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Efficacy and safety exposure–response analyses of entrectinib in patients with advanced or metastatic solid tumors

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Abstract

Purpose

Entrectinib is an anti-cancer agent that inhibits TRKA/B/C, ROS1, and ALK. Secondary pharmacokinetic (PK) exposure parameters for entrectinib derived from a previously described population PK model were used to characterize exposure–response relationships in patients treated with entrectinib.

Methods

Data were pooled from Phase 1 and 2 studies of entrectinib (600–800 mg/day in adults, 250–750 mg/m2/day in children) in 293 patients with NTRK-, ROS1-, or ALK-positive, locally advanced or metastatic tumors. Efficacy was evaluated by the changes in sum of target lesion diameters and best overall response defined by RECIST1.1. A longitudinal nonlinear mixed-effect model described the relationship between entrectinib exposure and tumor size data in patients with ROS1-positive non-small-cell lung cancer (NSCLC) or NTRK fusion-positive solid tumors. The relationship between exposure and treatment-emergent (TEAEs) or serious (SAEs) adverse events was assessed by logistic regression in all patients for whom secondary PK parameter estimates were derived.

Results

Among the 89 patients with evaluable efficacy data included in the exposure-efficacy analysis, 73% (65/89) achieved a complete or partial response. Entrectinib exposure distribution was similar in responders and non-responders. Model-described tumor shrinkage rates were 8–12 times greater than growth rates in both ROS-1-positive NSCLC patients and NTRK fusion-positive solid tumor patients, with no relationship between exposure and these rates. The probability of experiencing a Grade ≥ 3 TEAE or SAE increased with exposure, primarily at doses > 600 mg/day.

Conclusion

These analyses supported that entrectinib at 600 mg/day provides an acceptable benefit–risk ratio in adults with NTRK-, ROS1-, or ALK-positive tumors, considered as rare disease.

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Availability of data and materials

Qualified researchers may request access to individual patient-level data through the clinical study data request platform (https://vivli.org/). Further details on Roche’s criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

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Acknowledgements

Third-party medical writing assistance, under the direction of the authors, was provided by Holly Capasso-Harris, Ben Small, and Darren Bentley of Certara, and was funded by F. Hoffmann-La Roche AG. Administrative support was provided by Ashfield Health, and was funded by F. Hoffmann-La Roche AG. We thank the anonymous reviewers for their constructive comments, which helped in improving the quality of this manuscript.

Funding

Funding for these analyses was provided by F. Hoffmann-La Roche Ltd (no grant number is applicable).

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Authors and Affiliations

  1. Roche Innovation Center, Roche Pharmaceutical Research and Early Development, Basel, Switzerland

    Francois Mercier, Nassim Djebli & Felix Jaminion

  2. Modeling Great Solutions, Escalades-Engordany, Andorra

    Mario González-Sales

  3. Roche Innovation Centre, Roche Pharmaceutical Research and Early Development, Welwyn, United Kingdom

    Georgina Meneses-Lorente

Authors
  1. Francois Mercier
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  2. Nassim Djebli
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Corresponding author

Correspondence to Francois Mercier.

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Conflict of interest

FM, ND, FJ, and GM-L are employed by F. Hoffmann-La Roche AG and have no other disclosures to report. MG-S is an employee of Modelling Great Solutions and has received a consultant honorarium from by F. Hoffmann-La Roche AG.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Mercier, F., Djebli, N., González-Sales, M. et al. Efficacy and safety exposure–response analyses of entrectinib in patients with advanced or metastatic solid tumors. Cancer Chemother Pharmacol 89, 363–372 (2022). https://doi.org/10.1007/s00280-022-04402-w

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  • DOI: https://doi.org/10.1007/s00280-022-04402-w

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