Polatuzumab Vedotin Plus Bendamustine and Rituximab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Updated Results of a Phase Ib/II Randomized Study and Preliminary Results of a Single-Arm Extension

Introduction:

Polatuzumab vedotin (Pola) is a novel antibody-drug conjugate targeting CD79b on B-cell non-Hodgkin lymphoma. In the randomized cohort of GO29365, a Phase [Ph] Ib/II study (NCT02257567; data cut-off: April 30, 2018), Pola plus bendamustine and rituximab (Pola+BR) improved progression-free survival (PFS) and overall survival (OS) compared with BR alone in patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). The study met its primary endpoint, with an independent review committee (IRC)-assessed complete response (CR) rate of 40.0% with Pola+BR vs 17.5% with BR. These results led to regulatory approvals of Pola+BR for the treatment of pts with R/R DLBCL. The study was later amended to include a single-arm Ph II extension (Ext) cohort of additional pts who received Pola+BR. Here, we report updated results from the GO29365 study, including the Ph Ib safety run-in cohort, Ph II randomized arms, and previously unpublished results from the Ext cohort.

Methods:

This open-label study enrolled pts with R/R DLBCL (aged ≥18 years, stem cell transplant [SCT]-ineligible, ECOG performance status of 0–2). Pts with Grade [Gr] >1 peripheral neuropathy [PN] were excluded. In the initial study, Pola+BR was investigated in DLBCL in a Ph Ib safety run-in cohort (Pola+BR; N=6) and Ph II randomized arms (Pola+BR vs BR; N=80); full methods were previously described (Sehn et al. J Clin Oncol 2020). Pts in the Ext cohort received Pola+BR with the same dosing regimen (Pola 1.8mg/kg IV with each cycle of BR). The primary endpoint was IRC-assessed CR at primary response assessment [PRA] by PET-CT (modified Lugano criteria). Secondary endpoints included objective response rate (ORR), best objective response (BOR), OS, PFS, duration of response (DOR), and safety.

Results:

As of January 2, 2020, median follow-up for pts treated with Pola+BR was 56.1 mo in the safety run-in cohort (N=6), 42.9 mo in the randomized arm (N=40), and 9.7 mo for the Ext cohort (N=106). Baseline characteristics (Table 1) were largely similar between the randomized Pola+BR arm and the Ext cohort. Updated survival data from the randomized cohort (Pola+BR vs BR) showed the median IRC-assessed PFS (95% confidence interval [CI]) was 9.2 (6.0–13.0) vs 3.7 (2.1–4.5) mo (hazard ratio [HR] 0.4; 95% CI: 0.2–0.7); median OS (95% CI) was 12.4 (9.0–32.0) vs 4.7 (3.7–8.3) mo (HR 0.4; 95% CI: 0.2–0.7), respectively (Figure). In the Pola+BR arm, 6 pts (15%) had an IRC-assessed DOR of >24 mo (range: 26.6–38.6 mo) at last follow-up; 5 pts received no new treatment, 1 pt underwent an allogeneic SCT.

In the Ext cohort (N=106), the primary endpoint of IRC-assessed PET-CR at PRA was 39.6% (n=42; 95% CI: 30.3–49.6) (Table 2), consistent with that observed in the randomized Pola+BR arm (16/40; 40.0%). The BOR rate was 56.6% and best CR rate was 52.8%. The median (95% CI) IRC-assessed PFS and OS were 6.1 (5.1–8.0) and 11.0 (8.3–14.2) mo, respectively; however, OS was not fully mature. An exploratory subgroup analysis of all Pola+BR-treated pts (N=152) showed differences in median (m) PFS and OS between: pts who were primary refractory (n=97) vs non-primary refractory (n=55) (mPFS: 4.8 vs 12.6 mo; mOS: 7.8 vs 32 mo); pts who were refractory to last treatment (n=116) vs pts who were not (n=36) (mPFS: 5.3 vs 14.2 mo; mOS: 9.1 mo vs not reached); and pts who had received 1 (n=50) vs ≥2 (n=102) prior lines of therapy (mPFS: 10.4 vs 6 mo; mOS: 14 vs 9.5 mo).

There were no new safety signals with Pola+BR. A safety analysis of all pts who received Pola+BR in the safety run-in, randomized and Ext cohorts (N=151) showed that 121 (80.1%) pts had Gr 3–4 adverse events (AEs), 84 (55.6%) had serious AEs, most commonly infections, febrile neutropenia, and pyrexia, and 18 (11.9%) had Gr 5 AEs, which were primarily infections. PN events of any grade were reported in 46 (30.5%) pts; 3 pts experienced Gr 3 PN, 2 of which were reported as muscular weakness. Secondary malignancies were reported in 4 (2.6%) pts.

Conclusions:

With additional follow-up for the randomized arms, the significant improvement in PFS and OS seen with Pola+BR vs BR persisted. The Ext cohort of additional pts who received Pola+BR (N=106) shows overall consistent efficacy with the randomized Pola+BR arm. No new safety signals were identified with Pola+BR. These data further strengthen the evidence that Pola+BR is an effective treatment for R/R DLBCL. An updated clinical cut-off date providing more mature data will be presented.