Published OnlineFirst April 2, 2013; DOI: 10.1158/1078-0432.CCR-12-3069 Clinical Cancer Predictive Biomarkers and Personalized Medicine Research Prespecified Candidate Biomarkers Identify Follicular Lymphoma Patients Who Achieved Longer Progression-Free Survival with Bortezomib–Rituximab Versus Rituximab Bertrand Coiffier1, Weimin Li2, Erin D. Henitz3, Jayaprakash D. Karkera3, Reyna Favis3, Dana Gaffney3, Alice Shapiro3, Panteli Theocharous6, Yusri A. Elsayed3, Helgi van de Velde9, Michael E. Schaffer2, Evgenii A. Osmanov10, Xiaonan Hong11, Adriana Scheliga12, Jiri Mayer13, Fritz Offner8, Simon Rule7, Adriana Teixeira14, Joanna Romejko-Jarosinska15, Sven de Vos4, Michael Crump16, Ofer Shpilberg17, Pier Luigi Zinzani18, Andrew Cakana6, Dixie-Lee Esseltine5, George Mulligan5, and Deborah Ricci3 Abstract Purpose: Identify subgroups of patients with relapsed/refractory follicular lymphoma deriving substan- tial progression-free survival (PFS) benefit with bortezomib–rituximab versus rituximab in the phase III LYM-3001 study. Experimental Design: 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. Results: 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/GþC/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 ¼ 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. Conclusions: Patients with PSMB1 P11A (G allele) and low CD68 expression seemed to have signif- icantly longer PFS and greater clinical benefit with bortezomib–rituximab versus rituximab. Clin Cancer Res; 19(9); 2551–61. Ó2013 AACR. Introduction non-Hodgkin lymphoma (NHL; refs. 1, 2), is to prolong The goal of treatment for patients with follicular lym- progression-free survival (PFS) and improve overall survival phoma, a generally incurable, common indolent subtype of (OS). Follicular lymphoma is a highly heterogeneous Authors' Affiliations: 1Hematologie, Hospices Civils de Lyon and Uni- Cancer Centre, Warszawa, Poland; 16Princess Margaret Hospital, versity Lyon 1, Lyon, France; 2Janssen Research and Development, University of Toronto, Toronto, Ontario, Canada; 17Institute of Hema- Spring House, Pennsylvania; 3Janssen Research and Development, tology, Rabin Medical Center, Petah Tikva, Israel; and 18Policlinico S. Raritan, New Jersey; 4David Geffen School of Medicine at the University Orsola,MalpigliIstitutodiEmatologia e Oncologia Medica, Bologna, of California and Translational Oncology Research International, Los Italy Angeles, California; 5Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts; 6Janssen Research and Development, High Wycombe; Note: Supplementary data for this article are available at Clinical Cancer 7Department of Haematology, Derriford Hospital, Plymouth, United Research Online (http://clincancerres.aacrjournals.org/). Kingdom; 8Dienst Hematologie, UZ Gent, Gent, Belgium; 9Janssen fi Research and Development, Beerse, Belgium; 10Cancer Research Cen- Corresponding Author: Bertrand Coif er, Hematologie, Hospices Civils ter, Moscow, Russia; 11Cancer Hospital, FuDan University, Shanghai, de Lyon and University Lyon 1, 69310 Pierre-Benite, Lyon, France. Phone: China; 12Instituto Nacional de Cancer,^ Rio de Janeiro, Brazil; 13CEITEC 33-478-86-4300; Fax: 33-478-86-4355; E-mail: fi Brno, and Department of Internal Medicine, Hematology and Oncology, bertrand.coif [email protected] University Hospital Brno and School of Medicine, Masaryk University, doi: 10.1158/1078-0432.CCR-12-3069 Brno, Czech Republic; 14HospitaisdaUniversidadedeCoimbra,Coim- bra, Portugal; 15The Maria Skłodowska-Curie Memorial Institute and Ó2013 American Association for Cancer Research. www.aacrjournals.org 2551 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst April 2, 2013; DOI: 10.1158/1078-0432.CCR-12-3069 Coiffier et al. morphisms were specified on the basis of prior studies of Translational Relevance prognostic molecular markers for lymphoma and of target Given the heterogeneity of follicular lymphoma and or response markers for bortezomib or rituximab. Here, we range of possible therapeutic options for patients with present the findings of this exploratory biomarker analysis. relapsed/refractory