LAG-3 protein, PD-1 inhibitor and chemotherapy triple combination therapy

Abstract

Triple Combination Therapy A triple combination therapy for the treatment of cancer is described. The treatment comprises use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor, and a chemotherapy agent. The LAG-3 protein, or a derivative thereof, is to be administered simultaneously or sequentially with the PD-1 pathway inhibitor and chemotherapy agent. The triple combination improves overall survival (OS), overall response rate (ORR), disease control rate (DCR), or progression-free survival (PFS), of a subject with a cancer, in particular with non-small cell lung cancer (NSCLC). Methods of treatment are also described.

Description

[0001] Triple Combination Therapy

[0002] FIELD OF THE INVENTION

[0003] This invention relates to the use of a LAG-3 protein or derivative thereof as part of a combination therapy for the treatment of cancer.

[0004] BACKGROUND OF THE INVENTION

[0005] Over the past decade, PD-1 and CTLA-4 immune checkpoint inhibitors such as OPDIVO (nivolumab), KEYTRUDA (pembrolizumab) and YERVOY (ipilimumab) have become the standard of care therapies for many forms of cancer, however unfortunately, many patients still fail to respond to these modern medicines. In some cases, these new medicines are combined with chemotherapy (chemo-IO) to improve response rates, although this can lead to undesirable toxic effects. In other cases, combinations of immune checkpoint inhibitors (IO-IO) are used, but this can also lead to undesirable toxic effects.

[0006] To improve patient outcomes, significant work has been undertaken to investigate other immune checkpoints, such as LAG-3, TIM-3, VISTA, CD47, IDO, and TIGIT. LAG-3 in particular has emerged as a promising checkpoint and several companies are developing new inhibitors that target this checkpoint. The aim of a LAG-3 inhibitor, as with the currently approved PD-1 and CTLA-4 inhibitors, is to block the down-regulation of the immune system i.e. take the “brakes off” the body’s immune processes. Significant work has also been undertaken to explore combinations of PD-1 and CTLA-4 immune checkpoint inhibitors with other approved or experimental therapies.

[0007] Another type of active immunotherapy being investigated are the antigen presenting cell (APC) activators. APC activators bind to antigen presenting cells such as dendritic cells, monocytes and macrophages via MHC II molecules. This activates the APCs causing them to become professional antigen presenting cells, thereby presenting antigen to the adaptive immune system. This leads to activation and proliferation of CD4+ (helper) and CD8+ (cytotoxic) T cells. Thus, the aim of APC activators is to “push the gas” on the body’s immune system.

[0008] Eftilagimod alpha (INN: eftilagimod alfa; or IMP321 or efti), a soluble dimeric recombinant form of LAG-3, is a first-in-class APC activator under clinical development. By stimulating dendritic cells and other APCs through MHC class II molecules, IMP321 induces a powerful anti-cancer T cell response. IMP321 is described in WO 2009 / 044273, which also describes the use of IMP321 alone and in combination with a chemotherapy agent for the treatment of cancer. In addition, WO 2016 / 110593 describes the use of IMP321 in combination with a PD-1 pathway inhibitor for the treatment of cancer and infectious disease.

[0009] There remains a need in the art for improved cancer therapies and treatment regimens leading to better outcomes for patients. This is especially so for cancers where the prognosis for patients undertaking treatment with current approved medicines is poor and / or where current medicines are poorly tolerated.

[0010] SUMMARY OF THE INVENTION

[0011] In one embodiment, the invention relates to (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHO class II molecules, (b) a programmed cell death protein-1 (PD-1) pathway inhibitor, and (c) a chemotherapy agent, for use in preventing, treating, or ameliorating a cancer in a subject.

[0012] In another embodiment, the invention relates to the use of (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, (b) a programmed cell death protein-1 (PD-1) pathway inhibitor, and (c) a chemotherapy agent, in the manufacture of a medicament for the prevention, treatment, or amelioration of a cancer in a subject.

[0013] In yet another embodiment, the invention relates to the use of (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, (b) a programmed cell death protein- 1 (PD-1) pathway inhibitor, and (c) a chemotherapy agent, for the prevention, treatment, or amelioration of a cancer in a subject.

[0014] In a further embodiment, the invention provides a method of preventing, treating, or ameliorating a cancer in a subject, the method comprising administering to the subject in need of such prevention, treatment, or amelioration (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, (b) a programmed cell death protein-1 (PD-1) pathway inhibitor, and (c) a chemotherapy agent.

[0015] In yet a further embodiment, the invention relates to a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, for use in preventing, treating, or ameliorating a cancer in a subject, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent. In one embodiment, the invention relates to the use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, in the manufacture of a medicament for the prevention, treatment, or amelioration of a cancer in a subject, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

[0016] In yet a further embodiment, the invention relates to a programmed cell death protein-1 (PD-1) pathway inhibitor for use in preventing, treating, or ameliorating a cancer in a subject, wherein the PD-1 pathway inhibitor is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a chemotherapy agent.

[0017] In one embodiment, the invention relates to the use of a programmed cell death protein-1 (PD-1) pathway inhibitor in the manufacture of a medicament for preventing, treating, or ameliorating a cancer in a subject, wherein the PD-1 pathway inhibitor is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a chemotherapy agent.

[0018] In yet a further embodiment, the invention relates to a chemotherapy agent for use in preventing, treating, or ameliorating a cancer in a subject, wherein the chemotherapy agent is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a programmed cell death protein-1 (PD-1) pathway inhibitor.

[0019] In one embodiment, the invention relates to the use of a chemotherapy agent in the manufacture of a medicament for preventing, treating, or ameliorating a cancer in a subject, wherein the chemotherapy agent is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a programmed cell death protein-1 (PD-1) pathway inhibitor.

[0020] In another embodiment, the invention provides a method of preventing, treating, or ameliorating a cancer in a subject, the method comprising administering to the subject in need of such prevention, treatment, or amelioration a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, wherein the LAG-3 protein or derivative thereof is administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent. In yet another embodiment, the invention provides a combined preparation, comprising: (a) a LAG-3 protein, or derivative thereof that is able to bind to MHC class II molecules, (b) a programmed cell death protein-1 (PD-1) pathway inhibitor, and

[0021] (c) a chemotherapy agent.

[0022] In a further embodiment, the invention provides a pharmaceutical composition, comprising: (a) a LAG-3 protein, or derivative thereof that is able to bind to MHC class II molecules, (b) a programmed cell death protein-1 (PD-1) pathway inhibitor,

[0023] (c) a chemotherapy agent, and

[0024] (d) a pharmaceutically acceptable carrier, excipient, or diluent.

[0025] Surprisingly, such triple combination therapy of the invention has been found to improve overall survival (OS) (in particular, median OS, and 24-month OS rate), and progression-free survival (PFS) (in particular, median PFS), of subjects with cancer. In particular, for subjects with non-small cell lung cancer (NSCLC) the following results were obtained:

[0026]

[0027] These results compare favourably to the 22.0-month median OS, 9.0-month median PFS, and 24-month OS rate of 45.5% from treatment with anti-PD-1 antibody and doublet chemotherapy in non-squamous 1L NSCLC, regardless of PD-L1 expression.

[0028] The results also compare favourably to our calculation of a weighted average of 20.53-month median OS (mOS) from treatment with anti-PD-1 antibody and doublet chemotherapy, calculated from the results reported by Rodriguez-Abreu et al. (Annals of Oncology, Volume 32, Issue 7, 2021, 881-895) for Keynote 189 (mOS: 22.0), and Paz-Ares et al. (Journal of Thoracic Oncology Vol. 15 No. 10: 1657-69) for Keynote 407 (mOS: 17.1), assuming a 70:30 ratio of non-squamous to squamous NSCLC in the general NSCLC population (McKeage and Jameson, J Thorac Dis. 2010 Dec;2(4): 199-204).

[0029] Significant improvement of Overall Response Rate (ORR) was also observed across all levels of PD-L1 expression compared to historical control:

[0030] • 75.0% ORR versus 62.1% ORR in patients with high PD-L1 expression (TPS >50%) • 58.8% ORR versus 49.2% ORR in patients with low PD-L1 expression (TPS 1-49%) 47.4% ORR versus 32.3% ORR in patients with negative PD-L1 expression (TPS <1%)

[0031] A 55.0% ORR and 87.5% Disease Control Rate (DCR) are from the following breakdown of patients by PD-L1 expression: TPS >50% (N=4), TPS 1-49% (N=17), and TPS <1% (N=19). As compared to the general 1L NSCLC patient population of which each of these PD-L1 levels represents roughly one-third, these results are biased towards low and negative PD-L1 (TPS <50%) patients who are typically less responsive to anti-PD-1 therapy. In the patients with low and negative PD-L1 expression (N=36), a combination therapy of the invention achieved a 52.8% ORR and 86.1% DCR. Of note, all 19 patients in the expansion cohort have TPS <50% and several with stable disease have potential to become responders.

[0032] Initial results from a full cohort of 54 patients (51 evaluable patients) show that ORR was comparable among TPS strata, with confirmed ORR of 54.5% in TPS < 1% (N=22); 60% in TPS 1-49% (N=25) and 75% in TPS > 50% (N=4), respectively (see Example 4). This is especially encouraging in patients with TPS score <1% and TPS 1-49%, where the unmet medical need is high. DCR was 86.4% in TPS < 1% (N=22); 92.0% in TPS 1-49% (N=25) and 100% in TPS > 50% (N=4), respectively.

[0033] There is also provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, for use in treating a cancer, wherein the treatment improves overall survival (OS) of a subject with the cancer.

[0034] According to the invention there is also provided a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, for use in improving overall survival (OS) of a subject with a cancer.

[0035] There is also provided according to the invention use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor, and a chemotherapy agent, in the manufacture of a medicament for improving overall survival (OS) of a subject with a cancer.

[0036] There is further provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, for use in improving overall survival (OS) of a subject with a cancer, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

[0037] There is also provided according to the invention use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, in the manufacture of a medicament for improving overall survival (OS) of a subject with a cancer, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

[0038] Optionally the LAG-3 protein, or derivative, is for use in improving overall survival (OS) of a subject with a cancer compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0039] Optionally the LAG-3 protein, or derivative, is for use in improving OS of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0040] Optionally the LAG-3 protein, or derivative, is for use in improving OS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0041] Optionally the LAG-3 protein, or derivative, is for use in improving OS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0042] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject.

[0043] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject to at least 25, 26, 27, 28, 29, or 30 months.

[0044] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject to at least 30 months.

[0045] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject to at least 32 months. Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject by at least 6 months compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0046] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject by at least 9 months compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0047] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject by at least 10 months compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0048] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject by at least 6 months, 9 months, or 10 months, compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0049] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject by at least 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0050] For example, the median OS of pembrolizumab + chemo in non-squamous NSCLC is 22.0 months (Rodriguez-Abreu et al., Annals of Oncology, Volume 32, Issue 7, 2021, 881-895, Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189) and in squamous NSCLC is 17.1 months (Paz-Ares, et al., A Randomized, Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407, Journal of Thoracic Oncology Vol. 15 No. 10: 1657-69). Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject by at least 12 months, compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0051] For example, a weighted average of 20.53-month median OS (mOS) can be calculated from the results of Rodriguez-Abreu etal. (supra), for Keynote 189 (mOS: 22.0), and Paz-Ares et al. (supra), for Keynote 407 (mOS: 17.1), assuming a 70:30 ratio of non-squamous to squamous NSCLC in the general NSCLC population (McKeage and Jameson, J Thorac Dis.

[0052] 2010 Dec;2(4): 199-204).

[0053] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0054] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0055] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0056] Optionally the LAG-3 protein, or derivative, is for use in improving 24-month OS rate of the subject.

[0057] Optionally the LAG-3 protein, or derivative, is for use in improving 24-month OS rate of the subject to at least 50%, preferably to at least 60%, more preferably to at least 70%, more preferably to at least 80%.

[0058] Optionally the LAG-3 protein, or derivative, is for use in improving 24-month OS rate of the subject by at least 20%, preferably by at least 30%, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0059] Optionally the LAG-3 protein, or derivative, is for use in improving 24-month OS rate of the subject by at least 20% and to at least 50%, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0060] Optionally the LAG-3 protein, or derivative, is for use in improving 24-month OS rate of the subject by at least 20%, preferably by at least 30%, and to at least 50%, preferably to at least 60%, more preferably to at least 70%, more preferably to at least 80%, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0061] Optionally the LAG-3 protein, or derivative, is for use in improving 24-month OS rate of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0062] Optionally the LAG-3 protein, or derivative, is for use in improving 24-month OS rate of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0063] Optionally the LAG-3 protein, or derivative, is for use in improving 24-month OS rate of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0064] There is further provided according to the invention a programmed cell death protein- 1 (PD-1) pathway inhibitor for use in improving overall survival (OS) of a subject with a cancer, wherein the PD-1 pathway inhibitor is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHO class II molecules, and a chemotherapy agent.

[0065] There is also provided according to the invention use of a programmed cell death protein-1 (PD-1) pathway inhibitor in the manufacture of a medicament for improving overall survival (OS) of a subject with a cancer, wherein the PD-1 pathway inhibitor is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHO class II molecules, and a chemotherapy agent.

[0066] There is further provided according to the invention a chemotherapy agent for use in improving overall survival (OS) of a subject with a cancer, wherein the chemotherapy agent is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHO class II molecules, and a programmed cell death protein-1 (PD-1) pathway inhibitor.

[0067] There is further provided according to the invention use of a chemotherapy agent in the manufacture of a medicament for improving overall survival (OS) of a subject with a cancer, wherein the chemotherapy agent is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHO class II molecules, and a programmed cell death protein-1 (PD-1) pathway inhibitor.

[0068] There is also provided according to the invention a method of treating a cancer in a subject, which comprises administering to the subject an effective amount of: (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; (b) a programmed cell death protein-1 (PD-1) pathway inhibitor; and (c) a chemotherapy agent, wherein the treatment improves overall survival (OS) of the subject.

[0069] There is also provided according to the invention a method of improving overall survival (OS) of a subject with a cancer, which comprises administering to the subject an effective amount of: (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; (b) a programmed cell death protein-1 (PD-1) pathway inhibitor; and (c) a chemotherapy agent.

[0070] Optionally the method improves overall survival (OS) of the subject compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0071] Optionally the method improves OS of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0072] Optionally the method improves OS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0073] Optionally the method improves OS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0074] Optionally the method improves median OS of the subject. Optionally the method improves median OS of the subject to at least 25, 26, 27, 28, 29, or 30 months.

[0075] Optionally the method improves median OS of the subject to at least 30 months.

[0076] Optionally the method improves median OS of the subject to at least 32 months.

[0077] Optionally the method improves median OS of the subject by at least 6 months, preferably by at least 9 months, more preferably by at least 10 months, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0078] Optionally the method improves median OS of the subject by at least 6 months compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0079] Optionally the method improves median OS of the subject by at least 9 months compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0080] Optionally the method improves median OS of the subject by at least 10 months compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0081] Optionally the method improves median OS of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0082] Optionally the method improves median OS of the subject by at least 6 months, 9 months, or 10 months, compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone. Optionally the method improves median OS of the subject by at least 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0083] Optionally the method improves median OS of the subject by at least 12 months, compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0084] Optionally the method improves median OS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0085] Optionally the method improves median OS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0086] Optionally the method improves 24-month OS rate of the subject.

[0087] Optionally the method improves 24-month OS rate of the subject to at least 50%, preferably to at least 60%, more preferably to at least 70%, more preferably to at least 80%.

