The Potential of Gazyva in Advanced Indolent Non-Hodgkin Lymphoma

In the phase 3 GADOLIN trial, adding the targeted therapy Gazyva (obinutuzumab) to the chemotherapy Treanda (bendamustine) reduced the risk of disease progression by nearly 50 percent in patients with Rituxan (rituximab)-refractory indolent non-Hodgkin lymphoma (iNHL).

After a median follow-up of approximately 20 months, median progressive-free survival (PFS) was 14.9 months for patients in the Treanda-only cohort, while in the Gazyva combination arm, median PFS had not yet been reached. The results were presented at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of nearly 30,000 oncology professionals in Chicago.

Bruce D. Cheson, professor of medicine, head of Hematology, and director of Hematology Research at Georgetown University, and an author on the GADOLIN study, said the results could “change the treatment paradigm” for the disease. CURE spoke with Cheson to gain a deeper understanding about the significance of the results.

CURE: What were the goals of the GADOLIN trial?

Cheson: The GADOLIN trial was designed to evaluate whether Gazyva would be effective in patients who were refractory to Rituxan for follicular and low-grade NHL. Approximately 400 patients who were considered refractory to Rituxan, meaning they had no response or had a response that lasted less than six months, received Treanda with or without Gazyva. There was an induction regimen of six months of therapy, followed by two years of maintenance with Gazyva.

What were the findings?

This study made some very important observations. First of all, there was no improvement in response rate when we added Gazyva to Treanda. However, there was a significant prolongation of PFS. There were some imbalances in the arms with regard to the treatment, and this is important. In the combination arm, Treanda was given at 90 mg per day on days 1 and 2, whereas in the single-agent arm, Treanda was given at 120 mg per day for days 1 and 2, because that is the label indication.

Did the combination and single-agent arms have the same response rate because the Gazyva brought up the efficacy of the lower dose Treanda? We can only speculate. The fact that the PFS was so significant is interesting. This was the first study to show efficacy of a second-generation anti-CD20 monoclonal antibody like Gazyva in Rituxan-refractory patients.

What can be taken away from these findings?

Adding an anti-CD20 monoclonal antibody like Gazyva to the standard treatment, which is in this case was Treanda, makes an enormous difference in patient outcomes. The survival curves are not sufficiently mature enough to comment on yet, but hopefully they will separate over time, as well.

This could clearly change the treatment paradigm. There are two camps among oncologists with regard to the initial patient therapy for follicular low-grade lymphoma. There is the R-CHOP (Rituxan plus cyclophosphamide, doxorubicin, vincristine, prednisone) and R-CVP (Rituxan, cyclophosphamide, vincristine, prednisone) camp and the Treanda camp. Therefore, for those patients who currently are given either R-CHOP or R-CVP, this will certainly change the treatment paradigm for those who are refractory to initial therapy. In fact, this study did include some patients who had not taken prior Treanda, so it may work in that population.

Were there any significant toxicities in the GADOLIN trial?

The toxicities experienced by patients in the combination arm were no different from those seen in the Treanda alone arm. It didn’t really add too much. The biggest problem was the standard myelosuppression. Infusion reactions were relatively common, but that is because they included any kind of reaction within 24 hours of treatment, not the standard antibody infusion reaction. It was a very well-tolerated regimen.

How do you envision the treatment paradigm for iNHL evolving?

I think the treatment paradigm is rapidly evolving. We have several new therapeutic agents that target the cell surface: Treanda; antibody-drug conjugates; drugs that target intercellular pathways, such as Imbruvica (ibrutinib), Zydelig (idelalisib), and other BTK and PI3 kinase inhibitors; as well as the BCL-2 inhibitor ABT-199. All these have activity as single-agents and are also active in combination with CD20-antibodies. We also have drugs that target the microenvironment, including Revlimid (lenalidomide) and multiple checkpoint inhibitors.

The challenge is going to be figuring out how can we use these together to form more active regimens. This has to be done with caution. We have combined a number of these drugs and had unexpected toxicities. We can’t just put them together because they are out there. It is very encouraging to have so many active, exciting drugs that are revolutionizing the approach to all B-cell malignancies. It is a whole new world ahead. What we are all striving for is getting to the point where we do not use chemotherapy. I think we have the tools to do it, we just have to figure out what drugs to put together.