An FDA-approved drug, selinexor, typically used for multiple myeloma and lymphoma, has demonstrated promising efficacy in treating non-small cell lung cancer (NSCLC) with KRAS mutations. A clinical trial conducted by researchers at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center revealed that selinexor shrank tumors in NSCLC patients harboring KRAS mutations. The findings, published in Clinical Cancer Research, suggest a potential new treatment avenue for a significant subset of lung cancer patients.
Addressing an Unmet Need in NSCLC
Lung cancer remains a major health challenge, with over 234,000 new diagnoses expected in the U.S. this year. NSCLC accounts for approximately 85% of lung cancer cases, and about 25% of NSCLC patients have mutations in the KRAS gene. While KRAS mutations have long been recognized in NSCLC, targeted therapies have only recently become available, and their efficacy is limited. Sotorasib and adagrasib, approved in 2021 and 2022 respectively, provide cancer control for about six months but are effective in only 30% of cases with a specific KRAS mutation.
"Effective treatments for KRAS mutant lung cancer remain a major unmet clinical need," said Dr. Mitchell S. von Itzstein, Assistant Professor of Internal Medicine at UT Southwestern.
Selinexor's Efficacy in KRAS-Mutated NSCLC
Prior preclinical studies at UTSW indicated that selinexor could kill cancer cells and reduce tumor size in NSCLC models with KRAS mutations. To evaluate these findings in patients, researchers enrolled 40 individuals with NSCLC harboring various KRAS mutation types. These patients had previously undergone multiple lines of treatment, including chemotherapy, immunotherapy, and/or targeted therapies, but their tumors continued to progress.
The trial involved a weekly oral dose of selinexor, a nuclear export inhibitor, followed by docetaxel, a standard chemotherapy for NSCLC, one week later. Tumor size was monitored through periodic imaging, and blood tests were conducted to assess safety and changes in cancer-related biomarkers.
Clinical Trial Results
While most patients experienced side effects such as nausea, fatigue, diarrhea, and neutropenia, the treatment regimen appeared to control the cancer in approximately 80% of cases, a rate higher than expected with docetaxel alone. The combination of selinexor and docetaxel demonstrated efficacy across various KRAS mutation types. Tumors that did not respond to treatment were more likely to have inactivating mutations in TP53, a tumor suppressor gene.
"Our results suggest that selinexor could be a useful addition to our toolbox to treat lung cancer and could offer hope for other cancers with KRAS mutations," added Dr. Gerber.
Further data indicated that selinexor exhibited anti-tumor activity independently before the administration of docetaxel, a finding that researchers plan to investigate in future clinical trials.
