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SHIVA01 and SHIVA02 are large-scale trials run in France to evaluate the efficacy of precision medicine that have created ripples in the oncology field. Although molecular alterations are shared among different types of cancer, drug development today is still mainly based on tumor localization. The only recent exception is MSD’s Keytruda (pembrolizumab) an antibody approved by the FDA in May 2017 for any solid tumor, independently from its location, that expresses MSI-H or dMMR biomarkers of errors in DNA replication. However, the clinical utility and validity of precision medicine approach remain to be demonstrated. The frequency of molecular alterations that can be targeted using precision medicine is low - you could screen thousands of patients before finding one with the relevant biomarkers. Clinical trials need to include a huge number of patients in order to draw robust conclusions. To face these challenges, Institut Curie launched in 2012 the French precision medicine SHIVA01 trial, led by Prof. Christophe Le Tourneau, senior Medical Oncologist and Head of Clinical Research in the Department of Medical Oncology at Institut Curie. So far, nobody has demonstrated the concept of precision medicine in oncology, where every single cancer patient would be treated based on its tumor molecular profile. The SHIVA01 trial coordinated by the Institut Curie, however, suggested that this approach is relevant in some cases,” says Le Tourneau. SHIVA01 was a multicentric Phase II trial that compared targeted therapy based on tumor molecular profiling versus conventional therapy in patients with any kind of refractory cancer. Molecular profiles were performed on biopsies using high throughput next generation sequencing and estimations of the number of gene copies and expression of hormonal receptors. Using a predefined algorithm, patients whose tumor harbored a molecular alteration matching one of the 11 targeted therapies available within the trial were randomized between the targeted therapy and a conventional approach. The study managed to include an impressive total of 741 patients at eight sites in France. The SHIVA01 trial finished only recently, but it has already made noise in the field, producing an impressive amount of publications in major journals besides the principal publication in The Lancet Oncology in 2015. These papers cover everything from bioinformatics to circulating tumor DNA, biological interpretation of variants, and interventional radiology. In the end, this trial can be definitely considered as a major step forward in terms of clinical trial design, even if results were negative for its primary endpoint. In fact, the SHIVA trial did not show that patients treated with targeted therapy had a better outcome, but demonstrated, however, that the administration of targeted therapy outside their indications might be a valid approach in a subgroup of patients with a molecular alteration in the MEK/RAF signaling pathway. Based on these results and experience gained, a second trial has already started. SHIVA02 aims to recruit 400 patients within 2 years using the patient as its own control and will focus on patients with alterations in MEK/RAF, also known as the Ras-Raf-MEK-ERK pathway. Compared to the first edition, the treatment algorithm for SHIVA02 is more refined. The researchers will use an NGS panel designed in house to capture relevant mutations, amplifications and deletions in the target genes. In order to run this trial, the Institut Curie will receive funding of €1.6M over a period of 5 years from the MSDAvenir Foundation, an autonomous entity created by MSD in 2015 to foster research and social initiatives in France. What makes the SHIVA trials different is that they only evaluate the whole strategy of precision medicine and not the efficacy of each drug separately. In addition, they are also definitely interesting for biotech industries. The resulting curated sample database opens the door to a broad range of retrospective studies that can be valuable to refine the understanding of a disease and improve research models. Even if there is still a long way to go, Prof. Le Tourneau says, "Several precision medicine trials are currently ongoing worldwide, each with a unique design but all aiming to address the main question: does a targeted treatment strategy based on tumor molecular alteration is more efficacious than standard treatment based on tumor localization?” He's already considering a SHIVA03 trial that will include immunotherapies in the protocol. Special thanks to Prof. Christophe Le Tourneau and Maud Kamal for their assistance in writing this article. Images via smart.art / Shutterstock; Institut Curie; Le Tourneau C. et al. The Lancet Oncology (2015). Volume 16, No. 13, p1324–1334

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