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 MSDs Keytruda (pembrolizumab) an antibodyapproved 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 targetedusing 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 drawrobust conclusions.

To face these challenges, Institut Curielaunched 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.

Christophe Le Tourneau discussing precision medicine studies at ASCO 2017

SHIVA01 was a multicentricPhase II trial thatcompared targeted therapy based on tumor molecular profiling versus conventional therapy in patients with any kind of refractory cancer. Molecular profileswere performed on biopsies using high throughput next generation sequencing andestimations 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 anda conventional approach. The study managed to include an impressive total of 741 patients at eight sites in France.

The SHIVA01 trialfinishedonly 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 paperscover everything frombioinformaticstocirculating tumor DNA, biological interpretation of variants, andinterventional radiology.

Results of the primary endpoint of SHIVA01: Progression-free survival in patients with molecular alterations in the hormone receptor RAF/MEK pathway

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. SHIVA02aims to recruit 400 patients within 2 years using the patient as its own controland will focus on patients with alterations inMEK/RAF,also known as the RasRaf-MEK-ERK pathway.Compared to the first edition, the treatment algorithm for SHIVA02 is more refined. The researchers will use anNGS panel designed in house to capture relevant mutations, amplifications and deletions in the target genes.

In order to run thistrial, the Institut Curie will receivefunding of 1.6M over a period of 5 yearsfrom the MSDAvenir Foundation,an autonomous entity created by MSD in 2015 to foster research and social initiatives in France.

Dominique Blazy (President of the Scientific Council at MSDAvenir); Prof. Christophe Le Tourneau and Pr Thierry Philip (President of the Institut Curie)

What makes the SHIVA trials different is that theyonly evaluate the whole strategy of precision medicine and not the efficacy of each drug separately. In addition, they arealso definitely interesting for biotech industries. The resultingcurated sample databaseopens the door to a broad range of retrospective studies that can be valuable to refine theunderstanding of a disease and improve researchmodels.

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?Hes already considering aSHIVA03 trial that will include immunotherapies in theprotocol.

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, p13241334

Read more:

SHIVA Trial: France's Big Shot at Precision Medicine for Cancer - Labiotech.eu (blog)