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

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.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Diffuse large B-cell lymphoma (DLBCL) represents approximately 25% of all newly diagnosed patients with non-Hodgkin lymphoma.[1,2] Although DLBCL is often curable, 30%-40% of patients are refractory to, or relapse after treatment with, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemo-immunotherapy, the current standard of care.[3,4] Higher treatment failure rates are observed in poor-risk subgroups, including activated B-cell–like (ABC) and MYC/BCL2 double-expressor lymphomas (DEL).[5,6]

Platinum-based salvage therapy followed by high-dose chemotherapy and autologous stem-cell transplantation (ASCT) can cure 30%-40% of patients with relapsed/refractory (R/R) disease able to undergo this therapy.[7,8] However, prognosis is poor for most patients with R/R DLBCL who are ineligible for ASCT because of age, comorbidity, or inadequate response to salvage chemotherapy and for those who relapse after ASCT, with a median overall survival (OS) of approximately 6 months.[8] Currently, there is no standard of care in this setting, and treatment options include gemcitabine and/or platinum-based therapies, as well as bendamustine and rituximab (BR).[9] Recently, CD19-directed chimeric antigen receptor (CAR) T-cell therapy was approved for use in the third-line or later setting in the United States and Europe.[10,11] Although CAR T-cell therapy appears promising, generalized use is restricted by lack of effective bridging therapies, treatment toxicity, and limited access because of high cost and need for specialized centers. Therefore, significant unmet medical need remains for patients with transplantation-ineligible R/R DLBCL, including those who experienced ASCT treatment failure.

Polatuzumab vedotin is a CD79b-targeted antibody-drug conjugate delivering monomethyl auristatin E (MMAE), a microtubule inhibitor.[12,13] CD79b is a signaling component of the B-cell receptor located on normal B cells and most mature B-cell malignancies, including > 95% of DLBCL.[14,15] Polatuzumab vedotin demonstrated encouraging activity in R/R DLBCL as monotherapy[16] and combined with an anti-CD20 monoclonal antibody,[17] yielding overall response rates (ORRs) of 13%-56%. However, complete response (CR) rates are low (0%-15%), prompting combination with additional agents. BR has been evaluated in patients with transplantation-ineligible R/R DLBCL, with median progression-free survival (PFS) of 3.6-6.7 months.[18,19] Given the limited treatment options in this setting, combining polatuzumab vedotin with BR (pola-BR) was considered rational and avoided the risk of overlapping neurotoxicity that could occur with platinum-based regimens. Obinutuzumab, an alternative CD20-targeted agent designed to promote greater antibody-dependent cellular cytotoxicity and increased direct B-cell death compared with rituximab,[20,21] was considered a promising agent to evaluate in combination with polatuzumab vedotin and bendamustine. However, this trial was designed before availability of GOYA trial (ClinicalTrials.gov identifier: NCT01287741) results, when obinutuzumab combinations in DLBCL were of greater interest.[3]

We report a phase Ib/II trial evaluating polatuzumab vedotin combined with bendamustine and obinutuzumab (pola-BG), and of pola-BR versus BR alone, in transplantation-ineligible R/R DLBCL, including patients who experienced treatment failure with prior ASCT. Results from a cohort of patients with follicular lymphoma (FL) will be reported separately.

METHODS

Trial Conduct

This international, multicenter, open-label, phase Ib/II trial (GO29365; ClinicalTrials.gov identifier: NCT02257567), approved by the institutional review board at each participating site, was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation guidelines for Good Clinical Practice. All patients provided written informed consent.

The study was designed with input from investigators and sponsored by Genentech and F. Hoffmann-La Roche. All authors reviewed the data, vouch for the completeness and accuracy of the results and the trial’s fidelity to the Protocol, reviewed the manuscript, and agreed on its submission for publication. Editorial support was funded by F. Hoffmann-La Roche.

Patients

Patients aged ≥ 18 years were eligible if they had biopsy-confirmed R/R DLBCL (excluding transformed lymphoma) after ≥ 1 prior line of therapy, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, grade ≤ 1 peripheral neuropathy (PN), and were considered transplantation ineligible by the treating physician or experienced treatment failure with prior ASCT. Double- and triple-hit lymphomas were not excluded. Complete eligibility and exclusion criteria are available in the Protocol.

