Geoffrey Shouse, DO, PhD

Targeted therapies have shifted the treatment paradigm for patients with follicular lymphoma, reinforcing the role molecular targets play in this realm, according to Geoffrey Shouse, DO, PhD.

Shouse highlighted the March 2024 FDA accelerated approval of zanubrutinib (Brukinsa) in combination with obinutuzumab (Gazyva) for patients with relapsed or refractory follicular lymphoma,¹ which was supported by data from the phase 2 ROSEWOOD trial (NCT03332017). Findings demonstrated that patients treated with the combination (n = 145) experienced an overall response rate of 69% (95% CI, 60.8%-76.4%) vs 46% (95% CI, 34%-58%) with obinutuzumab alone (n = 72; two-sided P = .0012).² The respective complete response rates were 39.3% and 19.4% (P = .0035).

“Molecular targeted therapy is useful, and it's safe and well tolerated for the most part. However, I would say the greatest potential [for targeted therapy] is going to come from combinations,” Shouse emphasized.

In an interview with OncLive^®, Shouse discussed the role of targeted therapy approaches in the treatment of patients with follicular lymphoma, highlighted notable molecular targets in this patient population, and expanded on the need for additional research evaluating combination approaches for these patients.

Shouse is a hematologist-oncologist and assistant professor in the Division of Lymphoma, Department of Hematology and Hematopoietic Cell Transplantation, at City of Hope in Duarte, California.

OncLive: How has targeted therapy evolved within the follicular lymphoma treatment paradigm?

Shouse: Over the years, there have been quite a few molecular targets in follicular lymphoma, including cereblon, EZH2, BTK, BCL2, and PI3K. For PI3K, the most recent inhibitor, copanlisib [Aliqopa], was withdrawn from the market [in November 2023]. As far as [targeting] BTK, zanubrutinib [plus obinutuzumab] received an accelerated FDA approval [in March 2024] as one of the most recent approvals for a targeted therapy.

Lenalidomide [Revlimid] is one of the first that had FDA approval in combination with rituximab [Rituxan] in [pretreated follicular lymphoma]. Tazemetostat [Tazverik] has approval in the third-line setting, but there are promising data using it in combinations in earlier lines of therapy.

How do targeted therapies differ from traditional systemic therapies, and what advantages do they offer patients?

Chemotherapy, for example, is designed to target cells that are rapidly dividing, [irrespective of] whether that cell is [cancerous] or normal. Instead, chemotherapy destroys everything that is viable in their wake, and [these agents can] cause a lot of toxicity.

Molecular targeted therapies, on the other hand, are designed to focus on pathways that are active specifically within a type of cancer. Hopefully, [this allows treatment to] be more specific and less toxic for patients. Targeted therapies are more easily administered as well; many are given orally, which is a lot easier for patients.

Are there any common adverse effects (AEs) associated with targeted therapies? How do you manage these AEs in your patients?

[AEs] differ by class. For example, cereblon inhibitors such as lenalidomide are associated with thrombosis. We assess patients’ baseline thrombosis risk and then give them medication to prevent thrombosis. Most of the time it's aspirin; sometimes it's blood thinners, depending on whether they have [a history of] prior thrombosis and how high their risk is.

As far as BTK inhibitors such as zanubrutinib, most commonly, we worry about bleeding, irregular heart rhythms, and low blood counts. The low blood counts are easy to manage; we can administer growth factors and put patients on prophylactic medications to prevent infections. For bleeding, we monitor closely, and for patients who have severe bleeding episodes, we may decrease the dose or stop the medication and switch to a different treatment.

For patients [being treated with a BTK inhibitor] who have an irregular heartbeat at baseline, there are studies that suggest that ibrutinib is still well tolerated, so we usually give it a try. If we can manage any irregular heartbeat as they go through [treatment], then we can keep them on the medication; however, if [the irregular heartbeat] becomes severe, then we take them off.

How do you determine eligibility for different targeted therapies, and what factors influence your choice of a specific treatment?

The main factors—since most [targeted therapies] are well tolerated—is whether patients have any of the toxicities associated with [a particular] drug therapy at baseline. For example, patients who have poorly controlled atrial fibrillation probably wouldn't be the best candidates for a BTK inhibitor, or if they have a history of severe bleeding episodes, [a BTK inhibitor] is probably not the best choice. [In] patients who have had multiple thromboses or a stroke in the past, lenalidomide may not be the best option for them.

What is the importance of testing for genetic abnormalities through next-generation sequencing (NGS), and how do you integrate that into your practice for patients with follicular lymphoma?

The full utility of NGS testing has not been harnessed yet. It's a field that's continuing to move forward and will be helpful at many levels as we go forward. One of the potential ways [NGS] could be used is to identify targets that may not be standard of care in patients whose disease has relapsed multiple times. Additionally, [NGS] can identify high-risk mutations such as TP53 mutations. We know things like chemotherapy won't work well for patients who have a TP53 mutation.

As far as selection for the currently approved targeted therapies, for tazemetostat, there's evidence that EZH2 mutations do increase the likelihood of patient response, so that's something we check for regularly in patients with follicular lymphoma. As far as resistance to treatment, BTK mutations and downstream mutations from BTK in other cancers like chronic lymphocytic leukemia do predict resistance to zanubrutinib; however, that same resistance mechanism hasn't been proven for follicular lymphoma. In the future, with more use of BTK inhibitors in this setting, it'll be important to evaluate that more.

How do you hope to see the utility of targeted therapies evolve over time?

Because [targeted therapies] are [generally] well tolerated, it allows for combinations with additional therapies without causing too much toxicity for the patient. Many of the resistance mechanisms and the reasons why patients relapse after targeted therapies is that other pathways become active or are selected for in the cancer. If we start targeting multiple pathways up front, there's a potential for deeper and longer remissions, and longer disease control. Combination treatments in their infancy in terms of being tested in follicular lymphoma, and the full potential for these therapies has yet to be exploited.

References

1. FDA grants accelerated approval to zanubrutinib for relapsed or refractory follicular lymphoma. FDA. March 7, 2024. Accessed August 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zanubrutinib-relapsed-or-refractory-follicular-lymphoma
2. Flowers C, Zinzani PL, Mayer J, et al. Zanubrutinib plus obinutuzumab versus obinutuzumab in patients with relapsed/refractory follicular lymphoma: Updated analysis of the ROSEWOOD study. J Clin Oncol. 2023;41(suppl 16):7545. doi:10.1200/JCO.2023.41.16_suppl.7545