Results from the Phase 3 GADOLIN trial reveal that combining Gazyva (obinutuzumab) with bendamustine (available as Bendeka and Treanda) in patients with indolent non-Hodgkin’s lymphoma who are not responding to Rituxan (rituximab) leads to better progression-free survival than treating patients with bendamustine alone.
The study, “Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial,” published in the journal The Lancet Oncology, suggests the therapy is a new treatment option for patients not benefiting from Rituxan.
After obtaining positive results that met its goals, the trial (NCT01059630) stopped in 2014, although analyses of its results are ongoing. This study was performed by the British Columbia Cancer Agency and University of British Columbia, and sponsored by Roche.
The slow-growing nature of indolent non-Hodgkin’s lymphoma makes it a difficult cancer to treat, and when patients do not respond to Rituxan, physicians are left with few treatment options. Comparing bendamustine, which is considered the standard of care, with the combination of bendamustine and Gazyva in six 28-day cycles — followed by Gazyva maintenance therapy for two years in patients responding well to it — gave scientists some surprising insights.
The study included 396 patients, with 194 receiving the combination treatment and 202 on bendamustine monotherapy. After following patients for a median of more than 20 months, those receiving the combination were seen to have “significantly longer” progression-free survival, although a median was not reached, than the 14.9 months of progression-free survival recorded in the group receiving only bendamustine.
Researchers noted that adverse events occurred in about the same extent in both groups. Low levels of blood cells called neutrophils and platelets, as well as red blood cells, were among the most common adverse events, and reactions to the intravenous infusions were also common.
Serious adverse events occurred in 38 percent in the combination group, and in 33 percent in the bendamustine group. In each group, 12 patients died after having serious adverse events. These events were linked to the treatment in 25 percent of the combination therapy patients and 42 percent of the monotherapy patients.
Roche’s Gazyva is an antibody targeting the CD20 molecule, just like Rituxan, but is thought to have improved properties.
In a linked comment in The Lancet Oncology, Paul A. Hamlin of Memorial Sloan Kettering Cancer Center, in New York, pointed out that the trial had some interesting features. At the end of the combination phase, patients treated with Gazyva (obinutuzumab) and bendamustine did not show any differences in response to those treated with bendamustine alone. He argues that this would suggest that it is the quality of remission that determines the long-term outcomes. The proportion of patients in the combination group who had no traces of cancer cells left at this stage — a measure scientists call minimal residual disease — was nearly twice as high as in those receiving bendamustine.
Despite this, Hamlin argued that the study left several questions unanswered. Since Rituxan in combination with bendamustine is the first line of treatment for patients with indolent non-Hodgkin lymphoma, it is not known how the treatment will work in patients previously exposed to bendamustine.
It is also not clear how much the maintenance phase contributed to the result, since the trial did not include a control group receiving the Gazyva (obinutuzumab) and bendamustine combination but without maintenance treatment.
Finally, Hamlin noted that about 30 percent of patients also seemed to be refractory (unresponsive) to the combination treatment. He insisted that future studies need to take a closer look at these patients to understand how they differ, and so attempt to find other suitable treatment approaches.