[0088] Optionally the method improves 24-month OS rate of the subject by at least 20%, preferably by at least 30%, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0089] Optionally the method improves 24-month OS rate of the subject by at least 20% and to at least 50%, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0090] Optionally the method improves 24-month OS rate of the subject by at least 20%, preferably by at least 30%, and to at least 50%, preferably to at least 60%, more preferably to at least 70%, more preferably to at least 80%, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG- 3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0091] Optionally the method improves 24-month OS rate of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0092] Optionally the method improves 24-month OS rate of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0093] Optionally the method improves 24-month OS rate of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0094] There is also provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, for use in treating a cancer, wherein the treatment improves overall response rate (ORR) of a subject with the cancer.

[0095] There is further provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, for use in improving overall response rate (ORR) of a subject with a cancer.

[0096] There is also provided according to the invention use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, in the manufacture of a medicament for improving overall response rate (ORR) of a subject with a cancer.

[0097] There is further provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, for use in improving overall response rate (ORR) of a subject with a cancer, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

[0098] There is also provided according to the invention use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, in the manufacture of a medicament for improving overall response rate (ORR) of a subject with a cancer, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

[0099] Optionally the LAG-3 protein, or derivative, is for use in improving overall response rate (ORR) of a subject with a cancer compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0100] Optionally the LAG-3 protein, or derivative, is for use in improving overall response rate (ORR) of the subject to: at least 40% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 50% where the subject has low PD-L1 expression (TPS 1-49%); or at least 65% where the subject has high PD-L1 expression (TPS >50%).

[0101] Optionally the LAG-3 protein, or derivative, is for use in improving overall response rate (ORR) of the subject to: at least 50% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 55% where the subject has low PD-L1 expression (TPS 1-49%); at least 70% where the subject has high PD-L1 expression (TPS >50%); or at least 50% where the subject has low or negative PD-L1 expression (TPS <50%).

[0102] Optionally the LAG-3 protein, or derivative, is for use in improving overall response rate (ORR) of the subject to at least 45%, preferably at least 50%, where the subject has a Tumor Proportion Score (TPS) from 0 to 100%.

[0103] Optionally the LAG-3 protein, or derivative, is for use in improving overall response rate (ORR) of the subject to at least 45%, preferably at least 50%, where the subject has negative or low PD-L1 expression (Tumor Proportion Score, TPS <50%).

[0104] Optionally the LAG-3 protein, or derivative, is for use in improving overall response rate (ORR) of the subject by at least 9% compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0105] Optionally the LAG-3 protein, or derivative, is for use in improving overall response rate (ORR) of the subject by at least 9%, and to: at least 40% where the subject has negative PD- L1 expression (Tumor Proportion Score, TPS <1%); at least 50% where the subject has low PD-L1 expression (TPS 1-49%); or at least 65% where the subject has high PD-L1 expression (TPS >50%), compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0106] Optionally the LAG-3 protein, or derivative, is for use in improving overall response rate (ORR) of the subject by at least 9%, and to: at least 50% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 55% where the subject has low PD-L1 expression (TPS 1-49%); at least 70% where the subject has high PD-L1 expression (TPS >50%); or at least 50% where the subject has low or negative PD-L1 expression (TPS <50%), compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0107] Optionally the LAG-3 protein, or derivative, is for use in improving overall response rate (ORR) of the subject by at least 9%, and to at least 45%, preferably at least 50%, where the subject has a Tumor Proportion Score (TPS) from 0 to 100%, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0108] Optionally the LAG-3 protein, or derivative, is for use in improving overall response rate (ORR) of the subject by at least 9%, and to at least 45%, preferably at least 50%, where the subject has negative or low PD-L1 expression (Tumor Proportion Score, TPS <50%), compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0109] Optionally the LAG-3 protein, or derivative, is for use in improving ORR of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone. Optionally the LAG-3 protein, or derivative, is for use in improving ORR of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0110] Optionally the LAG-3 protein, or derivative, is for use in improving ORR of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0111] There is further provided according to the invention a programmed cell death protein- 1 (PD-1) pathway inhibitor for use in improving overall response rate (ORR) of a subject with a cancer, wherein the PD-1 pathway inhibitor is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHO class II molecules, and a chemotherapy agent.

[0112] There is also provided according to the invention use of a programmed cell death protein-1 (PD-1) pathway inhibitor in the manufacture of a medicament for improving overall response rate (ORR) of a subject with a cancer, wherein the PD-1 pathway inhibitor is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a chemotherapy agent.

[0113] There is further provided according to the invention a chemotherapy agent for use in improving overall response rate (ORR) of a subject with a cancer, wherein the chemotherapy agent is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a programmed cell death protein-1 (PD-1) pathway inhibitor.

[0114] There is also provided according to the invention use of a chemotherapy agent in the manufacture of a medicament for improving overall response rate (ORR) of a subject with a cancer, wherein the chemotherapy agent is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a programmed cell death protein-1 (PD-1) pathway inhibitor.

[0115] There is also provided according to the invention a method of treating a cancer in a subject, which comprises administering to the subject an effective amount of: (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; (b) a programmed cell death protein-1 (PD-1) pathway inhibitor; and (c) a chemotherapy agent, wherein the treatment improves overall response rate (ORR) of the subject. There is also provided according to the invention a method of improving overall response rate (ORR) of a subject with a cancer, which comprises administering to the subject an effective amount of: (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; (b) a programmed cell death protein-1 (PD-1) pathway inhibitor; and (c) a chemotherapy agent.

[0116] Optionally the method improves overall response rate (ORR) of the subject compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0117] Optionally the method improves overall response rate (ORR) of the subject to: at least 40% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 50% where the subject has low PD-L1 expression (TPS 1-49%); or at least 65% where the subject has high PD-L1 expression (TPS >50%).

[0118] Optionally the method improves overall response rate (ORR) of the subject to: at least 50% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 55% where the subject has low PD-L1 expression (TPS 1-49%); at least 70% where the subject has high PD-L1 expression (TPS >50%); or at least 50% where the subject has low or negative PD-L1 expression (TPS <50%).

[0119] Optionally the method improves overall response rate (ORR) of the subject to at least 45%, preferably at least 50%, where the subject has a Tumor Proportion Score (TPS) from 0 to 100%.

[0120] Optionally the method improves overall response rate (ORR) of the subject to at least 45%, preferably at least 50%, where the subject has negative or low PD-L1 expression (Tumor Proportion Score, TPS <50%).

[0121] Optionally the method improves overall response rate (ORR) of the subject by at least 9% compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0122] Optionally the method improves overall response rate (ORR) of the subject by at least 9%, and to: at least 40% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 50% where the subject has low PD-L1 expression (TPS 1-49%); or at least 65% where the subject has high PD-L1 expression (TPS >50%), compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0123] Optionally the method improves overall response rate (ORR) of the subject by at least 9%, and to: at least 50% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 55% where the subject has low PD-L1 expression (TPS 1-49%); at least 70% where the subject has high PD-L1 expression (TPS >50%); or at least 50% where the subject has low or negative PD-L1 expression (TPS <50%), compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0124] Optionally the method improves overall response rate (ORR) of the subject by at least 9%, and to at least 45%, preferably at least 50%, where the subject has a T umor Proportion Score (TPS) from 0 to 100%, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0125] Optionally the method improves overall response rate (ORR) of the subject by at least 9%, and to at least 45%, preferably at least 50%, where the subject has negative or low PD-L1 expression (Tumor Proportion Score, TPS <50%), compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0126] Optionally the method improves ORR of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0127] Optionally the method improves ORR of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed. Optionally the method improves ORR of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0128] There is also provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, for use in treating a cancer, wherein the treatment improves disease control rate (DCR) of a subject with the cancer.

[0129] There is further provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, for use in improving disease control rate (DCR) of a subject with a cancer.

[0130] There is also provided according to the invention use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, in the manufacture of a medicament for improving disease control rate (DCR) of a subject with a cancer.

[0131] There is further provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, for use in improving disease control rate (DCR) of a subject with a cancer, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

[0132] There is also provided according to the invention use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, in the manufacture of a medicament for improving disease control rate (DCR) of a subject with a cancer, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

[0133] Optionally the LAG-3 protein, or derivative, is for use in improving disease control rate (DCR) of a subject with a cancer compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone. Optionally the LAG-3 protein, or derivative, is for use in improving disease control rate (DCR) of the subject to at least 80%.

[0134] Optionally the LAG-3 protein, or derivative, is for use in improving disease control rate (DCR) of the subject to at least 80% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 85% where the subject has low PD-L1 expression (TPS 1-49%); at least 90% where the subject has high PD-L1 expression (TPS >50%); or at least 80% where the subject has low or negative PD-L1 expression (TPS <50%).

[0135] Optionally the LAG-3 protein, or derivative, is for use in improving DCR of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0136] Optionally the LAG-3 protein, or derivative, is for use in improving DCR of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0137] Optionally the LAG-3 protein, or derivative, is for use in improving DCR of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0138] There is further provided according to the invention a programmed cell death protein- 1 (PD-1) pathway inhibitor for use in improving disease control rate (DCR) of a subject with a cancer, wherein the PD-1 pathway inhibitor is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a chemotherapy agent.

[0139] There is also provided according to the invention use of a programmed cell death protein-1 (PD-1) pathway inhibitor in the manfucature of a medicament for improving disease control rate (DCR) of a subject with a cancer, wherein the PD-1 pathway inhibitor is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a chemotherapy agent.

[0140] There is further provided according to the invention a chemotherapy agent for use in improving disease control rate (DCR) of a subject with a cancer, wherein the chemotherapy agent is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a programmed cell death protein-1 (PD-1) pathway inhibitor. There is also provided according to the invention use of a chemotherapy agent in the manufacture of a medicament for improving disease control rate (DCR) of a subject with a cancer, wherein the chemotherapy agent is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a programmed cell death protein-1 (PD-1) pathway inhibitor.

[0141] There is also provided according to the invention a method of treating a cancer in a subject, which comprises administering to the subject an effective amount of: (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; (b) a programmed cell death protein-1 (PD-1) pathway inhibitor; and (c) a chemotherapy agent, wherein the treatment improves disease control rate (DCR) of the subject.

[0142] There is also provided according to the invention a method of improving disease control rate (DCR) of a subject with a cancer, which comprises administering to the subject an effective amount of: (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; (b) a programmed cell death protein-1 (PD-1) pathway inhibitor; and (c) a chemotherapy agent.

[0143] Optionally the method improves disease control rate (DCR) of the subject compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0144] Optionally the method improves disease control rate (DCR) of the subject to at least 80%.

[0145] Optionally the method improves disease control rate (DCR) of the subject to at least 80% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 85% where the subject has low PD-L1 expression (TPS 1-49%); at least 90% where the subject has high PD-L1 expression (TPS >50%); or at least 80% where the subject has low or negative PD-L1 expression (TPS <50%).

[0146] Optionally the method improves DCR of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0147] Optionally the method improves DCR of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed. Optionally the method improves DCR of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0148] There is also provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, for use in treating a cancer, wherein the treatment improves progression-free survival (PFS) of a subject with the cancer.

[0149] There is further provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, for use in improving progression-free survival (PFS) of a subject with a cancer.

[0150] There is also provided according to the invention use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, in the manufacture of a medicament for improving progression-free survival (PFS) of a subject with a cancer.

[0151] There is further provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, for use in improving progression-free survival (PFS) of a subject with a cancer, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

[0152] There is also provided according to the invention use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, in the manufacture of a medicament for improving progression-free survival (PFS) of a subject with a cancer, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

[0153] Optionally the LAG-3 protein, or derivative, is for use in improving progression-free survival (PFS) of a subject with a cancer compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone. Optionally the LAG-3 protein, or derivative, is for use in improving PFS of the subject compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0154] Optionally the LAG-3 protein, or derivative, is for use in improving PFS of the subject compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0155] Optionally the LAG-3 protein, or derivative, is for use in improving PFS of the subject compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0156] Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject.

[0157] Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject to at least 10, 11, or 12 months.

[0158] Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject to at least 12 months.

[0159] Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject by at least one month compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0160] Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject by at least 2 months compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0161] Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject by at least 3 months compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone. Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject by at least one month, and to at least 10, 11, or 12 months, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0162] Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject by at least two months, and to at least 10, 11, or 12 months, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0163] Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject by at least three months, and to at least 10, 11, or 12 months, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0164] Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0165] Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0166] Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0167] There is further provided according to the invention a programmed cell death protein- 1 (PD-1) pathway inhibitor for use in improving progression-free survival (PFS) of a subject with a cancer, wherein the PD-1 pathway inhibitor is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a chemotherapy agent.

[0168] There is also provided according to the invention use of a programmed cell death protein-1 (PD-1) pathway inhibitor in the manufacture of a medicament for improving progression-free survival (PFS) of a subject with a cancer, wherein the PD-1 pathway inhibitor is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a chemotherapy agent.

[0169] There is further provided according to the invention a chemotherapy agent for use in improving progression-free survival (PFS) of a subject with a cancer, wherein the chemotherapy agent is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a programmed cell death protein-1 (PD-1) pathway inhibitor.

[0170] There is also provided according to the invention use of a chemotherapy agent in the manufacture of a medicament for improving progression-free survival (PFS) of a subject with a cancer, wherein the chemotherapy agent is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a programmed cell death protein-1 (PD-1) pathway inhibitor.

[0171] There is also provided according to the invention a method of treating a cancer in a subject, which comprises administering to the subject an effective amount of: (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; (b) a programmed cell death protein-1 (PD-1) pathway inhibitor; and (c) a chemotherapy agent, wherein the treatment improves progression-free survival (PFS) of the subject.

[0172] There is also provided according to the invention a method of improving progression-free survival (PFS) of a subject with a cancer, which comprises administering to the subject an effective amount of: (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; (b) a programmed cell death protein-1 (PD-1) pathway inhibitor; and (c) a chemotherapy agent.

[0173] Optionally the method improves progression-free survival (PFS) of a subject with a cancer compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0174] Optionally the method improves PFS of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone. Optionally the method improves PFS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0175] Optionally the method improves PFS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0176] Optionally the method improves median PFS of the subject.

[0177] Optionally the method improves median PFS of the subject to at least 10, 11, or 12 months.

[0178] Optionally the method improves median PFS of the subject to at least 12 months.

[0179] Optionally the method improves median PFS of the subject by at least one month, preferably by at least 2 months, more preferably by at least 3 months, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0180] Optionally the method improves median PFS of the subject by at least one month, and to at least 10, 11, or 12 months, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0181] Optionally the method improves median PFS of the subject by at least two months, and to at least 10, 11, or 12 months, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0182] Optionally the method improves median PFS of the subject by at least three months, and to at least 10, 11, or 12 months, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone. Optionally the method improves median PFS of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0183] Optionally the method improves median PFS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0184] Optionally the method improves median PFS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0185] In methods of the invention, the LAG-3 protein, or derivative, the programmed cell death protein-1 (PD-1) pathway inhibitor; and the chemotherapy agent, may administered simultaneously or sequentially in any order.

[0186] The term “overall survival” (OS) is used herein to mean the length of time from either the date of diagnosis or the start of treatment for a disease, such as a cancer, that subjects diagnosed with the disease are still alive.

[0187] The term “median overall survival” is used herein to mean the length of time from either the date of diagnosis or the start of treatment for a disease, such as a cancer, that half of the subjects in a group of subjects diagnosed with the disease are still alive.

[0188] The term “overall survival rate” is used herein to mean the percentage of subjects in a study or treatment group who are still alive for a certain period of time after they were diagnosed with or started treatment for a disease, such as a cancer. For example, a 24-month overall survival rate is the percentage of subjects in a study or treatment group who are alive 24 months after their diagnosis or the start of treatment.

[0189] The term “overall response rate” (ORR) is used herein to mean the percentage of subjects in a study or treatment group who have a partial response or complete response to the treatment within a certain period of time. A partial response is a decrease in the size of a tumor or in the amount of cancer in the body, and a complete response is the disappearance of all signs of cancer in the body. The term “disease control rate” (DCR) is used herein to mean the percentage of subjects with advanced cancer whose therapeutic intervention has led to a complete response, partial response, or stable disease.

