Phase 2B SADAL Trial in R/R DLBCL

John M. Burke, MD: Let’s transition to selinexor, which is the third of these new targeted drugs. Nathan, tell us about selinexor and how you see this drug being used in lymphoma.

Nathan H. Fowler, MD: This is a new class of drugs called SINE, a selective inhibitor of nuclear export, which essentially inhibits a shuttle protein called XPO1. This protein moves certain key pro-survival and tumor suppression proteins in and out of the nucleus. That is relevant to TP53 and others because they contribute to cell survival and cancer. If you can inhibit those by keeping them from shuttling in and out of the nucleus, you could potentially design an anticancer drug.

Selinexor is an inhibitor of this XPO1 protein. It has been approved in multiple myeloma, and recently it received approval for large cell lymphoma based upon a large trial. Initially the trial was nearly 300 patients and centered on examining several different doses. Eventually, if you bore down on the FDA-approved dose, which was around 60 mg twice daily, they had around 120 to 130 patients. Here, those patients are all beat up. These are all relapsed large cell lymphoma patients. I believe nearly 75% of them had been refractory to their last therapy. With this oral drug they saw an overall response rate of possibly 28% or 29% with a CR [complete response] rate of around 12%, and there was a small population of patients who had durable benefit.

However, this isn’t going to replace CAR-T cells, but for a population of people who are failing other lines of therapy, the drug has a place. It is FDA approved for patients who have failed 2 prior lines of therapy with a diagnosis of large cell lymphoma. In practice, it will likely be used for that select group of patients who are either failing CAR [chimeric antigen receptor] T cells or ineligible for some other treatments. However, it does have benefits with an almost 30% response rate, particularly in a small population of patients who have good and long responses. I would like to see a biomarker to identify who those patients are because despite the small population, some of these patients do well.

Adverse effects of the drug, especially at the higher doses, were associated with anorexia and GI [gastrointestinal] adverse effects. My sense is with these lower doses, it is much more tolerable. I personally was involved with the phase 1 studies and in those studies, we were at high doses, and it was tough on patients. My sense is with more reasonable doses, most patients can tolerate the drug relatively well.

John M. Burke, MD: The response rates were not as impressive as the tafasitamab-lenalidomide, but if you look at the details of the eligibility, the patients were a more heavily pretreated. There were more patients who had had prior transplant, and more patients who were refractory to their last line of therapy. I believe it was a different patient population making it tough to compare across trials to see which is the more effective treatment.

Nathan H. Fowler, MD: Looking at the study closely, there are some patients who are well over a year out and remain in remission. It has activity, but like many of these drugs, the future is defining who those good responders are.

Grzegorz S. Nowakowski, MD: I think some of the supportive care around use of selinexor has improved as well, which makes this therapy more tolerable to patients. Based on response rate, the drug has good potential for combination with other drugs, particularly novel agents. It’s a different mechanism of action from other drugs and possesses preclinical data, which could build interesting combinations to watch in the future.

Julio Chavez, MD: The other advantage is it’s administered orally. Patients do not have to go to an infusion center or need to have a line. I agree with Dr Fowler, we need to identify which patients benefit and then as Dr Nowakowski said, open the options for combination that will likely improve the efficacy of this drug.

Transcript Edited for Clarity