Therapeutic and diagnostic methods for cancer
Inventors
Bourgon, Richard • Fabrizio, David • FINE, Gregg • FRAMPTON, Garrett M. • Hegde, Priti • Mariathasan, Sanjeev • Stephens, Philip J. • Sun, James Xin • Yelensky, Roman
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12331128-B2
Publication Date
2025-06-17
Expiration Date
Abstract
The present invention provides therapeutic and diagnostic methods and compositions for cancer, for example, bladder cancer. The invention provides methods of treating bladder cancer, methods of determining whether a patient suffering from bladder cancer is likely to respond to treatment comprising a PD-L1 axis binding antagonist, methods of predicting responsiveness of a patient suffering from bladder cancer to treatment comprising a PD-L1 axis binding antagonist, and methods of selecting a therapy for a patient suffering from bladder cancer, based on somatic mutation levels of genes of the invention (e.g., somatic mutation levels in a tumor sample obtained from the patient).
Core Innovation
The invention provides methods of treating a patient suffering from urothelial bladder cancer or locally advanced or metastatic urothelial carcinoma using a PD-L1 binding antagonist, specifically an anti-PD-L1 antibody. The method requires that a tumor sample obtained from the patient has been determined to have an increased level of mutation load relative to a reference level of mutation load, and the mutation load reflects the level of somatic mutations in at least one-third of the genes set forth in Table 1.
The anti-PD-L1 antibody comprises defined heavy chain hypervariable region sequences and defined light chain hypervariable region sequences. The heavy chain comprises the HVR-H1 sequence of SEQ ID NO: 19, the HVR-H2 sequence of SEQ ID NO: 20, and the HVR-H3 sequence of SEQ ID NO: 21, and the light chain comprises the HVR-L1 sequence of SEQ ID NO: 22, the HVR-L2 sequence of SEQ ID NO: 23, and the HVR-L3 sequence of SEQ ID NO: 24.
The approach links increased mutation load to therapy selection for PD-L1 axis binding antagonist therapy. The partial content further describes increased rearrangement levels in genes listed in Table 2 and elevated somatic mutation levels in genes listed in Table 1 as correlating with likelihood of response, including described fraction-based and quantitative increase thresholds relative to reference levels.
Claims Coverage
The document provides two independent claims covering patient treatment with a PD-L1 binding antagonist selected based on increased tumor mutation load relative to a reference level, with mutation load reflecting somatic mutations in at least one-third of the genes in Table 1. Across the independent claims, the core inventive features include determining increased mutation load from a tumor sample and administering a therapeutically effective amount of a PD-L1 binding antagonist defined by specific antibody hypervariable region sequences, with additional eligibility constraints in the locally advanced or metastatic context.
Mutation load-based eligibility for PD-L1 binding antagonist treatment
A method in which a tumor sample obtained from the patient has been determined to have an increased level of mutation load relative to a reference level of mutation load, wherein mutation load of the tumor sample reflects the level of somatic mutations in at least one-third of the genes set forth in Table 1.
Anti-PD-L1 antibody with specified heavy- and light-chain hypervariable region sequences
A PD-L1 binding antagonist that is an anti-PD-L1 antibody comprising a heavy chain comprising the hypervariable region (HVR)-H1 sequence of SEQ ID NO: 19, the HVR-H2 sequence of SEQ ID NO: 20, and the HVR-H3 sequence of SEQ ID NO: 21; and a light chain comprising the HVR-L1 sequence of SEQ ID NO: 22, the HVR-L2 sequence of SEQ ID NO: 23, and the HVR-L3 sequence of SEQ ID NO: 24.
Platinum-ineligible, treatment-naive locally advanced or metastatic setting
A method of treating a patient suffering from a locally advanced or metastatic urothelial carcinoma, wherein the patient is ineligible for treatment with a platinum-based chemotherapeutic agent and has not received prior treatment for locally advanced or metastatic urothelial carcinoma, and wherein the mutation load criteria are satisfied based on the tumor sample.
Defined dosing and administration schedule for the anti-PD-L1 antibody
Administering an anti-PD-L1 antibody intravenously on Day 1 of each 21-day cycle, including administration of 1200 mg of the anti-PD-L1 antibody as recited.
The independent claims collectively cover administering an anti-PD-L1 antibody with specified heavy- and light-chain hypervariable region sequences to treat urothelial bladder cancer or locally advanced or metastatic urothelial carcinoma when a tumor sample shows increased mutation load versus a reference, with mutation load defined by somatic mutations in at least one-third of the genes set forth in Table 1. The second independent claim further conditions treatment on platinum ineligibility and lack of prior treatment, and it specifies an intravenous dosing schedule.
Stated Advantages
Supports selecting patients for treatment of urothelial bladder cancer or locally advanced or metastatic urothelial carcinoma based on tumor mutation load relative to a reference level.
Supports predicting responsiveness based on tumor genomic mutation load signals and, in some stratification approaches, rearrangements.
Documented Applications
Therapeutic treating of a patient suffering from urothelial bladder cancer with a PD-L1 binding antagonist where the patient's tumor sample has increased mutation load relative to a reference level and mutation load reflects somatic mutations in at least one-third of genes set forth in Table 1.
Therapeutic treating of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for platinum-based chemotherapeutic agents and have not received prior treatment, using an anti-PD-L1 antibody dosing regimen, where tumor mutation load is increased relative to a reference and reflects somatic mutations in at least one-third of Table 1 genes.
Patient stratification using tumor genomic mutation load signals based on fraction of genes with increased somatic mutations and/or whole-genome mutation load relative to a reference level, and stratification using rearrangements described with a rearranged-in-cancer gene set in combination with mutation signals.
Interested in licensing this patent?