[0190] The term “progression-free survival” (PFS) is used herein to mean the length of time during and after the treatment of a disease, such as a cancer, that a subject lives with the disease but it does not get worse.

[0191] The term ’’response” is used herein to include a response based on response evaluation criteria in solid tumours (RECIST) criteria version 1.1 (Eisenhauer, et al., 2009: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1); EurJ Cancer, 45, 228-47). Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics. Both tumour shrinkage (objective response), and time to the development of disease progression, are important endpoints in cancer clinical trials. Both of these tumour endpoints are useful only if based on widely accepted and readily applied standard criteria based on anatomical tumour burden. Eisenhauer et al., 2009 describes a standard approach to solid tumour measurement and definitions for objective assessment of change in tumour size for use in adult and paediatric cancer clinical trials. It is expected these criteria will be useful in all trials where objective response is the primary study endpoint, as well as in trials where assessment of stable disease, tumour progression, or time to progression analyses are undertaken, since all of these outcome measures are based on an assessment of anatomical tumour burden and its change on study.

[0192] Definitions of the RECIST criteria used to determine objective tumour response for target lesions (from Eisenhauer, et al., 2009) are:

[0193] • CR (complete response): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

[0194] • PR (partial response): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

[0195] • SD (stable disease): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

[0196] • PD (progressive disease): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).

[0197] The terms “patient” and “subject” are used herein interchangeably.

[0198] BRIEF DESCRIPTION OF THE DRAWINGS

[0199] Figure 1 illustrates the amino acid sequence of mature human LAG-3 protein. The four extracellular Ig superfamily domains are at amino acid residues: 1-149 (D1); 150-239 (D2); 240-330 (D3); and 331-412 (D4). The amino acid sequence of the extra-loop structure of the D1 domain of human LAG-3 protein is shown underlined in bold.

[0200] Figure 2 illustrates shrinkage of a target tumour lesion of a NSCLC patient measured by computed tomography (CT) (A: August 2021 and B: May 2022). The lesion shrunk from 22.62 mm in diameter to “evaluable but not measurable”. The lesion is shown with a dashed circle.

[0201] Figure 3 illustrates shrinkage of another target tumour lesion of the NSCLC patient measured by computed tomography (CT) (A: August 2021 and B: May 2022). The lesion shrunk from 35.92 mm to 25.70 mm (in diameter) and is shown with a dashed circle.

[0202] Figure 4 shows examples of BMS PD-1 / PD-L1 inhibitors (BMS molecules) (taken from Javed etal., 2024, Front. Immunol. 15:1383456).

[0203] Figure 5 shows examples of non-BMS PD-1 / PD-L1 inhibitors (taken from Figure 4 of Javed et al.).

[0204] Figure 6 shows further examples of non-BMS PD-1 / PD-L1 inhibitors (taken from Figure 5 of Javed et al.).

[0205] Figure 7 shows further examples of non-BMS PD-1 / PD-L1 inhibitors (taken from Figure 6 of Javed et al.).

[0206] Figure 8 shows a bifunctional small molecule designed to target PD-L1 and CXCL12 simultaneously.

[0207] Figure 9 shows PD-L1 inhibitors identified by structural-based virtual screening and machine learning (taken from Figure 9 of Fantacuzzi et al.). Figure 10 shows the mechanism of action of efti.

[0208] Figure 11 shows the study design for the clinical study described in Example 4.

[0209] Figure 12 shows the results of a case study of a patient with partial response (PR).

[0210] Figure 13 shows the best change in tumor size by RECIST 1.1. 44 of 51 patients (86.3%) experienced tumor shrinkage.

[0211] Figure 14 illustrates examples of different treatment schedules according to embodiments of the invention for NSCLC patients with non-squamous and squamous histology.

[0212] DETAILED DESCRIPTION OF THE INVENTION

[0213] Triple Combination Therapy

[0214] In one embodiment, the invention relates to (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, (b) a programmed cell death protein-1 (PD-1) pathway inhibitor, and (c) a chemotherapy agent, for use in preventing, treating, or ameliorating a cancer in a subject.

[0215] In another embodiment, the invention relates to (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, (b) a programmed cell death protein-1 (PD-1) pathway inhibitor, and (c) a chemotherapy agent, for use in the prevention, treatment, or amelioration of a cancer in a subject.

[0216] In another embodiment, the invention relates to the use of (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, (b) a programmed cell death protein-1 (PD-1) pathway inhibitor, and (c) a chemotherapy agent, in the manufacture of a medicament for the prevention, treatment, or amelioration of a cancer in a subject.

[0217] In yet another embodiment, the invention relates to the use of (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, (b) a programmed cell death protein- 1 (PD-1) pathway inhibitor, and (c) a chemotherapy agent, for the prevention, treatment, or amelioration of a cancer in a subject.

[0218] In a further embodiment, the invention provides a method of preventing, treating, or ameliorating a cancer in a subject, the method comprising administering to the subject in need of such prevention, treatment, or amelioration (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, (b) a programmed cell death protein-1 (PD-1) pathway inhibitor, and (c) a chemotherapy agent.

[0219] In yet a further embodiment, the invention relates to a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, for use in preventing, treating, or ameliorating a cancer in a subject, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

[0220] In one embodiment, the invention relates to the use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, in the manufacture of a medicament for the prevention, treatment, or amelioration of a cancer in a subject, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

[0221] In yet a further embodiment, the invention relates to a programmed cell death protein-1 (PD-1) pathway inhibitor for use in preventing, treating, or ameliorating a cancer in a subject, wherein the PD-1 pathway inhibitor is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a chemotherapy agent.

[0222] In one embodiment, the invention relates to the use of a programmed cell death protein-1 (PD-1) pathway inhibitor in the manufacture of a medicament for preventing, treating, or ameliorating a cancer in a subject, wherein the PD-1 pathway inhibitor is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a chemotherapy agent.

[0223] In yet a further embodiment, the invention relates to a chemotherapy agent for use in preventing, treating, or ameliorating a cancer in a subject, wherein the chemotherapy agent is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a programmed cell death protein-1 (PD-1) pathway inhibitor.

[0224] In one embodiment, the invention relates to the use of a chemotherapy agent in the manufacture of a medicament for preventing, treating, or ameliorating a cancer in a subject, wherein the chemotherapy agent is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a programmed cell death protein-1 (PD-1) pathway inhibitor.

[0225] In another embodiment, the invention provides a method of preventing, treating, or ameliorating a cancer in a subject, the method comprising administering to the subject in need of such prevention, treatment, or amelioration a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, wherein the LAG-3 protein or derivative thereof is administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

[0226] In yet another embodiment, the invention provides a combined preparation, comprising: (a) a LAG-3 protein, or derivative thereof that is able to bind to MHC class II molecules, (b) a programmed cell death protein-1 (PD-1) pathway inhibitor, and

[0227] (c) a chemotherapy agent.

[0228] In a further embodiment, the invention provides a pharmaceutical composition, comprising: (a) a LAG-3 protein, or derivative thereof that is able to bind to MHC class II molecules, (b) a programmed cell death protein-1 (PD-1) pathway inhibitor,

[0229] (c) a chemotherapy agent, and

[0230] (d) a pharmaceutically acceptable carrier, excipient, or diluent.

[0231] There is also provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, for use in treating a cancer, wherein the treatment improves overall survival (OS) of a subject with the cancer.

[0232] According to the invention there is also provided a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, for use in improving overall survival (OS) of a subject with a cancer.

[0233] There is also provided according to the invention use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor, and a chemotherapy agent, in the manufacture of a medicament for improving overall survival (OS) of a subject with a cancer.

[0234] There is further provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, for use in improving overall survival (OS) of a subject with a cancer, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

[0235] There is also provided according to the invention use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, in the manufacture of a medicament for improving overall survival (OS) of a subject with a cancer, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

[0236] Optionally the LAG-3 protein, or derivative, is for use in improving overall survival (OS) of a subject with a cancer compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0237] Optionally the LAG-3 protein, or derivative, is for use in improving OS of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0238] Optionally the LAG-3 protein, or derivative, is for use in improving OS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0239] Optionally the LAG-3 protein, or derivative, is for use in improving OS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0240] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject.

[0241] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject to at least 25, 26, 27, 28, 29, or 30 months.

[0242] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject to at least 30 months.

[0243] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject to at least 32 months. Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject by at least 6 months compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0244] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject by at least 9 months compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0245] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject by at least 10 months compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0246] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject by at least 6 months, 9 months, or 10 months, compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0247] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject by at least 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0248] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject by at least 12 months, compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0249] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0250] Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed. Optionally the LAG-3 protein, or derivative, is for use in improving median OS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0251] Optionally the LAG-3 protein, or derivative, is for use in improving 24-month OS rate of the subject.

[0252] Optionally the LAG-3 protein, or derivative, is for use in improving 24-month OS rate of the subject to at least 50%, preferably to at least 60%, more preferably to at least 70%, more preferably to at least 80%.

[0253] Optionally the LAG-3 protein, or derivative, is for use in improving 24-month OS rate of the subject by at least 20%, preferably by at least 30%, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0254] Optionally the LAG-3 protein, or derivative, is for use in improving 24-month OS rate of the subject by at least 20% and to at least 50%, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0255] Optionally the LAG-3 protein, or derivative, is for use in improving 24-month OS rate of the subject by at least 20%, preferably by at least 30%, and to at least 50%, preferably to at least 60%, more preferably to at least 70%, more preferably to at least 80%, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0256] Optionally the LAG-3 protein, or derivative, is for use in improving 24-month OS rate of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0257] Optionally the LAG-3 protein, or derivative, is for use in improving 24-month OS rate of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed. Optionally the LAG-3 protein, or derivative, is for use in improving 24-month OS rate of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0258] There is further provided according to the invention a programmed cell death protein- 1 (PD-1) pathway inhibitor for use in improving overall survival (OS) of a subject with a cancer, wherein the PD-1 pathway inhibitor is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHO class II molecules, and a chemotherapy agent.

[0259] There is also provided according to the invention use of a programmed cell death protein-1 (PD-1) pathway inhibitor in the manufacture of a medicament for improving overall survival (OS) of a subject with a cancer, wherein the PD-1 pathway inhibitor is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHO class II molecules, and a chemotherapy agent.

[0260] There is further provided according to the invention a chemotherapy agent for use in improving overall survival (OS) of a subject with a cancer, wherein the chemotherapy agent is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHO class II molecules, and a programmed cell death protein-1 (PD-1) pathway inhibitor.

[0261] There is further provided according to the invention use of a chemotherapy agent in the manufacture of a medicament for improving overall survival (OS) of a subject with a cancer, wherein the chemotherapy agent is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHO class II molecules, and a programmed cell death protein-1 (PD-1) pathway inhibitor.

[0262] There is also provided according to the invention a method of treating a cancer in a subject, which comprises administering to the subject an effective amount of: (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; (b) a programmed cell death protein-1 (PD-1) pathway inhibitor; and (c) a chemotherapy agent, wherein the treatment improves overall survival (OS) of the subject.

[0263] There is also provided according to the invention a method of improving overall survival (OS) of a subject with a cancer, which comprises administering to the subject an effective amount of: (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; (b) a programmed cell death protein-1 (PD-1) pathway inhibitor; and (c) a chemotherapy agent.

[0264] Optionally the method improves overall survival (OS) of the subject compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0265] Optionally the method improves OS of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0266] Optionally the method improves OS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0267] Optionally the method improves OS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0268] Optionally the method improves median OS of the subject.

[0269] Optionally the method improves median OS of the subject to at least 25, 26, 27, 28, 29, or 30 months.

[0270] Optionally the method improves median OS of the subject to at least 30 months.

[0271] Optionally the method improves median OS of the subject to at least 32 months.

[0272] Optionally the method improves median OS of the subject by at least 6 months, preferably by at least 9 months, more preferably by at least 10 months, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0273] Optionally the method improves median OS of the subject by at least 6 months compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone. Optionally the method improves median OS of the subject by at least 9 months compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0274] Optionally the method improves median OS of the subject by at least 10 months compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0275] Optionally the method improves median OS of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0276] Optionally the method improves median OS of the subject by at least 6 months, 9 months, or 10 months, compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0277] Optionally the method improves median OS of the subject by at least 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0278] Optionally the method improves median OS of the subject by at least 12 months, compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0279] Optionally the method improves median OS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0280] Optionally the method improves median OS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0281] Optionally the method improves 24-month OS rate of the subject.

[0282] Optionally the method improves 24-month OS rate of the subject to at least 50%, preferably to at least 60%, more preferably to at least 70%, more preferably to at least 80%. Optionally the method improves 24-month OS rate of the subject by at least 20%, preferably by at least 30%, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0283] Optionally the method improves 24-month OS rate of the subject by at least 20% and to at least 50%, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0284] Optionally the method improves 24-month OS rate of the subject by at least 20%, preferably by at least 30%, and to at least 50%, preferably to at least 60%, more preferably to at least 70%, more preferably to at least 80%, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0285] Optionally the method improves 24-month OS rate of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0286] Optionally the method improves 24-month OS rate of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0287] Optionally the method improves 24-month OS rate of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0288] There is also provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, for use in treating a cancer, wherein the treatment improves overall response rate (ORR) of a subject with the cancer.

[0289] There is further provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, for use in improving overall response rate (ORR) of a subject with a cancer.

[0290] There is also provided according to the invention use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, in the manufacture of a medicament for improving overall response rate (ORR) of a subject with a cancer.

[0291] There is further provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, for use in improving overall response rate (ORR) of a subject with a cancer, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

[0292] There is also provided according to the invention use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, in the manufacture of a medicament for improving overall response rate (ORR) of a subject with a cancer, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

[0293] Optionally the LAG-3 protein, or derivative, is for use in improving overall response rate (ORR) of a subject with a cancer compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0294] Optionally the LAG-3 protein, or derivative, is for use in improving overall response rate (ORR) of the subject to: at least 40% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 50% where the subject has low PD-L1 expression (TPS 1-49%); or at least 65% where the subject has high PD-L1 expression (TPS >50%).

[0295] Optionally the LAG-3 protein, or derivative, is for use in improving overall response rate (ORR) of the subject to: at least 50% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 55% where the subject has low PD-L1 expression (TPS 1-49%); at least 70% where the subject has high PD-L1 expression (TPS >50%); or at least 50% where the subject has low or negative PD-L1 expression (TPS <50%). Optionally the LAG-3 protein, or derivative, is for use in improving overall response rate (ORR) of the subject to at least 45%, preferably at least 50%, where the subject has a Tumor Proportion Score (TPS) from 0 to 100%.

[0296] Optionally the LAG-3 protein, or derivative, is for use in improving overall response rate (ORR) of the subject to at least 45%, preferably at least 50%, where the subject has negative or low PD-L1 expression (Tumor Proportion Score, TPS <50%).

[0297] Optionally the LAG-3 protein, or derivative, is for use in improving overall response rate (ORR) of the subject by at least 9% compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0298] Optionally the LAG-3 protein, or derivative, is for use in improving overall response rate (ORR) of the subject by at least 9%, and to: at least 40% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 50% where the subject has low PD-L1 expression (TPS 1-49%); or at least 65% where the subject has high PD-L1 expression (TPS >50%), compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0299] Optionally the LAG-3 protein, or derivative, is for use in improving overall response rate (ORR) of the subject by at least 9%, and to: at least 50% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 55% where the subject has low PD-L1 expression (TPS 1-49%); at least 70% where the subject has high PD-L1 expression (TPS >50%); or at least 50% where the subject has low or negative PD-L1 expression (TPS <50%), compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0300] Optionally the LAG-3 protein, or derivative, is for use in improving overall response rate (ORR) of the subject by at least 9%, and to at least 45%, preferably at least 50%, where the subject has a Tumor Proportion Score (TPS) from 0 to 100%, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0301] Optionally the LAG-3 protein, or derivative, is for use in improving overall response rate (ORR) of the subject by at least 9%, and to at least 45%, preferably at least 50%, where the subject has negative or low PD-L1 expression (Tumor Proportion Score, TPS <50%), compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0302] Optionally the LAG-3 protein, or derivative, is for use in improving ORR of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0303] Optionally the LAG-3 protein, or derivative, is for use in improving ORR of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0304] Optionally the LAG-3 protein, or derivative, is for use in improving ORR of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0305] There is further provided according to the invention a programmed cell death protein- 1 (PD-1) pathway inhibitor for use in improving overall response rate (ORR) of a subject with a cancer, wherein the PD-1 pathway inhibitor is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHO class II molecules, and a chemotherapy agent.

