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Phase I/II Trial of Exportin 1 Inhibitor Selinexor plus Docetaxel in Previously Treated, Advanced KRAS-Mutant
Mitchell S von Itzstein1, Timothy F Burns2, Jonathan E Dowell1
1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
Purpose:
Patients with Kirsten rat sarcoma viral oncogene (KRAS)-mutant non-small cell lung cancer (NSCLC) have limited therapeutic options. Based on the activity of nuclear export inhibition in preclinical models, we evaluated this strategy in previously treated, advanced KRAS-mutant NSCLC.
Patients And Methods:
The primary outcomes of this multicenter phase I/II dose-escalation trial of selinexor plus docetaxel were safety and tolerability. Selinexor was started 1 week before docetaxel to permit monotherapy pharmacodynamic assessment.
Results:
Among 40 enrolled patients, the median age was 66 years, 55% were female, and 85% were White. The MTD was selinexor 60 mg orally weekly plus docetaxel 75 mg/m2 every 3 weeks. The most common adverse events were nausea (73%, 8% grade ≥3), fatigue (70%, 5% grade ≥3), neutropenia (65%, 60% grade ≥3), and diarrhea (58%, 10% grade ≥3). Of 32 efficacy-evaluable patients, 7 (22%) had partial responses and 18 (56%) had stable disease. Outcomes were not associated with KRAS mutation type but were significantly better in cases with wild-type TP53 (42%), including response and disease control rates (27% and 80% vs. 9% and 27%, respectively; P = 0.03) and progression-free survival (median 7.4 vs. 1.8 months; HR, 0.2; 95% confidence interval, 0.07-0.67; P = 0.003). After selinexor initiation and prior to docetaxel administration, serum lactate dehydrogenase levels increased an average of 51 U/L in TP53-altered cases and decreased an average of 48 U/L in TP53 wild-type cases (P = 0.06).
Conclusions:
Selinexor plus docetaxel was relatively well tolerated in patients with advanced KRAS-mutant NSCLC. The regimen has promising efficacy in TP53 wild-type cases, in which selinexor monotherapy may also have activity.
Insights
Selinexor plus docetaxel shows promise for advanced KRAS-mutant non-small cell lung cancer (NSCLC). Efficacy was notably higher in patients with wild-type TP53, suggesting a potential targeted therapy approach.
Area of Science:
- Oncology
- Medical Research
- Clinical Trials
Background:
- Limited therapeutic options exist for patients with Kirsten rat sarcoma viral oncogene (KRAS)-mutant non-small cell lung cancer (NSCLC).
- Nuclear export inhibition has shown preclinical activity, prompting evaluation in advanced NSCLC.
Purpose of the Study:
- To assess the safety and tolerability of selinexor plus docetaxel in previously treated, advanced KRAS-mutant NSCLC.
- To evaluate the efficacy of this combination regimen, particularly in relation to TP53 status.
Main Methods:
- A multicenter phase I/II dose-escalation trial was conducted.
- Selinexor was administered weekly for one week prior to docetaxel (every 3 weeks) to allow for monotherapy pharmacodynamic assessment.
- Safety, tolerability, and efficacy (response rates, progression-free survival) were primary outcomes.
Main Results:
- The maximum tolerated dose (MTD) was determined as selinexor 60 mg weekly plus docetaxel 75 mg/m2 every 3 weeks.
- Common adverse events included nausea, fatigue, neutropenia, and diarrhea.
- Among 32 efficacy-evaluable patients, 7 (22%) had partial responses and 18 (56%) had stable disease.
- Outcomes were significantly better in patients with wild-type TP53 compared to those with TP53 alterations (e.g., progression-free survival: 7.4 vs. 1.8 months).
Conclusions:
- Selinexor plus docetaxel is relatively well tolerated in advanced KRAS-mutant NSCLC.
- The combination demonstrates promising efficacy in the subset of patients with wild-type TP53.
- Selinexor monotherapy may also possess activity in TP53 wild-type NSCLC.
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