CUSTOM Study Sheds Light on Cancer Treatments Based on Genetics

Cancer research continues to be focused more on genetics and less on tumor histology – the tumor’s cellular component and structure. At the same time, researchers are recognizing the need to identify the best research models for such investigations while also examining the results of new therapies targeting these genetic aberrations rather than cancer types. Ariel Lopez-Chavez, M.D., Director of the Lung Cancer and Thoracic Malignancies Clinic at the University of Miami Miller School of Medicine’s Sylvester Comprehensive Cancer Center, recently completed an unprecedented trial with encouraging findings that highlight how targeting genes versus histology can more effectively treat cancer.

“By exclusively targeting the type of cancer based on tumor histology, clinical trials are often too specific, making them more costly and lengthy to perform,” Lopez-Chavez said. “The CUSTOM study instead looked at the type of genetic abnormality present in each patient rather than the site of the cancer or the tumor histology.”

The CUSTOM study is the first completed “basket” trial to investigate the effects of targeted agents against specific molecular aberrations across multiple histological subtypes at the same time. Conducted by Lopez-Chavez while at the National Cancer Institute and the Knight Cancer Institute at Oregon Health & Science University, the trial evaluated whether this broad basket approach was effective for genomic/oncologic research and also looked at genetic mutation response to treatments. Initial findings, which are published in the February issue of the Journal of Clinical Oncology, showed that this type of trial works well, and by targeting those genetic factors, it was easier to identify promising treatments, requiring fewer patients and less time compared with traditional clinical trials.

From 2011 to 2012, the study focused on 647 patients with advanced non-small cell lung cancer, small cell lung cancer and thymic malignancies. Patients were divided into five different biomarker treatment groups, including EGFR mutations; KRAS, NRAS, HRAS and BRAF mutations; PIK3CA, AKT or PTEN mutations; ERBB2 mutations/amplifications; and KIT and PDGFRA mutations or amplifications. The trial then evaluated the efficacy of multiple targeted therapies in specific molecular subsets of patients.

Each treatment arm of the CUSTOM study functioned as an independent phase II trial, purposed to identify drugs with response rates of more than 40 percent. Results were particularly successful in two of the arms. For example, patients with EGFR mutations achieved response rates of 60 percent with only 17 patients enrolled, while those with KRAS or BRAF mutations only had 11 percent success with only 9 patients enrolled.

“The results demonstrate the potential capability of identifying treatments with high and low clinical activity in small groups of molecularly selected patients by using CUSTOM’s clinical trial design,” said Lopez-Chavez.

One of the benefits of a basket trial, such as the CUSTOM study, is that fewer patients are needed, and because response rates are consistent, the length of the trial is typically reduced from standard models. These findings could shift the way trials are conducted, reduce treatment costs and uncover more effective drugs more quickly.
Because of these results, the National Cancer Institute and other groups are launching more trials with a similar design. University of Miami Sylvester Comprehensive Cancer Center patients will begin enrolling in the follow-up MOTHERN trial in summer/fall 2015.

The trial will be open to patients with any type of cancer, provided they meet certain genetic criteria. In addition, the MOTHERN trial will incorporate an adaptive element, allowing new arms to be created as different molecular targets become available. New drugs will also be added as certain therapies prove ineffective.

“We are very excited with the findings from the CUSTOM study and to begin work on the MOTHERN trial,” Lopez-Chavez said. “MOTHERN will look at even more genes, which will enable many more patients with less common forms of the disease to have access to the latest drugs for their cancers. MOTHERN will be a benefit for science and patients.”

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