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US-12624383-B2 - Kinase activity signatures for predicting the response of non-small-cell lung carcinoma patients to a PD-1 or PD-L1 immune checkpoint inhibitor

US12624383B2US 12624383 B2US12624383 B2US 12624383B2US-12624383-B2

Abstract

The present invention relates to a method for determining or predicting the response of a patient diagnosed with non-small-cell lung carcinoma a PD-1 or PD-L1 immune checkpoint inhibitor. The present invention also aims to provide methods and devices for predicting the response of patients diagnosed with non-small-cell lung carcinoma to PD-1 or PD-L1 immune checkpoint inhibitors. More specifically, the present invention provides methods which measure kinase-activity and profiles and inhibitions thereof by drugs in blood samples of said patients.

Inventors

  • Richard De Wijn
  • Dirgje Maria Adriana VAN DEN HEUVEL

Assignees

  • PAMGENE BV

Dates

Publication Date
20260512
Application Date
20200904
Priority Date
20190905

Claims (9)

  1. 1 . A method of treating a patient diagnosed with non-small-cell lung carcinoma (NSCLC) with a medicament selected from the group consisting of a programmed death 1 (PD-1) immune checkpoint inhibitor or a programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor, the method comprising: (a) obtaining a prediction of a response of the patient diagnosed with NSCLC to a medicament selected from the group consisting of a PD-1 immune checkpoint inhibitor or a PD-L1 immune checkpoint inhibitor, wherein the obtaining comprises the steps of: (i) measuring the kinase activity of at least one kinase of the vascular endothelial growth factor receptor (VEGFR) or platelet-derived growth factor receptor (PDGFR) family of kinases selected from the group consisting of: fms-like tyrosine kinase 1 (FLT1), fms-like tyrosine kinase 3 (FLT3) and fms-like tyrosine kinase 4 (FLT4); at least one kinase of the proto-oncogene tyrosine-protein kinase Src (SRC) family of kinases selected from the group consisting of: SRC, B lymphocyte kinase (BLK), leukocyte C-terminal Src kinase (LCK), proto-oncogene c-Fyn (FYN) and tyrosine-protein kinase Yes (YES); and at least one kinase of the spleen tyrosine kinase (SYKyk) family of kinases selected from the group consisting of SYK and 70 kDa zeta-chain associated protein (ZAP70), in a blood sample comprising peripheral blood mononuclear cells obtained from said patient, thereby providing a kinase activity profile of said blood sample; and (ii) determining a response of said patient to said medicament from said kinase activity profile; wherein the response of said patient to said medicament is determined from said kinase activity profile by: comparing said kinase activity profile to a first and a second reference kinase activity profile; said first reference kinase activity profile being representative of a good responder to said medicament and said second reference kinase activity profile being representative for a poor responder to said medicament; and determining a response of said patient to said medicament on the basis of the comparison of said kinase activity profile with said first and said second reference kinase activity profile; or wherein the response of said patient to said medicament is determined from said kinase activity profile by: calculating a classifier parameter from said kinase activity profile; and determining the response of said patient to said medicament on the basis of said classifier parameter, wherein said classifier parameter being above a first predetermined threshold level indicates a good responder and said classifier parameter being below a second predetermined threshold level indicates a poor responder; wherein the kinase activity in step (i) is measured by contacting the blood sample from the patient with one or more protein kinase substrate(s) thereby generating one or more phosphorylation profile(s), and said kinase activity profile is determined from said phosphorylation profile(s) using upstream kinase analysis; and (b) categorizing the patient as a good responder to said medicament, wherein said categorization is based on a level of kinase activity in said kinase activity profile of at least one kinase selected from FLT1, FLT3, FLT4, at least one kinase selected from SRC, BLK, LCK, FYN and YES, and at least one kinase of the selected from SYK and ZAP70 and (c) treating said patient found to be a good responder with the medicament.
  2. 2 . The method according to claim 1 , wherein said method further comprises measuring the kinase activity of Janus kinase 2 (JAK2), tyrosine kinase-type cell surface receptor HER4 (HER4) and/or tropomyosin-related kinase B (TRKB).
  3. 3 . The method according to the claim 1 , wherein said method comprises measuring the kinase activity of FLT1, FLT3, FLT4, SRC, BLK, LCK, FYN, YES, SYK, and ZAP70.
  4. 4 . The method according to claim 1 , wherein said medicament is selected from the group consisting of: Nivolumab, Pembrolizumab, Durvalumab, Atezolizumab, Avelumab and Cemiplimab.
  5. 5 . The method according to claim 1 , wherein in step (a) said kinase activity is determined by contacting the sample with at least one protein kinase substrate, thereby providing a phosphorylation profile of said sample, said phosphorylation profile comprising the phosphorylation levels of phosphorylation sites present in peptide markers with SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92 and 93.
