Keywords
selinexor - XPO-1 - oncoprotein - multiple myeloma
Introduction
Therapeutic intervention for hematological malignancies has made rapid advancement
in recent years, thanks to discoveries at the molecular level. Selinexor, an orally
active exportin-1 (XPO-1) inhibitor, is the latest to join the armamentarium directed
against recurrent refractory or relapsed multiple myeloma (MM) and diffuse large B
cell lymphoma (DLBCL).[1] Combinations of proteasome inhibitors, immunomodulatory drugs (IMiDs), and monoclonal
antibodies (MABs) produce excellent outcomes, but ultimately patients turn resistant
to these drugs and are termed “triple-class refractory.”[2] Selinexor is a welcome weapon against this group. Similarly, it has also been approved
in patients of DLBCL who progressed on at least two lines of chemotherapy.[3] The compound is also being tested in hard to treat cancers such as soft tissue sarcomas
and glioblastoma.[4]
Development
The first XPO-1 inhibitor, leptomycin B, is a natural compound derived from bacteria,
Streptomyces. It was initially studied for its antifungal properties, and it was only later that
its anticancer properties were discovered. Studies showed that it works by complete
XPO-1 inhibition, which is toxic to organisms. Many semisynthetic XPO-1 inhibitors
were studied after that in the preclinical setting, but none of them proved effective.
Further modifications led to the development of the next-generation compounds called
selective inhibitor of nuclear export (SINE) compounds, which included KPT-185, KPT-
249, KPT-251, KPT-276, and KPT-330. These compounds cause a temporary deterioration
of XPO-1 that was reversible on discontinuation of the SINE compound. Selinexor is
the lead compound of this class.[5]
Mechanism of Action[6]
XPO1 is one of the eight nucleocytoplasmic shuttling proteins involved in the export
of proteins from the nucleus to the cytoplasm. It is a member of the karyopherin B
family and has two main activities.
-
It acts as a carrier for tumor suppressor proteins (TSPs) from the nucleus to the
cytoplasm. These include p53, p21, p73, FOXO1, NPM1, BCR-ABL, BRCA 1 & 2, and IκB-α.
This builds up the activity of TSPs in the nucleus.
-
It plays a major role in the transport of the eukaryotic translation initiation factor
(eIF4E). This factor is responsible for the transport of oncoprotein mRNA like c-Myc,
Pim1, and cyclines. The blockade of XPO1 prevents these oncoprotein mRNAs from exiting
the nucleus. Hence, the translation of oncoprotein is prevented.
XPO1 is overexpressed in multiple cancers, and the activity of XPO1 results in the
functional inactivation of multiple TSPs; XPO1 blockade ensures their nuclear retention.
Oncoprotein translation is inhibited, providing additional benefit. Selinexor thus
induces nuclear accumulation and activation of TSPs while simultaneously reducing
levels of oncoproteins. This leads to transient cell cycle arrest, suppression of
growth of the tumor, and induction of apoptosis with minimal effects on normal lymphocytes.[6]
Indications
Currently, there is U.S. Food and Drug Administration (FDA) approval for relapsed
or refractory MM and DLBCL.
Contraindications
There are no absolute contraindications for this drug.
Pivotal Trials
Selinexor and Backbone Treatment of MM Patients (STOMP) (NCT02343042)
A phase I/II, multicentric, open-label study in MM patients was conducted to determine
the maximum tolerated dose, efficacy, and the safety profile of eight combination
therapies in nine different arms. The population comprised of newly diagnosed multiple
myeloma patients and patients who were relapsed from their treatment. The enrollment
eligibility was that the patient should have received ≥ 1 therapy prior to the trial.
The dose of selinexor was escalated in three regimens: 80 mg once weekly, 60 mg twice
weekly, and 60 mg once weekly, along with low-dose dexamethasone and novel anti-MM
drugs. The novel anti-MM drugs included were pomalidomide (Arm 1), bortezomib (Arm
2), lenalidomide in RRMM (Arm 3), pomalidomide+ bortezomib (Arm 4), daratumumab (Arm
5), carfilzomib (Arm 6), lenalidomide in newly diagnosed multiple myeloma (NDMM) (Arm
7), ixazomib (Arm 8), and pomalidomide + elotuzumab (Arm 9). This study showed that
all the regimens produced good response rates; for instance, the selinexor-pomalidomide-
dexamethasone arm showed a 55% overall response rate (ORR) and 11.6 months median
progression-free survival (PFS).[7] The selinexor-Velcade-dexamethasone arm showed an 83% ORR with a 17.8-month median
PFS.[8] The study is still ongoing.
Selinexor Treatment for Refractory Myeloma (STORM) (NCT02336815)
STORM was a phase 2b, multicentric, open-label study that recruited refractory MM
patients who had received ≥ 4 lines of treatment (i.e., who were refractory to ≥2
IMiD, ≥2 proteasome inhibitors, and an anti-CD38 monoclonal antibody).[9] The single arm study used a combination of selinexor (80 mg) and dexamethasone (20
mg) dosed twice weekly for a 4-week cycle. The response rate was 26%. The major adverse
events included thrombocytopenia, neutropenia, and hyponatremia. FDA approval was
granted for the use of selinexor in this group. The results of the STORM study were
compared with a matched group treated with standard of care (MAMMOTH study)[10] and those treated with selinexor in the STORM study had clear overall survival benefit.
