Behind the FDA Approval of Zanubrutinib and Obinutuzumab in Follicular Lymphoma

Lymphoma cell, a cancer of the lymphatic system: © Dr_Microbe - stock.adobe.com

On March 7, 2024, the FDA granted accelerated approval to zanubrutinib (Brukinsa) plus obinutuzumab (Gazvya) for the treatment of relapsed/refractory follicular lymphoma. The approval was supported by findings from the phase 2 ROSEWOOD trial (NCT03332017) that found that the combination to be more effective than obinutuzumab alone.

A total of 217 patients who had received at least 2 prior treatments for follicular lymphoma were randomized to receive either zanubrutinib 160 mg orally twice daily plus obinutuzumab or obinutuzumab alone.

The overall response rate was 69% (95% CI, 61%-76%) in the combination arm compared with 46% (95% CI, 34%-58%) in the obinutuzumab alone arm (2-sided P =.0012). At a median follow-up of 19.0 months, the median duration of response (DOR) was not reached (95% CI, 25.3-not evaluable) in the zanubrutinib/obinutuzumab arm vs 14.0 months (95% CI, 9.2-25.1) in the obinutuzumab arm. In the zanubrutinib and obinutuzumab arm, the estimated 18-month DOR was 69% (95% CI, 58%-78%).

“I am excited to see the results of this trial and the fact that this now offers a new opportunity for a therapy in the relapse setting for follicular lymphoma. This is a disease that has a relapsing and remitting course, and so having multiple agents and combinations available to patients really offers an overall benefit to patients and to clinicians,” said Christopher Flowers, MD, MS, Department of Lymphoma - Myeloma, Division of Cancer Medicine at MD Anderson Cancer Center, said in an interview with Targeted Oncology^TM.

In the interview, Flowers, an investigator on the ROSEWOOD study, discussed its findings and implications in the follicular lymphoma treatment landscape.

Christopher Flowers, MD, MS

Targeted Oncology: What does the current treatment landscape of follicular lymphoma look like?

Flowers: Follicular lymphoma as a disease can be quite complicated. In terms of its management strategies, I think it is a disease that is considered not to be curable with standard therapy, and a disease that typically affects older individuals, patients in their 70s and older being the average time when people are first diagnosed. There are a variety of treatments that can be used in the first-line. Those can vary from things like just watching and waiting after someone is diagnosed until they develop signs or symptoms that require treatment, to treatments that are much more aggressive, like multiagent chemotherapy combined with antibody therapy as first-line therapies and things that are aggressive like [chimeric antigen receptor] T-cell therapy and autologous stem cell transplantation when patients have relapses of their diseases. There are multiple other options that are included in between.

The other thing that has become challenging about the management for patients with follicular lymphoma is that there have been various classes of agents that were available for patients in the relapsing setting, like the PI3 kinase inhibitors, where we found toxicity over time with those drugs being on the marketplace, or that the benefits that were originally viewed for those agents no longer outweigh the risks of those agents. Those treatments have been withdrawn from the market more recently.

Can you provide some background on the ROSEWOOD study?

If we think about the context for the ROSEWOOD study, this is a study that was used for patients with relapsed and refractory follicular lymphoma who had received 2 or more prior lines of therapy. As I mentioned, the first-line of therapy for patients with follicular lymphoma can involve a variety of choices. In that relapse setting for follicular lymphoma, that typically can involve other agents like combinations of chemo immunotherapy like bendamustine [Bendeka], rituximab [Rituxan], the [rituximab, cyclophosphamide, doxorubicin hydrochloride (Hydroxydaunomycin), vincristine sulfate (Oncovin), prednisone (R-CHOP)] regimen, or regimens like rituximab and lenalidomide [Revlimid] if that was not used as a first-line therapy.

ROSEWOOD sits in the context of those kinds of regimens being the typical regimens that are used in in the first line or second line in some combination. The other background that exists for ROSEWOOD is that there was a phase 1B/2 clinical trial that actually occurred before ROSEWOOD occurred looking at the combination of zanubrutinib and obinutuzumab where that was administered to patients with relapsed and refractory [chronic lymphocytic leukemia (CLL)] and about 36 patients with relapsed and refractory follicular lymphoma, where we saw that there was an overall response rate of 72% and a complete response rate of 39% in that setting, which raised the promise of that combination being used.