  6. 6 . The method according to claim 1 , wherein said NSCLC is a stage III or stage IV NSCLC.
  7. 7 . The method according to claim 1 , wherein susceptibility of a patient having NSCLC to a PD-1 or PD-L1 immune checkpoint inhibitor is assessed.
  8. 8 . The method according to claim 1 , wherein a pharmaceutical or clinical value of a PD-1 or PD-L1 immune checkpoint inhibitor is assessed.
  9. 9 . The method according to claim 1 , wherein the medicament is selected from Nivolumab or Pembrolizumab.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a U.S. national stage entry under 35 U.S.C. § 371 of PCT International Patent Application No. PCT/EP2020/074703, filed Sep. 4, 2020, which claims priority to European Patent Application No. 19195591.3.0, filed Sep. 5, 2019, the contents of each of which are incorporated herein by reference in their entirety. FIELD OF THE INVENTION The present invention relates to methods and devices for determining or predicting the response of a patient diagnosed with non-small cell lung carcinoma to specific medicaments. More specifically, the present invention provides methods which measure kinase activity in blood samples of said patients. BACKGROUND OF THE INVENTION At present lung cancer is considered to be one of the most important causes of death, especially in adults at the ages from 50 to 69 years old. Long term exposure to smoking is the cause of lung cancer for 90% of the cases. Among male smokers, the lifetime risk of developing lung cancer is about 17%; among female smokers the risk is about 11%. For non-smokers, the risk of developing lung cancer is about 1%. The main causes for lung cancer in non-smokers are genetic factors, radon gas, asbestos, air pollution and passive smoking. There are two main types of lung cancer: non-small cell lung cancer (NSCLC) (in about 80% of the cases) and small cell lung cancer (in about 17% of the cases). NSCLC can further be classified according to the growth type and spread of the cancer cells. NSCLC can therefore be classified into squamous cell carcinoma, large cell carcinoma and adenocarcinoma. Adenocarcinoma is more frequent in women, Asians and non-smokers. Other less common types of NSCLC are pleomorphic, carcinoid tumor, salivary gland carcinoma, and unclassified carcinoma. For the diagnosis of NSCLC a lung tissue biopsy is taken. Based on a primary biopsy diagnosis nearby lymph nodes may be biopsied to see if the cancer has spread. Staging of NSCLC is based on the American Joint Committee on Cancer (AJCC) TNM system. The T stands for tumor (how far it has grown within the lung and other factors). The T category is assigned a number (from 0 to 4) based on the tumor's size. N stands for spread to nearby lymph nodes (bean-sized collections of immune system cells, to which cancers often spread first). The N category is assigned a number (from 0 to 3) based on whether the NSCLC cells have spread to lymph nodes or are found in the lymphatic channels connecting the lymph nodes. The M category is based on whether the NSCLC has metastasized (spread) to distant organs, which organs it has reached. It is generally known that most types of lung cancer have a poor prognosis. According to the TNM standards the different stages and survival in the United States are as follows: Stage IA: The 5-year survival rate is around 49%.Stage IB: The 5-year survival rate is around 45%.Stage IIA: The 5-year survival rate is around 30%.Stage IIB: The 5-year survival rate is around 30%.Stage IIIA: The 5-year survival rate is around 14%.Stage IIIB: The 5-year survival rate is around 5%.Stage IV: The 5-year survival rate is about 1%-2%. NSCLC treatment options are based on the stage of the disease and may include: surgery, chemotherapy, targeted therapy, immunotherapy and radiation therapy. Early-stage NSCLC can often be cured with surgery alone, but more advanced NSCLC can be much harder to treat because standard cancer treatments such as chemotherapy are not very effective. But in recent years, newer types of immunotherapy and targeted therapies have changed the treatment of this disease, and many new treatments have shown a great deal of promise in treating advanced NSCLC. The development of molecularly targeted therapy (e.g. small molecules and monoclonal antibodies) has significantly improved outcomes in the metastatic setting for patients with NSCLC whose tumors harbor activated oncogenes such as epidermal growth factor receptor (EGFR) and translocated genes like anaplastic lymphoma kinase (ALK). In addition, immune checkpoint inhibitors have been successfully used to treat NSCLC. This therapy is based upon the fact that T lymphocytes are critical to antitumor immunity, and this antitumor immunity requires activation by an antigen-specific T cell receptor in the context of costimulatory activation. Excess immune activation is being prevented by a naturally occurring feedback mechanism that leads to the expression of negative costimulatory molecules (“checkpoints”). Examples of such checkpoints are cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), T cell immunoglobulin 3, and lymphocyte-activation gene 3. Antibodies directed against these checkpoints may restore or augment an antitumor immune response and produce tumor responses in patients with advanced or metastatic NSCLC. Examples of such antibodies are antibodies directed against PD-1 (such as Nivolumab (e.g. Opdivo™), Pembrolizumab (e.g. Keytruda™), or Durvalu