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Sendino et al. Cancer Drug Resist 2018;1:139-63 I http://dx.doi.org/10.20517/cdr.2018.09 Page 153
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60 mg/m . The most common grade 3 or 4 toxicities in this series were thrombocytopenia, neutropenia,
anemia, leukopenia, fatigue, and hyponatremia. Twenty-two objective responses (4 of them complete re-
sponses) were observed in 70 evaluable patients. The authors concluded that Selinexor shows encouraging
2
activity in NHL patients, and proposed 35 mg/m Selinexor (60 mg flat dose) as the RP2D.
[197]
Garzon et al. carried out a phase I dose-escalation study in 95 patients with relapsed or refractory acute
myeloid leukemia (AML). Several doses and administration schedules were tested. The most common
grade 3 or 4 toxicities were thrombocytopenia, anemia, fatigue, and neutropenia. Objective responses were
observed in 11 of the 81 evaluable patients. The authors concluded that Selinexor is a safe therapy in AML
patients, and established the RP2D at 35 mg/m (60 mg flat dose) given twice weekly. Another phase I dose-
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escalation trial in AML evaluated the combination of Selinexor with high-dose cytarabine and mitoxan-
[198]
trone in 20 patients . Selinexor doses of 60 mg or 80 mg were administered. Serious toxicities, including
one fatal adverse event, occurred in 30% of the patients. The overall response rate was 70%, including 10
patients achieving complete remission. The authors concluded that Selinexor combined with high-dose
cytarabine and mitoxantrone is a feasible and tolerable treatment in AML patients, and proposed 80 mg
Selinexor twice weekly as the RP2D in this combination.

[199]
Chen et al. evaluated Selinexor in 84 patients with heavily pretreated MM (81 patients) or Waldenstrom
macroglobulinemia (3 patients). Single agent Selinexor was given to 25 patients in the dose-escalation
phase. In the dose-expansion phase, Selinexor was administered in combination with dexamethasone to 59
patients. The most commonly reported grade 3 or 4 toxicity in this series was thrombocytopenia. Although
the efficacy of Selinexor as single agent was modest, its combination with dexamethasone resulted in a
significantly increased activity, with an objective response rate of 50%. The authors proposed a RP2D of
80 mg Selinexor plus 20 mg dexamethasone given twice weekly. This treatment regimen was administered
to 79 patients with multi-refractory MM in a recently reported phase II study [200] . The overall response rate
(the primary endpoint of the study) was 21% and the most frequent grade 3 or 4 toxicity was thrombocyto-
penia. In relation to these studies, a more extensive and detailed discussion on the clinical implementation
[189]
of Selinexor in MM has been recently published .

The last clinical study on Selinexor published to date (May 2018) is a phase II trial that evaluated its efficacy
and tolerability in 14 patients with metastatic, castration-resistant, prostate cancer [201] . Selinexor was ad-
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ministered twice weekly at a dose of 65 mg/m that had to be subsequently reduced to a flat dose of 60 mg
to improve tolerability. In fact, although Selinexor showed some evidence of clinical activity (reduction in
prostate-specific antigen levels, and radiographic response), it was poorly tolerated in this patient population.

In summary, the results of these studies show that Selinexor, as single agent or in combination with other
drugs, has broad clinical activity in multiple types of solid tumors and hematological malignancies and is
generally well tolerated by patients. One of the most common high-grade toxicities experienced by patients
treated with Selinexor is thrombocytopenia. The mechanism underlying this adverse event has been re-
[202]
cently elucidated. Machlus et al. have shown that thrombocytopenia results from reduced maturation of
megakaryocyte progenitors due to Selinexor-mediated inhibition of thrombopoietin signaling. Important-
ly, the severity of thrombocytopenia could be reduced by temporary interruption of Selinexor treatment
[202]
and administration of thrombopoietin mimetics to patients .

Altogether, these clinical data support the view that inhibition of XPO1 represents a valid therapeutic strat-
egy in cancer.

CONCLUSION AND FUTURE DIRECTIONS
Twenty years after its identification as a receptor that mediates the nuclear export of proteins, there is com-
pelling evidence that XPO1 represents a relevant target in cancer. Further basic, preclinical and clinical in-