In the ROSEWOOD trial, I think there are 2 other key components to the setting the context. One is the use of Bruton tyrosine kinase inhibitors, or BTK inhibitors, in patients with follicular lymphoma. BTK inhibitors as single agents previously had not been thought of as being significantly useful in follicular lymphoma. That’s in part owing to the low single-agent activity of ibrutinib [Imbruvica], the first of the approved BTK inhibitors in other settings like mantle cell lymphoma and CLL in the past, and that its use in follicular lymphoma was of much less value in that setting. BTK inhibitors had not previously been thought to be of great value in follicular lymphoma.

The other thing that set the context is the role of obinutuzumab. Obinutuzumab is an anti-CD20 antibody that has been shown in randomized controlled trials that when it is used in combination with chemotherapy as a form of chemo immunotherapy, that obinutuzumab plus chemotherapy improved progression-free survival compared [with] rituximab plus chemotherapy in the frontline setting. Although that had been demonstrated as a benefit, because of some of the adverse events, particularly the infusion-related adverse events that have been associated with obinutuzumab, it has not been commonly used in follicular lymphoma despite that benefit.

That sets the stage for the ROSEWOOD trial, where this was a randomized trial in the phase 2setting, looking at zanubrutinib plus obinutuzumab vs obinutuzumab alone in [patients with] relapsed/refractory follicular lymphoma who had 2 or more lines of therapy.

Can you summarize the findings?

First is the efficacy. The trial was designed with a primary end point being overall response rate. The trial, when it reached the timeframe for his primary analysis, met its primary end point with zanubrutinib and obinutuzumab having an overall response rate of 68% vs approximately 46% for obinutuzumab alone.

When you look at the safety of that combination, there [are] some interesting things about the safety of the combination in the context of this study. The first is that this combination was fairly well-tolerated. When you look at the grade 3 or greater nonhematologic adverse events, they were relatively uncommon overall, with the most common of those being pneumonia that occurred and approximately 10% of patients. This [study] occurred directly during the COVID-19 pandemic, and about 5.6% of patients had grade 3 or greater COVID-19, and 3.5% had grade 3 or greater COVID-19 pneumonia as compared [with] 2.8% for both of those in the group that received obinutuzumab alone.

The interesting thing about the safety is that the combination of zanubrutinib plus obinutuzumab abrogated some of those safety effects that I mentioned earlier about obinutuzumab alone. When you look at fevers that commonly occur with the infusion of obinutuzumab, that occurred in almost 20% of patients who had obinutuzumab alone and only 13% of those who had the combination of zanubrutinib and obinutuzumab. If you look overall at infusion-related reactions, that was about 10% of patients who got obinutuzumab alone and only 2.8% of patients who got the combination of zanubrutinib plus obinutuzumab. It looks like the zanubrutinib reduces the risk of some of those troubling adverse events that occur with the infusion of obinutuzumab.

What are the next steps? Are any end points continuing to be evaluated?

The other end points that were presented at meetings [in the summer of 2023] and published in an article in the Journal of Clinical Oncology include progression-free survival, where we saw a hazard ratio of 0.50, meaning that the group with zanubrutinib and obinutuzumab had an improvement in the risk of progression, death, or relapse, compared [with] the group that received obinutuzumab alone, with a median progression-free survival for the group that got zanubrutinib plus obinutuzumab of 28 months.

One of the things that has been lobbied against this trial is that obinutuzumab alone as a single-agent is something that is much less commonly used in patients with relapsed and refractory follicular lymphoma. That being said, the median progression-free survival for this group that had had 2 or more lines of therapy and received single-agent obintuzumab was about 10 months. That looks fairly similar to what we saw for the groups that have received PI3 kinase inhibitors and actually led to the approval of the PI3 kinase inhibitors in this space and to other kinds of regimens that had been used in the relapse setting for follicular lymphoma. While the single-agent obinutuzumab alone may be a comparator that some might think is different from what they would use the way that it performed in this clinical trial, it looks like it performed similar to many of the regimens that most clinicians use in the relapse setting.

REFERENCES:

1. FDA grants accelerated approval to zanubrutinib for relapsed or refractory follicular lymphoma. U.S. FDA. March 7, 2024. Accessed March 7, 2024. https://tinyurl.com/5sx5k4s4