Ganetespib Showed Activity in KRAS-Mutant NSCLC as Monotherapy and in Combinations
- Novel Hsp90 inhibitor shows activity in slowing KRAS-mutant NSCLC tumor cell growth.
- Use with traditional chemotherapy resulted in increased cancer cell death.
- Phase 2b/3 trial combined with docetaxel under way.
SAN DIEGO — The investigational drug ganetespib, a synthetic second-generation Hsp90 inhibitor, slowed the growth of cancer cells taken from non-small cell lung cancer tumors with a mutation in the KRAS gene. The drug was even more active when combined with traditional lung cancer treatments and other investigational targeted therapies, according to preclinical study data.
David A. Proia, Ph.D., and Jaime Acquaviva, Ph.D., scientists at Synta Pharmaceuticals Corp., presented the data at the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer: Biology, Therapy and Personalized Medicine, held Jan. 8-11, 2012.
Currently, patients with non-small cell lung cancer (NSCLC) with KRAS mutations have no effective treatment strategy. A phase 2 trial showed tumor shrinkage in more than 60 percent of patients with KRAS-mutant NSCLC at eight weeks after treatment with ganetespib administered once weekly as a monotherapy, indicating the drug’s potential effectiveness, according to Proia.
He and his colleagues examined whether ganetespib was effective against several different cell lines of KRAS-mutant NSCLC and confirmed it was effective in 15 different cell lines. They then sought to determine which combination treatments would enhance the activity of ganetespib in this cancer type.
First, the researchers combined ganetespib with several standard-of-care chemotherapies currently available in the clinic for KRAS-mutant NSCLC tumor samples. They found that the combination of ganetespib with alkylating agents, antimitotics and topoisomerase inhibitors resulted in an increased cell death of 1.4-, 1.5- and 2.6-fold, respectively, compared with ganetespib alone.
“We saw great activity with, for example, docetaxel and [ganetespib],” Proia said. “What we are doing now is conducting a large phase 2b/phase 3 trial with docetaxel and [ganetespib] in NSCLC patients. Activity in the KRAS-mutant subpopulation is a coprimary endpoint in this trial.”
The researchers also tested ganetespib in combination with two therapies that target pathways known to be involved in NSCLC: a MEK inhibitor or a PI3K/mTOR inhibitor. Results in tumor samples revealed that combining ganetespib with either therapy was also more active in slowing tumor growth compared with ganetespib alone.
“Not only was ganetespib activity enhanced in combination with traditional chemotherapies, which may be understood in terms of the ability of Hsp90 inhibition to block certain resistance or repair mechanisms, but activity was also enhanced in combination with a number of targeted therapies for which recent work has shown very interesting complementary inhibition of signaling pathways,” Proia said.
Finally, the researchers further validated their results by combining ganetespib with the PI3K/mTOR inhibitor in mice with KRAS-mutant NSCLC. Both drugs alone promoted tumor shrinkage, but the combination resulted in a greater inhibition of tumor growth.
If further validated, this research could open up avenues for future treatment options for patients with KRAS-mutant NSCLC.
About the AACR:
The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, the AACR is the world’s oldest and largest professional organization dedicated to advancing cancer research. The membership includes 33,000 laboratory, translational and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 90 other countries. The AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants, research fellowships and career development awards to young investigators, and it also funds cutting-edge research projects conducted by senior researchers. The AACR has numerous fruitful collaborations with organizations and foundations in the United States and abroad and functions as the Scientific Partner of Stand Up To Cancer, a charitable initiative that supports groundbreaking research aimed at getting new cancer treatments to patients in an accelerated time frame. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment and patient care, and Educational Workshops are held for the training of young cancer investigators. The AACR publishes seven major peer-reviewed journals: Cancer Discovery; Cancer Research; Clinical Cancer Research; Cancer Epidemiology, Biomarkers & Prevention; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Prevention Research. In 2010, AACR journals received 20 percent of the total number of citations given to oncology journals. The AACR also publishes Cancer Today, a magazine for cancer patients, survivors and their caregivers, which provides practical knowledge and new hope for cancer survivors. A major goal of the AACR is to educate the general public and policymakers about the value of cancer research in improving public health, the vital importance of increases in sustained funding for cancer research and biomedical science, and the need for national policies that foster innovation and the acceleration of progress against the 200 diseases we call cancer.
About the IASLC:
The International Association for the Study of Lung Cancer (IASLC) is the only global organization dedicated to the study of lung cancer. Founded in 1974, the association’s membership includes more than 3,500 lung cancer specialists in 80 countries.
IASLC members promote the study of etiology, epidemiology, prevention, diagnosis, treatment and all other aspects of lung cancer and thoracic malignancies. IASLC disseminates information about lung cancer to scientists, members of the medical community and the public and uses all available means to eliminate lung cancer as a health threat for individual patients throughout the world. Membership is open to any physician, scientist, nurse or allied health professional interested in lung cancer, including patients, survivors, caregivers and advocates.
IASLC publishes the Journal of Thoracic Oncology, a valuable resource for medical specialists and scientists who focus on the detection, prevention, diagnosis and treatment of lung cancer.
To learn more about IASLC, visit http://iaslc.org
In San Diego, Jan. 8-11: