Polatuzumab Vedotin Plus BR Demonstrates Higher PET-CR in DLBCL

Laurie H. Sehn, MD

The addition of polatuzumab vedotin to bendamustine and rituximab (Rituxan; BR) induced a higher rate of complete responses by PET scan (PET-CR) compared with BR alone in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to phase II findings presented by Laurie H. Sehn, MD, during the 2018 European Hematology Association Congress.

Of the 80 patients who received polatuzumab vedotin with BR, 40% achieved a PET-CR. This is in comparison to a 15% CR rate in the 80 patients who received BR alone. The primary endpoint of CR rate determined by PET scan at the end of treatment was met.

Additionally, the 3-drug regimen demonstrated a longer progression-free survival (PFS) and overall survival (OS) versus BR alone. The median PFS for the 3-drug combination was 6.7 months versus 2 months for BR, and the median OS was 11.8 and 4.7 months, respectively.

“Thus far, this is the only head-to-head comparison of a novel targeted agent against the standard therapy in this patient population that is ineligible for stem cell transplant. It demonstrated that the combination of polatuzumab vedotin with BR significantly improved the response rates, PFS, and OS,” said Sehn, a medical oncologist at the BC Cancer Agency, and clinical associate professor at the University of British Columbia. “Based on these encouraging results, this drug has been granted breakthrough therapy designation by the FDA, as well as prime designation by the [European Medicines Agency]. It will be explored further in other combinations and ongoing studies.”

This trial enrolled 160 patients with DLBCL and follicular lymphoma and randomized them 1:1 to polatuzumab vedotin at 1.8 mg/kg plus BR (B: 90 mg/m² twice daily and R: 375 mg/m²) or BR for 6 cycles.

While DLBCL is curable in a large number of patients via upfront therapy of chemoimmunotherapy or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), about 40% of patients either will not respond to initial therapy or will ultimately relapse. According to Sehn, this signaled a need to develop new therapies for the relapsed/refractory population.

"Many of these patients are considered for high-dose chemotherapy and a stem cell transplant as a potential next curative intent. Unfortunately, many patients are not eligible for transplant due to age or comorbidities,” explained Sehn. “The treatment options for these transplant-ineligible patients, or patients who relapse after transplant, are really limited.”

Generally, survival for these patients is short, and the responses to therapy worsens with multiple relapses. This led to investigators seeking out new and better treatment options for this population, Sehn said.

The PET-CR was similar between combination and BR monotherapy arms in the follicular lymphoma cohort (69% vs 63%). Moreover, the median PFS and OS was 17 and 17.3 months, respectively; the median OS was not reached.

Polatuzumab vedotin is a novel, first-in-class anti-CD79b antibody-drug conjugate (ADC) that targets cells that express CD79b. CD79b is a protein that is present on the surface of many B cells. It is typically universally expressed in DLBCL, as well as in follicular lymphoma.

“This ADC is essentially an antibody targeting CD79b, so it specifically seeks out the tumor target,” explained Sehn. “It’s attached to a toxin, and when it attaches to the tumor cell, it actually gets absorbed into the tumor cell and the toxin is selectively released into the tumor. It is a way of specifically delivering the toxin to the tumor cell while trying to protect the normal body cells.”

Grade 3/4 adverse events (AEs) of cytopenia, febrile neutropenia, and infections were higher in the polatuzumab vedotin arm in both the DLBCL and follicular lymphoma cohorts. Although, this did not translate into a higher rate of grade ≥3 infection. Serious AEs were similar between the 2 arms.

“Nothing is without side effects. In terms of the safety, importantly, in the combination there were no unexpected toxicities, so it was typical to what we would expect with what is known with this drug alone and BR alone,” Sehn said.

Sehn reported that there were an equal number of deaths in both arms of the study, but they were deemed to be non-treatment related.

Polatuzumab vedotin, which was granted a breakthrough therapy designation by the FDA and PRIME status by the EMA in 2017, continues to be investigated in the phase III, randomized, multicenter POLARIX clinical trial (NCT03274492). This trial is evaluating the drug in combination with R-CHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) versus R-CHOP for patients with DLBCL in the first-line setting. POLARIX aims to evaluate this novel combination, which investigators believe may improve on outcomes compared with R-CHOP.

Sehn LH, Kamdar M, Herrara AF, et al. Adding polatuzumab vedotin to bendamustine and rituximab treatment improves survival in patients with relapsed/refractory ALBCL: results of a phase 2 clinical trial. In: Proceedings from the 2018 EHA Congress; June 14-17, 2018; Stockholm, Sweden. Abstract S802.

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