Kate Johnson

June 05, 2015

CHICAGO — The new anti-CD20 antibody obinutuzumab (Gazyva, Genentech, Inc) produced results described as "remarkable" in patients with indolent non-Hodgkin lymphoma (NHL) who were refractory to the older anti-CDA20 product rituximab (Rituxan, Genentech/Roche).

Obinutuzumab was added to the standard of care in such patients, which is chemotherapy with bendamustine (Treanda, Cephalon, Inc), and it more than doubled the rate of progression-free survival (PFS) compared with bendamustine alone.

The phase 3 GADOLIN study is "remarkable" in that "it is the first randomized evidence of a clinical benefit" of the anti-CD20 monoclonal antibody for such patients, said investigator Laurie Helen Sehn, MD, MPH, a medical oncologist at the BC Cancer Agency, in Vancouver, Canada, during a press conference at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting.

"Based on the study results, we would conclude that... [obinutuzumab] represents a novel and effective treatment for patients with relapsed, refractory, indolent non-Hodgkin lymphoma who are refractory to rituximab," she said.

The trial was stopped early after a planned interim analysis showed efficacy.

This approach stalled cancer progression by more than a year. Dr Merry-Jennifer Markham

"It's encouraging to see such impressive results for a novel anti-CD20 monoclonal antibody in a difficult-to-treat patient population such as those with rituximab-refractory indolent non- Hodgkin lymphoma," said ASCO expert Merry-Jennifer Markham, MD, a hematologist/oncologist from the University of Florida, in Gainesville. "The fact that this approach stalled cancer progression by more than a year will be good news to patients, who urgently need additional treatment options."

Indolent NHL "continues to be incurable with standard available therapies," said Dr Sehn. The addition of rituximab to chemotherapy has resulted in a significant improvement in both PFS and overall survival. However, patients who are refractory to rituximab "have a relatively poor outcome and limited treatment options," she said. With bendamustine therapy, remission duration is short, only 7 to 9 months.

Obinutuzumab is engineered to have "potentially higher efficacy" than rituximab and "has been shown to induce a higher rate of direct cell death as well as a higher cellular immune response against lymphoma cells," she explained.

Lymphoma is a potential new indication of the drug, which is currently marketed for chronic lymphocytic leukemia.

Study Details

The GADOLIN trial included 413 NHL patients (80% with follicular lymphoma subtype; median age, 63 years) who were randomly assigned to receive standard chemotherapy with bendamustine alone (n = 202) or in combination with obinutuzumab.

In the bendamustine monotherapy arm, the dose was 120 mg/m2 on days 1 and 2 of a 28-day cycle for up to six cycles, but in the combination arm, a lower dose of bendamustine was used, 90 mg/m2 on days 1 and 2, along with obinutuzumab at a dose of 1000 mg on days 1, 8, and 15 of cycle one and subsequently one dose with every cycle of chemotherapy for up to 6 cycles.

Patients in the combination arm who showed benefit went on to receive a maintenance dose of obinutuzumab every 2 months for up to 2 years.

The primary endpoint of the study was PFS, assessed by an independent radiology facility; investigator-assessed PFS was a secondary endpoint along with response rates, duration of response, pharmacokinetic parameters, and safety.

"Importantly, these patients had a high level of treatment resistance ― they had received a median of two prior lines of therapy ― and over 90% of patients in each arm had been designated refractory to their last treatment," said Dr Sehn.

At a median follow-up of 21 months, a significant difference was seen in PFS on independent radiology assessment.

"The combination of obinutuzumab and bendamustine followed by obinutuzumab maintenance resulted in a statistically significant but, more importantly, a clinically meaningful increase in PFS compared with bendamustine alone," she commented.

"The median PFS in the bendamustine arm was approximately 14.9 months but had not yet been reached in the combination arm," she said. "The hazard ratio was 0.55, indicating a 45% reduction in the rate of progression with the combination therapy."

Obinutuzumab was associated with a doubling of PFS, as assessed by the study investigators (29 vs 14 months with bendamustine monotherapy), she added.

Toxicity in the combination therapy was "as expected," with no new safety signals.

There were no differences between the two study arms with regard to adverse events (AEs), serious AEs, high-grade toxicities, deaths, or withdrawal from therapy.

The most common grade 3-4 hematologic AEs included neutropenia (in 33% of the combination arm and 26.3% of the monotherapy arm), thrombocytopenia (10.8% vs 16.2%), anemia (7.7% vs 10.1%), febrile neutropenia (4.6% vs 3.5%), and leukopenia (1% vs 1.5%).

The most common nonhematologic AEs included vomiting, decreased appetite, and fatigue.

"The fact that this new approach doubled average remission time marks a major step forward for our patients," said Dr Sehn in a press release. "Obinutuzumab may offer patients the chance to stay well for a significantly longer period of time, putting off the need for additional chemotherapy."

This study received funding from Genentech and Roche. Dr Sehn reports receiving honoraria from Roche/Genentech, Celgene, Gilead Sciences, Pfizer, Janssen, Lundbeck, and Amgen; performing in consulting or advisory roles with Roche/Genentech, Celgene, Gilead Sciences, Pfizer, Janssen, Lundbeck, and Amgen; and receiving research funding (institutional) from Roche Pharma AG and Genentech. Several coauthors were company employees.

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting. Abstract LBA8502. Presented June 1, 2015.


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