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Clinical Trial
. 2025 Feb 17;31(4):639-648.
doi: 10.1158/1078-0432.CCR-24-1722.

Phase I/II Trial of Exportin 1 Inhibitor Selinexor plus Docetaxel in Previously Treated, Advanced KRAS-Mutant Non-Small Cell Lung Cancer

Mitchell S von Itzstein  1 , Timothy F Burns  2 , Jonathan E Dowell  1 , Leora Horn  3 , D Ross Camidge  4 , Sally J York  3 , Keith D Eaton  5 , Kelly Kyle  1 , Farjana Fattah  1 , Jialiang Liu  1 , Hong Mu-Mosley  1 , Arjun Gupta  6 , Urooba Nadeem  1 , Ang Gao  1 , Song Zhang  1 , David E Gerber  1
Affiliations
Clinical Trial

Phase I/II Trial of Exportin 1 Inhibitor Selinexor plus Docetaxel in Previously Treated, Advanced KRAS-Mutant Non-Small Cell Lung Cancer

Mitchell S von Itzstein et al. Clin Cancer Res. .

Abstract

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.

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Conflict of interest statement

T.F.B reports he serves or has served on the following scientific advisory board in the last 24 months: Janssen Scientific Affairs, LLC, Amgen, AstraZeneca, Eli Lilly and Company and Takeda Pharmaceuticals U.S.A., Inc. He has served as a consultant for Eli Lilly and Company and Pfizer, Inc. He serves on a DSMB for Advarra, Inc (Lantern Pharma). He has received research support from Novartis.

J.E.D reports consulting funds from Catalyst; research funding from Novocure, SeaGen, Verastem, and Lantern.

L.H is an employee of AstraZeneca.

D.R.C. reports serving on the advisory boards and/or consulting for the following in the last 36 months: Abbvie, Amgen, Anheart, Apollomics, AstraZeneca, Aveo, Beigene, Bio-Thera, Blueprint, BMS, Coherus, Daiichi-Sankyo, Dizal, Eli Lilly, EMD Serono, Elevation, Genentech, Gilead, Helsinn, Hengrui, Hummingbird, Imagene, Immunocore, Janssen, Kestrel, Lianbio, Merck KGa, Medtronic, Mersana, Mirati, Nalo Therapeutics, Onkure, Newsoara, Nextcure, Nuvalent, Prelude, Puma, Regeneron, Ribon, Roche, Sanofi, Seattle Genetics, Sutro, Takeda, Theseus, Turning Point, Valence, Xencor, Xcovery.

D.E.G. reports consulting fees from Catalyst Pharmaceuticals; U.S. patent 11,747,345; pending patents 17/045,482, 18/504,868, 63/386,387, 63/382,972, and 63/382,257; research funding from AstraZeneca, Karyopharm, and Novocure; participating in advisory boards for Astra-Zeneca, Daiichi-Sankyo, Elevation Oncology, Janssen Scientific Affairs, Jazz Pharmaceuticals, Regeneron Pharmaceuticals, and Sanofi; stock shares in Gilead; and serving as co-founder and Chief Medical Officer of OncoSeer Diagnostics, Inc. The remaining authors declare no potential conflicts of interest.

Figures

Figure 1.
Figure 1.. Radiographic response according KRAS mutation type.
(a) Waterfall plot. (b) Spider plot. *Patient remained on therapy for 163 weeks.
Figure 2.
Figure 2.. Radiographic response according to TP53 status.
(a) Waterfall plot. (b) Spider plot. *Patient remained on therapy for 163 weeks.
Figure 3.
Figure 3.. Progression-free and overall survival.
(a) Entire cohort. (b) KRAS G12C vs. KRAS non-G12C mutations. (c) TP53 altered vs. TP53 wild type.
See this image and copyright information in PMC

Comment in

References

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