Obinutuzumab Benefit in Frontline Follicular Lymphoma Sustained With Longer Follow-Up

Wolfgang Hiddemann, MD, PhD

At more than 40 months’ follow-up, combining obinutuzumab (Gazyva) with chemotherapy in the first-line setting reduced the risk of disease progression or death by 32% versus rituximab (Rituxan) plus chemotherapy in patients with follicular lymphoma, according to updated data from the phase III GALLIUM trial.

Findings presented at the 2017 International Conference on Malignant Lymphoma (ICML) biennial meeting in Lugano, Switzerland, showed that the hazard ratio for progression-free survival (PFS) was 0.68 (95% CI, 0.54-0.87; P = .0016) for the comparison of obinutuzumab/chemotherapy versus rituximab/chemotherapy.

“I think the main message [is] that obinutuzumab is better than rituximab. It’s simply the more effective and more beneficial antibody,” lead study author Wolfgang Hiddemann, MD, PhD, said in an interview with OncLive at ICML.

In the international GALLIUM study, 1202 patients with follicular lymphoma were randomized to obinutuzumab plus chemotherapy followed by obinutuzumab alone, or rituximab plus chemotherapy followed by rituximab alone. Physicians chose among chemotherapy regimens of bendamustine, CHOP, or CVP.

The PFS benefit with obinutuzumab was consistent across chemotherapy regimens. In the overall population and within the chemotherapy subgroups, toxicities were higher in obinutuzumab arms versus rituximab arms. The highest rates of adverse events occurred with bendamustine regimens.

Hiddemann, a professor at the Ludwig-Maximilians-University Munich, discussed the updated GALLIUM findings and further steps needed to advance treatment for patients with follicular lymphoma.

Please provide an overview of the GALLIUM update?

I had the privilege to update the GALLIUM trial here in Lugano. We can say with the follow-up of more that 40 months, the originally reported results hold up. This means that obinutuzumab-treated patients have a significantly longer PFS as compared to rituximab treated patients, with the reduction of the risk of progression being approximately 30%.

In clinical terms, it means that we can anticipate that patients who receive obinutuzumab have a 3 year longer PFS as compared to our standard treatment patients.

What were the most significant results?

Here we presented not only an update but also a more detailed analysis on the chemotherapy backbones. In the beginning, the center had to decide whether patients should receive bendamustine, CHOP, or CVP as basic chemotherapy. This was not a randomized comparison, but investigator’s choice. Approximately 60% of participating centers decided for bendamustine, [30%] for CHOP, and 10% for CVP.

In particular, we observed the relatively high-rate of infections in bendamustine-treated patients. It was almost double as it was in CHOP or CVP. When we looked at the time of occurrence of infections, we found that most infections in bendamustine-treated patients were observed in maintenance with the longer follow-up. This means that there is a slightly higher acute toxicity with obinutuzumab treated-patients particularly, with CHOP and CVP. But the long-term toxicities and particularly fatal events and severe infections are more frequent in bendamustine. In the future, we have to be more careful with the indication for bendamustine in first-line therapy for follicular lymphoma.

Are there any challenges that still remain that you would like to see addressed?

We are not satisfied with the results. They are good and are certainly a step forward, but a problem which is currently still unsolved is why patients relapse early. Patients who have an occurrence of their lymphoma within the first 24 months have a distinct prognosis. We are analyzing whether the different GALLIUM arms have different impacts on those patients and I think for the future, we have to put our attention on that subgroup because there is an unmet need where we have to explore new agents for the high-risk population.

What are those agents that are being investigated for the high-risk population?

It’s a large variety of different agents that are currently being explored. Many of them are targeting the B-cell receptor pathways. There was promising data on a couple of phase II studies with PI3-kinase inhibitors, for example. There is the Bcl-2 pathway which is also targeted by newer agents. There are immune modulatory agents, particularly the PD-L1 inhibitors, which had very promising early results that were also reported here. I think the whole field of treatment right now is in a big move which is a favorable aspect when you think of the effect it has on the lives of our patients.

What are the key points that you hope the audience takes away?

I think the main message would be that obinutuzumab is better than rituximab. It’s simply the more effective and more beneficial antibody. The chemotherapies that we applied have very good response rates for bendamustine and CHOP and slightly less for CVP, however with bendamustine we have to be careful concerning the late side-effects of [the drug].

Can you discuss how manageable the side effects were?

Overall, they were manageable, but we had a couple of fatal events. We had approximately 15% of fatal events particularly in bendamustine treated patients, and that is quite a lot.

Is there anything else you would like to add?

I think one of the future aspects is if we develop predictive markers before treating patients. As you might know, we have published the m7-FLIPI about a year and a half ago, which uses a mutational analysis together with clinical factors and allows us to discriminate or identify patients with a very certain prognosis. Those data were confirmed by results from the French group. I think the next step would be to refine this risk score and hopefully make a decision prior to treatment on how patients should be treated and with what type of treatments.

Hiddemann W, Barbui AM, Canales Albendea MA, et al. Immunochemotherapy with obinutuzumab or rituximab in previously untreated follicular lymphoma in the randomised phase III GALLIUM study: analysis by chemotherapy regimen. Hematological Oncology, 35(S2): 117—119. doi: 10.1002/hon.2437_106.

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More from the International Conference on Malignant Lymphoma

When we looked into the different chemotherapy backbones, we first found that there is an advantage of obinutuzumab over rituximab in the chemotherapeutic regimens. But we also see a difference in the side effects. We had more acute side effects, particularly neutropenia and febrile infections in patients who received obinutuzumab plus CHOP or obinutuzumab plus CVP. There were higher [toxicity rates] with obinutuzumab regimens than with rituximab regimens. [The highest rates of AE-related fatal events occurred] in patients who underwent the bendamustine treatment. Within the bendamustine group, there was not as big of a difference between rituximab- and obinutuzumab-treated patients.