FDA Grants Polatuzumab Vedotin Priority Review for DLBCL

Sandra Horning, MD

The FDA has granted a priority review designation to polatuzumab vedotin for use in combination with bendamustine and rituximab (Rituxan; BR) for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to Genentech (Roche), the manufacturer of the antibody-drug conjugate (ADC).

Genentech’s biologics license application (BLA) for polatuzumab vedotin is based on results from the phase Ib/II GO29365 study (NCT02257567), which were presented at the 2018 ASH Annual Meeting. In the study 40% of patients receiving the polatuzumab vedotin regimen reached a complete response (CR)—the primary endpoint of the study—compared with 18% of patients in the BR-alone arm (P = .026). Adding the ADC also showed an improvement in the exploratory endpoint of overall survival (OS), with a median OS of 12.4 months versus 4.7 months with BR alone (HR, 0.42; 95% CI, 0.24-0.75; P = .0023).

Under the expedited priority review, the FDA will review the BLA within 6 months from the acceptance of the filing, compared with the standard 10 months. An approval decision is scheduled to be made on or before August 19, 2019.

“Polatuzumab vedotin, a potential first-in-class antibody drug conjugate, in combination with bendamustine and Rituxan, improved clinical outcomes including survival in some people with relapsed or refractory diffuse large B-cell lymphoma compared to bendamustine and Rituxan alone,” Sandra Horning, MD, chief medical officer and head of Global Product Development, Roche, said in a press release. “We are working with the FDA to bring this important new option to patients with this aggressive disease as quickly as possible."

Patients with relapsed/refractory DLBCL and those who are ineligible for transplant have limited treatment options and a poor prognosis. CD79b is a component of the B-cell receptor and is expressed ubiquitously in DLBCL. Polatuzumab vedotin is an anti-CD79b antibody linked to microtubule-disrupting monomethyl auristatin E.

Preliminary results from the phase Ib part of the trial provided evidence of the ADC’s safety and efficacy in safety run-in, expansion, and randomized cohorts, which were reported prior to the 2018 ASH meeting. The data presented at ASH included 6 patients from the safety cohort, 27 from the expansion phase, and 80 from the randomized comparison of bendamustine-rituximab with or without polatuzumab vedotin.

The median age across the cohorts ranged from 65 to 71, and from two-thirds to three-fourths of the patients in each cohort had received 2 or more prior lines of therapy. Additionally, 20% of the patients in the randomized study had undergone a transplant.

The primary endpoint of CR was determined by independent review of PET—CT imaging at the end of treatment. Secondary endpoints included duration of response (DOR) and progression-free survival (PFS) by independent review. Exploratory endpoints included DOR and PFS by investigator review, OS, and efficacy by cell of origin and MYC/BCL2 double-expression (DE) status.

Median follow-up was 37.6 months for the safety cohort, 27.0 months for the expansion cohort, and 22.3 months for the randomized comparison.

Three of 6 patients in the safety cohort attained CR with the polatuzumab vedotin-bendamustine-rituximab regimen. DOR, PFS, and OS could not be determined.

In the expansion cohort, 11 patients (41%) had objective responses by independent review. Median DOR, median PFS, and OS were 28.4 months, 5.4 months, and 10.8 months, respectively.

In the randomized, phase II component of the evaluation, 16 (40%) patients had CRs in the polatuzumab-vedotin arm as compared with 7 (18%) patients who received bendamustine-rituximab without the ADC (P = .026). Median DOR by independent review had yet to be reached in the polatuzumab-vedotin arm as compared with 7.7 months in the control arm (HR, 0.40; 95% CI, 0.16-1.101; P = .0462). By investigator assessment, median DOR was 10.3 months with polatuzumab-vedotin versus 4.1 months without (HR, 0.44; 95% CI, 0.20-0.95; P =.0321).

Median PFS by independent review was 11.1 months with the ADC and 3.7 months without (HR, 0.36; 95% CI, 0.21-0.63; P = .0002). By investigator assessment, the median values were 7.6 versus 2.0 months without (HR, 0.34; 0.20-0.57; P <.0001).

Analyses by cell of origin—activated B-cell like (ABC) or germinal B-cell like (GCB)&mdash;showed consistent advantages for the addition of polatuzumab vedotin. Median PFS by investigator assessment and OS in the ABC subgroup were 10.8 months and 15.4 months, respectively, versus 2.0 and 4.7 months without polatuzumab vedotin. The GBC subgroup had inferior outcomes but still favored the ADC: 2.5 versus 1.9 months for median PFS and 7.2 versus 3.8 months for OS.

Analysis by DE status showed median PFS of 7.0 versus 1.4 months for the polatuzumab-vedotin group among patients with DE and 6.2 versus 3.1 months for those without. OS was 8.9 versus 4.6 months for the DE subgroup and 10.0 versus 4.5 months for patients without DE.

With continued follow-up, no new safety signals emerged, and the safety data remained consistent with initial reports from the study. The most common grade 3/4 adverse events overall were infections and cytopenias. While infection and transfusion rates were similar with BR alone or the addition of polatuzumab vedotin, the rates of grade 3/4 cytopenias were higher in the ADC arm.

Sehn LH, Herrera AF, Matasar M, et al. Polatuzumab vedotin (pola) plus bendamustine (B) with rituximab (R) or obinutuzumab (G) in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): updated results of a phase (Ph) Ib/II study. Poster presented at: 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. P1683.