[0306] There is also provided according to the invention use of a programmed cell death protein-1 (PD-1) pathway inhibitor in the manufacture of a medicament for improving overall response rate (ORR) of a subject with a cancer, wherein the PD-1 pathway inhibitor is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a chemotherapy agent.

[0307] There is further provided according to the invention a chemotherapy agent for use in improving overall response rate (ORR) of a subject with a cancer, wherein the chemotherapy agent is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a programmed cell death protein-1 (PD-1) pathway inhibitor.

[0308] There is also provided according to the invention use of a chemotherapy agent in the manufacture of a medicament for improving overall response rate (ORR) of a subject with a cancer, wherein the chemotherapy agent is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a programmed cell death protein-1 (PD-1) pathway inhibitor.

[0309] There is also provided according to the invention a method of treating a cancer in a subject, which comprises administering to the subject an effective amount of: (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; (b) a programmed cell death protein-1 (PD-1) pathway inhibitor; and (c) a chemotherapy agent, wherein the treatment improves overall response rate (ORR) of the subject.

[0310] There is also provided according to the invention a method of improving overall response rate (ORR) of a subject with a cancer, which comprises administering to the subject an effective amount of: (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; (b) a programmed cell death protein-1 (PD-1) pathway inhibitor; and (c) a chemotherapy agent.

[0311] Optionally the method improves overall response rate (ORR) of the subject compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0312] Optionally the method improves overall response rate (ORR) of the subject to: at least 40% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 50% where the subject has low PD-L1 expression (TPS 1-49%); or at least 65% where the subject has high PD-L1 expression (TPS >50%).

[0313] Optionally the method improves overall response rate (ORR) of the subject to: at least 50% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 55% where the subject has low PD-L1 expression (TPS 1-49%); at least 70% where the subject has high PD-L1 expression (TPS >50%); or at least 50% where the subject has low or negative PD-L1 expression (TPS <50%). Optionally the method improves overall response rate (ORR) of the subject to at least 45%, preferably at least 50%, where the subject has a Tumor Proportion Score (TPS) from 0 to 100%.

[0314] Optionally the method improves overall response rate (ORR) of the subject to at least 45%, preferably at least 50%, where the subject has negative or low PD-L1 expression (Tumor Proportion Score, TPS <50%).

[0315] Optionally the method improves overall response rate (ORR) of the subject by at least 9% compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0316] Optionally the method improves overall response rate (ORR) of the subject by at least 9%, and to: at least 40% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 50% where the subject has low PD-L1 expression (TPS 1-49%); or at least 65% where the subject has high PD-L1 expression (TPS >50%), compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0317] Optionally the method improves overall response rate (ORR) of the subject by at least 9%, and to: at least 50% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 55% where the subject has low PD-L1 expression (TPS 1-49%); at least 70% where the subject has high PD-L1 expression (TPS >50%); or at least 50% where the subject has low or negative PD-L1 expression (TPS <50%), compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0318] Optionally the method improves overall response rate (ORR) of the subject by at least 9%, and to at least 45%, preferably at least 50%, where the subject has a T umor Proportion Score (TPS) from 0 to 100%, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone. Optionally the method improves overall response rate (ORR) of the subject by at least 9%, and to at least 45%, preferably at least 50%, where the subject has negative or low PD-L1 expression (Tumor Proportion Score, TPS <50%), compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0319] Optionally the method improves ORR of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0320] Optionally the method improves ORR of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0321] Optionally the method improves ORR of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0322] There is also provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, for use in treating a cancer, wherein the treatment improves disease control rate (DCR) of a subject with the cancer.

[0323] There is further provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, for use in improving disease control rate (DCR) of a subject with a cancer.

[0324] There is also provided according to the invention use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, in the manufacture of a medicament for improving disease control rate (DCR) of a subject with a cancer.

[0325] There is further provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, for use in improving disease control rate (DCR) of a subject with a cancer, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent. There is also provided according to the invention use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, in the manufacture of a medicament for improving disease control rate (DOR) of a subject with a cancer, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

[0326] Optionally the LAG-3 protein, or derivative, is for use in improving disease control rate (DCR) of a subject with a cancer compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0327] Optionally the LAG-3 protein, or derivative, is for use in improving disease control rate (DCR) of the subject to at least 80%.

[0328] Optionally the LAG-3 protein, or derivative, is for use in improving disease control rate (DCR) of the subject to at least 80% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 85% where the subject has low PD-L1 expression (TPS 1-49%); at least 90% where the subject has high PD-L1 expression (TPS >50%); or at least 80% where the subject has low or negative PD-L1 expression (TPS <50%).

[0329] Optionally the LAG-3 protein, or derivative, is for use in improving DCR of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0330] Optionally the LAG-3 protein, or derivative, is for use in improving DCR of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0331] Optionally the LAG-3 protein, or derivative, is for use in improving DCR of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0332] There is further provided according to the invention a programmed cell death protein- 1 (PD-1) pathway inhibitor for use in improving disease control rate (DCR) of a subject with a cancer, wherein the PD-1 pathway inhibitor is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a chemotherapy agent. There is also provided according to the invention use of a programmed cell death protein-1 (PD-1) pathway inhibitor in the manfucature of a medicament for improving disease control rate (DCR) of a subject with a cancer, wherein the PD-1 pathway inhibitor is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a chemotherapy agent.

[0333] There is further provided according to the invention a chemotherapy agent for use in improving disease control rate (DCR) of a subject with a cancer, wherein the chemotherapy agent is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a programmed cell death protein-1 (PD-1) pathway inhibitor.

[0334] There is also provided according to the invention use of a chemotherapy agent in the manufacture of a medicament for improving disease control rate (DCR) of a subject with a cancer, wherein the chemotherapy agent is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a programmed cell death protein-1 (PD-1) pathway inhibitor.

[0335] There is also provided according to the invention a method of treating a cancer in a subject, which comprises administering to the subject an effective amount of: (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; (b) a programmed cell death protein-1 (PD-1) pathway inhibitor; and (c) a chemotherapy agent, wherein the treatment improves disease control rate (DCR) of the subject.

[0336] There is also provided according to the invention a method of improving disease control rate (DCR) of a subject with a cancer, which comprises administering to the subject an effective amount of: (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; (b) a programmed cell death protein-1 (PD-1) pathway inhibitor; and (c) a chemotherapy agent.

[0337] Optionally the method improves disease control rate (DCR) of the subject compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0338] Optionally the method improves disease control rate (DCR) of the subject to at least 80%. Optionally the method improves disease control rate (DCR) of the subject to at least 80% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 85% where the subject has low PD-L1 expression (TPS 1-49%); at least 90% where the subject has high PD-L1 expression (TPS >50%); or at least 80% where the subject has low or negative PD-L1 expression (TPS <50%).

[0339] Optionally the method improves DCR of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0340] Optionally the method improves DCR of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0341] Optionally the method improves DCR of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0342] There is also provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, for use in treating a cancer, wherein the treatment improves progression-free survival (PFS) of a subject with the cancer.

[0343] There is further provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, for use in improving progression-free survival (PFS) of a subject with a cancer.

[0344] There is also provided according to the invention use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, in the manufacture of a medicament for improving progression-free survival (PFS) of a subject with a cancer.

[0345] There is further provided according to the invention a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, for use in improving progression-free survival (PFS) of a subject with a cancer, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent. There is also provided according to the invention use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, in the manufacture of a medicament for improving progression-free survival (PFS) of a subject with a cancer, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

[0346] Optionally the LAG-3 protein, or derivative, is for use in improving progression-free survival (PFS) of a subject with a cancer compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0347] Optionally the LAG-3 protein, or derivative, is for use in improving PFS of the subject compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0348] Optionally the LAG-3 protein, or derivative, is for use in improving PFS of the subject compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0349] Optionally the LAG-3 protein, or derivative, is for use in improving PFS of the subject compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0350] Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject.

[0351] Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject to at least 10, 11, or 12 months.

[0352] Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject to at least 12 months.

[0353] Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject by at least one month compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone. Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject by at least 2 months compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0354] Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject by at least 3 months compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0355] Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject by at least one month, and to at least 10, 11, or 12 months, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0356] Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject by at least two months, and to at least 10, 11, or 12 months, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0357] Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject by at least three months, and to at least 10, 11, or 12 months, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0358] Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0359] Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed. Optionally the LAG-3 protein, or derivative, is for use in improving median PFS of the subject compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0360] There is further provided according to the invention a programmed cell death protein- 1 (PD-1) pathway inhibitor for use in improving progression-free survival (PFS) of a subject with a cancer, wherein the PD-1 pathway inhibitor is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a chemotherapy agent.

[0361] There is also provided according to the invention use of a programmed cell death protein-1 (PD-1) pathway inhibitor in the manufacture of a medicament for improving progression-free survival (PFS) of a subject with a cancer, wherein the PD-1 pathway inhibitor is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a chemotherapy agent.

[0362] There is further provided according to the invention a chemotherapy agent for use in improving progression-free survival (PFS) of a subject with a cancer, wherein the chemotherapy agent is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a programmed cell death protein-1 (PD-1) pathway inhibitor.

[0363] There is also provided according to the invention use of a chemotherapy agent in the manufacture of a medicament for improving progression-free survival (PFS) of a subject with a cancer, wherein the chemotherapy agent is to be administered simultaneously or sequentially with a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, and a programmed cell death protein-1 (PD-1) pathway inhibitor.

[0364] There is also provided according to the invention a method of treating a cancer in a subject, which comprises administering to the subject an effective amount of: (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; (b) a programmed cell death protein-1 (PD-1) pathway inhibitor; and (c) a chemotherapy agent, wherein the treatment improves progression-free survival (PFS) of the subject.

[0365] There is also provided according to the invention a method of improving progression-free survival (PFS) of a subject with a cancer, which comprises administering to the subject an effective amount of: (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; (b) a programmed cell death protein-1 (PD-1) pathway inhibitor; and (c) a chemotherapy agent.

[0366] Optionally the method improves progression-free survival (PFS) of a subject with a cancer compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0367] Optionally the method improves PFS of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0368] Optionally the method improves PFS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0369] Optionally the method improves PFS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0370] Optionally the method improves median PFS of the subject.

[0371] Optionally the method improves median PFS of the subject to at least 10, 11, or 12 months.

[0372] Optionally the method improves median PFS of the subject to at least 12 months.

[0373] Optionally the method improves median PFS of the subject by at least one month, preferably by at least 2 months, more preferably by at least 3 months, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0374] Optionally the method improves median PFS of the subject by at least one month, and to at least 10, 11, or 12 months, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone. Optionally the method improves median PFS of the subject by at least two months, and to at least 10, 11, or 12 months, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0375] Optionally the method improves median PFS of the subject by at least three months, and to at least 10, 11, or 12 months, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0376] Optionally the method improves median PFS of the subject with a cancer compared to treatment of a subject with the cancer with the PD-1 pathway inhibitor and the chemotherapy agent alone.

[0377] Optionally the method improves median PFS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with cisplatin or carboplatin, and pemetrexed.

[0378] Optionally the method improves median PFS of the subject with a cancer compared to treatment of a subject with the cancer with pembrolizumab in combination with carboplatin, and paclitaxel or nab-paclitaxel.

[0379] In methods of the invention, the LAG-3 protein, or derivative, the programmed cell death protein-1 (PD-1) pathway inhibitor; and the chemotherapy agent, may administered simultaneously or sequentially in any order. Exemplary cancers that may be treated according to the invention include, but are not limited to, breast cancer, skin cancer, lung cancer (for example NSCLC or SCLC), ovarian cancer, renal cancer (for example renal cell carcinoma), colon cancer, colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, bladder cancer, urothelial cancer, liver cancer, melanoma (for example, metastatic malignant melanoma), prostate cancer (for example hormone refractory prostate adenocarcinoma), head and neck cancer (for example, head and neck squamous cell carcinoma), cervical cancer, endometrial cancer, uterine cancer, thyroid cancer, glioblastoma, glioma, leukemia, lymphoma (for example, a B cell lymphoma or Hodgkin lymphoma), adrenal gland cancer, AIDS-associated cancer, alveolar soft part sarcoma, astrocytic tumor, bone cancer, brain and spinal cord cancer, metastatic brain tumor, carotid body tumor, chondrosarcoma, chordoma, cutaneous benign fibrous histiocytoma, desmoplastic small round cell tumor, ependymoma, Ewing's tumor, extraskeletal myxoid chondrosarcoma, fibrogenesis imperfecta ossium, fibrous dysplasia of the bone, gallbladder or bile duct cancer, gestational trophoblastic disease, germ cell tumor, haematological malignancy, hepatocellular carcinoma, islet cell tumor, Kaposi's sarcoma, kidney cancer, lipoma / benign lipomatous tumor, liposarcoma / malignant lipomatous tumor, medulloblastoma, meningioma, Merkel cell carcinoma, multiple endocrine neoplasia, multiple myeloma, myelodysplasia syndrome, neuroblastoma, neuroendocrine tumor, papillary thyroid carcinoma, parathyroid tumor, pediatric cancer, peripheral nerve sheath tumor, phaeochromocytoma, pituitary tumor, prostate cancer, posterior uveal melanoma, rare hematologic disorder, rhabdoid tumor, rhabdomysarcoma, sarcoma, soft-tissue sarcoma, squamous cell cancer, synovial sarcoma, mesothelioma, cutaneous squamous cell carcinoma, testicular cancer, thymic carcinoma, thymoma, and thyroid metastatic cancer.

[0380] Exemplary cancers that may be treated according to the invention include, but are not limited to, rectal cancer, anal cancer, small intestine cancer, gastrointestinal stromal tumours.

[0381] In one embodiment, the cancer is a lung cancer. In another embodiment, the lung cancer is non-small cell lung cancer (NSCLC). In yet another embodiment, the lung cancer is small cell lung cancer (SCLC).

[0382] NSCLC includes: (a) non-squamous cell carcinoma (adenocarcinoma, large cell, and undifferentiated carcinoma), (b) squamous cell carcinoma, and (c) non-small cell carcinoma not otherwise specified.

[0383] In one embodiment, the NSCLC is non-squamous NSCLC. In another embodiment, the NSCLC is squamous NSCLC.

[0384] In one embodiment, the cancer is a gastrointestinal cancer. Suitably, the gastrointestinal cancer is anal cancer, bile duct cancer, colon cancer, rectal cancer, esophageal cancer, gallbladder cancer, gastrointestinal stromal tumours, liver cancer, pancreatic cancer, small intestine cancer, or gastric cancer.

[0385] In one embodiment, the cancer is a head and neck cancer. In another embodiment, the head and neck cancer is head and neck squamous cell carcinoma (HNSCC).

[0386] In one embodiment, the cancer is a breast cancer. Suitably, the breast cancer is an adenocarcinoma of the breast. According to embodiments of the invention, the cancer may have progressed to metastatic disease.

[0387] In one particular embodiment, the cancer is metastatic NSCLC. In an embodiment, the metastatic NSCLC is non-squamous NSCLC. In another embodiment, the metastatic NSCLC is squamous NSCLC.

