identify patient subgroups most likely to benefit from specific therapies is important. Candidate proteins and target gene polymorphisms were prespecified as potential prognostic markers for exploratory biomarker analyses in the phase III LYM-3001 study of bortezomib–rituximab versus rituximab in patients with relapsed/refractory follicular lymphoma. Comprehensive pairwise analyses, with genetic model testing, identified a biomarker pair, PSMB1 P11A (C/GþG/G) plus low CD68 expression, associated with a significant progression-free survival benefit, improved response rates, and longer overall survival with bortezomib–rituximab versus rituximab. The two biomarkers identified, for which a mechanistic hypothesis is provided for the reported efficacy benefit, would be feasible and practical to screen for in the clinical setting
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