Obinutuzumab Falls Short in Phase III DLBCL Trial

Sandra Horning, MD

Adding the anti-CD20 agent obinutuzumab (Gazyva) to CHOP chemotherapy (G-CHOP) in the frontline setting did not improve progression-free survival (PFS) compared with the standard regimen of rituximab (Rituxan) plus CHOP (R-CHOP) in patients with diffuse large B-cell lymphoma (DLBCL), according to results from the phase III GOYA trial.

The safety profiles for obinutuzumab and rituximab were similar to previously reported adverse event (AE) data for the 2 agents, according to Genentech, the manufacturer of both drugs. Complete data from the GOYA study will be presented at an upcoming scientific meeting, the company reported.

“Two previous studies showed Gazyva helped people with previously untreated follicular lymphoma or chronic lymphocytic leukemia live longer without their disease worsening compared to Rituxan, when each was combined with chemotherapy. We were hopeful we could show a similar result for people with diffuse large B-cell lymphoma and once again improve on the standard of care,” Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech, said in statement. “We will continue to analyze the GOYA data to better understand the results, and to study other investigational treatments in this disease with the goal of further helping these patients.”

The multicenter, open-label, GOYA trial (NCT01287741) randomized 1418 treatment-naïve patients with CD20-positive DLBCL to either G-CHOP or R-CHOP. The primary endpoint of the trial was investigator-assessed PFS. Secondary outcome measures included overall survival, overall response rate, disease-free survival, and safety.

The first study to directly compare obinutuzumab with rituximab was the CLL11 trial, in which obinutuzumab plus chlorambucil reduced the risk of disease progression by 58% compared with rituximab plus chlorambucil in previously untreated patients with chronic lymphocytic leukemia (CLL; HR, 0.42; 95% CI, 0.33-0.54; P <.0001). Among patients in the obinutuzumab arm, the most common AEs were infusion reactions, low white blood cell counts, low platelet counts, low red blood cell counts, fever, cough, nausea, and diarrhea.

Based on data from the CLL11 trial the FDA approved obinutuzumab plus chlorambucil in November 2013 as a first-line treatment for patients with CLL.

The phase III GALLIUM study in follicular lymphoma was the second trial to show superior PFS outcomes with frontline obinutuzumab plus chemotherapy versus rituximab plus chemotherapy.

The international phase III GALLIUM study included 1401 treatment-naive patients with indolent non-Hodgkin lymphoma, of whom 1202 patients had follicular lymphoma. Patients were randomized to obinutuzumab plus chemotherapy, followed by obinutuzumab alone (up to 2 years), or rituximab plus chemotherapy, followed by rituximab alone (up to 2 years). The chemotherapy regimens used were CHOP, CVP, or bendamustine, based on the discretion of the physicians at each study location.

When the positive GALLIUM results were announced in May 2016, Genentech reported that the data would be presented at an upcoming medical meeting and that the company would enter discussions with regulatory authorities about a new indication for obinutuzumab.

In February 2016, the FDA approved obinutuzumab plus bendamustine followed by obinutuzumab alone for the treatment of patients who relapse after, or are refractory to, a rituximab-containing regimen.

The approval was based on the phase III GADOLIN study, in which obinutuzumab plus bendamustine followed by obinutuzumab monotherapy reduced the risk of disease progression by 52% compared with bendamustine alone (HR, 0.48; 95% CI 0.34-0.68; P <.0001) in patients with follicular lymphoma who progressed on rituximab-based therapy.

Obinutuzumab is a glycoengineered antibody against CD20. Through the glycoengineering process, sugar molecules are removed from immune-effector antibody cells in the posttranslational setting, significantly impacting antigen binding and function. Specifically, obinutuzumab is designed to lack fucose molecules.