Oral selinexor demonstrated durable activity and a 28% response rate in patients with previously treated relapsed and refractory diffuse large B-cell lymphoma (DLBCL), according to results from the phase II SADAL trial recently published in Lancet Hematology. Study authors, led by Nagesh Kalakonda, PhD, MBBS, of the University of Liverpool in England, suggested that selinexor could represent a new non-cytotoxic treatment option for this patient population.
Results from this trial supported the FDA’s accelerated approval on June 22 of selinexor for the treatment of adults with relapsed or refractory DLBCL after at least 2 lines of systemic therapy, but critics contest that the treatment is associated with only modest activity and high adverse event burden, with an unknown effect on survival or quality of life.
“Selinexor is often presented as a ‘chemotherapy-free’ option, which would be appealing if only it were true,” said David Iberri, MD, of Stanford Medicine in California, when asked to comment on the findings of the SADAL trial. “Advanced supportive care measures are often needed in patients receiving selinexor, and these are not unlike those typically reserved for patients receiving conventional cytotoxic chemotherapy.”
The open-label, multicenter, phase II SADAL trial enrolled adults with pathologically confirmed DLBCL at 59 sites across 19 countries. All recruited patients had an Eastern Cooperative Oncology Group performance status of ≤2, had been previously treated with 2 to 5 lines of therapy, and had either progressed after or were deemed ineligible for an autologous hematopoietic cell transplantation.
Patients received oral selinexor 60 mg twice weekly until either disease progression or unacceptable toxicity. Initially, the study design included a 60 mg and 100 mg twice-weekly dosing schedule, but the 100-mg dose was discontinued following the observation of an improved tolerability with the 60-mg dose, the investigators noted. Although the target selinexor dose was 120 mg per week, due to dose reductions, the actual weekly median average dose was 100 mg.
A total of 127 patients, with a median age of 67 years, were included in the analysis. Patients had a median of 2.7 years between initial DLBCL diagnosis and start of selinexor. During follow-up, 118 patients (93%) discontinued therapy because of either disease progression (n=80), death (n=9), physician decision (n=7), adverse event (AE; n=9), or patient withdrawal (n=13).
The objective response rate (ORR), the study’s primary endpoint, was 28.3%, including a complete response (CR) rate of 11.8% and a partial response (PR) rate of 16.5%. The median duration of response (DOR) over the 11.1-month median follow-up period was 9.3 months. In patients who achieved CR, the median DOR was 23.0 months; in patients who achieved PR, the median DOR was 4.4 months.
At the last disease assessment and prior to the data cutoff date, a total of 9 patients (7%) had ongoing response, including 7 with ongoing CR and 2 with ongoing PR.
Median progression-free and overall survival (OS), the study’s secondary endpoints, were 2.6 months and 9.1 months, respectively. The median OS was not reached in patients with a response, the authors reported. In contrast, the median OS was 4.3 months in patients with progressive disease or who were not evaluable for response.
In terms of safety, the most common grade 3/4 AEs included thrombocytopenia (46%), neutropenia (24%), anemia (22%), fatigue (11%), hyponatremia (8%), and nausea (6%). The most common serious AEs were pyrexia (7%), pneumonia (5%), and sepsis (5%). There were 5 deaths attributable to treatment-emergent AEs, but none of the investigators judged any of the deaths as related to selinexor.
“There are no direct comparisons of the toxicity profiles of selinexor versus other conventional therapies, but based on the toxicities described with selinexor in the STORM trial for relapsed/refractory myeloma and the SADAL trial in DLBCL, it is likely that gastrointestinal toxicities are more frequent with selinexor than with other commonly used regimens such as gemcitabine- or bendamustine-based regimens, lenalidomide plus rituximab, and others,” Dr. Iberri said.
Dr. Iberri added that the SADAL trial findings also are limited by the study’s single-arm design and somewhat restrictive inclusion criteria. “Also, the fact that some patients had at least 98 days between last systemic therapy and study enrollment necessarily selects for a rarified group of patients with relapsed/refractory DLBCL with indolent biology, which is not representative of most patients seen in clinic,” he told ASH Clinical News.
Although the SADAL findings led to selinexor’s regulatory approval, the study’s primary endpoint of ORR means that until longer-term data and comparative data are available, “clinicians lack the data necessary to have an informed discussion with patients regarding potential benefits and risks of selinexor versus other regimens,” Dr. Iberri noted. “In my opinion, FDA approval should have been deferred until efficacy could be confirmed in a randomized phase III study with the primary endpoint of OS.”
The randomized phase III study of R-GDP (rituximab-gemcitabine-dexamethasone-platinum) plus selinexor or placebo (NCT04442022) is “a step in the right direction,” Dr. Iberri added.
Study authors report relationships with Karyopharm Therapeutics, which sponsored this trial.
Kalakonda N, Maerevoet M, Cavallo F, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020;7:e511-e522.