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Cited by 1,137Cancer Genomics and DiagnosticsLung Cancer Treatments and MutationsColorectal Cancer Treatments and Studies

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

Le Tourneau, Christophe, Delord, Jean-Pierre, Gonçalves, Anthony, Gavoille, Céline, Dubot, Coraline, Isambert, Nicolas, Campone, Mario, Trédan, Olivier +15 more·2015·The Lancet Oncology
DOI 10.1016/s1470-2045(15)00188-6
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Abstract

Background Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to increased off-label use of molecularly targeted agents on the basis of identified molecular alterations. We assessed the efficacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profiling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed.Methods The open-label, randomised, controlled phase 2 SHIVA trial was done at eight French academic centres. We included adult patients with any kind of metastatic solid tumour refractory to standard of care, provided they had an Eastern Cooperative Oncology Group performance status of 0 or 1, disease that was accessible for a biopsy or resection of a metastatic site, and at least one measurable lesion. The molecular profile of each patient's tumour was established with a mandatory biopsy of a metastatic tumour and large-scale genomic testing. We only included patients for whom a molecular alteration was identified within one of three molecular pathways (hormone receptor, PI3K/AKT/mTOR, RAF/MEK), which could be matched to one of ten regimens including 11 available molecularly targeted agents (erlotinib, lapatinib plus trastuzumab, sorafenib, imatinib, dasatinib, vemurafenib, everolimus, abiraterone, letrozole, tamoxifen). We randomly assigned these patients (1:1) to receive a matched molecularly targeted agent (experimental group) or treatment at physician's choice (control group) by central block randomisation (blocks of size six). Randomisation was done centrally with a web-based response system and was stratified according to the Royal Marsden Hospital prognostic score (0 or 1 vs 2 or 3) and the altered molecular pathway. Clinicians and patients were not masked to treatment allocation. Treatments in both groups were given in accordance with the approved product information and standard practice protocols at each institution and were continued until evidence of disease progression. The primary endpoint was progression-free survival in the intention-to-treat population, which was not assessed by independent central review. We assessed safety in any patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01771458.Findings Between Oct 4, 2012, and July 11, 2014, we screened 741 patients with any tumour type. 293 (40%) patients had at least one molecular alteration matching one of the 10 available regimens. At the time of data cutoff, Jan 20, 2015, 195 (26%) patients had been randomly assigned, with 99 in the experimental group and 96 in the control group. All patients in the experimental group started treatment, as did 92 in the control group. Two patients in the control group received a molecularly targeted agent: both were included in their assigned group for efficacy analyses, the patient who received an agent that was allowed in the experimental group was included in the experimental group for the purposes of safety analyses, while the other patient, who received a molecularly targeted agent and chemotherapy, was kept in the control group for safety analyses. Median follow-up was 11·3 months (IQR 5·8-11·6) in the experimental group and 11·3 months (8·1-11·6) in the control group at the time of the primary analysis of progression-free survival. Median progression-free survival was 2·3 months (95% CI 1·7-3·8) in the experimental group versus 2·0 months (1·8-2·1) in the control group (hazard ratio 0·88, 95% CI 0·65-1·19, p=0·41). In the safety population, 43 (43%) of 100 patients treated with a molecularly targeted agent and 32 (35%) of 91 patients treated with cytotoxic chemotherapy had grade 3-4 adverse events (p=0·30).Interpretation The use of molecularly targeted agents outside their indications does not improve progression-free survival compared with treatment at physician's choice in heavily pretreated patients with cancer. Off-label use of molecularly targeted agents should be discouraged, but enrolment in clinical trials should be encouraged to assess predictive biomarkers of efficacy.

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  • Functional precision medicine is based on testing drug responses on patient tumors to identify effective regimens and does not require prior knowledge of a tumor molecular profile.

    “FPM is based on testing drug responses on patient tumors to identify effective regimens and does not require any knowledge of a tumor molecular profile or characteristics a priori.”

    From Organoids (2022) · cites this paper as [161]

  • The SHIVA trial showed that strategies based on tumor sequencing do not outperform conventional physician's choice.

    “In addition, the SHIVA trial has shown how this strategies based on tumor sequencing do not outperform better than the conventional physician’s choice161,162.”

    From Organoids (2022) · cites this paper as [161]

  • Only a small proportion of patients, approximately 10-20%, have an actionable alteration that can be coupled to a specific intervention.

    “However, as shown in several clinical trials161–165, only a small proportion of patients (approx. 10–20%) have an actionable alteration that can be coupled to a specific intervention161.”

    From Organoids (2022) · cites this paper as [161]

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Authors
Le Tourneau, C., 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.
Affiliations
  • Institut Claudius Regaud (FR)
  • Institut Curie (FR)
  • Centre Léon Bérard (FR)
  • Hôpital Foch (FR)
  • Inserm (FR)
ORCID
Venue
The Lancet Oncology
Publisher
Elsevier BV
Published
2015-10
Volume
16
Issue
13
Pages
1324-1334
ISSN
1470-2045 (ISSN-L)
DOI
10.1016/s1470-2045(15)00188-6
OpenAlex
W2104287359
Cited by
1,137
References
28
Citations by year
2026: 49 · 2025: 51 · 2024: 79 · 2023: 100 · 2022: 109 · 2021: 109 · 2020: 113 · 2019: 141 · 2018: 131 · 2017: 138 · 2016: 101 · 2015: 14 · 2012: 1
FWCI
42.30
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • The Lancet Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
Agence Nationale de la Recherche (ANR-10-INBS-0009, ANR-10-EQPX-0003)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Keywords
targeted therapy, tumor molecular profiling, advanced cancer, metastatic solid tumors, off-label drug use, PI3K/AKT/mTOR pathway, progression-free survival, imatinib, vemurafenib, sorafenib, dasatinib, abiraterone, letrozole, tamoxifen
MeSH terms
Aged, Antineoplastic Agents, Biopsy, Female, France, Humans, Male, Middle Aged, Neoplasm Metastasis, Neoplasms, Phenotype, Predictive Value of Tests, Risk Factors, Time Factors, Biomarkers, Tumor, Signal Transduction, Proportional Hazards Models, Treatment Outcome, Disease Progression, Disease-Free Survival, Patient Selection, Genetic Predisposition to Disease, Gene Expression Profiling, Molecular Diagnostic Techniques, Kaplan-Meier Estimate, Off-Label Use, Intention to Treat Analysis, Precision Medicine, Molecular Targeted Therapy

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