. 2022 Jan 3;89(2):151–164. doi: 10.1007/s00280-021-04381-4

Table 3.

Predicted effects of dosing algorithm on efficacy and safety endpoints

Dose change of dosing algorithm	PK-PD predicted PO4 change	Effect OR/HR (95% CI)
Increase starting dose from 6 to 8 mg (regimen 1 vs. regimen 2)	+ 0.56 mg/dL	Decrease in HR of: 27% (95% CI 17, 35%) for OS 12% (95% CI 3.4, 20%) for PFS Increase in OR of: 20% (95% CI 1, 42%) for ORR
Up-titrate to 9 mg based on PO4 level at 2–3 weeks	+ 0.38 mg/dL	Decrease in HR of: 19% (95% CI 17, 26%) for OS 8.1% (95% CI 3.4, 14%) for PFS Increase in OR of: 13% (95% CI 0.8, 42%) for ORR
Reduce dose from 8 to 6 mg in case of AE	− 0.56 mg/dL	Decrease in OR (95% CI) of: 39% (24, 51%) for eye disorders 32% (14, 46%) for CSR 44% (30, 56%) for nail disorders 26% (7.5, 41%) for PPES 23% (7.1, 37%) for skin disorders

Dose change of dosing algorithm

PK-PD predicted PO4 change

Effect OR/HR (95% CI)

Increase starting dose from 6 to 8 mg (regimen 1 vs. regimen 2)

+ 0.56 mg/dL

Decrease in HR of:

27% (95% CI 17, 35%) for OS

12% (95% CI 3.4, 20%) for PFS

Increase in OR of:

20% (95% CI 1, 42%) for ORR

Up-titrate to 9 mg based on PO4 level at 2–3 weeks

+ 0.38 mg/dL

Decrease in HR of:

19% (95% CI 17, 26%) for OS

8.1% (95% CI 3.4, 14%) for PFS

Increase in OR of:

13% (95% CI 0.8, 42%) for ORR

Reduce dose from 8 to 6 mg in case of AE

− 0.56 mg/dL

Decrease in OR (95% CI) of:

39% (24, 51%) for eye disorders

32% (14, 46%) for CSR

44% (30, 56%) for nail disorders

26% (7.5, 41%) for PPES

23% (7.1, 37%) for skin disorders

CI confidence interval; CSR central serous retinopathy; HR hazard ratio; OR odds ratio; ORR objective response rate; PFS progression-free survival; PPES palmar-plantar erythrodysaesthesia syndrome