3907 - Exploration of efficacious alternative regorafenib regimens to manage hand-foot-skin-reaction (HFSR)

Background

Regorafenib 160 mg/day 3 weeks on/1 week off (1 cycle) significantly improved overall survival (OS) in patients with refractory metastatic colorectal cancer (mCRC) compared to placebo. While most common regorafenib-related toxicities, i.e. hypertension, diarrhea, fatigue, and HFSR can be managed by dose modifications, there is a need to explore alternative dosing regimens during the first cycle to improve tolerability in clinical practice.

Methods

The relationship between dose, regorafenib plasma concentration, OS, and time-to-first grade 3 HFSR event were analyzed using dose-exposure-time-to-event modelling, considering the effect of preselected baseline covariates and dose modifications. The OS analysis included 957 mCRC patients whereas HFSR included 1722 mCRC, HCC, and GIST patients from four phase-3 trials. The number of patients alive not having grade 3 HFSR or dose modifications over three cycles were simulated with the developed models for the following scenarios: 80 or 120mg/day for 3 cycles or 80 mg/day on week 1, escalated to 120 mg/day week 2, and 160 mg/day on week 3 followed by either 120 or 160 mg/day in cycles 2 and 3 compared to the standard 160 mg/day regimen. The observed lower drop-out due to disease progression in regorafenib-treated patients was accounted for.

Results

Maximal OS was reached in most patients with 160 mg/day, as regorafenib concentrations were >10 times the concentration associated with a 50% decrease in the hazard of death compared to placebo_. After 160 mg/day maximal OS was reached at ∼6 times lower concentrations than the maximal hazard of grade 3 HSFR, demonstrating a clear benefit-risk profile. While all other schedules showed a lower grade 3 HFSR incidence with reduced OS compared to 160 mg/day, a considerable overlap in grade 3 HFSR incidence and OS among the regimens was predicted. The largest numerical difference was between 80 and 160 mg/day.

Conclusions

Exploration of alternative dosing regimens by modeling and simulation indicates a numerically lower incidence of grade 3 HFSR and lower OS for a starting dose of 80 mg/day versus 160 mg/day. A starting dose of 80 mg/day might result in reduced efficacy if not escalated to either 120 or 160 mg/day.

Clinical trial identification

NCT01103323, EudraCT: 2009-012787-14 GRID, 14874, NCT01271712, EudraCT: 2009-017957-37 CONCUR, 15808, NCT01584830 RESORCE, 15982, NCT01774344, EudraCT: 2012-003649-14.

Editorial acknowledgement

Legal entity responsible for the study

Bayer AG.

Funding

Bayer AG.

Disclosure

A. Grothey: Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Boston Biomedical; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech/Roche; Advisory / Consultancy: Guardant Health; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Eisai; Research grant / Funding (institution), Travel / Accommodation / Expenses: Boehringer Ingelheim; Travel / Accommodation / Expenses: Merck Sharp & Dohme. S. Hoefman: Advisory / Consultancy: Bayer AG. M. Ruppert: Advisory / Consultancy: Bayer AG. P. Vis: Advisory / Consultancy: Bayer AG. J. Zisowsky: Full / Part-time employment: Bayer AG. S. Fiala-Buskies: Full / Part-time employment: Bayer AG. E. Van Cutsem: Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Servier; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Merck KGaA; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Sanofi. E. Dochy: Full / Part-time employment: Bayer AG; Shareholder / Stockholder / Stock options: Sanofi. A. Cleton: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bayer AG. B.A. Ploeger: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bayer AG.