Combination of a PD-1 antagonist and a RAF inhibitor for treating cancer
Disclosed herein is a pharmaceutical combination for use in the prevention, delay of progression or treatment of cancer, wherein the pharmaceutical combination exhibits a synergistic efficacy. The pharmaceutical combination comprises a humanized antagonist monoclonal antibody against PD- and a RAF inhibitor. Also disclosed herein is a combination for use in the prevention, delay of progression or treatment of cancer in a subject, comprising administering to the subject a therapeutically effective amount of a humanized antagonist monoclonal antibody against PD-1 and a therapeutically effective amount of a RAF inhibitor.
1. A method for the treatment of lung cancer or colorectal cancer in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a PD-1 antagonist in combination with a therapeutically effective amount of a RAF inhibitor,
wherein the PD-1 antagonist is an antibody or an antigen binding fragment thereof, which specifically binds to human PD-1 and which comprises a heavy chain variable region (Vh) and a light chain variable region (Vk), wherein the Vh comprises complimentary determining region (CDR) 1, CDR2, and CDR3 comprising SEQ ID NOs: 31, 32, and 33, respectively; and the Vk comprises CDR1, CDR2, and CDR3 comprising SEQ ID NOs: 34, 35, and 36, respectively; and
wherein the RAF inhibitor is a compound of Formula (II),
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the (Vh) of the antibody comprises SEQ ID NO: 24 and the (Vk) of the antibody comprises SEQ ID NO: 26.
3. The method of claim 1 , wherein the antibody contains a IgG4 heavy chain effector or constant domain comprising any of SEQ ID NOs: 83-88.
4. The method according to claim 1 , wherein the PD-1 antagonist is an antibody which comprises an IgG4 heavy chain effector or constant domain comprising SEQ ID NO: 88, wherein the heavy chain variable region (Vh) and the light chain variable region (Vk) comprises SEQ ID NO: 24 and SEQ ID NO: 26, respectively.
5. The method of claim 1 , wherein the RAF inhibitor is a compound of Formula (III),
wherein n is a number from about 0.5 to about 1.5.
6. The method of claim 1 , wherein the RAF inhibitor is a compound of Formula (IIIa),
7. The method of claim 1 , wherein the PD-1 antagonist and the RAF inhibitor are administered simultaneously, sequentially or separately.
8. The method of claim 1 , wherein the RAF inhibitor is administrated orally at a dose of 5-80 mg QD.
9. The method of claim 1 , wherein the PD-1 antagonist is administered parenterally at a dose of 0.5-10 mg/kg QW, or Q2W, or Q3W, or Q4W.
10. The method of claim 1 , wherein the PD-1 antagonist is an antibody which comprises a heavy chain variable region (Vh) and a light chain variable region (Vk), and a IgG4 heavy chain effector or constant domain comprising SEQ ID NO: 88, wherein the heavy chain variable region (Vh) and the light chain variable region (Vk) comprise SEQ ID NO: 24 and SEQ ID NO: 26, respectively; and the RAF inhibitor is the compound of Formula (IIIa)
11. The method of claim 10 , wherein the PD-1 antagonist is administrated at a dose of 0.5-10 mg/kg QW or Q2W or Q3W, and the compound of Formula (IIIa) as the RAF inhibitor is administrated at a dose of 5-80 mg QD.
12. The method of claim 10 , wherein the PD-1 antagonist is administrated at a dose of 0.5-10 mg/kg QW or Q2W or Q3W, and the compound of Formula (IIIa) as the RAF inhibitor is administrated at a dose of 10-30 mg QD.
13. A pharmaceutical combination for use in the treatment of lung cancer or colorectal cancer, comprising a PD-1 antagonist and a RAF inhibitor,
wherein the PD-1 antagonist is an antibody or a fragment antigen binding thereof, which specifically binds to human PD-1, comprising a heavy chain variable region (Vh) and a light chain variable region (Vk) that contain complement determinant regions (CDRs) listed as follows:
CDR-H1, CDR-H2 and CDR-H3 (SEQ ID NOs: 31, 32, 33, respectively); and
CDR-L1, CDR-L2 and CDR-L3 (SEQ ID NOs: 34, 35, 36, respectively); and
wherein the RAF inhibitor is a compound of Formula (H),
or a pharmaceutically acceptable salt thereof.