CANCER TREATMENT METHODS AND THEIR PHARMACEUTICAL COMPOSITIONS

Claims

1. A method of treating cancer in a patient, comprising administering to the patient a bispecific antibody having binding specificity to EGFR and HER3, and a therapeutic agent, wherein the therapeutic agent comprises a tyrosine kinase inhibitor (TKI), an alkylating agent, an antimetabolite, an antimicrotubule agent, a cytotoxic antibiotic, a topoisomerase inhibitor, a chemoprotectant, or a combination thereof.

2. The method according to claim 1, wherein the bispecific antibody comprises 3 complementarity determining regions (CDRs) with SEQ ID NO: 1, 3 CDRs with SEQ ID NO: 2 or 3 CDRs with SEQ ID NO:

4.

3. The method according to claim 1, wherein the bispecific antibody comprises a heavy chain variable region (VH) having an amino acid sequence with at least 98% sequence identity to SEQ ID NO: 1, a heavy chain scFv domain having an amino acid sequence with at least 98% sequence identity to SEQ ID NO: 2, and a light chain variable region (VL) having an amino acid sequence with at least 98% sequence identity to SEQ ID NO:

4.

4. The method according to claim 1, wherein the bispecific antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence with at least 98% sequence identity to SEQ ID NO: 3, and the light chains comprise an amino acid sequence with at least 98% sequence identity to SEQ ID NO:

5.

5. The method of claim 1, wherein the therapeutic agent comprises osimertinib, paclitaxel, docetaxel, irinotecan, carboplatin, pemetrexed, cisplatin, or a combination thereof.

6. The method of claim 1, wherein the bispecific antibody and the therapeutic agent are administered simultaneously or sequentially during a single treatment session.

7. The method of claim 1, wherein the bispecific antibody and the therapeutic agent are administered to the patient separately during alternating treatment sessions.

8. The method of claim 1, wherein the bispecific antibody is administered during a first treatment session and the therapeutic agent is administered during a second treatment session, wherein the antibody is administered once a week (Q1W), once two weeks (Q2W), once every three weeks (Q3W), or once a week for two weeks every three weeks (D1D8, Q3W), and wherein the antibody is administered at a fixed dose, a dose expressed in mg / kg, or a dose expressed in mg / m 2 .

9. The method of claim 8, wherein the duration of the first treatment session is from about 7 days to about 728 days.

10. The method according to claim 8, wherein the duration of the second treatment session is from approximately 1 day to 728 days.

11. The method of claim 8, wherein the interval between the first treatment session and the second treatment session is from about 7 to about 21 days.

12. The method of claim 1, wherein the bispecific antibody is administered at a dose of at least about 0.3 mg / kg, about 1.2 mg / kg, about 3.0 mg / kg, about 6.0 mg / kg, about 9.0 mg / kg, about 12.0 mg / kg, about 14.0 mg / kg, about 16.0 mg / kg, about 21.0 mg / kg, or about 28.0 mg / kg.

13. The method of claim 1, wherein the therapeutic agent is administered at a dose of from about 6.0 mg / kg to about 8.0 mg / kg.

14. The method according to claim 1, wherein the tyrosine kinase inhibitor (TKI) comprises erlotinib, gefitinib, icotinib, AZD3759, sapatinib, afatinib, dacomitinib, deratinib, poziotinib, tarlox-TK1, osimertinib, nazartinib, olmutinib, rociletinib, naquotinib, lasertinib, EAI045, CLN081, AZ5104, mobocertinib, a derivative thereof, or a combination thereof.

15. The method of claim 1, wherein the alkylating agent comprises busulfan, cyclophosphamide, temozolomide, carboplatin, cisplatin, or a combination thereof.

16. The method of claim 1, wherein the antimetabolite comprises 6-mercaptopurine, fludarabine, 5-fluorouracil, gemcitabine, cytarabine, pemetrexed, methotrexate, a derivative thereof, or a combination thereof.

17. The method of claim 1, wherein the antimicrotubule agent comprises docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, a derivative thereof, or a combination thereof.

18. The method according to claim 1, wherein the cytotoxic antibiotics comprise dactinomycin, bleomycin, daunorubicin, doxorubicin, a derivative thereof, or a combination thereof.

19. The method of claim 1, wherein the topoisomerase inhibitor comprises etoposide, irinotecan, topotecan, a derivative thereof, or a combination thereof.