Trial Design

The phase Ib safety run-in included 6 pola-BR–treated patients and 6 pola-BG–treated patients (Fig 1A). The phase II portion included an expansion cohort evaluating pola-BG (21 patients) and a randomly assigned cohort (80 patients: 40 per treatment arm) comparing pola-BR with BR alone, stratified by duration of response (DOR) to last prior therapy (≤ 12 months v > 12 months; Fig 1A). Cohorts treated with pola-BG in the safety and expansion phases were combined.

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.

All patients received bendamustine 90 mg/m2 intravenously (IV) on days 2 and 3 of cycle 1 and then days 1 and 2 of subsequent cycles, and either rituximab IV (375 mg/m2 on day 1 of each cycle) or obinutuzumab IV (1,000 mg on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles). Those treated with polatuzumab vedotin received 1.8 mg/kg IV on day 2 of cycle 1 and day 1 of subsequent cycles. Patients were treated for up to six 21-day cycles.

Assessments and End Points

Primary end points were safety and tolerability (phase Ib) and CR rate of pola-BR versus BR (phase II), as measured by [18F]fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) using modified Lugano Response Criteria[22] (Appendix, online only) at the end of treatment (EOT; 6-8 weeks after cycle 6 day 1 or last dose of study treatment) by an independent review committee (IRC). If no scans were performed, the IRC considered the patient missing or unevaluable and he or she was treated as a nonresponder. Secondary end points included ORR at EOT, best overall response, DOR, and PFS as assessed by the IRC. Exploratory end points included biomarker evaluation of efficacy by cell of origin (COO), determined by either NanoString (NanoString Technologies, Seattle, WA) or Hans criteria, and immunohistochemical staining for DEL, investigator-assessed (INV) DOR and PFS, and OS.

Responses were assessed by CT, PET-CT, and bone marrow examination (if required to confirm CR) after 3 cycles (interim) and at EOT (primary response assessment). Follow-up CT scans were performed every 6 months for 2 years or until progressive disease (PD) or patient withdrawal.

The National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03) was used to assess and grade all adverse events (AEs) throughout the study. All AEs, including serious AEs (SAEs), were reported from cycle 1 day 1 until 90 days after last dose of study drug, regardless of relationship to treatment. All SAEs were reported indefinitely.

Biomarkers

Methodology for exploratory biomarker evaluation of CD79b expression, COO, and DEL is described in the Appendix.

Statistical Analysis

A sample size of 12 patients was planned for the phase Ib safety run-in portion (6 pola-BR; 6 pola-BG). The study could proceed to phase II if < 33.3% of patients in each cohort experienced safety events. The sample size of the phase II randomly assigned cohort was determined based on an assumed 25% difference in CR rate from 40% in BR to 65% in pola-BR, allowing exclusion of zero as the lower boundary of the 95% exact Clopper–Pearson CI of the difference in CR rate (CI, 3.8% to 46.2%), with a margin of error not exceeding ± 17%. For the phase II safety assessment, the sample size of 20 patients in the expansion arm and 40 patients in each of the randomized arms provided a ≥ 85% likelihood of observing ≥ 1 AE based on true incidence rates of 10% and 5%, respectively.

The safety-evaluable population comprised patients who received ≥ 1 dose of any study treatment. Efficacy analyses were performed based on the intent-to-treat principle (ie, all randomly assigned patients were analyzed according to their treatment assignment at the time of randomization or at study entry for nonrandomly assigned patients). The intent-to-treat population included all patients with DLBCL by investigator/site pathology. Additional efficacy analyses were conducted for the population of patients with DLBCL according to central pathology review (performed retrospectively to classify patients by WHO 2016 criteria) who received ≥ 1 dose of any study treatment.

Response rates were reported as percentages with associated 95% Clopper–Pearson (ie, exact binomial) CIs. Time-to-event end points, including DOR, PFS, and OS, were summarized as median survival time estimated using Kaplan–Meier methodology with 95% Greenwood’s CIs. Differences in response rate and time-to-event end points between the pola-BR and BR arms were compared for exploratory purposes and reported as absolute differences and hazard ratios (HRs) using stratified Wilson and Cox regression methods, respectively. Multiple Cox regression analyses were conducted for OS and PFS, adjusting for potential prognostic factors and baseline characteristics (Ann Arbor stage, ECOG performance status, and bulky disease for OS; Ann Arbor stage and ECOG performance status for PFS; and International Prognostic Index [IPI] score for both OS and PFS). All reported P values are 2 sided.

