Efficacy of molecularly targeted agents given in the randomised trial SHIVA01 according to the ESMO Scale for Clinical Actionability of molecular Targets.

Moreira A1, Masliah-Planchon J2, Callens C3, Vacher S4, Lecerf C5, Frelaut M6, Borcoman E7, Torossian N8, Ricci F9, Hescot S10, Sablin MP11, Tresca P12, Loirat D13, Melaabi S14, Trabelsi-Grati O15, Pierron G16, Gentien D17, Bernard V18, Vincent Salomon A19, Servant N20, Bieche I21, Le Tourneau C22, Kamal M23.

Author information

1: Department of Drug Development and Innovation (D3i), Institut Curie, Paris, Saint-Cloud, France. Electronic address: aurelie.moreira@curie.fr.
2: Department of Genetics, Institut Curie, PSL Research University, Paris, France. Electronic address: julien.masliahplanchon@curie.fr.
3: Department of Genetics, Institut Curie, PSL Research University, Paris, France. Electronic address: celine.callens@curie.fr.
4: Department of Genetics, Institut Curie, PSL Research University, Paris, France. Electronic address: sophie.vacher@curie.fr.
5: Department of Drug Development and Innovation (D3i), Institut Curie, Paris, Saint-Cloud, France. Electronic address: charlotte.lecerf@curie.fr.
6: Department of Drug Development and Innovation (D3i), Institut Curie, Paris, Saint-Cloud, France. Electronic address: maxime.frelaut@curie.fr.
7: Department of Drug Development and Innovation (D3i), Institut Curie, Paris, Saint-Cloud, France. Electronic address: edith.borcoman@curie.fr.
8: Department of Drug Development and Innovation (D3i), Institut Curie, Paris, Saint-Cloud, France. Electronic address: nouritza.torossian@curie.fr.
9: Department of Drug Development and Innovation (D3i), Institut Curie, Paris, Saint-Cloud, France. Electronic address: francesco.ricci@curie.fr.
10: Department of Drug Development and Innovation (D3i), Institut Curie, Paris, Saint-Cloud, France. Electronic address: segolene.hescot@curie.fr.
11: Department of Drug Development and Innovation (D3i), Institut Curie, Paris, Saint-Cloud, France. Electronic address: mariepaule.sablin@curie.fr.
12: Department of Drug Development and Innovation (D3i), Institut Curie, Paris, Saint-Cloud, France. Electronic address: patricia.tresca@curie.fr.
13: Department of Drug Development and Innovation (D3i), Institut Curie, Paris, Saint-Cloud, France. Electronic address: delphine.loirat@curie.fr.
14: Department of Genetics, Institut Curie, PSL Research University, Paris, France. Electronic address: samia.melaabi@curie.fr.
15: Department of Genetics, Institut Curie, PSL Research University, Paris, France. Electronic address: olfa.trabelsigrati@curie.fr.
16: Department of Genetics, Institut Curie, PSL Research University, Paris, France. Electronic address: gaelle.pierron@curie.fr.
17: Department of Translational Research, Institut Curie, PSL Research University, Paris, France. Electronic address: david.gentien@curie.fr.
18: Department of Genetics, Institut Curie, PSL Research University, Paris, France. Electronic address: Virginie.Bernard@curie.fr.
19: Department of Pathology, Institut Curie, PSL Research University, Paris, France. Electronic address: anne.salomon@curie.fr.
20: INSERM U900, Institut Curie, Mines Paris Tech, Paris, France. Electronic address: nicolas.servant@curie.fr.
21: Department of Genetics, Institut Curie, PSL Research University, Paris, France; INSERM U1016 Research Unit, Cochin Institute, Paris, France. Electronic address: ivan.bieche@curie.fr.
22: Department of Drug Development and Innovation (D3i), Institut Curie, Paris, Saint-Cloud, France; INSERM U900, Institut Curie, Mines Paris Tech, Paris, France; Paris-Saclay University, Paris, France. Electronic address: christophe.letourneau@curie.fr.
23: Department of Drug Development and Innovation (D3i), Institut Curie, Paris, Saint-Cloud, France. Electronic address: maud.kamal@curie.fr.

Abstract

BACKGROUND:

A randomised trial SHIVA01 compared the efficacy of matched molecularly targeted therapy outside their indications based on a prespecified treatment algorithm versus conventional chemotherapy in patients with metastatic solid tumours who had failed standard of care. No statistical difference was reported between the two groups in terms of progression-free survival (PFS), challenging treatment algorithm. The European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT) recently defined criteria to prioritise molecular alterations (MAs) to select anticancer drugs. We aimed to retrospectively evaluate the efficacy of matched molecularly targeted agents (MTAs) given in SHIVA01 according to ESCAT tiers.

PATIENTS AND METHODS:

MAs used in SHIVA01 were retrospectively classified into ESCAT tiers, and PFS and overall survival (OS) were compared using log-rank tests.

RESULTS:

One hundred fifty-three patients were treated with matched MTAs in SHIVA01. MAs used to allocate MTAs were classified into tiers II, IIIA, IIIB and IVA according to the ESCAT. Median PFS was 2.0 months in tier II, 3.1 in tier IIIA, 1.7 in tier IIIB and 3.2 in tier IVA (p = 0.13). Median OS in tier IIIB was worse than that in tiers II, IIIA and IVA (6.3 months versus 11.7, 11.2 and 12.1, p = 0.002).

CONCLUSIONS:

Most MAs used to allocate therapy in SHIVA01 were shown to improve outcomes in other tumour types (tier IIIA). Worst outcome was observed in patients treated based on another type of alteration than the one reported to improve outcomes (tier IIIB), highlighting the crucial impact of the type of the alterations beyond the gene and the signalling pathway.

KEYWORDS:

Actionable molecular alterations; ESMO Scale for Clinical Actionability of molecular Targets (ESCAT); Molecularly targeted agents; Precision medicine; SHIVA01; Treatment algorithms