20. The method according to claim 1, wherein the chemoprotectant comprises leucovorin or a derivative thereof.

21. The method of claim 1, wherein the therapeutic agent comprises osimertinib, and wherein osimertinib is administered at a dose of at least about 40 mg / kg, about 80 mg / kg, about 120 mg / kg, or about 160 mg / kg.

22. The method of claim 1, wherein the therapeutic agent comprises carboplatin, and wherein carboplatin is administered at a dose of at least about 200 mg / m 2 , approximately 250 mg / m 2 , approximately 300 mg / m 2 , approximately 360 mg / m 2 , approximately 400 mg / m3 2 , approximately AUC 5 mg / ml / min, approximately AUC 6 mg / ml / min, or approximately AUC 7 mg / ml / min.

23. The method of claim 1, wherein the therapeutic agent comprises cisplatin, and wherein cisplatin is administered at a dose of at least about 15 mg / m 2 , approximately 20 mg / m 2, approximately 30 mg / m 2 , approximately 50 mg / m 2 , approximately 75 mg / m 2 , approximately 100 mg / m 2 or approximately 120 mg / m 2 .

24. The method of claim 1, wherein the therapeutic agent comprises pemetrexed and wherein pemetrexed is administered at a dose of at least about 250 mg / m 2 , approximately 500 mg / m3 2 or approximately 750 mg / m 2 .

25. The method of claim 1, wherein the therapeutic agent comprises paclitaxel, and wherein paclitaxel is administered at a dose of at least about 40 mg / m 2 , approximately 80 mg / m3 2 , approximately 135 mg / m 2 or approximately 175 mg / m 2 .

26. The method of claim 1, wherein the therapeutic agent comprises docetaxel, and wherein docetaxel is administered at a dose of at least about 35 mg / m 2 on day 1 and day 8 every three weeks (D1D8Q3W).

27. The method of claim 1, wherein the bispecific antibody and the therapeutic agent are administered simultaneously and sequentially.

28. The method of claim 1, wherein the bispecific antibody is administered at a separate time from the therapeutic agent.

29. The method of claim 1, wherein the cancer is a solid tumor that tests positive for EGFR expression and is selected from the group consisting of: lung adenocarcinoma, head / neck squamous cell carcinoma, rectal cancer, colon cancer, lung squamous cell carcinoma, thyroid cancer, bladder cancer, melanoma, cervical cancer, prostate cancer, breast cancer, uterine / endometrial cancer, pancreatic cancer, ovarian cancer, and papillary renal cell carcinoma.

30. A therapeutic composition comprising a combination of a bispecific antibody having binding specificity to EGFR and HER3 and a therapeutic agent, wherein the therapeutic agent comprises a tyrosine kinase inhibitor (TKI), an alkylating agent, an antimetabolite, an antimicrotubule agent, a cytotoxic antibiotic, a topoisomerase inhibitor, a chemoprotectant, or a combination thereof.

31. The therapeutic composition of claim 30, wherein the bispecific antibody comprises 3 complementarity determining regions (CDRs) with SEQ ID NO: 1, 3 CDRs with SEQ ID NO: 2, or 3 CDRs with SEQ ID NO: 4, and wherein the therapeutic agent comprises osimertinib, carboplatin, cisplatin, pemetrexed, paclitaxel, a derivative thereof, or a combination thereof.

32. The therapeutic composition of claim 30, wherein the bispecific antibody and the therapeutic agent are in the form of a pharmaceutical composition for administration simultaneously, sequentially, or in parallel.

33. A kit comprising a first container, a second container, and a package insert, wherein the first container contains at least one dose of a first therapeutic composition comprising a bispecific antibody having binding specificity to EGFR and HER3, the second container contains at least one dose of a second therapeutic composition comprising a therapeutic agent, and the package insert contains instructions for treating cancer in a patient using the first and second therapeutic compositions, wherein the therapeutic agent comprises a tyrosine kinase inhibitor (TKI), an alkylating agent, an antimetabolite, an antimicrotubule agent, a cytotoxic antibiotic, a topoisomerase inhibitor, a chemoprotectant, or a combination thereof.

34. The kit of claim 33, wherein the instructions indicate that the first and second therapeutic compositions are intended for use in the treatment of a patient suffering from cancer that tests positive for EGFR expression.