RESULTS

Between October 15, 2014, and June 10, 2016, 113 patients with transplantation-ineligible R/R DLBCL were enrolled. The safety run-in included 12 patients (6 pola-BR; 6 pola-BG). The phase II pola-BG cohort enrolled 21 and treated 20 patients. For the phase II randomly assigned cohort, 40 patients per arm were enrolled, and 39 patients per arm were treated (Fig 1B). Demographics and disease characteristics are shown in Table 1. Although patients receiving BR were slightly older (median age, 71 years v 67 years), baseline characteristics of the randomly assigned patients were generally balanced. The median number of prior lines of therapy was 2, with most patients refractory to the last treatment (75% pola-BR; 85% BR).

TABLE 1.

Baseline Characteristics

Two patients in the intent-to-treat randomly assigned cohort were determined by central pathology review to have FL and Burkitt’s lymphoma. By investigator and site pathology, all patients had a DLBCL diagnosis. No double-/triple-hit lymphomas were confirmed by central pathology.

Efficacy

Response rates at EOT and median time-to-event end points are shown in Table 2. In the phase Ib pola-BR arm, EOT IRC-assessed CR rate was 50% (3/6), with all 3 patients remaining in remission at a median follow-up of 37.6 months (DOR, > 28.9 to ≥ 38.2 months). One nonresponder received subsequent therapy and remained alive at the time of data cutoff; 2 died as a result of PD. In the combined phase Ib/II pola-BG cohort, the EOT IRC-assessed CR rate was 29.6%. At a median follow-up of 27.0 months, median PFS (IRC) and OS were 6.3 and 10.8 months, respectively. Two patients proceeded to consolidative stem-cell transplantation (SCT; 1 autologous and 1 allogeneic). Four patients (15%) had documented responses lasting at least 20 months (range, > 20.7 to ≥ 22.5 months) without additional therapy. At last follow-up, 8 patients remained alive, 17 had died (12 PD; 5 AEs), and 2 discontinued the study (1 physician decision; 1 AE).

TABLE 2.

Summary of Efficacy Outcomes

The primary analysis for the randomly assigned cohort showed significantly higher IRC-assessed CR rates at EOT with pola-BR versus BR (40.0% v 17.5%; P = .026; Table 2), with > 90% concordance between the IRC and investigator. Best OR and CR rates were also higher with pola-BR versus BR (Table 2). Discrepancies in PD assessments between the IRC and the investigator were mainly due to INV assessment of clinical progression without confirmatory scans, which were required for IRC assessment. Such patients were considered missing/not evaluable by the IRC (Appendix Table A1, online only).

TABLE A1.

Reasons for “Not Evaluable” at EOT

After a median follow-up of 22.3 months, PFS (Figs 2A and 2B), OS (Fig 2C), and DOR were significantly improved with pola-BR versus BR. Consistent benefit in risk reduction was seen for IRC- and INV-assessed PFS (IRC: HR, 0.36; 95% CI, 0.21 to 0.63; P < .001; INV: HR, 0.34; 95% CI, 0.20 to 0.57; P < .001) and for DOR (IRC: HR, 0.47; 95% CI, 0.19 to 1.14; INV: HR, 0.44, 95% CI, 0.20 to 0.95), although IRC-assessed DOR did not reach statistical significance. IRC assessments of DOR and PFS were longer than INV assessments due primarily to a lag in obtaining confirmatory scans or not performing scans required for IRC review after INV-determined clinical progression.

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.

OS was significantly improved in the pola-BR arm, with risk of death reduced by 58% (HR, 0.42; 95% CI, 0.24 to 0.75; P = .002) and a longer median OS with pola-BR (12.4 months; 95% CI, 9.0 to not evaluable) compared with BR alone (4.7 months; 95% CI, 3.7 to 8.3 months; Fig 2C). Eleven pola-BR–treated patients and 4 BR-treated patients remained alive in follow-up. Post hoc subgroup analyses demonstrated consistent survival benefit across all clinical and biological subgroups examined (Fig 2D; Appendix Fig A1, online only). Importantly, patients benefited regardless of refractory status and number of prior lines of therapy, although sample sizes were small and statistical significance could not be established.

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.

