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Clinical results of the EVESOR trial, a multiparameter phase I trial of everolimus and sorafenib combination in solid tumors

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Abstract

Purpose

Everolimus (EVE) and sorafenib (SOR) combination was associated with synergistic activity in preclinical models. However, previous clinical studies were hampered by cumulative toxicities when both were given continuously. The academic EVESOR trial (NCT01932177) was designed to assess alternative doses and intermittent dosing schedules of EVE and SOR combination therapy to improve the benefit-risk ratio for patients with solid tumors.

Methods

EVESOR is a multiparameter dose-escalation phase I trial investigating different doses and dosing schedules, with the final objective of generating data for modeling and simulation. Patients were allocated into continuous (A and B) or intermittent (C and D) schedules to determine the recommended phase II dose (RP2D). The clinical outcomes are presented here.

Results

Forty-three patients were included from 2013 to 2019. Most of them had gynecological (25.6%), cholangiocarcinomas (23.2%), colorectal (14.0%), and breast cancers (11.6%). Dose-escalation up to EVE 10 mg QD and SOR 400 mg BID was possible on intermittent schedules. Five dose-limiting toxicities were observed, and dose reductions were required in 39.5% patients, stabilizing at EVE 5 mg and SOR 200 mg BID for 58.1% of them. The overall response rate was 6.3%, and disease control rate was 75.0%. The median progression-free survival (PFS) was 3.6 months. The longest median PFS were observed in cholangiocarcinomas (9.9 months), and gynecological adenocarcinomas (9.2 months).

Conclusion

Intermittent arms were associated with improved efficacy/toxicity profiles; and EVE 5 mg QD and SOR 200 mg BID was defined a clinically feasible dose. Strong signs of efficacy were found in cholangiocarcinomas and gynecologic carcinomas.

Trial registration

ClinicalTrials.gov Identifier: NCT01932177.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The study has been supported by the Hospices Civils de Lyon (bourse Actions Incitatives); Ligue contre le Cancer; Association de Recherche contre le Cancer; Novartis SAS (everolimus furniture); and the Institut National du Cancer.

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Authors and Affiliations

  1. Medical Oncology, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), CITOHL, Centre Hospitalier Lyon-Sud, 165 Chemin du Grand Revoyet, Pierre-Benite, 69495, Lyon, France

    Romain Varnier, Julien Peron, Denis Maillet, Sophie Tartas, Nathalie Bonnin, Gilles Freyer & Benoit You

  2. Faculté de Médecine Lyon Sud, EA 3738 CICLY, Université Claude Bernard Lyon 1, Lyon, France

    Alicja Puszkiel, Michel Tod, Denis Maillet, Olivier Colomban, Gilles Freyer & Benoit You

  3. Pharmacy, Hôpital de La Croix-Rousse, Hospices Civils de Lyon, Lyon, France

    Michel Tod

  4. Clinical Research, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), CITOHL, Centre Hospitalier Lyon-Sud, Lyon, France

    Sara Calattini & Diane Augu-Denechere

  5. Biochemistry and Molecular Biology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Lyon, France

    Lea Payen & Jonathan Lopez

  6. Pharmacology, Pharmacogenetic, Toxicology Laboratory, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Lyon, France

    Jérome Guitton

  7. Faculté de Pharmacie, Université Claude Bernard Lyon 1, Lyon, France

    Jérome Guitton

  8. Clinical Oncology Pharmacy, Centre Hospitalier Lyon-Sud, Lyon, France

    Vérane Schwiertz

  9. Pathology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Lyon, France

    Juliette Fontaine

  10. UMR UCBL/CNRS 5538 « Biometry and Evolutionary Biology Laboratory, Health and Biostatistics Team », Faculté de Médecine Lyon-Sud, Université Claude Bernard Lyon 1, Lyon, France

    Julien Peron

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  1. Romain Varnier
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Correspondence to Benoit You.

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Varnier, R., Puszkiel, A., Tod, M. et al. Clinical results of the EVESOR trial, a multiparameter phase I trial of everolimus and sorafenib combination in solid tumors. Cancer Chemother Pharmacol 91, 361–373 (2023). https://doi.org/10.1007/s00280-023-04508-9

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