by UT Southwestern Medical Center

UT Southwestern researchers (l-r) Farjana Fattah, Ph.D., Mitchell S. von Itzstein, M.D., David E. Gerber, M.D., and Kelly Kyle, B.S., discovered a drug that shows promise in treating non-small cell lung cancer with KRAS mutations. Credit: UT Southwestern Medical Center

An FDA-approved drug used to treat multiple myeloma and lymphoma also shrank tumors in non-small cell lung cancer (NSCLC) with KRAS mutations, a clinical trial led by UT Southwestern Harold C. Simmons Comprehensive Cancer Center researchers showed.

The findings, published in Clinical Cancer Research, could lead to new treatments for a major subset of lung cancer patients.

“This novel treatment appears promising for one of the most common and difficult-to-treat forms of lung cancer,” said David E. Gerber, M.D., Professor of Internal Medicine and in the Peter O’Donnell Jr. School of Public Health. Dr. Gerber, who is also Co-Director of the Office of Education and Training in the Simmons Cancer Center, co-led the study with first author Mitchell S. von Itzstein, M.D., Assistant Professor of Internal Medicine.

More than 234,000 patients will be diagnosed with lung cancer in the U.S. this year, according to the American Cancer Society. About 85% of lung cancer patients have the NSCLC subtype, and about a quarter of NSCLC patients carry mutations in KRAS, a gene frequently mutated in many cancer types, including colorectal cancers, pancreatic cancers, and leukemias.

Despite the long-standing and widespread recognition of KRAS mutations in NSCLC, no targeted therapies for these cancers were available until recently. Furthermore, these treatments work only modestly and only in a subset of KRAS mutations. Sotorasib, approved by the Food and Drug Administration (FDA) in 2021, and adagrasib, approved in 2022, each control cancer for about six months and are used only in 30% of cases with a specific KRAS mutation.

“Effective treatments for KRAS mutant lung cancer remain a major unmet clinical need,” Dr. von Itzstein said.

Several years ago, researchers at UTSW discovered that a drug called selinexor killed cancer cells and decreased tumor size in preclinical models of NSCLC with KRAS mutations, but not in tumors without those mutations.

To test the promise of these findings in cancer patients, Drs. Gerber and von Itzstein and their colleagues recruited 40 individuals with NSCLC harboring various KRAS mutation types. These patients had already received multiple types of cancer treatment, including chemotherapy, immunotherapy, and/or targeted therapies, yet their tumors continued to grow.

The patients started on a weekly oral dose of selinexor, a drug in the class known as nuclear export inhibitors. A week later, patients received docetaxel, a common chemotherapy for NSCLC. Patients underwent periodic imaging to assess tumor size as well as blood tests to assess safety and to look for changes in cancer-related biomarkers.

Treatment caused side effects in most patients, including nausea, fatigue, diarrhea, and a decline in white blood cells known as neutropenia. Despite these side effects, the treatment appeared to control the cancer in about 80% of cases, more than would be expected from docetaxel alone.

Selinexor plus docetaxel appeared to be effective against all types of KRAS mutations. Tumors that did not benefit from treatment were more likely to have inactivating mutations in TP53, a gene that suppresses tumor growth.

Additional data suggested that selinexor had anti-tumor effects on its own before patients received docetaxel, a finding that the researchers plan to test in future clinical trials, Dr. Gerber said.

“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,” he added.

More information: Mitchell S. von Itzstein et al, Phase 1/2 trial of XPO1 inhibitor selinexor plus docetaxel in previously treated, advanced KRAS mutant non-small cell lung cancer, Clinical Cancer Research (2024). DOI: 10.1158/1078-0432.CCR-24-1722

Journal information:Clinical Cancer Research

Provided by UT Southwestern Medical Center

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