Multiple Cox regression analyses showed that after adjusting for potential prognostic factors and baseline characteristics, the treatment effects on survival of pola-BR remained consistent with the primary analysis. For investigator-assessed PFS, the adjusted HR was between 0.34 (95% CI, 0.20 to 0.58; P < .001) and 0.38 (95% CI, 0.22 to 0.64; P < .001), whereas for IRC-assessed PFS, the adjusted HR was between 0.37 (95% CI, 0.21 to 0.66; P < .001) and 0.40 (95% CI, 0.23 to 0.70; P = .001). For OS, the adjusted HR was between 0.43 (95% CI, 0.24 to 0.78; P = .005) and 0.46 (95% CI, 0.26 to 0.82; P = .008).

Seven pola-BR patients (18%) had ongoing DOR of > 20 months (range, > 20.0 to ≥ 22.5 months) and remained in complete remission at last follow-up. One patient underwent consolidative allogeneic SCT; the other 6 received no additional therapy. Only 2 BR patients (5%) remained in follow-up without progression; both received consolidative therapy (1 allogeneic SCT and the other radiation). Overall, efficacy results for the as-treated DLBCL population (according to central pathology review, excluding the 2 patients with FL or Burkitt’s lymphoma) were similar to those of the intent-to-treat population, as summarized in Appendix Table A2 (online only).

TABLE A2.

Summary of Efficacy Outcomes in the As-Treated DLBCL Population (according to central pathology review)

Safety

In the phase Ib pola-BR and phase Ib/II pola-BG cohorts, treatment delivery and AEs were similar to the phase II randomized pola-BR arm (Appendix). Among randomly assigned patients, the treatment completion rate was higher in the pola-BR arm compared with BR (46.2% v 23.1%), as was the median number of completed cycles (5 v 3), primarily due to a higher rate of PD in the BR arm. In the randomly assigned cohort, 53.8% of pola-BR patients and 38.5% of BR patients had treatment delays (Appendix Table A3, online only). PD resulted in treatment discontinuation in 53.8% and 15.4% of patients treated with BR and pola-BR, respectively. AEs were the most common reason for discontinuation of pola-BR (33.3%; Appendix Table A3). In both arms, the most common reason for bendamustine dose reduction was cytopenias (4 pola-BR; 3 BR).

TABLE A3.

Summary of Treatment Exposure (safety-evaluable population)

The most common all-grade and grade 3-4 AEs are shown in Table 3. Although rates of grade 3-4 anemia and thrombocytopenia were higher with pola-BR, transfusion rates were similar between pola-BR and BR (red cells: 25.6% v 20.5%; platelets: 15.4% v 15.4%). Grade 3-4 neutropenia was higher with pola-BR (46.2% v 33.3%), but grade 3-4 infections and infestations were similar in both arms (23.1% pola-BR; 20.5% BR). Use of granulocyte-colony stimulating factor (GCSF) was permitted per investigator’s discretion. For pola-BR versus BR, 71.8% versus 61.5% of patients received at least 1 dose of GCSF.

TABLE 3.

Adverse Events in Patients Treated With Pola-BR Compared With BR

Overall incidence of PN was 43.6% (17/39) in pola-BR patients (11 grade 1; 6 grade 2), with resolution in 10 patients and improvement in 1 patient at clinical cutoff. PN was the only reason for polatuzumab vedotin dose reduction, which occurred in 2 patients (5.1%; both grade 2 PN), and in both cases, the PN resolved.

Fatal AEs occurred in 9 pola-BR patients and 11 BR patients, with infection being the most common cause (4 pola-BR; 4 BR). Many fatal AEs occurred after PD (Appendix).

Biomarkers: CD79b, COO, and DEL

Among 83 patient samples stained, 80 (96.4%) had detectable CD79b (immunohistochemistry [IHC] H-score 1-300 or 1+-3+). RNA assessments demonstrated measurable expression of CD79b in all samples, including 3 that were negative by IHC (Appendix Fig A2, online only). No relationship was observed between levels of CD79b expression and clinical outcome for both response rate and time-to-event clinical end points, including PFS and OS (Appendix Figs A3-A5, online only).

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 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).

COO assessment was performed in 107 patient samples, with 97 evaluable. COO distribution was 46.4% ABC, 47.4% germinal center B-cell–like (GCB), and 6.2% unclassifiable. In the randomly assigned cohort, improved outcome with pola-BR was observed in both ABC and GCB subgroups (Appendix Table A4; Appendix Fig A6, online only).