[0388] Suitably, patients with metastatic NSCLC are treated with the triple combination therapy as a 1stline therapy. Alternatively, patients with metastatic NSCLC are treated with the triple combination therapy as a 2ndline therapy.

[0389] PD-L1 expression status is a well-known predictive marker for response to PD-1 pathway inhibitors including in NSCLC and HNSCC. For example, PD-L1 expression is typically reported in three groups for NSCLC: < 1%, 1-49% and > 50% (Tumour Proportion Score or TPS) and in HNSCC: < 1, 1-19 and > 20 (Combined Positive Score or CPS). Patients with a high PD-L1 status are typically more responsive to PD-1 pathway inhibitors, whereas those with a low or negative PD-L1 status are overall significantly less responsive.

[0390] In an embodiment, the subject has NSCLC and a low or negative PD-L1 expression status (e.g. < 50%, 1-49%, or < 1%) and would otherwise be less likely to respond to therapy with a PD-1 pathway inhibitor, if not for the triple combination therapy of the invention.

[0391] In an embodiment, the subject has NSCLC and is treated without regard to their PD-L1 expression status.

[0392] In another embodiment, the subject has NSCLC and a PD-L1 expression status of < 50%.

[0393] In yet another embodiment, the subject has NSCLC and a PD-L1 expression status of 1-49%.

[0394] In a further embodiment, the subject has NSCLC and a PD-L1 expression status of < 1%.

[0395] In yet a further embodiment, the subject has NSCLC and a PD-L1 expression status of > 1%.

[0396] In an embodiment, the subject has NSCLC and a PD-L1 expression status of > 50%.

[0397] Suitably, the NSCLC is metastatic NSCLC.

[0398] Suitably, the NSCLC is locally advanced NSCLC. LAG-3 Protein and Derivatives

[0399] According to embodiments of the invention, the LAG-3 protein may be an isolated natural or recombinant LAG-3 protein. The LAG-3 protein may comprise an amino acid sequence of LAG-3 protein from any suitable species, such as a primate or murine LAG-3 protein, but preferably a human LAG-3 protein. The amino acid sequence of human and murine LAG-3 protein is provided in Figure 1 of Huard et al (Proc. Natl. Acad. Sci. USA, 11: 5744-5749, 1997). The sequence of human LAG-3 protein is repeated in Figure 1 herein (SEQ ID NO: 1). The amino acid sequences of the four extracellular Ig superfamily domains (D1, D2, D3, and D4) of human LAG-3 are also identified in Figure 1 of Huard etal., at amino acid residues: 1-149 (D1); 150-239 (D2); 240-330 (D3); and 331-412 (D4).

[0400] Derivatives of LAG-3 protein include soluble fragments, variants, or mutants of LAG-3 protein that are able to bind to MHC class II molecules. Several derivatives of LAG-3 protein are known that are able to bind to MHC class II molecules. Many examples of such derivatives are described in Huard et al (Proc. Natl. Acad. Sci. USA, 11: 5744-5749, 1997). This document describes characterization of the MHC class II binding site on LAG-3 protein. Methods for making mutants of LAG-3 are described, as well as a quantitative cellular adhesion assay for determining the ability of LAG-3 mutants to bind to class Il-positive Daudi cells. Binding of several different mutants of LAG-3 to MHC class II molecules was determined. Some mutations were able to reduce class II binding, while other mutations increased the affinity of LAG-3 for class II molecules. Many of the residues essential for binding of LAG-3 to MHC class II proteins are clustered at the base of a large 30 amino acid extra-loop structure in the LAG-3 D1 domain. The amino acid sequence of the extra-loop structure of the D1 domain of human LAG-3 protein is GPPAAAPGHPLAPGPHPAAPSSWGPRPRRY (SEQ ID NO:2). The amino acid sequence of the extra-loop structure of the D1 domain of human LAG-3 protein is shown underlined in bold in Figure 1.

[0401] In an embodiment of the invention, the derivative of LAG-3 protein comprises the 30 amino acid extra-loop sequence of the human LAG-3 D1 domain, or a variant of such sequence with one or more amino acid substitutions (e.g. a conservative amino acid substitution). The variant may comprise an amino acid sequence that has at least 70%, 80%, 90%, or 95% amino acid identity with the 30 amino acid extra-loop sequence of the human LAG-3 D1 domain. The derivative of LAG-3 protein may comprise an amino acid sequence of domain D1, domain D1 and optionally D2, or domains D1 and D2, of LAG-3 protein, preferably human LAG-3 protein.

[0402] The derivative of LAG-3 protein may comprise an amino acid sequence that has at least 70%, 80%, 90%, or 95% amino acid identity with domain D1, domain D1 and optionally D2, or domains D1 and D2, of LAG-3 protein, preferably human LAG-3 protein.

[0403] The derivative of LAG-3 protein may comprise an amino acid sequence of domains D1, D2, and D3, domains D1, D2, D3 and optionally D4, or domains D1, D2, D3 and D4, of LAG-3 protein, preferably human LAG-3 protein.

[0404] The derivative of LAG-3 protein may comprise an amino acid sequence that has at least 70%, 80%, 90%, or 95% amino acid identity with domains D1, D2 and D3, domains D1, D2, D3 and optionally D4, or with domains D1, D2, D3 and D4, of LAG-3 protein, preferably human LAG-3.

[0405] Sequence identity between amino acid sequences can be determined by comparing an alignment of the sequences. When an equivalent position in the compared sequences is occupied by the same amino acid, then the molecules are identical at that position. Scoring an alignment as a percentage of identity is a function of the number of identical amino acids at positions shared by the compared sequences. When comparing sequences, optimal alignments may require gaps to be introduced into one or more of the sequences to take into consideration possible insertions and deletions in the sequences. Sequence comparison methods may employ gap penalties so that, for the same number of identical molecules in sequences being compared, a sequence alignment with as few gaps as possible, reflecting higher relatedness between the two compared sequences, will achieve a higher score than one with many gaps. Calculation of maximum percent identity involves the production of an optimal alignment, taking into consideration gap penalties.

[0406] Suitable computer programs for carrying out sequence comparisons are widely available in the commercial and public sector. Examples include MatGat (Campanella et al., 2003, BMC Bioinformatics 4: 29; program available from http: / / bitincka.com / ledion / matgat), Gap (Needleman & Wunsch, 1970, J. Mol. Biol. 48: 443-453), FASTA (Altschul et al., 1990, J. Mol. Biol. 215: 403-410; program available from http: / / www.ebi.ac.uk / fasta), Clustal W 2.0 and X 2.0 (Larkin et al., 2007, Bioinformatics 23: 2947-2948; program available from http: / / www.ebi.ac.uk / tools / clustalw2) and EMBOSS Pairwise Alignment Algorithms (Needleman & Wunsch, 1970, supra; Kruskal, 1983, In: Time warps, string edits and macromolecules: the theory and practice of sequence comparison, Sankoff & Kruskal (eds), pp 1-44, Addison Wesley; programs available from http: / / www.ebi.ac.uk / tools / emboss / align). All programs may be run using default parameters.

[0407] For example, sequence comparisons may be undertaken using the “needle” method of the EMBOSS Pairwise Alignment Algorithms, which determines an optimum alignment (including gaps) of two sequences when considered over their entire length and provides a percentage identity score. Default parameters for amino acid sequence comparisons (“Protein Molecule” option) may be Gap Extend penalty: 0.5, Gap Open penalty: 10.0, Matrix: Blosum 62.

[0408] The sequence comparison may be performed over the full length of the reference sequence.

[0409] The derivative of LAG-3 protein may be fused to Immunoglobulin Fc amino acid sequence, preferably human I gG 1 Fc amino acid sequence, optionally by a linker amino acid sequence.

[0410] The ability of a derivative of LAG-3 protein to bind to MHO class II molecules may be determined using a quantitative cellular adhesion assay as described in Huard et al (Proc. Natl. Acad. Sci. USA, 11: 5744-5749, 1997). The affinity of a derivative of LAG-3 protein for MHC class II molecules may be at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of the affinity of human LAG-3 protein for MHC class II molecules.

[0411] Preferably, the affinity of a derivative of LAG-3 protein for MHC class II molecules is at least 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100% of the affinity of human LAG-3 protein for MHC class II molecules.

[0412] Examples of suitable derivatives of LAG-3 protein that are able to bind to MHC class II molecules include derivatives comprising:

[0413] amino acid residues 23 to 448 of the human LAG-3 sequence;

[0414] amino acid sequence of domains D1 and D2 of LAG-3;

[0415] amino acid sequence of domains D1 and D2 of LAG-3 with an amino acid substitution at one or more of the following positions: position 30 where ASP is substituted with ALA; position 56 where HIS is substituted with ALA; position 73 where ARG is substituted with GLU; position 75 where ARG is substituted with ALA or GLU; position 76 where ARG is substituted with GLU; or position 103 where ARG is substituted with ALA; and a recombinant soluble human LAG-3lg fusion protein (IMP321) - a 160-kDa dimer produced in Chinese hamster ovary cells transfected with a plasmid encoding for the extracellular domain of hLAG-3 fused to the human lgG1 Fc. The sequence of IMP321 is given in SEQ ID NO: 17 of US 2011 / 0008331.

[0416] In an embodiment, the subject is a mammal, preferably a human.

[0417] According to the invention, the LAG-3 protein or derivative thereof is administered in a therapeutically effective amount. A “therapeutically effective amount” refers to an amount of the active ingredient sufficient to have a therapeutic effect upon administration. Effective amounts of the active ingredient may vary, for example, with the particular disease or diseases being treated, the severity of the disease, the duration of the treatment, and characteristics of the patient (e.g. sex, age, height and weight).

[0418] Optionally the LAG-3 protein, or derivative thereof, is to be administered to the subject at a dosage of a molar equivalent of about 0.1 mg to about 200 mg of the LAG-3 derivative LAG-3lg fusion protein IMP321.

[0419] In an embodiment, the LAG-3 protein or derivative thereof is administered at a dose which is a molar equivalent of about 0.1 mg to about 60 mg, about 6 mg to about 60 mg, about 10 mg to about 50 mg, about 20 mg to about 40 mg, about 25 mg to about 35 mg, or about 30 mg of the LAG-3 derivative LAG-3lg fusion protein IMP321.

[0420] In another embodiment, the LAG-3 protein or derivative thereof is administered at a dose which is a molar equivalent of about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, or about 35 mg of the LAG-3 derivative LAG-3lg fusion protein IMP321.

[0421] Suitably, the LAG-3 protein or derivative thereof is administered at a dose which is a molar equivalent of about 30 mg of the LAG-3 derivative LAG-3lg fusion protein IMP321.

[0422] In yet another embodiment, the LAG-3 protein or derivative thereof is administered at a dose which is a molar equivalent from about 25 mg to about 60 mg, such as about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg, of the LAG-3 derivative LAG-3lg fusion protein IMP321. In one embodiment, the LAG-3 protein or derivative thereof is IMP321 and is administered at a dose of about 0.1 mg to about 60 mg, about 6 mg to about 60 mg, about 10 mg to about 50 mg, about 20 mg to about 40 mg, about 25 mg to about 35 mg, or about 30 mg.

[0423] In another embodiment, the IMP321 is administered at a dose of about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, or about 35 mg.

[0424] Suitably, IMP321 is administered at a dose of about 30 mg.

[0425] In other embodiments, IMP321 is administered at a dose from about 25 mg to about 60 mg, such as about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg.

[0426] Doses of 6-30 mg per subcutaneous (s.c.) injection of IMP321 have been shown, thus far, to be safe and provide an acceptable systemic exposure based on the results of pharmacokinetics data obtained in cancer patients. A blood concentration of IMP321 superior to 1 ng / ml for at least 24 hours after s.c. injection is obtained in patients injected with IMP321 doses of more than 6 mg. No dose limiting toxicity has been observed to date.

[0427] In another embodiment, the LAG-3 protein, or derivative thereof, is to be administered to the subject at a dosage of a molar equivalent of >30 mg to 200 mg of IMP321.

[0428] Optionally the LAG-3 protein, or derivative thereof, is to be administered to the subject at a dosage of a molar equivalent of 40 mg to 200 mg of IMP321.

[0429] Optionally the LAG-3 protein, or derivative thereof, is to be administered to the subject at a dosage of a molar equivalent of 40 mg to 180 mg of IMP321.

[0430] Optionally the LAG-3 protein, or derivative thereof, is to be administered to the subject at a dosage of a molar equivalent of 40 mg to 150 mg of IMP321.

[0431] Optionally the LAG-3 protein, or derivative thereof, is to be administered to the subject at a dosage of a molar equivalent of 40 mg to 120 mg of IMP321.

[0432] Optionally the LAG-3 protein, or derivative thereof, is to be administered to the subject at a dosage of a molar equivalent of 50 mg to 200 mg of IMP321. Optionally the LAG-3 protein, or derivative thereof, is to be administered to the subject at a dosage of a molar equivalent of 50 mg to 180 mg of IMP321.

[0433] Optionally the LAG-3 protein, or derivative thereof, is to be administered to the subject at a dosage of a molar equivalent of 50 mg to 150 mg of IMP321.

[0434] Optionally the LAG-3 protein, or derivative thereof, is to be administered to the subject at a dosage of a molar equivalent of 50 mg to 120 mg of IMP321.

[0435] Optionally the LAG-3 protein, or derivative thereof, is to be administered to the subject at a dosage of a molar equivalent of 50 to 100 mg of IMP321.

[0436] Optionally the LAG-3 protein, or derivative thereof, is to be administered to the subject at a dosage of a molar equivalent of 60 mg to 200 mg of IMP321.

[0437] Optionally the LAG-3 protein, or derivative thereof, is to be administered to the subject at a dosage of a molar equivalent of 60 mg to 180 mg of IMP321.

[0438] Optionally the LAG-3 protein, or derivative thereof, is to be administered to the subject at a dosage of a molar equivalent of 60 mg to 150 mg of IMP321.

[0439] Optionally the LAG-3 protein, or derivative thereof, is to be administered to the subject at a dosage of a molar equivalent of 60 mg to 120 mg of IMP321.

[0440] Optionally the LAG-3 protein, or derivative thereof, is to be administered to the subject at a dosage of a molar equivalent of 60 to 100 mg of IMP321, or 60 to 90 mg of IMP321.

[0441] Optionally the LAG-3 protein, or derivative thereof, is to be administered to the subject at a dosage of a molar equivalent of 80 to 100 mg of IMP321

[0442] Optionally the LAG-3 protein, or derivative thereof, is to be administered to the subject at a dosage of a molar equivalent of 90 mg of IMP321.

[0443] The dosage of the LAG-3 protein, or derivative thereof, may be administered to the subject in two or more separate administrations, each separate administration comprising a partial dose, to provide the full dose in combination. For example a 90 mg dose of IMP321 may be administered in two separate doses of 45 mg (for example, by s.c. injection). The separate administrations may be up to 30 minutes apart, for example, up to 15 minutes apart. In an embodiment, the LAG-3 protein or derivative thereof is administered about once every week to the subject. In another embodiment, the LAG-3 protein or derivative thereof is administered about once every two weeks to the subject. In yet another embodiment, the LAG-3 protein or derivative thereof is administered about once every three weeks to the subject. In a further embodiment, the LAG-3 protein or derivative thereof is administered about once every four weeks to the subject. In yet a further embodiment, the LAG-3 protein or derivative thereof is administered about once every month to the subject. As will be appreciated by those of skill in the art, the precise treatment regimen may vary and be adapted according to the particular cancer being treated and characteristics of the patient.

[0444] In one embodiment, the LAG-3 protein or derivative thereof is initially administered about once every two weeks to the subject and is then subsequently administered about once every three weeks to the subject. For example, in an embodiment, the LAG-3 protein, or derivative, is administered to a subject once every two weeks for the first 6 months, and thereafter once every three weeks for up to a further 18 months (up to 24 months in total).

