On June 22, 2020, the oral nuclear export inhibitor selinexor was granted accelerated approval for treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy.^1,2

Supporting Efficacy Data

Approval was based on findings in the multicenter, single-arm SADAL trial (KCP-330-009; ClinicalTrials.gov identifier NCT02227251),^2,3 in which 134 patients who had received two to five prior systemic regimens were treated with oral selinexor at 60 mg on days 1 and 3 of each week.  

Patients had to have an absolute neutrophil count ≥ 1,000/μL, platelet count ≥ 75,000/μL, hepatic transaminases ≤ 2.5 times the upper limit of normal (ULN) unless abnormal from lymphoma, and bilirubin ≤ two times ULN. Antiemetic prophylaxis with a 5HT-3 receptor antagonist was required. Patients could not be candidates for autologous hematopoietic stem cell transplantation (HSCT) and had to have had a minimum of 60 days since their last systemic therapy, or a minimum of 98 days in patients with refractory disease (defined as less than partial response to their last systemic therapy).

The median patient age was 67 years (range = 35–91 years); 59% were male, 79% were White, 7% were Asian, and 88% had an Eastern Cooperative Oncology Group performance status of 0 or 1. Diagnosis was de novo DLBCL, not otherwise specified, in 75% and transformed DLBCL in 23%. The median number of prior systemic therapies was two (range = 1–5), with 63% receiving two prior systemic therapies; 24%, three prior therapies; and 10%, four or five prior therapies. Overall, 28% had refractory disease to the most recent therapy, and 30% had prior autologous HSCT. The median time from the last systemic therapy to the start of treatment with selinexor was 5.4 months overall and 3.6 months in patients with refractory disease.

Efficacy was based on overall response rate and response duration, as assessed by an independent review committee using Lugano 2014 criteria. In 134 patients, the overall response rate was 29% (39 patients; 95% confidence interval [CI] = 22%–38%), with a complete response in 13% (18 patients). Among the 39 patients with a partial or complete response, response duration was at least 6 months in 38% and at least 12 months in 15%.

How It Works

In nonclinical studies, selinexor reversibly inhibits nuclear export of tumor-suppressor proteins, growth regulators, and mRNAs of oncogenic proteins by blocking exportin 1 (XPO1). XPO1 inhibition by selinexor leads to accumulation of tumor-suppressor proteins in the nucleus, reduction in several oncoproteins (such as c−Myc and cyclin D1), cell-cycle arrest, and apoptosis of cancer cells. Selinexor demonstrated proapoptotic activity in vitro in multiple myeloma cell lines and showed antitumor activity in murine xenograft models of multiple myeloma and DLBCL.

How It Is Used

The recommended dosage of selinexor in DLBCL is 60 mg orally on days 1 and 3 of each week until disease progression or unacceptable toxicity. Antiemetic prophylaxis should be administered; a 5-HT3 receptor antagonist and other antinausea agents should be given prior to and during treatment.

Patients should undergo monitoring for complete blood cell count with differential, standard blood chemistries, body weight, nutritional status, and volume status at baseline and during treatment as clinically indicated, and they should be monitored more frequently during the first 3 months of treatment. The need for dosage modifications for adverse reactions should be routinely assessed. Patients should be advised to maintain adequate fluid and caloric intake throughout treatment; intravenous hydration should be considered for patients at risk of dehydration. Sodium levels should be monitored throughout treatment, with correction for concurrent hyperglycemia and high serum paraprotein levels.

Recommended dose reductions for selinexor for adverse reactions are sequentially to 40 mg on days 1 and 3 of each week, 60 mg once weekly, and 40 mg once weekly. Treatment should be discontinued in patients requiring further dose reduction.

Prescribing information provides detailed instructions on dosage modification and management of thrombocytopenia, neutropenia, anemia, nausea and vomiting, diarrhea, weight loss and anorexia, hyponatremia, fatigue, ocular toxicity, and other grade 3 or 4 nonhematologic adverse reactions.

Safety Profile

In the SADAL trial, the median duration of selinexor treatment was 2.1 months (range = 1 week–3.7 years), with 38% of patients receiving at least 3 months of treatment and 22% receiving at least 6 months. Median exposure was 100 mg per week.

The most common adverse events of any grade (≥ 20%) were fatigue (63%), nausea (57%), diarrhea (37%), appetite decrease (37%), weight decrease (30%), constipation (29%), vomiting (28%), and pyrexia (22%). The most common grade 3 or 4 adverse events included fatigue (15%), pyrexia (4.5%), appetite decrease (3.7%), and mental status changes (3.7%). The most common grade 3 or 4 laboratory abnormalities were thrombocytopenia (49%), lymphopenia (37%), neutropenia (31%), anemia (25%), and hyponatremia (16%).

Serious adverse events occurred in 46% of patients, with the most common being infection (21%). Adverse reactions led to dose interruption in 61% of patients and dose reduction in 49%, with 17% of patients having two or more dose reductions. The most common causes of dose interruption or reduction were thrombocytopenia (40%), neutropenia (16%), fatigue (16%), nausea (10%), and anemia (10%). The median time to the first dose reduction or interruption was 4 weeks.

Treatment was discontinued due to adverse events in 17% of patients, with causes in at least 2% of patients including infection, fatigue, thrombocytopenia, and nausea. Fatal adverse events occurred in 3.7% of patients within 30 days and in 5% of patients within 60 days of the last treatment, with the most common cause being infection (4.5%).

Selinexor has warnings/precautions for thrombocytopenia; neutropenia; gastrointestinal toxicity, including nausea, vomiting, diarrhea, anorexia, and weight loss; hyponatremia; serious infections; neurologic toxicity; and embryofetal toxicity. Patients should be advised not to breastfeed while receiving selinexor. 

References

1. U.S. Food and Drug Administration: FDA approves selinexor for relapsed/refractory diffuse large B-cell lymphoma. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selinexor-relapsedrefractory-diffuse-large-b-cell-lymphoma. Accessed July 7, 2020.

2. Xpovio (selinexor) tablets prescribing information, Karyopharm Therapeutics Inc, June 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212306s001lbl.pdf. Accessed July 7, 2020.

3. 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 7:e511-e522, 2020.