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

Tourneau, Christophe Le; Delord, Jean Pierre; Gonçalvès, Anthony; Gavoille, Céline; Dubot, Coraline; Isambert, Nicolás; Campone, Mario; Trédan, O.; Massiani, Marie Ange; Mauborgne, Cécile; Armanet, Sébastien; Servant, Nicolas; Bièche, Ivan; Bernard, Virginie; Gentien, David; Jézéquel, Pascal; Attignon, Valéry; Boyault, Sandrine; Vincent‐Salomon, Anne; Servois, Vincent; Sablin, Marie Paule; Kamal, Maud; Paolettí, Xavier

doi:10.1016/s1470-2045(15)00188-6

Cited by 902 publications

(705 citation statements)

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“…Thus, BRAF V600E -mutant melanomas critically depend on increased MAPK pathway signaling, and hence such tumors respond well to selective inhibition of BRAF and/or MEK kinases (2)(3)(4). These and other encouraging results with targeted agents have sparked a number of histology-agnostic studies in which the presence of the oncogenic driver mutations is the sole selection criterion for treatment with the corresponding targeted agent in so-called basket studies (5)(6)(7). A first disappointment of these studies is that the number of "actionable" mutations (mutations for which a targeted drug is available as an approved indication or through a clinical trial) is relatively low.…”

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confidence: 99%

“…Similarly, in the SHIVA trial, a genotype-matched "off-label" drug could be identified for only 40% of the patients. A second disappointment was that the responses of the patients treated with molecularly targeted agents, defined by progression-free survival, were no better than those of patients treated by "physician's choice," leading the authors to conclude that the "off-label use of molecularly targeted agents should be discouraged" (7).…”

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confidence: 99%

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DNA-Guided Precision Medicine for Cancer: A Case of Irrational Exuberance?

Voest

Bernards

2016

Cancer Discovery

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confidence: 99%

DNA-Guided Precision Medicine for Cancer: A Case of Irrational Exuberance?

Voest

Bernards

2016

Cancer Discovery

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“…L'objectif principal de cette étude était la supériorité du bras expérimental par rapport au bras de référence ; il n'a pas été obtenu, mais les résultats du bras expérimental sont similaires à ceux du bras empirique, apportant également une information d'importance (25). De fait, ces études de « stratégie » ne permettent pas de s'assurer que le traitement ciblé est sans bénéfice chez les patients chez lesquels une anomalie moléculaire n'a pu être dépistée (26). Une étude utilisant ce plan expérimental et qui présenteraient des résultats positifs ne permettrait de conclure que sur la supériorité de la stratégie globale « Tests moléculaires guidant un traitement ciblé », par rapport à l'utilisation de la chimiothérapie empirique chez tous les patients, mais ne permettrait pas de savoir si, dans le cadre de la stratégie basée sur la biologie moléculaire, la sélection des patients devant recevoir le traitement ciblé en fonction de la présence de l'anomalie est cliniquement utile (seul un plan expérimental avec une double randomisation des stratégies thérapeutiques comparées -une dans chaque sous-population identifiée par son statut positif ou négatif pour la présence d'une anomalie moléculaire -pourrait permettre d'établir ou d'infirmer une différence).…”

Section: Premiers Resultats Des Essais De Medecine De Precisionunclassified

New Perspectives in Medical Oncology : Molecular Medicine and its Perspectives

Blay

Trédan

Pérol

2017

IJMS

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RESUMELa médecine moléculaire du cancer s'appuie sur l'identification d'anomalies génomique de l'ADN des cellules tumorales, permettant de guider le traitement des patients, en choisissant des inhibiteurs agissant sur les protéines mutées codées par les gènes mutés. Cependant, on assiste depuis 10 ans à l'émergence très rapide d'un nouveau corpus de connaissance décrivant les anomalies génomiques des cellules cancéreuses au sein des programmes internationaux comme ICGC ou TCGA, permettant de déboucher sur de nouvelles classifications nosologiques mais démontrant aussi l'extrême complexité et variabilité clonale des cellules cancéreuses chez le patient humain. Il s'agit désormais d'utiliser ces données nouvelles de manière efficace. Ceci requiert la constitution de plateformes de diagnostic explorant progressivement avec une plus grande profondeur les anomalies moléculaire de chaque patient individuel, et l'organisation de réunions de concertation pluridisciplinaires moléculaire permettant d'intégrer ces données au contexte clinique et global du patient, et requérant la contribution croissante des bio-informaticiens. Ce court article fait le point sur l'évolution de cette médecine moléculaire. ABSTRACTThe molecular medicine of cancer is based on the identification of genomic abnormalities in the DNA of tumor cells, guiding the treatment of patients, by choosing inhibitors acting on the mutated proteins encoded by the mutated genes. However, for the last 10 years, there has been a very rapid emergence of a new corpus of knowledge describing the genomic abnormalities of cancer cells in international programs such as ICGC or TCGA, leading to new nosological classifications, but also showing the extreme complexity and clonal variability of cancer cells in the human patient. The optimal use of this body of new data effectively. This requires 1) the construction of diagnostic platforms progressively exploring with greater depth the molecular anomalies of each individual patient and 2) the organization of multidisciplinary molecular consultation meetings to integrate these data into the clinical and global context of the patient. This evolution will also require a growing contribution of bio-informatics. This short article provides a short update on the evolution of this molecular medicine of cancer.

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“…Overall, following tumor profiling, off-label use only represented 2.8% of the patients [20] . Le Tourneau et al [21] investigated molecular tumor profiling representing 3 pathways (hormone receptor, PI3K/AKT/ mTOR and RAF/MEK) in 741 patients with refractory metastatic disease. Around 40% of the patients were eligible to a panel of 11 off-label targeted therapies including imatinib, dasatinib, vemurafenib, sorafenib, erlotinib, lapatinib, trastuzumab and everolimus.…”

Section: Prevalence and Clinical Evidencementioning

confidence: 99%

Off-label use of targeted therapies in oncology

Levêque

2016

WJCO

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Off-label use is defined by the prescription of a marketed drug outside the conditions described in the summary of product characteristics. In oncology, off-label prescribing of targeted therapies may occur in patients with other tumor types expressing the same target. Agents associated to phenotypic approaches such as therapies against the tumoral vasculature (anti-angiogenic drugs) and new immunotherapies (checkpoint inhibitors) also carry the potential of alternative indications or combinations. Off-label use of targeted therapies is little documented and appears to be in the same range than that regarding older drugs with wide variations among agents. When compared with older agents, off-label use of targeted therapies is probably more rational through tumoral genotyping but is faced with a limited clinical support, reimbursement challenges related to the very high pricing and the cost of genotyping or molecular profiling, when applicable. Core tip: Off-label use is defined by the prescription of a marketed drug outside the conditions described in the summary of product characteristics. This review is the first one focussing on the off-label use of targeted therapies in oncology. When compared with older agents, off-label use of targeted therapies is probably more rational through tumoral genotyping but is faced with a limited clinical support, reimbursement challenges related to the very high pricing and the cost of genotyping or molecular profiling, when applicable.Levêque D. Off-label use of targeted therapies in oncology.

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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

Cited by 902 publications

References 27 publications

DNA-Guided Precision Medicine for Cancer: A Case of Irrational Exuberance?

DNA-Guided Precision Medicine for Cancer: A Case of Irrational Exuberance?

New Perspectives in Medical Oncology : Molecular Medicine and its Perspectives

Off-label use of targeted therapies in oncology

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