disease, the use of selected biomar- kers based on mechanistic rationales to identify patient Materials and Methods subgroups most likely to benefit from specific therapies Patients and clinical study design is important. Candidate proteins and target gene poly- The LYM-3001 (ClinicalTrials.gov trial registration ID: morphisms were prespecified as potential prognostic NCT00312845) study design has been reported previously markers for exploratory biomarker analyses in the phase (13). Eligible patients were aged 18 years or more with III LYM-3001 study of bortezomib–rituximab versus relapsed/refractory, rituximab-na€ve, or rituximab-sensitive rituximab in patients with relapsed/refractory follicular (13) grade 1/2 follicular lymphoma. Patients with grade 2 lymphoma. Comprehensive pairwise analyses, with peripheral neuropathy or clinical evidence of transforma- genetic model testing, identified a biomarker pair, tion to aggressive lymphoma were excluded. Patients were PSMB1 P11A (C/GþG/G) plus low CD68 expression, randomized (1:1) to receive five 5-week cycles comprising associated with a significant progression-free survival bortezomib (1.6 mg/m2, days 1, 8, 15, and 22; all cycles) benefit, improved response rates, and longer overall plus rituximab (375 mg/m2, days 1, 8, 15, and 22, cycle 1, survival with bortezomib–rituximab versus rituximab. and day 1, cycles 2–5), or rituximab alone. Randomization The benefit with bortezomib–rituximab was substantial- was stratified according to Follicular Lymphoma Interna- ly greater than seen in the overall, unselected study tional Prognostic Index (FLIPI; ref. 14) score, previous population. The two biomarkers identified, for which rituximab treatment, time since last dose of antilymphoma a mechanistic hypothesis is provided for the reported treatment, and region. efficacy benefit, would be feasible and practical to screen The primary end point was PFS. Secondary efficacy end for in the clinical setting. points included ORR, CR rate, time to progression, and 1 year OS. Response was assessed using modified Interna- tional Working Group response criteria (15). Time to next antilymphoma treatment (TTNT; time from randomization disease, as evidenced by variability in disease course, to first dose of next treatment) was an additional predefined responsiveness to treatment, and outcomes (3–5). There- efficacy end point. fore, to optimize treatment for individual patients, identi- All patients provided written informed consent. Review fication of subgroups that are most likely to benefit from a boards at all participating Institutions approved the study, specific therapy is important. which was conducted according to the provisions of the The anti-CD20 monoclonal antibody rituximab is the Declaration of Helsinki, the International Conference on mainstay of treatment for follicular lymphoma (1). Addi- Harmonization, and the Guidelines for Good Clinical tional treatment options may enhance the activity of ritux- Practice. imab-based therapy in the relapsed setting. The proteasome inhibitor bortezomib has shown single-agent activity in Biomarker analysis study design follicular lymphoma and other indolent NHL subtypes This prespecified focused analysis of potential biomar- (6–8), as well as promising activity in combination with kers of sensitivity to bortezomib–rituximab or rituximab rituximab, with or without other agents, in patients with was an exploratory objective. All patients were required to relapsed/refractory follicular lymphoma (9–12). provide consent for biomarker testing, and were included in Results from the international, multicenter, randomized, the biomarker study if they had evaluable biomarker data phase III LYM-3001 study (13) showed improved PFS with and data for at least one clinical end point. Archived tumor bortezomib–rituximab versus rituximab alone in patients tissue (samples requested from diagnosis) was collected at with relapsed/refractory rituximab-na€ve or rituximab-sen- baseline, and samples were forwarded to a central labora- sitive follicular lymphoma (median 12.8 vs. 11.0 months, tory as paraffin-embedded,