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

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.

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.

(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.

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.

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.

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.

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.

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.

(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.

(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.