TABLE A4.

Response Rates (investigator assessed) at End of Treatment, by COO

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.

DEL status was assessed in 62 patient samples, with 41.9% identified as DEL. In the randomly assigned cohort, improved outcome with pola-BR was observed in both DEL and non-DEL patients (Appendix Table A5; Appendix Fig A7, online only).

TABLE A5.

Response Rates (investigator assessed) at End of Treatment in Patients With and Without DEL Treated With Pola-BR Compared With BR

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.

DISCUSSION

Patients with transplantation-ineligible R/R DLBCL, including those who experienced treatment failure with ASCT, have dismal outcomes with limited therapeutic options. In this randomized comparison, treatment with pola-BR resulted in a significantly improved CR rate, PFS, and OS compared with BR alone. BR-treated patients fared poorly despite 13 patients receiving additional therapy after progression, highlighting the limitation of currently available agents. To our knowledge, this is the first randomized trial demonstrating an OS benefit in patients with transplantation-ineligible R/R DLBCL.

OS was significantly longer in patients receiving pola-BR compared with BR alone (median, 12.4 months v 4.7 months). All subgroups examined appeared to benefit, including refractory patients and those who received multiple prior lines of therapy. Benefit was seen regardless of age, performance status, IPI score, and the presence of bulky disease. Furthermore, biomarker studies suggest that pola-BR benefited patients regardless of COO or DEL status. Ubiquitous expression of CD79b was confirmed, with no correlation noted between CD79b expression level and response. Although the independent contribution of bendamustine to overall efficacy cannot be measured, the 40% CR rate observed with pola-BR was notably higher than the 15% reported previously with polatuzumab vedotin in combination with an anti-CD20 monoclonal antibody.[17] Achievement of CR has been associated with improved outcomes in DLBCL, and the higher CR rate observed may partly explain the durable responses seen in some patients receiving pola-BR, 7 (18%) of whom remained disease free.

The CR rate was 30% and 40% in the pola-BG and pola-BR arms, respectively. The modest number of patients in the pola-BG cohort made estimation of the true CR rate difficult; however, there was no indication of benefit of obinutuzumab over rituximab in this setting. Similarly, the GOYA trial (NCT01287741) did not demonstrate superiority of obinutuzumab over rituximab in front-line DLBCL.[3]

PN is a recognized toxicity associated with MMAE-based antibody-drug conjugates and was closely monitored during this study. Although many patients had prior exposure to vincristine or platinum agents, the majority of PN observed was low grade and reversible, requiring dose reduction or delay in relatively few patients. A higher rate of grade 3-4 cytopenias was observed with pola-BR versus BR, but this did not result in a higher risk of infection or need for transfusion.

The phase II design and modest sample size are potential limitations of the study; nonetheless, a clear and significant PFS and OS benefit was observed with pola-BR. Although this study examined pola-BR as a stand-alone therapy, the high CR rates and prolonged disease control observed suggest it may provide an important bridge to further consolidative therapies, including SCT or CAR T-cell therapy. Additional research into the feasibility and safety of this approach is warranted. CAR T-cell therapy is a promising treatment for patients with R/R DLBCL, but its generalized use has been limited by the inability to achieve timely and sufficient disease control in patients with rapidly evolving disease to enable them to proceed to CAR T-cell treatment. Availability of an effective novel agent, such as polatuzumab vedotin, may enable more patients to receive CAR T-cell therapy in the R/R setting. Conversely, not all patients with R/R DLBCL are suitable for CAR T-cell therapy because of its toxicity, including cytokine release syndrome and neurologic events, and specialized care requirements. Pola-BR may offer a valuable treatment option that is readily deliverable to a wider population of patients.

Pola-BR represents a novel, effective therapeutic regimen to address the unmet need of patients with transplantation-ineligible R/R DLBCL. Only 25% of pola-BR–treated patients had received prior ASCT; therefore, definitive conclusions on this combination’s efficacy in the post-ASCT setting cannot currently be determined. Additional evaluation of polatuzumab vedotin with other agents in the R/R setting is ongoing, as is a phase III trial evaluating the substitution of polatuzumab vedotin for vincristine in R-CHOP for patients with untreated DLBCL (POLARIX; ClinicalTrials.gov identifier: NCT03274492).