In patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), nearly 30% responded to treatment with the selective inhibitor of nuclear export selinexor (Xpovio), a single-arm phase IIb trial showed.
In SADAL, 28% of the 127 patients with two to five lines of prior therapy responded to the twice-weekly 60-mg dose of the drug (a 100-mg arm was discontinued), with 12% of patients achieving complete response, according to Nagesh Kalakonda, MBBS, of the University of Liverpool in England, and colleagues. Results were published in the Lancet Hematology.
“When looking at people with large cell lymphoma who have failed standard therapy including transplant, the outcome is pretty dismal,” said Stephen Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, who was not involved with the study. “Even though response rates were modest, having a new class of drug with activity is what makes this interesting.”
Ansell noted that some of the responses were durable.
Among all patients, the median duration of response was 9.3 months. However, among those with a complete response, this increased to 23.0 months. Of the patients who achieved partial or complete response, 38% had a response for at least 6 months and 15% had a response for at least 1 year.
Based on the results of SADAL, the FDA last week granted accelerated approval to selinexor for treating relapsed or refractory DLBCL following at least two lines of systemic therapy.
According to Joshua Brody, MD, of the Tisch Cancer Institute at Mount Sinai, the approval of selinexor for relapsed/refractory DLBCL is exciting because the drug targets a “completely novel pathway” with a “new way to kill lymphoma cells.”
“XPO1 inhibition, which may decrease nuclear localization of critical oncoproteins like Myc, BCL2, or BCL6, is a very different way to starve lymphoma cells of the signals they require to proliferate and survive,” Brody told MedPage Today.
A subgroup analysis looking at disease subtype showed overall response rates of 34%, 20%, and 60% for patients with germinal center B-cell (GCB) subtype, patients with non-GCB subtype, and those with unclassified disease, respectively. Additionally, the response rate was 13% among patients with high levels of c-Myc compared with 42% in patients with low levels of c-Myc expression (P=0.002).
In an editorial that accompanied the study, Annalisa Chiappella, MD, and Paolo Corradini, MD, both of the Istituto Nazionale dei Tumori in Milan, Italy, pointed out the importance of even a subset of tumors overexpressing c-Myc responding to selinexor.
“Moreover, selinexor activity seems to be independent of the cell’s origin; this finding has clinical relevance because there are numerous novel drugs focused on activated B-cell subtype,” they wrote.
Brody agreed, adding that although “the monotherapy efficacy against DLBCL is moderate, the potential to have greater efficacy in particular patient subsets may be a great opportunity moving forward, as well as the potential to have higher potency in combination with immunotherapies such as rituximab.”
Treatment with selinexor was not without adverse effects: 98% of patients had at least one treatment-emergent adverse event. The most common grade 3 or 4 adverse events were thrombocytopenia (46%), neutropenia (24%), anemia (22%), fatigue (11%), hyponatremia (8%), and nausea (6%). Additionally, 80% of patients experienced gastrointestinal toxicity, and 61% had any grade hyponatremia. The researchers noted that these were typically reversible with standard supportive care or dose modification, which was necessary in 70% of patients.
Serious adverse events occurred in almost half (48%) of patients, and there were five deaths due to treatment-emergent adverse events.
Concerns about risk/benefit ratio plagued selinexor in its journey for approval in refractory multiple myeloma. In myeloma, thrombocytopenia and fatigue were commonly reported adverse events, in addition to gastrointestinal issues.
In the trial used as the basis for selinexor’s approval in myeloma, almost 30% of patients discontinued treatment because of toxicity. In SADAL, 17% of patients withdrew because of adverse events.
“With many agents given over a long course of time and given on an ongoing basis, tolerability is the challenge,” Ansell said. “In myeloma, gastrointestinal toxicities, hyponatremia, and other issues proved to be quite challenging.”
Clinicians will have to monitor for these things over time, Ansell noted, and work with patients to obtain an optimal dose.
The study included 267 patients randomly assigned to the 60-mg (n=175) or the 100-mg discontinued arm (n=92). The median age of patients was 67 years, and 45% of patients were older than 70.
The median time from initial DLBCL diagnosis to selinexor treatment was 2.7 years. About half of patients had two prior lines of therapy and half had three prior lines.
At a median follow-up of 14.7 months, the median progression-free survival was 2.6 months and median overall survival was 9.1 months. Median overall survival was not yet reached among those patients who responded to the drug.
The researchers noted that administration of selinexor allowed three patients who had previously progressed after autologous stem cell transplantation to become eligible for CAR T-cell therapy, further highlighting “the activity and clinical benefit of selinexor in patients with high-risk disease who can achieve responses and can enable chimeric antigen receptor T-cell therapy.”
Finally, FDA accelerated approval requires confirmatory trials to be conducted.
Ansell speculated that FDA may require a confirmatory trial comparing selinexor against another agent felt to be a standard of care in this treatment space to see if it provides additional benefit. Confirmatory trials may also combine selinexor with other active agents in earlier lines of treatment for DLBCL.
Kalakonda reported research support from Celgene, Gilead, Roche, and Verastem, and honoraria from Gilead, Janssen, and Karyopharm. His co-authors reported personal fees, and honoraria from various industry entities.
Corradini has been on advisory boards for AbbVie, Amgen, Celgene, Daiichi Sankyo, Gilead, Incyte, Janssen, Kite, Kyowa Kirin, Novartis, Roche, Sanofi, Servier, and Takeda; and has received honoraria for lectures from AbbVie, Amgen, Celgene, Janssen, Jazz Pharmaceuticals, Novartis, Roche, Sanofi, Sandoz, and Takeda. Chiappella has been on advisory boards for Celgene, Gilead-Kite, Janssen, iQone, and Takeda; and has received honoraria for lectures from Celgene, Gilead-Kite, Janssen, Roche, and Servier.
Ansell and Brody had no relevant conflicts of interest.