ArticlesMolecularly 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
Introduction
Normal cells become cancer cells via a succession of genomic alterations.1 This finding has led to the development of molecularly targeted agents that inhibit the proteins that are abnormally activated as a result of somatic genetic alterations. Theoretically, these agents are more specific to cancer cells than are cytotoxic agents that target cell replication. Some of these molecularly targeted agents have yielded previously unprecedented anti-tumour activity in specific tumour types in the presence of the matching molecular alteration.2, 3, 4, 5, 6, 7 Molecularly targeted agents have followed the same clinical development process as cytotoxic agents: per tumour location and histology. Most genetic molecular alterations exist across tumour types and histologies, although incidence varies.8 This observation challenges the existing drug development strategies for molecularly targeted agents and raises the possibility of a shift towards histology-agnostic molecularly based treatment with these drugs.
Advances in high-throughput technology have allowed the identification of multiple genomic molecular alterations in a timeframe compatible with clinical practice. The use of these technologies has been endorsed by physicians and patients with the aim of guiding therapy.9, 10 This histology-agnostic approach is supported by non-randomised studies. Using each patient as their own control, a pilot study11 reported that 27% of patients with any kind of recurrent cancer had a 30% increase in progression-free survival with treatment selected on the basis of tumour molecular profiling compared with progression-free survival for their previous treatment. Similarly, findings from a retrospective study12 showed improved progression-free survival and overall survival for cancer patients entering a phase 1 trial on the basis of a molecular alteration identified in their tumour.12 These results, together with the decreasing cost of genomic testing, have led to increased off-label use of molecularly targeted agents.13
However, in view of the absence of data from randomised trials, the clinical usefulness of large-scale genomic testing has not been formally shown. In the SHIVA trial, we aimed to assess whether histology-agnostic use of marketed molecularly targeted agents outside their indications based on tumour molecular profiling could improve outcomes for patients with any kind of cancer for whom standard of care had failed, compared with treatment at the physician's choice.
Section snippets
Study design and participants
SHIVA was a proof-of-concept, multicentre, open-label, randomised, controlled phase 2 trial of molecularly targeted agents based on tumour molecular profiling versus treatment at physician's choice in patients with refractory cancer. The study was done at eight academic sites in France (appendix 1 p 2).
Patients older than 18 years with any kind of recurrent or metastatic solid tumour for whom standard of care therapy had failed were eligible for the study, provided their disease was accessible
Results
Enrolment started on Oct 4, 2012, and stopped on July 11, 2014, after the inclusion of 741 patients in the screening programme because a preliminary analysis suggested that 200 of these patients would be suitable for inclusion. A complete molecular profile was available for 496 (67%) patients (figure 1). A molecular alteration matching one of the available molecularly targeted agents was detected in 293 (40%) patients.
At the cutoff date (Jan 20, 2015), 195 (26%) of the original 741 patients had
Discussion
The SHIVA trial is a histology-agnostic randomised trial that has many features in common with the proposed expansion platform type IIB design.18 Patient accrual went twice as fast as anticipated, which shows the enthusiasm that patients and physicians have for trials that use molecular information to guide therapy.9, 10, 19 Our findings indicate that the use of molecularly targeted agents outside their indications does not improve progression-free survival compared with treatment at
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