Novel Agents on Horizon for Follicular Lymphoma

John P. Leonard, MD

A diverse collection of novel agents are on the horizon that could further improve the long-term outcomes experienced by patients with follicular lymphoma, particularly those with relapsed or refractory disease, according to a presentation by John P. Leonard, MD, at the 2016 International Congress on Hematologic Malignancies.

“Most patients will not die from follicular lymphoma, and that's very reassuring. About 80% of patients will die with their follicular lymphoma and not of their follicular lymphoma,” said Leonard, Richard T. Silver Distinguished Professor of Hematology and Medical Oncology, NewYork-Presbyterian Weill Cornell Medical Center. “That really tells you something. If 80% of patients are not going to die from their disease, we can make a patient feel a lot better and can guide how we treat the patient.”

Next-generation anti-CD20 antibodies have been explored for relapsed follicular lymphoma, noted Leonard; however, superiority over traditional rituximab (Rituxan) has not yet been established. In late February 2016, the FDA approved the anti-CD20 agent obinutuzumab (Gazyva) in combination with bendamustine for patients with follicular lymphoma following rituximab-based therapy.

In the pivotal phase III GADOLIN study¹, obinutuzumab plus bendamustine followed by obinutuzumab maintenance reduced the risk of disease progression by 52% compared with bendamustine alone in patients with follicular lymphoma (HR, 0.55; P <.0001). At a median follow-up of 24.1 months, the risk of death was reduced by 38% with the obinutuzumab regimen compared with bendamustine alone (HR, 0.62; 95% CI, 0.39-0.98).

“I am not sure how much it is going to change practice, perhaps for some people it will,” said Leonard. “I would have honestly liked to know how rituximab would have stacked up, which in this setting is a more clinically relevant question.”

In another study², 90 patients with relapsed follicular lymphoma were randomized to receive lenalidomide (Revlimid) plus rituximab (n = 45) or lenalidomide alone (n = 45). The overall response rate (ORR) was 44% with lenalidomide alone and 75% with lenalidomide plus rituximab. The median event-free survival (EFS) was 1.2 and 2.0 years, with the single-agent and combination, respectively.

The phase III AUGMENT study is currently enrolling patients with follicular lymphoma and marginal zone lymphoma in order to compare rituximab plus placebo with rituximab plus lenalidomide. The primary endpoint of the study is progression-free survival (PFS), with secondary outcome measures focused on response, EFS, and time to next therapy.

“This seems like it has significant efficacy in relapsed, not refractory, patients. I think this is an interesting approach,” said Leonard.

The B-cell receptor also represents an important target for patients with B-cell malignancies. The PI3K delta inhibitor idelalisib (Zydelig) and the BTK inhibitor ibrutinib (Imbruvica) have shown promise for patients with relapsed follicular lymphoma.

In July 2014, the FDA approved idelalisib as a single agent for patients with indolent non-Hodgkin lymphoma, including follicular lymphoma. In the study that led to the FDA approval³, most patients were refectory to bendamustine and rituximab. The ORR with idelalisib was 56%. The median PFS was 11 months and the median overall survival (OS) was 20.3 months.

The main adverse events (AEs) associated with idelalisib include diarrhea/colitis, which occurs in 50% of patients (grade ≥3, 19%). Outside of this, the most common grade ≥3 AEs were neutrophil decrease (28%), platelet decrease (8%), and dyspnea (5%).

“This looks like a pretty meaningful response and duration of response in refractory patients,” said Leonard. “There has been some data reported recently that seem to show some toxicity when it is used in combination. For those using this drug now: be careful. There may be an infectious issue or other issues, but for me, at this point, I only use this drug as a single agent.”

There are several issues to consider when determining which therapy to administer following relapse for follicular lymphoma, including the indication for therapy, the bulk of disease, comorbidities, toxicity concerns, and the potential for transformation. However, in most cases, a majority of patients (80%) will live a normal lifespan, Leonard added.

“The biggest unmet need is the 20% of patients who are going to die of their disease or who are more likely to die of their disease,” he said. “This is the group of patients who progress. What do we do with these patients?”

There are a number of studies ongoing to address these concerns, including studies assessing the immune checkpoint inhibitors. The phase II CheckMate-140 trial is exploring nivolumab (Opdivo) for patients with follicular lymphoma following progression on a CD20 antibody and an alkylating agent (NCT02038946). Additionally, a phase II study is looking at the combination of rituximab and pembrolizumab (Keytruda) for patients with relapsed follicular lymphoma (NCT02446457).

In a small 30-patient study⁴, pidilizumab plus rituximab demonstrated an ORR of 66% in relapsed follicular lymphoma, which primarily consisted of complete responses. The median PFS was 18.8 months. In a second small phase I study assessing nivolumab as a single agent⁵, patients with pretreated follicular lymphoma (n = 10) experienced an ORR of 40% after 40 weeks of follow-up.

“These responses are meaningful, not as dramatic as we have seen in Hodgkin's, but it is meaningful,” said Leonard. “The question is, 'can you develop this drug in follicular lymphoma?' You would think that we would be able to develop a biomarker for response to an inhibitor, because the immune microenvironment makes a big difference in follicular lymphoma. Hopefully, we can identify a subset of patients where those response rates will be much better.”

As trials are conducted, questions still remain regarding whether PFS is a meaningful endpoint for patients with follicular lymphoma, Leonard said. Future studies should focus on more than efficacy, he noted, with an emphasis on the delivery of care and the costs.

“We need to focus on the goals of therapy. Are we curing the patients? What's the quality of life? I don't think PFS necessarily correlates with quality of life, we need to have quality of life endpoints that are real and robust and reflect what the value is to patients,” said Leonard. “We need to look at chronic toxicities and look at compliance issues.”

References

1. Sehn LH, Chua N, Mayer J, et al. GADOLIN: Primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2015;33 (suppl; abstr LBA8502).
2. Leonard JP, Jung SH, Johnson J, et al. Randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma: CALGB 50401 (Alliance). J Clin Oncol. 2015;33(31):3635-3640.
3. Gopal AK, Kahl BS, de Vos S, et al. Mature Follow up from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating agent)-Refractory Indolent B-Cell Non-Hodgkin Lymphoma (iNHL). Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 1708.
4. Westin JR, Chu F, Zhang M, et al. Safety and Activity of PD1 Blockade by Pidilizumab in Combination with Rituximab in Patients with Relapsed Follicular Lymphoma: a Single Group, Open-label, Phase 2 Trial. Lancet Oncol. 2014;15(1):69—77.
5. Armand P, Timmerman J, Lesokhin A, et al. Nivolumab in patients with relapsed or refractory lymphoid malignancies and classical Hodgkin lymphoma: updated safety and efficacy results of a phase 1 study (CA209-039). Presented at: 20th Congress of the European Hematology Association (EHA); Sunday, June 14, 2015; Vienna, Austria. Abstract #S808.

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