After CAR-T cell therapy Kymriah (tisagenlecleucel) became reimbursable in April, Korean doctors are shifting the treatment focus to CAR-T cell therapy to treat relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

However, only a limited number of Korean hospitals can prescribe Kymriah despite insurance benefits. Furthermore, it usually takes more than a month to administer Kymriah to a patient because of complicated manufacturing and supply procedures. In addition, it is still difficult for patients to get CAR-T cell therapy due to many obstacles.

In July 2021, Antengene obtained the regulatory nod for Xpovio (selinexor) as a third-line or higher treatment for relapsed/refractory DLBCL. The drug is the world’s first oral selective inhibitor of nuclear export protein XPO1.

Unlike conventional therapies, Xpovio can be administered orally. As a result, it is regarded as a “new weapon” with a new mechanism of action to respond to unmet medical needs that CAR-T cell therapy could not satisfy.

Korea Biomedical Review met with professor Jeon Young-woo, head of the clinical division of the Hematology Department at Yeuido St. Mary’s Hospital. He also leads Lymphoma Microenvironment Research Cluster at the Catholic Institute of Cell Therapy.

Question: What is the annual incidence of DLBCL in Korea, and how many relapse?

Answer: Epidemiologic characteristics of Korean DLBCL patients are similar to those of global peers. Some 8,000 to 9,000 patients are diagnosed with blood cancer, and lymphoma accounts for about 45 percent. DLBCL accounts for about 60 percent of lymphoma cases, and around 2,500 people are newly diagnosed with DLBCL every year.

About 60 percent of the newly diagnosed DLBCL patients are cured with R-CHOP's first-line therapy. This means that the rest 40 percent do not respond to the first-line treatment or relapse and require second-line or higher-stage therapy. Considering patients who die during treatment, about 300 patients are estimated to need third-line or higher-stage treatment annually.

Q: That is the standard therapy for the third-line or higher treatment of relapsed/refractory DLBCL, and what are the treatment results?

A: We have no standard of care in the third-line or higher treatment. Doctors choose different therapy options, but most use cytotoxic anticancer drugs or a combo of chemotherapy with targeted therapy. I actively consider hematopoietic stem cell transplantation for patients who respond to chemotherapy. But, not many patients can get transplantation because of recurrence. Although I also participated in a clinical study of a new drug candidate, only a few patients could join the trial.

But recently, the third-line or higher treatment for DLBCL started to change after Korea approved reimbursement for CAR-T cell therapy. The reimbursement drew much attention because patients who had to give up higher-stage treatment due to the lack of therapy or financial burdens could actively seek treatment.

Of course, CAR-T cell therapy does not solve every problem. Before introducing CAR-T cell therapy, the survival rate of patients who required third-line or higher treatment was about 15 percent. Although CAR-T cell therapy raised survival rates significantly, 60 percent of the patients died due to relapse. This means that they need another treatment option.

Q: Xpovio is another treatment option for the third-line or higher treatment in DLBCL. Can you explain what kind of treatment Xpovio is?

A: A cell, the basic unit of living things, is composed of a nucleus and a cytoplasm. The nucleus contains so-called DNA, and when it needs replication or protein production, it makes RNA and sends it to the cytoplasm to produce proteins. Nuclear export protein is located in the nuclear membrane that blocks the nucleus from the cytoplasm and controls the movement of necessary substances. Xpovio inhibits this process and blocks the proliferation of cancer cells. It is called an XPO1 inhibitor.

Xpovio approval was based on the global phase 2 clinical SADAL study that evaluated Xpovio as monotherapy in adult patients with relapsed and refractory DLBCL who received at least two prior treatments. When this study began, there was no standard third-line or higher treatment. So, the researchers could not select a comparative drug.

Xpovio received FDA approval as it was judged to demonstrate clinical efficacy based on the study's overall response rate (ORR). This shows no proper third-line or higher treatment for DLBCL for a long time.

The findings of the SADAL study showed that Xpovio ORR in monotherapy was 28 percent, and complete response (CR) accounted for 12 percent. What’s notable was that while the expected survival period of patients at the third-line therapy was around six months, the median overall survival (OS) of patients demonstrating stable disease (SD) was 18.3 months. Based on these results, the NCCN guidelines recommended Xpovio in the third-line or higher treatment in relapsed/refractory DLBCL.

Q: We heard that Yeouido St. Mary’s Hospital would begin CAR-T cell therapy in June. What kind of role can Xpovio play in the treatment environment changing toward CAR-T cell therapy?

A: Xpovio has not been compared to any other drug in a phase 3 study and the follow-up period is short, so it is difficult to compare it with CAR-T cell therapy. But I think Xpovio can help DLBCL patients as another treatment, separate from CAR-T cell therapy.

I expect Xpovio’s benefits in primary or secondary cerebral lymphoma. Most of the cerebral lymphomas with lesions in the brain are reported as subtype DLBCL. For a drug to reach lesions in the brain, it should penetrate the blood-brain-barrier (BBB). But the existing R-CHOP therapy and most drugs used for DLBCL cannot penetrate BBB.

Clinical results show that CAR-T cell therapy passes through BBB, but it cannot kill cancer cells effectively in legions in the brain. Much to my disappointment, DLBCL patients with brain metastasis do not have a suitable treatment option. But Xpovio is so small-sized that it can penetrate BBB and kill cancer cells by infiltrating into the cells, some data showed.

Xpovio’s other role could be adjuvant therapy when using CAR-T cell therapy. In advanced nations, accumulated experiences in CAR-T cell therapy led to higher interest in “Beyond CAR-T,” or treatment for patients who relapsed after getting CAR-T cell therapy. Xpovio is one of the treatment candidates.

It takes about six to eight weeks of waiting to get CAR-T cell therapy, and Xpovio is mentioned as a candidate “bridging therapy” that can suppress cancer cells during the waiting time.