The SHIVA clinical trial is a French multicentric phase II trial evaluating the efficacy of molecularly targeted treatment based on tumour molecular profiling versus conventional treatment in refractory cancer patients.
The trial (NCT01771458) is promoted by Institut Curie and led by Dr Christophe Le Tourneau (principal investigator).
Toward a therapeutic decision based on tumour molecular profile
The molecular profile was performed on a mandatory biopsy using high throughput next generation sequencing techniques, estimations of the number of gene copies and the expression of hormonal receptors. Using a predefined algorithm, patients whose tumour harboured a molecular alteration matching one of the 11 approved targeted therapies available within the trial were randomized between :
- An experimental branch with a targeted therapy based on the tumour’s molecular profile
- A control branch with a conventional treatment at the physician’s discretion
In order to control patient heterogeneity, randomisation was stratified according to three signalling pathways (the hormone receptors pathway, the PI3K/AKT/mTOR pathway, and the RAF/MEK pathway), and patients’ prognosis based on the Royal Marsden Hospital (RMH) score. The treatment algorithm was the key element evaluated in the trial.
The SHIVA trial was conducted at 8 sites in France : Institut Curie (Paris et Saint-Cloud), Centre Léon Bérard (Lyon), Centre René Gauducheau (Nantes), Institut Claudius Régaud (Toulouse), Institut Paoli Calmettes (Marseille), Centre Georges-François Leclerc (Dijon), et le Centre Alexis Vautrin (Nancy). In total, 741 patients were included between October 2012 and July 2014 and 197 randomised.
The efficacy results for 195 analysed patients were published in Lancet Oncology in September 2015.
Demonstration of feasability but no benefits found for patients in the study
Among the 195 randomised patients, 99 patients received the targeted therapy and 96 received conventional therapy. A complete molecular profile was available in 496 patients (67%) and a molecular alteration matching one of the 11 available drugs according to the SHIVA treatment algorithm was detected in 293 patients (40%).
The SHIVA trial did not demonstrate that the administration of targeted treatments outside their indications according to the pre-specified treatment algorithm improves survival rates as compared to conventional treatment in heavily pre-treated patients with refractory cancer. The observed rate of grade 3 and 4 adverse events was higher in the experimental branch as compared to the conventional treatment branch, although the difference was not statistically significant.
Despite a global negative result, the data suggest that this histology-agnostic approach warrants further investigation in the subgroup of patients who received a treatment targeting the RAF/MEK signalling pathway. A subsequent trial, SHIVA 02, will focus on the evaluation of targeted therapy in a subgroup of patients harbouring a molecular alteration in this specific pathway.
In conclusion, it’s essential to include patients in clinical trials and to discourage the use of targeted therapies outside of their indications.
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- Le Tourneau, C.L., Delord, J.-P., Gonçalves, A., Gavoille, C., Dubot, C., Isambert, N., Campone, M., Trédan, O., Massiani, M.-A., Mauborgne, C., Armanet, S., Servant, N., Bièche, I., Bernard, V., Gentien, D., Jezequel, P., Attignon, V., Boyault, S., Vincent-Salomon, A., Servois, V., Sablin, M.-P., Kamal, M., Paoletti, X., and SHIVA investigators Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial. Lancet Oncol. (2015).
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- Le Tourneau, C., Paoletti, X., Servant, N., Bièche, I., Gentien, D., Rio Frio, T., Vincent-Salomon, A., Servois, V., Romejon, J., Mariani, O., Bernard, V., Huppe, P., Pierron, G., Mulot, F., Callens, C., Wong, J., Mauborgne, C., Rouleau, E., Reyes, C., Henry, E., Leroy, Q., Gestraud, P., La Rosa, P., Escalup, L., Mitry, E., Trédan, O., Delord, J.-P., Campone, M., Goncalves, A., Isambert, N., Gavoille, C., and Kamal, M. Randomised proof-of-concept phase II trial comparing targeted therapy based on tumour molecular profiling vs conventional therapy in patients with refractory cancer: results of the feasibility part of the SHIVA trial. British Journal of Cancer. (2014).
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