[0445] In one embodiment, the LAG-3 protein or derivative thereof is present in the absence of any additional antigen added to the pharmaceutical composition, combined preparation, or medicament.

[0446] PD-1 Pathway Inhibitor

[0447] The PD-1 pathway inhibitor is an agent that inhibits binding of PD-1 to PD-L1 and / or PD-L2. In particular, the agent may inhibit binding of human PD-1 to human PD-L1 and / or human PD-L2. The agent may inhibit binding of PD-1 to PD-L1 and / or PD-L2 by at least 50%, 60%, 70%, 80%, or 90%. Suitable assays for determining binding of PD-1 to PD-L1 or PD-L2, by Surface Plasmon Resonance (SPR) analysis, or flow cytometry analysis, are described in Ghiotto et al (Int. Immunol. Aug 2010; 22(8): 651-660). The agent may inhibit binding of PD-1 to PD-L1 and / or PD-L2, for example, by binding to PD-1 , to PD-L1 , or to PD-L2.

[0448] The agent may be an antibody, suitably a monoclonal antibody, such as a human or humanized monoclonal antibody. The agent may be a fragment or derivative of an antibody that retains ability to inhibit binding of PD-1 to PD-L1 and / or PD-L2.

[0449] Exemplary PD-1 pathway inhibtors include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, atezolizumab, avelumab, and durvalumab, or a fragment or derivative thereof that retains ability to inhibit binding of PD-1 to PD-L1 and / or PD-L2.

[0450] Suitably, the PD-1 pathway inhibitor is an anti-PD-1 antibody selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, and dostarlimab, or a fragment or derivative thereof that retains ability to inhibit binding of PD-1 to PD-L1 and / or PD-L2.

[0451] Suitably, the PD-1 pathway inhibitor is an anti-PD-L1 antibody selected from the group consisting of atezolizumab, avelumab, and durvalumab, or a fragment or derivative thereof that retains ability to inhibit binding of PD-L1 to PD-1.

[0452] Suitably, the PD-1 pathway inhibitor is pembrolizumab.

[0453] Suitably, the PD-1 pathway inhibitor is nivolumab.

[0454] Suitably, the PD-1 pathway inhibitor is cemiplimab.

[0455] Suitably, the PD-1 pathway inhibitor is spartalizumab.

[0456] Suitably, the PD-1 pathway inhibitor is camrelizumab.

[0457] Suitably, the PD-1 pathway inhibitor is sintilimab.

[0458] Suitably, the PD-1 pathway inhibitor is tislelizumab.

[0459] Suitably, the PD-1 pathway inhibitor is toripalimab.

[0460] Suitably, the PD-1 pathway inhibitor is dostarlimab.

[0461] Suitably, the PD-1 pathway inhibitor is atezolizumab.

[0462] Suitably, the PD-1 pathway inhibitor is avelumab.

[0463] Suitably, the PD-1 pathway inhibitor is durvalumab.

[0464] Other exemplary PD-1 pathway inhibitors include JTX-4014, retifanlimab (INCMGA00012), AMP-224, MEDI0680 (AMP-514), envafolimab (KN035), cosibelimab (CK-301), AUNP12, CA-170 and BMS-986189. JTX-4014 is a human immunoglobulin G4 (lgG4) monoclonal antibody directed against PD-1. Papadopoulos et al. (Cancer Immunol Immunother. 2021 Mar;70(3):763-772) describe a phase I, first-in-human trial of JTX-4014 in adult patients with advanced, refractory, solid tumors.

[0465] Retifanlimab (INCMGA00012) is a humanized monoclonal antibody targeting PD-1 (Rao, et al., 2022 Aug;7(4): 100529).

[0466] AMP-224 is a recombinant fusion protein comprised of the extracellular domain of the PD-1 ligand programmed cell death ligand 2 (PD-L2) and the Fc region of human IgG (Smothers et al., Annals of Oncology 24 (Supplement 1): i7— i 17, 2013).

[0467] MEDI0680, previously named AMP-514, is a humanized lgG4K anti- PD-1 monoclonal antibody (Naing et al., J Immunother Cancer . 2019 Aug 22;7:225).

[0468] Envafolimab (KN035) is a subcutaneously injectable single-domain anti-PD-L1 monoclonal antibody (Shimizu et al., Invest New Drugs, 2022 Oct;40(5): 1021-1031).

[0469] Cosibelimab (CK-301) is a fully-human monoclonal antibody that binds PD-L1 and blocks its interaction with PD-1 (Clingan et al., J Immunother Cancer 2023; 11 :e007637).

[0470] AUNP-12 (CAS No. 1353563-85-5) is a small branched peptide inhibitor of the PD-1 / PD-L1 pathway , and is described in WO 2011 / 161699. It interacts with PD-1 and prevents binding of both PD-L1 and PD-L2. It is composed of two linked peptide chains (sequence 1: SNTSESFKFRVTQLAPKAQIKE (SEQ ID NO:3) and sequence 2: SNTSESF (SEQ ID NO:4)), with a total of 29 amino acids (Modifications: Amide bridge= 8-7*, Glu-22 = C-terminal amide).

[0471] CA-170 is a small molecule inhibitor of PD-L1 and VISTA derived from the interface of PD-1 and PD-L1 (Sasikumar et al., Communications Biology volume 4, Article number: 699 (2021).

[0472] BMS-986189 (CAS No. 1629665-96-8) is a macrocyclic peptide inhibitor of PD-L1 (IC50: 1.03 nM), with sequence: cyclo[-CH2-CO-Tyr-(N-Me-Ala)-Asn-Pro-(Ala-NH2)-Leu-Hyp-Trp-Dab-Trp(CH2COOH)-( N-Me-Nle)-(N-Me-Nle)-Leu-Cys-S-]-Gly-NH2 (SEQ ID NO:5).

[0473] In other embodiments, the PD-1 pathway inhibitor may be a bispecific anti-PD-1 or PD-L1 antibody. Synchronous inhibition of PD-1, or PD-L1, with other agents can expand antibody selectivity and improve therapeutic window through tightening cell-to-cell bridge (a process called immunological synapse) within tumor immune microenvironment (TIME). There is evidence of higher potency of this co-targeting approach over combined single-agent monoclonal antibodies in reinvigorating anti-tumor immune responses, retarding tumor growth, and improving patient survival. Immunological synapses formed by interactions of such bispecific agents with TIME cells directly mediate cytotoxicity against tumor cells, and durable anti-tumor immune responses are observed after application of such agents. Lower adverse events are reported for bispecific antibodies compared with individual checkpoint inhibitors. Acting on two complementary or synergistic signaling pathways increases the affinity of bispecific antibodies toward tumor tissues representing both targets. This will increase recruitment of effector cells to hamper two-expressing cells within TIME and reduce drug resistance.

[0474] A number of bispecific antibodies have been developed, including bispecific anti-PD-(L)1 with an inhibitory checkpoint (Mortezaee and Majidpoor, Biomedicine & Pharmacotherapy 162 (2023) 114621). PD-1 and PD-L1, PD-1 and CTLA-4, PD-(L)1 and an alternative checkpoint, and PD-(L)1 and a dominant signaling molecule are examples of bispecific antibodies constructed for clinical application in different types of solid cancers. Such agents boost the activity of anti-tumor immune cells, CD8+T cells within TIME, and show superior anti-cancer functions compared with mono- or combination therapy.

[0475] Li et al. (Cell Communication and Signaling (2024) 22:179) discuss various bispecific products targeting PD-1 signaling, highlighting their unique mechanisms of action and therapeutic potential. Noteworthy examples include anti-TGFp * PD-L1, anti-CD47 x PD-L1, anti-VEGF x PD-L1, anti-4-1 BB x PD-L1, anti-LAG-3 x PD-L1, and anti-PD-1 x CTLA-4 bispecific antibodies. Several examples of these agents are given in Table 1 of Li et al (supra).

[0476] Other examples of bispecific anti-PD-1 or PD-L1 antibodies include:

[0477] CTX-8371: a bispecific tetravalent molecule that strongly blocks PD-1 and PD-L1 simultaneously. CTX-8371 cleaves PD-1 on the T cell surface, represented by a sharp decrease in the number of PD-1+CD4+and CD8+T cells within peripheral blood, and a low dose of this agent (1-2 mg / kg) can cause an inhibitory effect on tumor growth (Albu et al., Oncoimmunology . 2024 Feb 16;13(1):2316945);

[0478] LY3434172: a PD-1 / PD-L1 bispecific antibody (Kotanides et al., Cancer Immunol. Res. 8 (10) (2020) 1300-1310); MEDI5752: anti-PD-1 / CTLA-4 (Dovedi et al., Cancer Discov. 11 (5) (2021) 1100-1117.);

[0479] FS118: anti-LAG-3 / PD-L1 (Kraman et al., Clin. Cancer Res. 26 (13) (2020) 3333-3344; Kraman et al., Cancer Res. 78 (13_Supplement) (2018), 2719-2719);

[0480] IBI323: anti-LAG-3 / PD-L1 (Jiang and Zhang, Oncoimmunology 10 (1) (2021) 1943180);

[0481] RG7769: Anti-TIM-3 / PD-1 (Deak et al., Cancer Res. 80 (16_Supplement) (2020), 2270-2270);

[0482] FS222: CD137 / PD-L1 (Lakins eta!., Clin. Cancer Res. 26 (15) (2020) 4154-4167);

[0483] ABL503: CD137 / PD-L1 (Jeong etal., J. Immunother. Cancer 9 (7) (2021);

[0484] MCLA-145: CD137 / PD-L1 (Geuijen etal., Nat. Commun. 12 (1) (2021) 1-19);

[0485] LM-299: a bispecific antibody targeting both PD-1 and VEGF to inhibit both PD-1 / PD-L1 and VEGFA / EGFR receptor signaling pathways. LM-299 has a differentiated molecular design, comprising an anti-VEGF antibody linked to two C-terminal single domain anti-PD-1 antibodies.

[0486] Whilst monoclonal antibody PD-1 pathway inhibitors are suitable for use according to the invention, they may have disadavantages, including high production costs, side effects, requirement for intravenous administration, prolonged tissue retention, and low membrane permeability. In contrast, small molecule inhibitors may provide short half-life effects beneficial in terms of immune-related adverse effects and elimination of immunogenicity problems, lower cost production, greater stability, greater tumor penetration, and improved bioavailability leading to increased bio-efficiency. Within the tumor microenvironment, small molecule inhibitors may display higher diffusion rate in comparison to antibodies and be able to target PD-1 protein in other cellular sources, which could avoid macrophage-mediated resistance that can occur with therapies involving anti-PD-1 antibodies.

[0487] In other embodiments, the PD-1 pathway inhibitor may be a non-peptide small molecule inhibitor. Several suitable examples of such inhibitors are described in WO 2015 / 034820A1 (Bristol-Myers Squibb), and WO 2015 / 160641 A2 (Bristol-Myers Squibb), and are referred to as “BMS molecules”, including pharmaceutically acceptable salts of the molecules described. The structures of some examples of the BMS molecules are shown in Figure 4 (taken from Javed etal., 2024, Front. Immunol. 15:1383456). Such molecules, and their pharmaceutically acceptable salts, are suitable for use according to the invention. Several of these molecules comprise the following structure (which includes a biphenyl group):

[0488]

[0489] Some of the BMS molecules (BMS-8 and BMS-202) have been shown to inhibit PD-1 / PD-L1 interaction by inducing PD-L1 dimerisation (Zak et al., Oncotarget 2016, 7, 30323-30335). Another mechanism identified for the BMS molecule BMS-1166 is partial and specific inhibition of PD-L1 glycosylation and functional inactivation of PD-L1 by preventing its export to Golgi from the endoplasmic reticulum (ER). Some of the biphenyl compounds have been shown to exert their action via induction of a two-step internalization process following initiation of the dimerization of PDL-1 at the cell surface, inhibiting its interaction with PD-1.

[0490] Optionally a non-peptide small molecule PD-1 pathway inhibitor is a PD-L1 dimer stabiliser. Optionally the PD-L1 dimer stabiliser comprises the following structure, which includes a biphenyl group (Skalniak et al., Oncotarget 2017, 8, 72167):

[0491]

[0492] Optionally the PD-1 pathway inhibitor is a non-BMS small molecule. Suitable non-BMS PD-1 / PD-L1 inhibitors are described in Javed et al., 2024 (Front. Immunol. 15:1383456). Their structures are shown in Figure 5 as compounds (1)-(11) (taken from Figure 4 of Javed etal.), in Figure 6 as compounds (12)-(20) (taken from Figure 5 of Javed et al.), and in Figure 7 as compounds (21)-(28) (taken from Figure 6 of Javed et al.). Compounds (1 )-(28), and their pharmaceutically acceptable salts, are suitable for use according to the invention.

[0493] Bifunctional small molecules have also been designed to target PD-L1 and CXCL12 simultaneously (Cheng et al., Sig Transduct Target Ther. (2023) 8:91). Compound (29) (shown in Figure 8) exhibited highest inhibitory effect on human PD-L1 (ICso=78.6 nM) and significant binding affinity to CXCL12. Fantacuzzi et al. (Pharmaceuticals 2024, 17, 316) is a review article providing a comprehensive computational insight into PD-L1 binding to PD-1 and small molecules. The article describes computational approaches that have been applied to identify new PD-L1 ligands. Only papers that include a biological assay demonstrating activity towards PD-L1, and confirming the validity of the computational results, were considered for the review. Figure 9 (taken from Figure 9 of Fantacuzzi et al.) provides chemical structures of PD-L1 inhibitors identified by structural-based virtual screening and machine learning. The activity of the compounds is provided in Table 7 of Fantacuzzi et al. Such molecules, and their pharmaceutically acceptable salts, are suitable for use according to the invention. The dose of the PD-1 pathway inhibitor will depend on the particular PD-1 pathway inhibitor being used. In general, a typically prescribed dose of a PD-1 pathway inhibitor for a human subject may be 0.1 to 10 mg / kg, for example 0.1 to 1 mg / kg, or 1 to 10 mg / kg. The term "typically prescribed dose" is used herein to include a dose which is the same as the dose, or within the dosage range, that is safe and therapeutically effective for administration to a subject (suitably a human subject).

[0494] Guzik et al (Molecules. 2019; 24, 2071) discuss several anti-PD-1 / PD-L1 small-molecule and peptide-based inhibitors. Guzik states that the first disclosed small-molecule inhibitors targeting PD-1 / PD-L1 were derivatives of antibiotics such as sulfamonomethoxines and sulfamethizoles and were developed by Sharpe et al prior to 2011. The in vivo efficacy of these compounds was confirmed in WO2011 / 082400.

[0495] Optionally the PD-1 pathway inhibitor is or comprises a peptide. Optionally the PD-1 pathway inhibitor is a macrocyclic peptide. WO 2014 / 151634 describes several macrocyclic peptides which inhibit the PD-1 / PD-L1 and PD-L1 / CD80 protein / protein interaction. Examples 1-119 describe preparation of several macrocyclic peptides. Examples 120 and 121 describe methods for testing the ability of macrocyclic peptides to bind to PD-L1, and provide IC50 values for inhibition of binding of PD-1 to PD-L1 for several compounds. It is concluded that the macrocyclic peptides demonstrated potent inhibition of PD-1-lg binding activity to PD-L1-His or PD-L1 (pages 1270 and 1271). Examples 122 and 123 describe methods for testing the ability of variant macrocyclic peptides to inhibit PD-1 binding to PD-L1. IC50 data is provided for several different compounds in Tables 8 and 9. The variant macrocyclic peptides are stated to demonstrate potent inhibition of PD-1 binding to PD-L1 (see page 1272 and 1275). Example 126 describes testing the ability of macrocyclic peptides to promote IFNy secretion in an HIV-specific T cell function assay. It is concluded that PD-L1 binding with a peptide inhibitor can enhance IFNy release from the T cell population responding to an ongoing viral infection, similar to anti-PD-L1 antibody.

