Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Laurie H Sehn, Alex F Herrera, Christopher R Flowers, Manali K Kamdar, Andrew McMillan, Mark Hertzberg, Sarit Assouline, Tae Min Kim, Won Seog Kim, Muhit Ozcan, Jamie Hirata, Elicia Penuel, Joseph N Paulson, Ji Cheng, Grace Ku, Matthew J Matasar, Laurie H Sehn, Alex F Herrera, Christopher R Flowers, Manali K Kamdar, Andrew McMillan, Mark Hertzberg, Sarit Assouline, Tae Min Kim, Won Seog Kim, Muhit Ozcan, Jamie Hirata, Elicia Penuel, Joseph N Paulson, Ji Cheng, Grace Ku, Matthew J Matasar

Abstract

Purpose: Patients with transplantation-ineligible relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) fare poorly, with limited treatment options. The antibody-drug conjugate polatuzumab vedotin targets CD79b, a B-cell receptor component.

Methods: Safety and efficacy of polatuzumab vedotin with bendamustine and obinutuzumab (pola-BG) was evaluated in a single-arm cohort. Polatuzumab vedotin combined with bendamustine and rituximab (pola-BR) was compared with bendamustine and rituximab (BR) in a randomly assigned cohort of patients with transplantation-ineligible R/R DLBCL (primary end point: independent review committee [IRC] assessed complete response [CR] rate at the end of treatment). Duration of response, progression-free survival (PFS), and overall survival (OS) were analyzed using Kaplan-Meier and Cox regression methods.

Results: Pola-BG and pola-BR had a tolerable safety profile. The phase Ib/II pola-BG cohort (n = 27) had a CR rate of 29.6% and a median OS of 10.8 months (median follow-up, 27.0 months). In the randomly assigned cohort (n = 80; 40 per arm), pola-BR patients had a significantly higher IRC-assessed CR rate (40.0% v 17.5%; P = .026) and longer IRC-assessed PFS (median, 9.5 v 3.7 months; hazard ratio [HR], 0.36, 95% CI, 0.21 to 0.63; P < .001) and OS (median, 12.4 v 4.7 months; HR, 0.42; 95% CI, 0.24 to 0.75; P = .002; median follow-up, 22.3 months). Pola-BR patients had higher rates of grade 3-4 neutropenia (46.2% v 33.3%), anemia (28.2% v 17.9%), and thrombocytopenia (41% v 23.1%), but similar grade 3-4 infections (23.1% v 20.5%), versus the BR group. Peripheral neuropathy associated with polatuzumab vedotin (43.6% of patients) was grade 1-2 and resolved in most patients.

Conclusion: Polatuzumab vedotin combined with BR resulted in a significantly higher CR rate and reduced the risk of death by 58% compared with BR in patients with transplantation-ineligible R/R DLBCL.

Trial registration: ClinicalTrials.gov NCT02257567.

Figures

FIG 1.
FIG 1.
(A) Study schema. (B) CONSORT diagram for randomly assigned cohort. BG, bendamustine-obinutuzumab; BR, bendamustine-rituximab; DLBCL, diffuse large B-cell lymphoma; DOR, duration of response; mo, month; pola, polatuzumab vedotin; pola-BG, polatuzumab vedotin combined with bendamustine-obinutuzumab; pola-BR, polatuzumab vedotin combined with bendamustine-rituximab; R/R, relapsed/refractory.
FIG 2.
FIG 2.
(A) Progression-free survival by independent review committee. (B) Progression-free survival by investigator. (C) Overall survival of polatuzumab vedotin combined with bendamustine-rituximab (pola-BR) compared with bendamustine-rituximab (BR). (D) Forest plot of overall survival according to clinical and biologic characteristics. Values are based on an unstratified analysis. WHO classification was by central pathology review that incorporated results from NanoString Technologies for cell-of-origin determination when available. ABC, activated B-cell–like; DLBCL, diffuse large B-cell lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; GCB, germinal center B-cell–like; IPI, International Prognostic Index; ph, phase; ref, refractory; yr, year.
FIG A1.
FIG A1.
Forest plot for progression-free survival by (A) investigator and (B) independent review committee (IRC) in patients treated with polatuzumab vedotin combined with bendamustine-rituximab (pola-BR) or bendamustine-rituximab (BR). ABC, activated B-cell–like; DLBCL, diffuse B-cell lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; GCB, germinal center B-cell; IPI, International Prognostic Index; ph, phase; ref, refractory.
FIG A2.
FIG A2.
CD79b gene expression. Of the 3 samples with undetectable CD79b by immunohistochemistry (IHC), parallel RNA assessments showed measurable expression significantly above background levels inconsistent with the IHC data. Each point represents an individual sample or negative control probes. Gene expression levels are median normalized as defaulted in the NanostringQCPro Bioconductor R-package.
FIG A3.
FIG A3.
CD79b protein expression (immunohistochemistry [IHC] H-scores) in patients with relapsed/refractory diffuse large B-cell lymphoma treated with polatuzumab vedotin–based therapy relative to responses at end of treatment (independent review committee [IRC] assessed). There was no significant difference in expression between responders and nonresponders (P = .69; Wilcoxon rank-sum test with continuity correction). CR, complete response; PD, progressive disease; PET, positron emission tomography; PR, partial response; SD, stable disease.
FIG A4.
FIG A4.
Polatuzumab vedotin (pola) treatment effect as seen across the range of CD79b expression for investigator-assessed progression-free survival (PFS). Subgroup Treatment Effect Pattern (STEP) plot for the phase II patients with relapsed/refractory diffuse large B-cell lymphoma comparing pola-bendamustine and rituximab with bendamustine and rituximab shows that there was no association between CD79b expression and pola treatment effect. The STEP plot shows the hazard ratios and 95% CIs from overlapping subpopulations of patients grouped by a sliding window of CD79b immunohistochemistry H-score values for investigator-assessed PFS. The result was robust to different draws (data not shown).
FIG A5.
FIG A5.
Polatuzumab vedotin (pola) treatment effect as seen across the range of CD79b expression for overall survival (OS). Subgroup Treatment Effect Pattern (STEP) plot for the phase II patients with relapsed/refractory diffuse large B-cell lymphoma comparing pola-bendamustine and rituximab with bendamustine and rituximab. It shows hazard ratios (HRs) and 95% CIs from overlapping subpopulations of patients grouped by a sliding window of CD79b immunohistochemistry H-score values for OS. In the STEP plot, we see a consistent HR that has natural variability around the “overall” HR of 0.43 in the biomarker-evaluable population. The result was robust to different draws (data not shown).
FIG A6.
FIG A6.
(A) Progression-free survival (PFS) by investigator (INV) and (B) overall survival (OS) in patients with activated B-cell–like (ABC) and germinal center B-cell–like (GCB) diffuse large B-cell lymphoma. BR, bendamustine-rituximab; HR, hazard ratio; NE, not estimable; pola-BR, polatuzumab vedotin combined with bendamustine-rituximab.
FIG A7.
FIG A7.
(A) Progression-free survival (PFS) by investigator (INV) and (B) overall survival (OS) in patients with double-expressor lymphoma (DEL) and non-DEL diffuse large B-cell lymphoma. BR, bendamustine-rituximab; HR, hazard ratio; pola-BR, polatuzumab vedotin combined with bendamustine-rituximab.

