Polatuzumab Vedotin Plus Bendamustine/Rituximab Shows Encouraging Activity in R/R DLBCL

Combining the antibody-drug conjugate polatuzumab vedotin with bendamustine (Bendeka) and rituximab (Rituxan; pola-BR) resulted in a significantly higher complete response (CR) rate in patients with transplantation-ineligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL) compared with patients who received BR alone. The international, multicenter, open-label, phase Ib/II trial (NCT02257567) also found that pola-BR reduced the risk of death by 58%, according to a recentJournal of Clinical Oncologypaper.

The CR rate for pola-BR patients was 40.0% v 17.5% for BR patients (P= .026). Pola-BR patients also experienced longer progression-free survival (PFS; median, 9.5 v 3.7 months; hazard ratio [HR], 0.36, 95% CI, 0.21 to 0.63;P< .001). With a median follow-up of 22.3 months, the same was true of overall survival (OS; median, 12.4 v 4.7 months; HR, 0.42; 95% CI, 0.24 to 0.75;P= .002).

&ldquo;All subgroups examined appeared to benefit, including refractory patients and those who received multiple prior lines of therapy,&rdquo; wrote the authors, led by Laurie H. Sehn, MD, MPH, of BC Cancer Centre for Lymphoid Cancer and The University of British Columbia in Vancouver. &ldquo;Benefit was seen regardless of age, performance status, IPI score, and the presence of bulky disease.&rdquo;

This trial also included a phase Ib safety-focused cohort of 6 patients each treated with pola-BR or the antibody-drug conjugate with bendamustine plus obinutuzumab (pola-BG). In addition to the comparative pola-BR/BR cohorts, the phase II portion also included an expansion cohort evaluating pola-BG. 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).

Eligible patients had at least 1 prior line of therapy, an ECOG performance score of 0-2, grade 1 or less peripheral neuropathy, and were considered transplantation ineligible.

All patients received bendamustine 90 mg/m²intravenously on days 2 and 3 of cycle 1 and then on the first 2 days of subsequent cycles. Depending on their randomization, patients received either rituximab IV (375 mg/m²on 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). Patients who received polatuzumab vedotin were given 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, Sehn et al reported.

The phase Ib primary endpoints were safety and tolerability. In the phase II portion, the primary endpoint was the CR rate of pola-BR versus BR, as measured by PET-CT at the end of treatment.

Total patient enrollment was 113 patients, including the 12 patients in the safety run-in cohort. The phase II pola-BG cohort enrolled 21 and treated 20 patients. For the phase II randomized cohort, 40 patients per arm were enrolled, while 39 patients per arm received treatment. Baseline characteristics of the randomly assigned patients were generally balanced, although the patients in the BR group were slightly older (median age, 71 years vs 67 years for pola-BR patients).

The authors found that the treatment completion rate was higher in the pola-BR arm than in the BR group (46.2% vs. 23.1%). This was also true of the median number of completed cycles (5 vs. 3), mainly due to a higher rate of PD in the BR arm. Significantly more patients in the pola-BR arm had treatment delays than in the BR group (53.8% vs. 38.5). Conversely, progressive disease resulted in treatment discontinuation in many more BR patients: 53.8% vs. 15.4% in the pola-BR group. Cytopenias were the most common reason for bendamustine dose reductions. Fully one-third (33.3%) of the pola-BR patients discontinued treatment due to adverse events (AEs).

Sehn et al found that, 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% vs. 20.5%; platelets: 15.4% vs. 15.4%). More pola-BR patients developed grade 3-4 neutropenia than BR patients did (42.6% vs. 33.3%). Grade 3-4 infections were comparable between groups (23.1% pola-BR; 20.5% BR).

Eleven BR patients experienced fatal AEs, while 9 pola-BR patients did. Infection was the most common cause of fatal AEs, with 4 in each group. The authors noted that many fatal AEs occurred after disease progression.

Biomarker studies suggested that pola-BR benefited patients regardless of COO or DEL status. &ldquo;Ubiquitous expression of CD79b was confirmed, with no correlation noted between CD79b expression level and response,&rdquo; Sehn et al wrote.

The authors believe that pola-BR may prove to be a valuable treatment option that is readily available to a wider population of patients than can currently benefit. &ldquo;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,&rdquo; Sehn et al wrote. &ldquo;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.&rdquo;

Reference:

Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2019;38:155-165.