[0496] The PD-1 pathway inhibitor may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds and compositions of the present disclosure may, for example, be administered orally, mucosally, rectally, or parentally including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intrasternally in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. For example, the pharmaceutical carrier may contain a mixture of mannitol or lactose and microcrystalline cellulose. The mixture may contain additional components such as a lubricating agent, e.g. magnesium stearate and a disintegrating agent such as crospovidone. The carrier mixture may be filled into a gelatin capsule or compressed as a tablet. The pharmaceutical composition may be administered as an oral dosage form or an infusion, for example.

[0497] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. For example, the pharmaceutical composition may be provided as a tablet or capsule comprising an amount of active ingredient in the range of from about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, and more preferably from about 0.5 to 100 mg. A suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but, can be determined using routine methods.

[0498] Any pharmaceutical composition contemplated herein can, for example, be delivered orally via any acceptable and suitable oral preparations. Exemplary oral preparations, include, but are not limited to, for example, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to any methods known in the art for manufacturing pharmaceutical compositions intended for oral administration. In order to provide pharmaceutically palatable preparations, a pharmaceutical composition in accordance with the disclosure can contain at least one agent selected from sweetening agents, flavoring agents, coloring agents, demulcents, antioxidants, and preserving agents. A tablet can, for example, be prepared by admixing at least one PD-1 pathway inhibitor and / or at least one pharmaceutically acceptable salt thereof with at least one non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets. Exemplary excipients include, but are not limited to, for example, inert diluents, such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, and alginic acid; binding agents, such as, for example, starch, gelatin, polyvinyl-pyrrolidone, and acacia; and lubricating agents, such as, for example, magnesium stearate, stearic acid, and talc.

[0499] Additionally, a tablet can either be uncoated, or coated by known techniques to either mask the bad taste of an unpleasant tasting drug, or delay disintegration and absorption of the active ingredient in the gastrointestinal tract thereby sustaining the effects of the active ingredient for a longer period. Exemplary water soluble taste masking materials, include, but are not limited to, hydroxypropyl-methylcellulose and hydroxypropyl- cellulose. Exemplary time delay materials, include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

[0500] Hard gelatin capsules can, for example, be prepared by mixing at least one compound of formula (I) and / or at least one salt thereof with at least one inert solid diluent, such as, for example, calcium carbonate; calcium phosphate; and kaolin.

[0501] Soft gelatin capsules can, for example, be prepared by mixing at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one water soluble carrier, such as, for example, polyethylene glycol; and at least one oil medium, such as, for example, peanut oil, liquid paraffin, and olive oil.

[0502] An aqueous suspension can be prepared, for example, by admixing at least one PD-1 pathway inhibitor and / or at least one pharmaceutically acceptable salt thereof with at least one excipient suitable for the manufacture of an aqueous suspension. Exemplary excipients suitable for the manufacture of an aqueous suspension, include, but are not limited to, for example, suspending agents, such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, such as, for example, a naturally-occurring phosphatide, e.g., lecithin; condensation products of alkylene oxide with fatty acids, such as, for example, polyoxy ethylene stearate; condensation products of ethylene oxide with long chain aliphatic alcohols, such as, for example heptadecaethylene-oxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as, for example, polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as, for example, polyethylene sorbitan monooleate. An aqueous suspension can also contain at least one preservative, such as, for example, ethyl and n-propyl p- hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and / or at least one sweetening agent, including but not limited to, for example, sucrose, saccharin, and aspartame.

[0503] Oily suspensions can, for example, be prepared by suspending at least one PD-1 pathway inhibitor and / or at least one pharmaceutically acceptable salt thereof in either a vegetable oil, such as, for example, arachis oil; olive oil; sesame oil; and coconut oil; or in mineral oil, such as, for example, liquid paraffin. An oily suspension can also contain at least one thickening agent, such as, for example, beeswax; hard paraffin; and cetyl alcohol. In order to provide a palatable oily suspension, at least one of the sweetening agents already described hereinabove, and / or at least one flavoring agent can be added to the oily suspension. An oily suspension can further contain at least one preservative, including, but not limited to, for example, an anti-oxidant, such as, for example, butylated hydroxyanisol, and alpha-tocopherol.

[0504] Dispersible powders and granules can, for example, be prepared by admixing at least one PD-1 pathway inhibitor and / or at least one pharmaceutically acceptable salt thereof with at least one dispersing and / or wetting agent; at least one suspending agent; and / or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents are as already described above. Exemplary preservatives include, but are not limited to, for example, anti-oxidants, e.g., ascorbic acid. In addition, dispersible powders and granules can also contain at least one excipient, including, but not limited to, for example, sweetening agents; flavoring agents; and coloring agents.

[0505] An emulsion of at least one PD-1 pathway inhibitor and / or at least one pharmaceutically acceptable salt thereof can, for example, be prepared as an oil-in-water emulsion. The oily phase of the emulsions comprising the PD-1 pathway inhibitor may be constituted from known ingredients in a known manner. The oil phase can be provided by, but is not limited to, for example, a vegetable oil, such as, for example, olive oil and arachis oil; a mineral oil, such as, for example, liquid paraffin; and mixtures thereof. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Suitable emulsifying agents include, but are not limited to, for example, naturally-occurring phosphatides, e.g., soy bean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as, for example, polyoxy ethylene sorbitan monooleate.

[0506] Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. An emulsion can also contain a sweetening agent, a flavoring agent, a preservative, and / or an antioxidant. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present disclosure include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other materials well known in the art.

[0507] The PD-1 pathway inhibitor and / or at least one pharmaceutically acceptable salt thereof can, for example, also be delivered intravenously, subcutaneously, and / or intramuscularly via any pharmaceutically acceptable and suitable injectable form.

[0508] Exemplary injectable forms include, but are not limited to, for example, sterile aqueous solutions comprising acceptable vehicles and solvents, such as, for example, water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsions; and aqueous or oleaginous suspensions. Formulations for parenteral administration may be in the form of aqueous or nonaqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and / or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or with cyclodextrin (i.e. Captisol), cosolvent solubilization (i.e. propylene glycol) or micellar solubilization (i.e. Tween 80).

[0509] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0510] A sterile injectable oil-in-water microemulsion can, for example, be prepared by 1) dissolving at least one compound of formula (I) in an oily phase, such as, for example, a mixture of soybean oil and lecithin; 2) combining the PD-1 pathway inhibitor-containing oil phase with a water and glycerol mixture; and 3) processing the combination to form a microemulsion.

[0511] A sterile aqueous or oleaginous suspension can be prepared in accordance with methods already known in the art. For example, a sterile aqueous solution or suspension can be prepared with a non-toxic parenterally-acceptable diluent or solvent, such as, for example, 1,3-butane diol; and a sterile oleaginous suspension can be prepared with a sterile non-toxic acceptable solvent or suspending medium, such as, for example, sterile fixed oils, e.g., synthetic mono- or diglycerides; and fatty acids, such as, for example, oleic acid.

[0512] Pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-alpha-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, polyethoxylated castor oil such as CREMOPHOR surfactant (BASF), or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene -block polymers, polyethylene glycol and wool fat. Cyclodextrins such as alpha-, beta-, and gammacyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3 -hydroxypropyl- cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.

[0513] The pharmaceutically active compounds of this disclosure can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and / or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and pills can additionally be prepared with enteric coatings. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

[0514] The amounts of compounds that are administered and the dosage regimen for treating a disease condition with the compounds and / or compositions of this disclosure depends on a variety of factors, including the age, weight, sex, the medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. A daily dose of about 0.001 to 100 mg / kg body weight, preferably between about 0.0025 and about 50 mg / kg body weight and most preferably between about 0.005 to 10 mg / kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day. Other dosing schedules include one dose per week and one dose per two day cycle.

[0515] For therapeutic purposes, the active compounds of this disclosure are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered orally, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.

[0516] In an embodiment, the PD-1 pathway inhibitor is administered about once every week to the subject. In another embodiment, the PD-1 pathway inhibitor is administered about once every two weeks to the subject. In yet another embodiment, the PD-1 pathway inhibitor is administered about once every three weeks to the subject. In a further embodiment, the PD-1 pathway inhibitor is administered about once every four weeks to the subject. In yet a further embodiment, the PD-1 pathway inhibitor is administered about once every month to the subject. In an embodiment, the PD-1 pathway inhibitor is administered about once every five weeks to the subject. In another embodiment, the PD-1 pathway inhibitor is administered about once every six weeks to the subject. In yet another embodiment, the PD-1 pathway inhibitor is administered about once every seven weeks to the subject. In yet another embodiment, the PD-1 pathway inhibitor is administered about once every eight weeks to the subject. In a further embodiment, the PD-1 pathway inhibitor is administered about once every two months to the subject.

[0517] As will be appreciated by those of skill in the art, the precise treatment regimen may vary and be adapted according to the particular cancer being treated and characteristics of the patient.

[0518] Examples of typically prescribed human doses of known PD-1 pathway inhibitors include:

[0519] Pembrolizumab: 200 mg every three weeks or 400 mg every six weeks.

[0520] Nivolumab: 240 mg every two weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks Avelumab: 800 mg every two weeks (or maximum dose 10 mg / kg if weight < 80kg).

[0521] In some embodiments, the PD-1 pathway inhibitor is administered parenterally (including by subcutaneous, intravenous, or intramuscular injection) or orally.

[0522] Suitably, the PD-1 pathway inhibitor is administered intravenously.

[0523]

[0524] Suitable chemotherapy agents include, but are not limited to, alkylating agents, plant alkaloids, antitumor antibiotics, antimetabolites, topoisomerase inhibitors, and miscellaneous antineoplastics, and mixtures thereof.

[0525] Suitably, the chemotherapy agent is an alkylating agent. Exemplary alkylating agents include mustard gas derivatives such mechlorethamine, cyclophosphamide, chlorambucil, melphalan, and ifosfamide; ethylenimines such as thiotepa and hexamethylmelamine; alkylsulfonates such as busulfan; hydrazines and triazines such as altretamine, procarbazine, dacarbazine and temozolomide; nitrosureas such as carmustine, lomustine and streptozocin; and platinum chemotherapy agents such as carboplatin, cisplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin.

[0526] Suitably, the chemotherapy agent is a plant alkaloid. Exemplary plant alkaloids include vinca alkaloids such as vincristine, vinblastine and vinorelbine; taxanes such as paclitaxel, nab-paclitaxel, docetaxel, cabazitaxel, larotaxel, milataxel, ortataxel, taxoprexin, opaxio, tesetaxel, and BMS- 184476; podophyllotoxins such as etoposide and tenisopide; and camptothecan analogs such as irinotecan and topotecan. Suitably, the chemotherapy agent is an antitumor antibiotic. Exemplary antitumor antibiotics include a nth racy clines such as doxorubicin, daunorubicin, epirubicin, mitoxantrone, and idarubicin; chromomycins such as dactinomycin and plicamycin; and miscellaneous antitumor antibiotics such as mitomycin and bleomycin.

[0527] Suitably, the chemotherapy agent is an antimetabolite. Exemplary antimetabolites include folic acid antagonists such as methotrexate and pemetrexed; pyrimidine antagonists such as 5-fluorouracil, tegafur, carmofur, doxifluridine, floxuridine, cytarabine, capecitabine and gemcitabine; purine antagonists such as 6-mercaptopurine and 6-thioguanine; and adenosine deaminase inhibitors such as cladribine, fludarabine, nelarabine and pentostatin.

[0528] Suitably, the chemotherapy agent is a topoisomerase inhibitor. Exemplary topoisomerase inhibitors include topoisomerase I inhibitors such as irinotecan and topotecan; and topoisomerase II inhibitors such as amsacrine, etoposide, etoposide phosphate and teniposide.

[0529] Suitably, the chemotherapy agent is a miscellaneous antineoplastic. Exemplary miscellaneous antineoplastics include ribonucleotide reductase inhibitors such as hydroxyurea; adrenocortical steroid inhibitors such as mitotane; enzymes such as asparaginase and pegaspargase; antimicrotubule agents such as estramustine; and retinoids such bexarotene, isotretinoin and tretinoin.

[0530] Suitably, the chemotherapy agent is a combination of two or more chemotherapy agents.

[0531] Suitably, the chemotherapy agent is a combination of two chemotherapy agents.

[0532] In one embodiment, the chemotherapy agent is a combination of pemetrexed and platinum chemotherapy such as carboplatin, cisplatin, or oxaliplatin.

[0533] In another embodiment, the chemotherapy agent is a combination of pemetrexed and cisplatin or carboplatin.

[0534] In an embodiment, the chemotherapy agent is a combination of pemetrexed and platinum chemotherapy such as carboplatin, cisplatin, or oxaliplatin, for the treatment of non-squamous NSCLC.

[0535] In an embodiment, the chemotherapy agent is a combination of pemetrexed cisplatin or carboplatin, for the treatment of non-squamous NSCLC. In yet another embodiment, the chemotherapy agent is carboplatin and a taxane such as paclitaxel or nab-paclitaxel.

[0536] In a further embodiment, the chemotherapy agent is carboplatin and paclitaxel or nab-paclitaxel.

[0537] In an embodiment, the chemotherapy agent is a combination of carboplatin and a taxane such as paclitaxel or nab-paclitaxel, for the treatment of squamous NSCLC.

[0538] In an embodiment, the chemotherapy agent is a combination of carboplatin and paclitaxel or nab-paclitaxel, for the treatment of squamous NSCLC.

[0539] The chemotherapy agent is administered in a therapeutically effective amount. A therapeutically effective amount refers to an amount of the chemotherapy agent sufficient to have a therapeutic effect upon administration. Effective amounts of the chemotherapy agent will vary with the chemotherapy agent selected, the particular disease or diseases being treated, the severity of the disease, the duration of the treatment, and characteristics of the patient (e.g. sex, age, height and weight).

[0540] In some embodiments, the chemotherapy agent is administered parenterally (including by subcutaneous, intravenous, or intramuscular injection) or orally.

[0541] Suitably, the chemotherapy is administered intravenously.

[0542] In an embodiment, the chemotherapy agent is administered about once every week to the subject. In another embodiment, the chemotherapy agent is administered about once every two weeks to the subject. In yet another embodiment, the chemotherapy agent is administered about once every three weeks to the subject. In a further embodiment, the chemotherapy agent is administered about once every four weeks to the subject. In yet a further embodiment, the chemotherapy agent is administered about once every month to the subject.

[0543] In an embodiment, the LAG-3 protein or derivative thereof is administered simultaneously or sequentially with the PD-1 pathway inhibitor and the chemotherapy agent.

[0544] In another embodiment, the LAG-3 protein or derivative thereof is administered sequentially with the PD-1 pathway inhibitor and the chemotherapy agent. The LAG-3 protein or derivative thereof is administered sequentially with the PD-1 pathway inhibitor and the chemotherapy agent may be administered in any order.

[0545] In yet another embodiment, the chemotherapy agent is administered and is followed by sequential administration of the LAG-3 protein or derivative thereof and the PD-1 pathway inhibitor.

[0546] Doses of Components of Triple Combination Therapy

[0547] The doses of the components used in the triple combination therapy according to the invention should be chosen to provide a therapeutically effective amount of the components in combination. An "effective amount" of the triple combination therapy may be an amount that results in a reduction of at least one pathological parameter associated with cancer. For example, in some embodiments, an effective amount of the triple combination therapy is an amount that is effective to achieve a reduction of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, in the pathological parameter, compared to the expected reduction in the parameter associated with the cancer without the triple combination therapy. For example, the pathological parameter may be tumor growth, or tumor growth rate.

[0548] Alternatively, an "effective amount" of the triple combination therapy may be an amount that results in an increase in a clinical benefit associated with cancer treatment. For example, in some embodiments, an "effective amount" of the combination therapy is an amount that is effective to achieve an increase of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175% or 200%, in the clinical benefit, compared to the expected clinical benefit without the triple combination therapy. For example, the clinical benefit may be response rate, progression-free survival, overall survival, disease control rate, depth of response, duration of response, quality of life, or increased sensitization to subsequent treatments.

