Dosing regimen of avelumab for the treatment of cancer
Inventors
ANDREWS, Glen Ian • BELLO, Carlo Leonel • BRAR, Satjit Singh • WANG, Shaonan • GIRARD, Pascal
Assignees
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Publication Number
US-11274154-B2
Publication Date
2022-03-15
Expiration Date
Abstract
The present invention relates to dosing regimen of avelumab for the treatment of cancer. In particular, the invention relates to improved dosing regimen of avelumab for the treatment of cancer.
Core Innovation
The disclosed invention provides improved avelumab dosing regimens for treating cancer in a patient. The regimens are designed to increase mean exposure, including higher Ctrough and AUC0-336h compared with the current 10 mg/kg Q2W regimen.
A central feature is a two-phase dosing regimen in which avelumab is administered as X mg/kg Q1W for n weeks followed by Y mg/kg Q2W, with X in the range 5-20 and Y in the range 10-20, and n equal to 6, 12, or 18 weeks. Corresponding flat-dose regimens are also disclosed, including 400-1600 mg Q1W for n weeks followed by 800-1600 mg Q2W, and a flat-dose Q2W regimen of 400-800 mg.
The dosing-regimen approach links exposure levels to overall response rate using observed phase trial data for MCC and NSCLC and evaluates probability models using Ctrough quartiles. The document provides PD-L1 biomarker context using tumor proportion score cutoffs and describes higher overall response rates in subsets with high exposure and high PD-L1.
Claims Coverage
The independent claims cover four inventive dosing-regimen frameworks for treating cancer with avelumab: two-phase weight-based and flat-dose Q1W/Q2W regimens, a flat-dose Q2W regimen, and specified regimen options combined with PD-L1 TPS thresholds. The inventive features comprise dosing schedule structure, specific dosing ranges or flat doses, duration parameter n, and PD-L1 tumor proportion score thresholds.
Two-phase weight-based Q1W/Q2W regimen with defined X, Y, and n
Administering avelumab according to a dosing regimen of X mg/kg Q1W for n weeks followed by Y mg/kg Q2W, wherein X is 5-20, Y is 10-20, and n is 6, 12 or 18.
Two-phase flat-dose Q1W/Q2W regimen with defined weekly/biweekly ranges
Administering avelumab according to a dosing regimen of 400-1600 mg Q1W for n weeks followed by 800-1600 mg Q2W, wherein n is 6, 12 or 18.
Flat-dose Q2W regimen with defined mg range
Administering avelumab according to a dosing regimen of 400-800 mg flat dose Q2W.
Selected regimen option combined with PD-L1 tumor proportion score thresholds
Administering avelumab according to a dosing regimen selected from the group consisting of 800 mg Q1W for 12 weeks followed by 800 mg Q2W and 10 mg/kg Q1W for 12 weeks followed by 10 mg/kg Q2W, wherein the cancer has a tumor proportion score of PD-L1 expression of 5% or above, 20% or above, 50% or above or 80% or above.
Collectively, the independent claims claim avelumab treatment using alternative dosing regimens that structurally change dosing phase, specify weight-based or flat-dose ranges and amounts, define the duration parameter n, and in one case require PD-L1 tumor proportion score thresholds of 5%, 20%, 50%, or 80% or above.
Stated Advantages
Increase mean exposure, including higher Ctrough and AUC0-336h, compared with the current 10 mg/kg Q2W regimen.
Higher overall response rate (ORR) associated with higher exposure levels using observed phase trial data and exposure-efficacy/probability modeling.
Higher ORRs in subsets characterized by high exposure and high PD-L1 tumor proportion score.
Exposure-safety modeling, including immune-related adverse events and infusion-related reactions, is used to support the dosing-regimen choices.
Documented Applications
Treating cancer in a patient by administering avelumab using dosing regimens that include a two-phase X mg/kg Q1W for n weeks followed by Y mg/kg Q2W, as well as flat-dose Q2W and flat-dose Q1W/Q2W regimens.
Use in phase trial contexts associated with MCC and NSCLC, where higher exposure levels are linked to ORR probabilities based on observed data and modeling.
Use with PD-L1 biomarker context using tumor proportion score (TPS) cutoffs to identify subsets with higher ORRs in relation to exposure levels.
Cancer indication subsets explicitly referenced in the document include non-small cell lung cancer (NSCLC), Merkel cell carcinoma (MCC), urothelial carcinoma/UC, renal cell carcinoma (RCC), bladder cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, and breast cancer.
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