LAG-3 antagonist therapy for lung cancer
The disclosure provides a method of treating a human subject afflicted with lung cancer with a lymphocyte activation gene-3 (LAG-3) antagonist. In some aspects, the method comprises combination of the LAG-3 antagonist with an additional therapeutic agent (e.g., a programmed death-1 pathway inhibitor) and/or anti-cancer therapy (e.g., chemotherapy such as a platinum doublet chemotherapy).
1 . A method of treating a non-small cell lung cancer (NSCLC) in a human subject, the method comprising administering to the subject:
(a) about 360 mg of an anti-LAG-3 antibody comprising a heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:5, SEQ ID NO: 6, and SEQ ID NO:7, respectively, and a light chain variable region CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:8, SEQ ID NO:9, and SEQ ID NO:10, respectively,
(b) about 360 mg of an anti-PD-1 antibody comprising a heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:15, SEQ ID NO: 16, and SEQ ID NO: 17, respectively, and a light chain variable region CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:18, SEQ ID NO: 19, and SEQ ID NO:20, respectively, and
(c) a platinum doublet chemotherapy (PDCT) comprising: (i) cisplatin, carboplatin, or nedaplatin, and (ii) gemcitabine, pemetrexed, paclitaxel, albumin-bound paclitaxel, docetaxel, vinorelbine, vinblastine, etoposide, or irinotecan,
wherein the anti-LAG-3 antibody and the anti-PD-1 antibody are administered in a cycle of once every three weeks.
2 . The method of claim 1 , wherein the PDCT comprises: (i) cisplatin or carboplatin, and (ii) paclitaxel, albumin-bound paclitaxel, or pemetrexed.
3 . The method of claim 2 , wherein the PDCT is administered in a cycle of once every three weeks.
4 . The method of claim 3 , wherein the PDCT is administered for four cycles.
5 . The method of claim 1 , wherein the NSCLC has a squamous histology.
6 . The method of claim 1 , wherein the NSCLC has a non-squamous histology.
7 . The method of claim 1 , wherein the NSCLC is unresectable, advanced, recurrent, and/or metastatic.
8 . The method of claim 1 , wherein the NSCLC is a stage IV NSCLC.
9 . The method of claim 1 , wherein the method is a first line therapy.
10 . The method of claim 1 , wherein one or more immune cells in tumor tissue from the subject express LAG-3 and/or one or more tumor cells in tumor tissue from the subject express PD-L1.
11 . The method of claim 10 , wherein:
(a) at least about 1% of the immune cells express LAG-3, and/or
(b) at least about 1% of the tumor cells express PD-L1.
12 . The method of claim 10 , wherein at least about 1% of the tumor cells express PD-L1.
13 . The method of claim 10 , wherein at least about 1% to about 50% of the tumor cells express PD-L1.
14 . The method of claim 1 , wherein the anti-LAG-3 antibody and the anti-PD-1 antibody are formulated together.
15 . The method of claim 1 , wherein the anti-LAG-3 antibody and the anti-PD-1 antibody are formulated separately.
16 . The method of claim 1 , wherein the anti-LAG-3 antibody and the anti-PD-1 antibody are administered to the subject intravenously from a single intravenous bag for about 30 minutes.
17 . The method of claim 1 , wherein:
(a) the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 3 and 4, respectively, and the anti-PD-1 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 13 and 14, respectively,
(b) the anti-LAG-3 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs: 1 and 2, respectively, and the anti-PD-1 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs: 11 and 12, respectively,
(c) the anti-LAG-3 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs: 21 and 2, respectively, and the anti-PD-1 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs: 11 and 12, respectively, or,
(d) the anti-LAG-3 antibody comprises relatlimab and the anti-PD-1 antibody comprises nivolumab.
18 . A method of treating a Stage IV or recurrent NSCLC that has a squamous histology in a human subject, the method comprising administering to the subject:
(a) about 360 mg of an anti-LAG-3 antibody comprising a heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:5, SEQ ID NO: 6, and SEQ ID NO:7, respectively, and a light chain variable region CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:8, SEQ ID NO:9, and SEQ ID NO:10, respectively,
(b) about 360 mg of an anti-PD-1 antibody comprising a heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:15, SEQ ID NO: 16, and SEQ ID NO: 17, respectively, and a light chain variable region CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:18, SEQ ID NO: 19, and SEQ ID NO:20, respectively, and
(c) a PDCT comprising:
(i) carboplatin for a target area under the concentration-time curve of about 6 mg/mL·min, and
(ii) about 200 mg/m 2 of paclitaxel or about 100 mg/m 2 of albumin-bound paclitaxel,
wherein the anti-LAG-3 antibody and the anti-PD-1 antibody are formulated together,
wherein the anti-LAG-3 antibody, the anti-PD-1 antibody, and the PDCT are administered in a cycle of once every three weeks, and the PDCT is administered for four cycles, and wherein the method is a first line therapy.
19 . The method of claim 18 , wherein:
(a) the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 3 and 4, respectively, and the anti-PD-1 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 13 and 14, respectively,
(b) the anti-LAG-3 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs: 1 and 2, respectively, and the anti-PD-1 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs: 11 and 12, respectively,
(c) the anti-LAG-3 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs: 21 and 2, respectively, and the anti-PD-1 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs: 11 and 12, respectively, or
(d) the anti-LAG-3 antibody comprises relatlimab and the anti-PD-1 antibody comprises nivolumab.
20 . A method of treating a Stage IV or recurrent NSCLC that has a non-squamous histology in a human subject, the method comprising administering to the subject:
(a) about 360 mg of an anti-LAG-3 antibody comprising a heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:5, SEQ ID NO: 6, and SEQ ID NO:7, respectively, and a light chain variable region CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:8, SEQ ID NO:9, and SEQ ID NO:10, respectively,
(b) about 360 mg of an anti-PD-1 antibody comprising a heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:15, SEQ ID NO: 16, and SEQ ID NO:17, respectively, and a light chain variable region CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:18, SEQ ID NO: 19, and SEQ ID NO:20, respectively, and
(c) a PDCT comprising:
(i) carboplatin for a target area under the concentration-time curve of about 5 mg/mL·min or about 6 mg/mL·min or about 75 mg/m 2 of cisplatin, and
(ii) about 500 mg/m 2 of pemetrexed,
wherein at least about 1% of tumor cells in tumor tissue from the subject express PD-L1, wherein the anti-LAG-3 antibody and the anti-PD-1 antibody are formulated together, wherein the anti-LAG-3 antibody, the anti-PD-1 antibody, and the PDCT are administered in a cycle of once every three weeks, and the PDCT is administered for four cycles, and wherein the method is a first line therapy.
21 . The method of claim 20 , wherein about 1% to about 50% of the tumor cells express PD-L1.
22 . The method of claim 20 , wherein:
(a) the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 3 and 4, respectively, and the anti-PD-1 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 13 and 14, respectively,
(b) the anti-LAG-3 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs: 1 and 2, respectively, and the anti-PD-1 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs: 11 and 12, respectively,
(c) the anti-LAG-3 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs: 21 and 2, respectively, and the anti-PD-1 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs: 11 and 12, respectively, or
(d) the anti-LAG-3 antibody comprises relatlimab and the anti-PD-1 antibody comprises nivolumab.