(BOSTON) (NCT03110562)
BOSTON was phase 3, multicentric open-label double arm study, which studied the safety,
efficacy, and the health-related quality of life in RRMM patients. The two arms were
selinexor with bortezomib with low dose of dexamethasone (Arm 1) versus bortezomib
and with low dose dexamethasone (Arm 2). The results showed that the selinexor containing
arm had superior PFS (13.3 vs. 9.46 months). There was a 30% reduction in disease
progression or death (hazard ratio [HR], 0.70; p = 0.0066). FDA approval for using this combination in patients progressing on at
least one line of chemotherapy is awaited.[11]
Selinexor in Relapsed or Refractory Diffuse Large Cell Lymphoma (DLBCL) (SADAL) (NCT02227251)
In a phase 2 trial called SADAL, 127 patients were enrolled in this study who were
either relapsed or refractory DLBCL patients, who were not eligible for transplant
or either progressed after a transplant was administered with monotherapy of selinexor.[10] The trial showed a response rate of 28% with 12% CR and 17% PR. The response rate
was comparatively better in the germinal center B (GCB) cell type (33.9%) than in
non-GCB (20.6%) type. The median overall survival and PFS of the study were 9.1 and
3.6 months, respectively. And it was based on the trial FDA approved the drug for
use in relapsed or refractory DLBCL who had received at least 2 lines of therapy.[3]
Selinexor in Advanced Liposarcoma (SEAL) (NCT02606461)
Selinexor in advanced liposarcoma (SEAL) is a randomized, double-blind, placebo-controlled,
multicenter phase 2/3 trial. The drug was administered twice a week, with a fixed
dose of 60 mg. The study population was patients who were on at least two lines of
systemic treatment for liposarcoma. When compared with the placebo, an improved PFS
was observed with a 30% reduction in the disease progression risk or death (HR, 0.70;
p =0.023). FDA approval is awaited for this indication.12
Pharmacokinetics
Selinexor reaches the maximum concentration (Cmax) within 4 hours of administration, and the absorption of the drug is not affected
by the presence of food. Selinexor undergoes hepatic metabolism by CYP3A4, UDP-glucuronosyltransferases,
and glutathione S transferases.[6]
Dosage and Administration
Dosage and Administration
The recommended dose for relapsed or refractory multiple myeloma is 80 mg once daily
on day 1 and 3 of every week along with 20 mg dexamethasone until disease progression
or unacceptable toxicity.[1] However, in DLBCL, the dose is 60 mg on day 1 and day 3 every week until disease
progression or unacceptable toxicity.[3] It can be taken with or without food.
Adverse Events
Other than hematological toxicities common with anticancer medicines (especially thrombocytopenia),
selinexor can cause hyponatremia,[3] gastrointestinal, and neurological toxicities (such as altered sensorium). Most
of the side effects were grade 1/2 and reversible.
Dose Modifications
According to the manufacturer label, there is no dosage modification for renal and
hepatic impairment. There was no significant difference observed in the pharmacokinetics
of the drug in this impairment.
Special Considerations
Like any chemotherapy drug, selinexor can be teratogenic and impair fertility. Contraceptive
measures are recommended for women of reproductive age as long as they are on this
drug and for a week after that.[1]
Cost-Effectiveness
The drug is not available in the Indian market.
Ongoing Clinical Trials
There are three ongoing clinical trials–XPORT-DLBCL-030 (NCT04442022), SIENDO (NCT03555422),
and SPRINT (NCT04256707), the details of which are given in [Table 1].
Table 1
Ongoing clinical trials
|
Trial name
|
Year of starting the trial
|
Phase
|
Treatment
|
Study population
|
|
Abbreviation: DLBCL, diffuse large B cell lymphoma.
|
|
XPORT-DLBCL-030 (NCT04442022)
|
2020
|
2
3
|
Arm 1 − selinexor + R-GDP
Arm 2 − placebo
Arm 1 − selinexor + R-GDP
Arm 2 − R-GDP + placebo
|
DLBCL
|
|
SIENDO (NCT03555422)
|
2018
|
3
|
Arm 1–selinexor
Arm 2 − placebo
|
Endometrial carcinoma
|
|
SPRINT (NCT04256707)
|
2020
|
1
|
Arm 1 − selinexor
Arm 2 − selinexor + docetaxel + pembrolizumab
|
Take-Home Points
-
Selinexor is an orally active XPO1 inhibitor.
-
It is approved in RRMM at a dose of 80 mg biweekly till progression or toxicity.
-
It is approved in RRDLBCL at a dose of 60 mg biweekly till progression or toxicity.
-
Side effects to watch for include thrombocytopenia and hyponatremia.
Conclusions
Selinexor is a welcome addition for the treatment of relapsed or refractory multiple
myeloma and diffuse large cell lymphoma as an orally active drug with reasonable toxicities.
The good safety profile allows it to be combined with other classes of drugs, and
it is expected that ongoing trials in other refractory cancers such as gynecological
malignancies and glioblastoma will reveal its true potential. Interestingly, it is
even being investigated as a treatment for COVID-19 infection.
