Treatment Options for Relapsed/Refractory Diffuse Large B-Cell Lymphoma - Episode 9

SADAL Trial Overview

, , ,

Brian Hill, MD, PhD: The mechanism of action for selinexor, which is a novel targeted agent, is that the medication works as a selective inhibitor of nuclear export. Nuclear exporters are proteins that cycle transcription factors and other regulatory proteins between the nucleus and the cytoplasm of the cell.

By inhibiting this nuclear export protein, selinexor leads to accumulation of various protein regulators that leads to reduction, cell proliferation, and apoptosis of the target cell. We know that certain malignant cells, including diffuse large B-cell lymphoma [DLBCL], are sensitive to this agent, and recent data have shown that it’s clinically active in this disease.

Andre Goy, MD: Selinexor is an exportin XPO1 that is an inhibitor. XPO1 is overexpressed in lymphoma and correlates with a poor outcome. This oral selective nuclear transport inhibitor has shown activity in a preclinical setting and was tested in aggressive lymphoma, in large cell lymphoma, in the third-line setting. It was testing a number of lymphomas in the SADAL study, including large B-cell lymphoma. These patients have really no options. This was a heavily pretreated population of 120-plus patients. And the response rate was 36% and 15% CR [complete response]. This was something that was very interesting because we had some patients who were not very high-risk large cell lymphoma but multiple failures and who had very durable response.

It was a single agent. This is really interesting, and it was approved last month in June. Based on that, the next step is to try to build up this activity and the mechanism that would make a lot of sense combined with other agents. It is being looked at in a very interesting trial that is looking at the number of different arms, combining selinexor with chemotherapy, biological agents, and checkpoint inhibitors to see how we can build a new regimen for patients who are not eligible for CAR T [chimeric antigen receptor T-cell therapy] or transplant or fail after CAR T cells.

Julio Chavez, MD, MS: Selinexor is a novel agent that has been recently approved for relapsed/refractory diffuse large B-cell lymphoma, after at least 2 lines of therapy. In the trial, about 17% of patients discontinued the drug because of side effects, mainly related to GI [gastrointestinal] toxicity, nausea and diarrhea, and also hematology toxicity, specifically neutropenia and thrombocytopenia. This trial, when it was studied in non-Hodgkin lymphoma, actually utilized a higher dose of selinexor. In the SADAL study, they actually used a lower dose of selinexor but also showed the adverse effects I just mentioned. Part of it included the use of olanzapine during the treatment, especially given the day before, following 5 days after the treatment. Also, they include the use of appetite stimulants and growth factor support to prevent the hematology toxicity. They reported that the adverse effects were manageable in those patients, but they still show a significant rate of GI toxicity specifically.

As I mentioned, in the SADAL study, selinexor in relapsed/refractory DLBCL, they administered the drug at 60 mg on days 1 and 3 every week until disease progression or development of intolerance. All patients were required to receive ondansetron, which is a common antiemetic medication for cancer patients. After patient discussion, they also received olanzapine to prevent nausea. In the non-Hodgkin lymphoma study, which was probably 3 years ago, they included all histologies, including DLBCL. They tested the selinexor at 3 mg/m2, all the way to 80 mg/m2, which was the highest dose. They actually break down in those levels, and essentially there was no significant difference in response rates, even with the lowest dose. They showed an overall response rate of 31%, but that was across all histologies. Based on that data, I don’t think those modifications could have affected the efficacy of the drug. I believe that actually was a good move from the investigators—to use a lower dose, a less toxic drug—because it seems that the toxicity was dose related.

Selinexor has an advantage. The main advantage is it’s a single agent and an oral agent. These 2 factors actually help physicians treat patients. Because they don’t need an IV [intravenous] line, the patients don’t have to come every time to get the therapy. So it’s convenient. The schedule could be a challenge. Patients get selinexor on days 1 and 3 every week, so I’m not sure whether patients will be able to remember. It’s easy when you take a drug every day or once a week, but if it’s twice a week, you may forget. It’s important for the clinicians or the nurses to follow up with the patients when they receive this therapy.

Also, it’s important to know that this is a novel agent with a novel mechanism of action, so the toxicity profile is also novel. Physicians are familiar to use monoclonal antibodies like tafasitamab, so there may be more appeal to use that drug as opposed to selinexor because it’s still unknown, it’s new, and no one has used it, unless they did it for myeloma patients with selinexor.

There are other drugs that are not approved for DLBCL but that doctors are familiar with, like lenalidomide. Lenalidomide has activity in relapsed/refractory DLBCL. Physicians know how to use it because it has been in the market for a while for other conditions such as MDS, myelodysplastic syndrome; mantle cell lymphoma; or even multiple myeloma. Physicians are very familiar with it, and even if it’s not approved, I don’t see any issues with insurance approval or around the co-pays that we sometimes see with this drug.

When using selinexor, physicians have to make sure they know the efficacy and toxicity, so that patients are not surprised and they’re managed appropriately.

Transcript edited for clarity.