Duocarmycin ADCs showing improved in vivo antitumor activity
The present invention relates to duocarmycin-containing antibody-drug conjugates (ADCs) for use in the treatment of human solid tumours and haematological malignancies expressing HER2, in particular breast cancer, gastric cancer, bladder cancer, ovarian cancer, lung cancer, prostate cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer or osteosarcoma, and acute lymphoblastic leukaemia. In particular, the present invention relates to duocarmycin-containing ADCs for use in the treatment of human solid tumours with HER2 IHC 2+ or 1+ and HER2 FISH negative tissue status. Advantageously, the present invention relates to duocarmycin-containing ADCs for use in the treatment of triple negative breast cancer (TNBC).
1. A method of treating cancer in a human patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I)
wherein
anti-HER2 Ab is trastuzumab,
n is 0, 1, 2, or 3,
m represents an average DAR of from 1 to 4,
R 1 is selected from the group consisting of
y is 1-16, and
R 2 is selected from the group consisting of
wherein the patient has a solid tumor expressing HER2, the solid tumor is HER2 IHC 2+ or 1+, and the solid tumor is HER2 FISH negative, and wherein the solid tumor is gastric cancer, bladder cancer, ovarian cancer, lung cancer, prostate cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer, or osteosarcoma.
2. The method of claim 1 , wherein
n is 0 or 1,
m represents an average DAR of from 1 to 4,
R l is selected from the group consisting of
y is 1-16, and
R 2 is
3. The method of claim 2 , wherein
n is 0 or 1,
m represents an average DAR of from 2 to 3,
R 1 is
y is 1, 2, 3, or 4, and
R 2 is
4. The method of claim 1 , wherein the compound of formula (I) is a compound of formula (II)
5. The method of claim 4 , wherein the compound of formula (II) has an average DAR of from 2.5 to 2.9.
6. The method of claim 5 , wherein the compound of formula (II) has an average DAR of from 2.6 to 2.9.
7. The method of claim 4 , wherein the compound of formula (II) is administered in an amount of from about 0.3 mg/kg to about 10 mg/kg.
8. The method of claim 1 , wherein the solid tumor is gastric cancer, bladder cancer, ovarian cancer, lung cancer, or prostate cancer.
9. The method of claim 8 , wherein the solid tumor is gastric cancer.
10. The method of claim 1 , further comprising administering an effective amount of a therapeutic antibody or a chemotherapeutic agent, or a combination thereof.
11. The method of claim 10 , wherein the therapeutic antibody is pertuzumab and the chemotherapeutic agent is a taxane or an anthracycline.
12. The method of claim 11 , wherein the taxane is docetaxel or paclitaxel, and the anthracycline is doxorubicin, epirubicin, daunorubicin or valrubicin.
13. A method of treating cancer in a human patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I)
wherein
anti-HER2 Ab is trastuzumab,
n is 0, 1, 2, or 3,
m represents an average DAR of from 1 to 4,
R 1 is selected from the group consisting of
y is 1-16, and
R 2 is selected from the group consisting of
wherein the patient has breast cancer that expresses HER2 at a level of IHC 0, IHC 1+, or IHC 2+/FISH negative.