References

    1. Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin’s lymphomas: Clinical features of the major histologic subtypes. Non-Hodgkin’s Lymphoma Classification Project. J Clin Oncol. 1998;16:2780–2795.
    1. Swerdlow SH, Campo E, Harris NL, et al: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Volume 2 (rev ed 4). Lyon, France, International Agency for Research on Cancer, 2017.
    1. Vitolo U, Trněný M, Belada D, et al. Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma. J Clin Oncol. 2017;35:3529–3537.
    1. Coiffier B, Lepage E, Brière J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235–242.
    1. Scott DW, Mottok A, Ennishi D, et al. Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fix paraffin-embedded tissue biopsies. J Clin Oncol. 2015;33:2848–2856.
    1. Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30:3452–3459.
    1. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28:4184–4190.
    1. Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: Results from the international SCHOLAR-1 study. Blood. 2017;130:1800–1808.
    1. National Comprehensive Cancer Network: NCCN guidelines for diffuse large B-cell lymphoma. .
    1. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531–2544.
    1. Schuster SJ, Bishop MR, Tam CS, et al. Primary analysis of JULIET: A global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. Blood. 2017;130:577.
    1. Okazaki M, Luo Y, Han T, et al. Three new monoclonal antibodies that define a unique antigen associated with prolymphocytic leukemia/non-Hodgkin’s lymphoma and are effectively internalized after binding to the cell surface antigen. Blood. 1993;81:84–94.
    1. Bai RL, Pettit GR, Hamel E. Binding of dolastatin 10 to tubulin at a distinct site for peptide antimitotic agents near the exchangeable nucleotide and vinca alkaloid sites. J Biol Chem. 1990;265:17141–17149.
    1. Dornan D, Bennett F, Chen Y, et al. Therapeutic potential of an anti-CD79b antibody-drug conjugate, anti-CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma. Blood. 2009;114:2721–2729.
    1. Pfeifer M, Zheng B, Erdmann T, et al. Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes. Leukemia. 2015;29:1578–1586.
    1. Palanca-Wessels MCA, Czuczman M, Salles G, et al. Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: A phase 1 study. Lancet Oncol. 2015;16:704–715.
    1. Morschhauser F, Flinn IW, Advani R, et al. Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS) Lancet Haematol. 2019;6:254–265.
    1. Ohmachi K, Niitsu N, Uchida T, et al. Multicenter phase II study of bendamustine plus rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2013;31:2103–2109.
    1. Vacirca JL, Acs PI, Tabbara IA, et al. Bendamustine combined with rituximab for patients with relapsed or refractory diffuse large B cell lymphoma. Ann Hematol. 2014;93:403–409.
    1. Mössner E, Brünker P, Moser S, et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood. 2010;115:4393–4402.
    1. Herter S, Herting F, Mundigl O, et al. Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models. Mol Cancer Ther. 2013;12:2031–2042.
    1. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano classification. J Clin Oncol. 2014;32:3059–3068.

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