Negative SHIVA Results Point Away From Personalised Treatment Strategy

Personalised solid cancer treatment on the basis of molecular pathway alterations alone does not boost progression-free survival

medwireNews: The SHIVA trial has failed to demonstrate a significant gain in progression-free survival for metastatic solid tumour patients matched to a molecular targeted therapy in a histology-agnostic manner compared with physician’s choice treatment.

The negative results of the open-label, phase II trial – the first to test a personalised molecular approach to treatment without using tumour histology – are reported in The Lancet Oncology.

“Our findings suggest that off-label use of molecularly targeted agents should be discouraged, and enrolment into clinical trials should be encouraged to help identify predictive biomarkers of efficacy”, recommend Christophe Le Tourneau, from Institut Curie, Paris & Saint-Cloud in France, and co-authors.

In all, metastatic biopsy samples from 40% of 741 patients with a tumour refractory to the standard of care tested positive for at least one molecular alteration in the hormone receptor, PI3K/AKT/mTOR or RAF/MEK pathways.

By data cutoff, 99 patients had been assigned to receive one of 11 targeted agents matched to specific molecular alteration from biopsy results, in particular, erlotinib , lapatinib plus trastuzumab , sorafenib , imatinib , dasatinib , vemurafenib , everolimus , abiraterone , letrozole , and tamoxifen .

After a median follow-up of 11.3 months, progression-free survival was comparable in the biopsy-driven and physician’s choice treatment groups, at 2.3 versus 2.0 months.

Nor was any significant survival benefit found for patients given personalised treatment when analysing results for patients according to which of their molecular pathways showed mutations, the authors report.

Furthermore, there was a trend towards a higher rate of grade III and IV adverse events in the safety population of 100 patients who received molecularly targeted treatment than the 91 patients who received their physician’s choice of a cytotoxic agent, at 43% versus 35%.

Daniel Catenacci, from the University of Chicago in Illinois, USA, agrees in a comment that the “sobering” results of this “notable trial” argue against matching patients to off-label agents on the basis of case reports, observational cohorts, meta-analyses or commercial data.

However, he notes that positive results from a similar trial in the future would raise challenges for the current regulatory infrastructure.

“Would 11 drugs in nine treatment groups, using various companion diagnostics, and for any histology, all be simultaneously approved for expanded indication if confirmed in a phase 3 trial?”, he questions.

“What if some drugs are not already commercially available? What should be done about development and approval pathways for multiple incorporated companion diagnostics?”

Citing the need to pre-empt such issues, Daniel Catenacci concludes that “next-generation regulation must accompany next-generation trials through the integration of next-generation companion diagnostics and the concept of personalised treatment strategies, to continue to advance clinical cancer care.”


Le Tourneau C, Delord J-P, Goncalves A, et al. 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; Advance online publication 2 September. DOI:

Catenacci DVT. Expansion platform type II: testing a treatment strategy. Lancet Oncol 2015; Advance online publication 2 September. DOI:

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