Brody Calls for Effective Predictive Biomarker of Response to Selinexor in DLBCL

Although the emergence of XPO1 inhibitors such as selinexor (Xpovio) in the diffuse large B-cell lymphoma treatment paradigm has resulted in improved outcomes, a pivotal next step for research is to develop a deeper understanding of which specific patients will derive the most benefit from this approach, according to Joshua Brody, MD.

“Biomarkers are absolutely critical. As a metaphor, we use trastuzumab deruxtecan (Enhertu) for patients with breast cancer, but only for those with HER2-positive breast cancer. If we used this therapy on all patients, it would be deemed ineffective,” explained Brody. “However, by only using it only for right patients, those who express HER2, the therapy plays a critical role in improving both remission and cure rates. Similarly, for these other targeted therapies in DLBCL, we need to define the optimal biomarker, whether it’s Myc or something else.”

In June 2020, the FDA approved selinexor for the treatment of adult patients with relapsed or refractory DLBCL, not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy. The decision was based on data from the phase 2b SADAL trial, which showed that the XPO1 inhibitor elicited a 29% overall response rate, including a complete response rate of 13%.

Selinexor is just 1 of 3 key agents that received regulatory approval for use in the third-line treatment setting in the past year alone, according to Brody. Polatuzumab vedotin (Polivy) and tafasitamab-cxix (Monjuvi) also joined the treatment arsenal in June 2019 and August 2020, respectively. Other novel approaches are also gaining ground in the space, including CAR T-cell therapies and bispecific antibodies.

In an interview with OncLive, Brody, an assistant professor of medicine, hematology and medical oncology, and director of the Lymphoma Immunotherapy Program at the Icahn School of Medicine at Mount Sinai, discussed the recent developments in DLBCL treatment, the role of selinexor, and the need for effective biomarkers of response in the space.

OncLive: Could you start off by briefly highlighting the current state of DLBCL treatment?

Brody: We're very lucky because we have effective therapies and are able to cure the majority of patients, even those with advanced disease. However, unfortunately, the majority of patients are far away from being cured 100%.

How does this compare to where we used to be?

Changes in the past 10 years have been slow. Notably, 20 years ago, the addition of immunotherapy to chemotherapy, specifically rituximab (Rituxan), was revolutionary in that [that approach] significantly increased both remission and cure rates in patients.

Since then, some other significant advances have been made, such as the approval of CAR T-cell therapy in the third-line setting. It appears that CAR T cells, which are another type of immunotherapy, may cure approximately 35% to 40% of the patients who receive them; however, this is a small number of patients.

In fact, a more powerful way to help these patients would be to use these effective therapies in earlier lines of treatment, especially for those who are less likely to be cured with current standard options.

What have some of the challenges been in this space?

DLBCL, in contrast to some other lymphomas, can progress extremely rapidly. Thus, getting patients access to clinical trials that are evaluating new therapies, such as CAR T-cells, or access to standard therapies in a timely manner, can be a challenge. These lymphomas can be quite aggressive with rapid kinetics. To some degree, this has slowed down our ability to have our patients benefit from some of these new advances.

What is the role of selinexor in this patient population?

Selinexor is 1 of 3 new therapies approved for use in the third-line treatment of patients with DLBCL over the past year. These 3 therapies are polatuzumab vedotin, tafasitamab, and selinexor; these drugs are exciting in the sense that they attack DLBCL in a novel way.

[These agents are] very distinct from standard chemotherapies. In fact, because they attack cancer cells in a different may, that could be the reason why they are effective in patients for whom chemotherapy has been insufficiently effective.

Selinexor is an exciting therapy because, as an XPO1 inhibitor, it has the opportunity to impact some of the critical oncogene drivers such as Myc and other transcription factors that have not been targetable by other therapies.

Could you discuss the phase 2b SADAL trial that led to the approval of selinexor in this patient population?

This trial was for patients for whom standard therapies have been insufficiently effective. Patients with relapsed/refractory DLBCL following more than 2 prior lines of therapy were enrolled.

What are the next steps of this research?

Truthfully, as exciting as it is to have a novel class of therapies available for these patients, this trial was insufficient. Some efficacy was observed and selinexor was well tolerated; however, this therapy will only be impactful when we achieve a deeper understanding of which specific patients derive the most benefit from this approach. As with many new therapies, only a minority of patients experienced significant remissions with selinexor. It would be much more meaningful if we could predict which patients will respond to the treatment.

That means we need a more thorough scientific understanding of how selinexor is killing lymphoma cells. especially in the worst subsets of DLBCL, which are double-hit lymphoma or double expressing lymphoma. These patients are defined by having high levels of the oncoproteins Myc and BCL-2 and they fare much worse than other patients with DLBCL.

Based on some preclinical data, it's conceivable that selinexor might provide specific benefit to patients with higher levels of Myc. If this could be confirmed, Myc [might represent] a biomarker [of response], [and] we would only offer this therapy to the patients who would derive the most benefit from it. This would be a huge step forward, especially for those who are high risk and have Myc-overexpressing lymphoma.

What is the take home message to any of your colleagues who are treating patients with DLBCL?

As exciting as these FDA approvals are, we foresee a few additional approvals of novel therapies in the upcoming years, including newer types of CAR T cells and bispecific antibodies. Both of these approaches have demonstrated extremely high remission rates. However, to get access to these promising therapies, we need to provide patients with the opportunity to join clinical trials where these options are available.

Reference

FDA approves selinexor for relapsed/refractory diffuse large B-cell lymphoma. News release. FDA. June 22, 2020. Accessed September 2, 2020.bit.ly/3jBc1t1.