[0549] Alternatively, an "effective amount" of the triple combination therapy may be an amount that results in a change of at least one beneficial parameter relating to cancer treatment. For example, in some embodiments, an "effective amount" of the triple combination therapy is an amount that is effective to achieve a change of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%, in the parameter, compared to the expected change in the parameter relating to cancer treatment without the combination therapy. For example, the parameter may be an increase in the number of circulating tumor antigen-specific CD8+T cells, or a reduction in the number of tumor antigen-specific regulatory T cells, or an increase in the number of activated T cells, in particular activated CD8+T cells, a reduction in the number of exhausted antigen-specific CD8+T cells, or an increase in the number of circulating functional (i.e. non-exhausted) antigen-specific CD8+T cells.

[0550] According to the invention, triple combination therapy may be employed to increase the therapeutic effect of the PD-1 pathway inhibitor and / or the chemotherapy agent, compared with (a) the effect of the PD-1 pathway inhibitor and the chemotherapy agent as monotherapies or (b) a combination therapy consisting of the PD-1 pathway inhibitor and the chemotherapy agent.

[0551] Triple combination therapy may also be employed to decrease the doses of the individual components in the combination while preventing or further reducing the risk of unwanted or harmful side effects of the individual components.

[0552] In an embodiment, the dosage of the PD-1 pathway inhibitor and / or chemotherapy agent is less than a typically prescribed dose for monotherapy with the PD-1 pathway inhibitor or chemotherapy agent, or below a typically prescribed dose for a combination therapy consisting of the PD-1 pathway inhibitor and chemotherapy agent, for example, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, or about 5%, of the typically prescribed dose of the PD-1 pathway inhibitor and / or chemotherapy agent.

[0553] In another embodiment, the dosage of the PD-1 pathway inhibitor and / or chemotherapy agent is less than a typically prescribed dose for monotherapy with the PD-1 pathway inhibitor or chemotherapy agent, or below a typically prescribed dose for a combination therapy consisting of the PD-1 pathway inhibitor and chemotherapy agent, for example, from about 25% to about 75%, or from about 1 % to about 50%, or from about 0.5% to about 25%, of the typically prescribed dose of the PD-1 pathway inhibitor and / or chemotherapy agent.

[0554] In yet another embodiment, the dosage of the PD-1 pathway inhibitor and the chemotherapy agent is in accordance with the prescribed standard of care.

[0555] Suitably, the course of triple combination therapy takes place over, for example, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months or about 12 months. Similarly, the course of combination therapy takes place over, for example, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks or about 52 weeks.

[0556] In one embodiment, the course of triple combination therapy takes place over about 12 weeks (for example, 4 cycles of 3 weeks).

[0557] In another embodiment, the course of triple combination therapy takes place over about 16 weeks.

[0558] In yet another embodiment, the course of triple combination therapy takes place over about 24 weeks.

[0559] Suitably, after the subject is treated with the triple combination therapy, the subject moves to a maintenance phase.

[0560] In an embodiment, the maintenance phase comprises a LAG-3 protein or derivative thereof, a PD-1 pathway inhibitor, and a chemotherapy agent, wherein the chemotherapy agent is a single chemotherapy agent.

[0561] Suitably, for non-sqamous NSCLC, the maintenance phase comprises a LAG-3 protein or derivative thereof, a PD-1 pathway inhibitor, and pemetrexed.

[0562] In another embodiment, the maintenance phase comprises a LAG-3 protein or derivative thereof and a PD-1 pathway inhibitor.

[0563] Suitably, for sqamous NSCLC, the maintenance phase comprises a LAG-3 protein or derivative thereof, and a PD-1 pathway inhibitor.

[0564] Suitably, the maintenance phase takes place over about 16 weeks to about 52 weeks, such as about 20 weeks, about 22 weeks, about 24 weeks, about 26 weeks, about 28 weeks, about 30 weeks, about 32 weeks, about 34 weeks, about 36 weeks, about 38 weeks, or about 40 weeks.

[0565] In an embodiment, the maintenance phase takes place over about 4 months to about 12 months, such as about 6 months. In another embodiment, the subject is treated with the triple combination therapy for up to 24 weeks and then proceeds to a maintenance phase for a total treatment duration of up to 52 weeks.

[0566] In one particular embodiment, the total treatment duration including the triple combination therapy and the maintenance phase is up to about 105 weeks (35 cycles of three weeks) (~ 2 years).

[0567] In another embodiment, the total duration of therapy including the triple combination therapy and maintenance phase is about 12 months, about 15 months, about 18 months, about 21 months, or about 24 months.

[0568] Alternatively, after the subject is treated with the triple combination therapy, the subject moves to a chemotherapy-free maintenance phase comprising the LAG-3 protein or derivative thereof and the PD-1 pathway inhibitor.

[0569] The chemotherapy-free maintenance phase may be, for example, for about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, about 21 months, or about 24 months.

[0570] In one particular embodiment, the subject is treated with the triple combination therapy for up to about 12 weeks (4 cycles of three weeks) and then proceeds to a maintenance phase of up to about 93 weeks (31 cycles of three weeks) for total treatment duration of up to about 105 weeks (35 cycles of three weeks) (~ 2 years in total).

[0571] In another particular embodiment, the subject is treated with the triple combination therapy for at least 12 weeks (4 cycles of three weeks) up to about 24 weeks (8 cycles of three weeks) and then proceeds to a maintenance phase of up to about 81 weeks (27 cycles of three weeks) for total treatment duration of up to about 105 weeks (35 cycles of three weeks) (~ 2 years in total).

[0572] For example, the subject may be treated with the triple combination therapy, for example for at least 12 weeks up to 24 weeks, wherein the triple combination therapy comprises administration of:

[0573] a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, for example administered every two weeks; a programmed cell death protein-1 (PD-1) pathway inhibitor, for example administered every three weeks; and

[0574] two chemotherapy agents, for example administered every three weeks, preferably wherein the two chemotherapy agents are pemetrexed and a platinum chemotherapy agent, or a taxane and a platinum chemotherapy agent.

[0575] Optionally the two chemotherapy agents are pemetrexed and a platinum chemotherapy agent, or a taxane and a platinum chemotherapy agent.

[0576] Optionally the two chemotherapy agents are pemetrexed and cisplatin, pemetrexed and carboplatin, paclitaxel and carboplatin, or nab-paclitaxel and carboplatin.

[0577] Optionally, for treatment of non-squamous NSCLC, the two chemotherapy agents are pemetrexed and cisplatin, or pemetrexed and carboplatin.

[0578] Optionally, for treatment of squamous NSCLC, the two chemotherapy agents are paclitaxel and carboplatin, or nab-paclitaxel and carboplatin.

[0579] Thereafter the subject proceeds to a maintenance therapy, for example for up to 93 weeks, wherein the maintenance therapy comprises administration of:

[0580] the LAG-3 protein, or derivative, for example every two or three weeks; and

[0581] the PD-1 pathway inhibitor and optionally a single chemotherapy agent, for example every three weeks.

[0582] Optionally the single chemotherapy agent is pemetrexed.

[0583] Optionally, for treatment of non-squamous NSCLC, the maintenance therapy comprises administration of:

[0584] the LAG-3 protein, or derivative, for example every two or three weeks; and

[0585] the PD-1 pathway inhibitor and a single chemotherapy agent (preferably pemetrexed), for example every three weeks.

[0586] Optionally, for treatment of squamous NSCLC, the maintenance therapy comprises administration of: the LAG-3 protein, or derivative, for example every two or three weeks; and

[0587] the PD-1 pathway inhibitor, for example every three weeks.

[0588] Optionally the LAG-3 protein derivative is eftilagimod alfa, and the PD-1 pathway inhibitor is pembrolizumab.

[0589] Optionally the two chemotherapy agents are pemetrexed and carboplatin, the LAG-3 protein derivative is eftilagimod alfa, and the PD-1 pathway inhibitor is pembrolizumab, and the single chemotherapy agent is pemetrexed.

[0590] Combined Preparations

[0591] In one embodiment, the LAG-3 protein or derivative thereof, the PD-1 pathway inhibitor and the chemotherapy agent are packaged separately. That is, in this embodiment, the LAG-3 protein or derivative thereof, the PD-1 pathway inhibitor, and the chemotherapy agent are separate unit dosage forms, which would typically (but not necessarily) be sourced from different suppliers, and then used in the methods of the invention.

[0592] In another embodiment, the LAG-3 protein or derivative thereof, the PD-1 pathway inhibitor and the chemotherapy agent are in the form of a combined preparation.

[0593] The three components of the “combined preparation” may be present:

[0594] (i) in one combined unit dosage form known as a fixed dose combination (FDC), or

[0595] (ii) as a first unit dosage form of component (a); a separate, second unit dosage form of component (b); and a separate, third unit dosage form of component (c) and where the three separate dosage forms are packaged together known as a kit-of-parts.

[0596] The ratio of the total amounts of the combination components (a), (b) and (c) to be administered in the combined preparation can be varied, for example, in order to cope with the needs of a patient sub-population to be treated, or the needs of the patient, which can be due, for example, to the particular disease, age, sex, or body weight of the patient.

[0597] That is, the combined preparation according to the invention may take the form of a pharmaceutical composition comprising the LAG-3 protein or derivative thereof, the PD-1 pathway inhibitor and the chemotherapy agent or, alternatively, as a kit-of-parts comprising the LAG-3 protein or derivative thereof, the PD-1 pathway inhibitor, and the chemotherapy agent as separate components, but packaged together.

[0598] Thus, in an embodiment, the invention provide a combined preparation, comprising:

[0599] (a) a LAG-3 protein, or derivative thereof that is able to bind to MHC class II molecules, (b) a PD-1 pathway inhibitor, and

[0600] (c) a chemotherapy agent.

[0601] The combined preparation may comprise a plurality of doses of the LAG-3 protein or derivative thereof, a plurality of doses of the PD-1 pathway inhibitor, and / or a plurality of doses of the chemotherapy agent.

[0602] In another embodiment, one of the three components is packaged separately and the other two components are packaged together as a combined preparation. The two components of the combined preparation may be present as (i) a FDC, or (ii) a kit-of-parts.

[0603] In one embodiment, the LAG-3 protein or derivative thereof is packaged separately and the the PD-1 pathway inhibitor and the chemotherapy agent are a combined preparation.

[0604] Pharmaceutical Compositions

[0605] The LAG-3 protein or derivative thereof, the PD-1 pathway inhibitor, and the chemotherapy agent are formulated with a pharmaceutically acceptable carrier, excipient, or diluent to provide a pharmaceutical composition. Typically these will be formulated as separate pharmaceutical compositions, although in the case of a fixed dose combination, the LAG-3 protein or derivative thereof, the PD-1 pathway inhibitor and the chemotherapy agent will be formulated together, along with a pharmaceutically acceptable carrier, excipient, or diluent.

[0606] The separate pharmaceutical compositions may be packaged together in the form of a kit-of-parts or sourced separately for use in the methods of the invention.

[0607] In general, the LAG-3 protein or derivative thereof, the PD-1 pathway inhibitor, and the chemotherapy agent may be administered by known means, in any suitable pharmaceutical composition, by any suitable route.

[0608] Suitable pharmaceutical compositions may be prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the relevant texts and literature, for example, in Remington: The Science and Practice of Pharmacy (Easton, Pa.: Mack Publishing Co., 1995). It is especially advantageous to formulate compositions of the invention in a unit dosage form for ease of administration and uniformity of dosage. The term “unit dosage form” as used herein refers to physically discrete units suited as unitary dosages for the individuals to be treated. That is, the compositions are formulated into discrete dosage units each containing a predetermined “unit dosage” quantity of an active agent calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier, excipient or diluent. The specifications of unit dosage forms of the invention are dependent on the unique characteristics of the active agent to be delivered. Dosages can further be determined by reference to the usual dose and manner of administration of the ingredients. It should be noted that, in some cases, two or more individual dosage units in combination provide a therapeutically effective amount of the active agent.

[0609] Preparations according to the invention for parenteral administration include sterile aqueous and non-aqueous solutions, suspensions, and emulsions. Injectable aqueous solutions contain the active agent in water-soluble form. Examples of non-aqueous solvents or vehicles include fatty oils, such as olive oil and corn oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, low molecular weight alcohols such as propylene glycol, synthetic hydrophilic polymers such as polyethylene glycol, liposomes, and the like. Parenteral formulations may also contain adjuvants such as solubilizers, preservatives, wetting agents, emulsifiers, dispersants, and stabilizers, and aqueous suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, and dextran. Injectable formulations may be rendered sterile by incorporation of a sterilizing agent, filtration through a bacteria-retaining filter, irradiation, or heat. They can also be manufactured using a sterile injectable medium. The active agent may also be in dried, e.g., lyophilized, form that may be rehydrated with a suitable vehicle immediately prior to administration via injection.

[0610] Preferably, there is at least one beneficial effect from the triple combination therapy, for example, advantageous therapeutic effects (e.g. overall response rate, progression-free survival, overall survival, disease control rate, depth of response or duration of response), fewer side effects, less toxicity, or improved QoL (quality of life) - compared with an effective dosage of one or two of components (a), (b) and (c).

[0611] Other aspects of the invention are defined in the numbered paragraphs below:

[0612] 1. Use of (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, (b) a programmed cell death protein-1 (PD-1) pathway inhibitor and (c) a chemotherapy agent, in the manufacture of a medicament for the prevention, treatment, or amelioration of a cancer in a subject.

[0613] Use of a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, in the manufacture of a medicament for the prevention, treatment, or amelioration of a cancer in a subject, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

[0614] Use according to numbered paragraph 1 or 2, wherein the derivative of LAG-3 protein comprises an amino acid sequence that has at least 70% amino acid identity with domain D1, and optionally domain D2, of LAG-3 protein, preferably human LAG-3 protein.

[0615] Use according to any preceding numbered paragraph, wherein the derivative of LAG-3 protein comprises an amino acid sequence that has at least 70% amino acid identity with domains D1, D2 and D3, and optionally domain D4, of LAG-3 protein, preferably human LAG-3 protein.

[0616] Use according to any preceding numbered paragraph, wherein the cancer is selected from the group consisting of breast cancer, skin cancer, lung cancer (NSCLC or SCLC), ovarian cancer, renal cancer (for example renal cell carcinoma), colon cancer, rectal cancer, colorectal cancer, anal cancer, small intestine cancer, gastrointestinal stromal tumours, gastric cancer, esophageal cancer, pancreatic cancer, bladder cancer, urothelial cancer, liver cancer, melanoma (for example, metastatic malignant melanoma), prostate cancer (for example hormone refractory prostate adenocarcinoma), head and neck cancer (for example, head and neck squamous cell carcinoma), cervical cancer, endometrial cancer, uterine cancer, thyroid cancer, glioblastoma, glioma, leukemia, lymphoma (for example, a B cell lymphoma or Hodgkin lymphoma), adrenal gland cancer, AIDS-associated cancer, alveolar soft part sarcoma, astrocytic tumor, bone cancer, brain and spinal cord cancer, metastatic brain tumor, carotid body tumor, chondrosarcoma, chordoma, cutaneous benign fibrous histiocytoma, desmoplastic small round cell tumor, ependymoma, Ewing's tumor, extraskeletal myxoid chondrosarcoma, fibrogenesis imperfecta ossium, fibrous dysplasia of the bone, gallbladder or bile duct cancer, gestational trophoblastic disease, germ cell tumor, haematological malignancy, hepatocellular carcinoma, islet cell tumor, Kaposi's sarcoma, kidney cancer, lipoma / benign lipomatous tumor, liposarcoma / malignant lipomatous tumor, medulloblastoma, meningioma, Merkel cell carcinoma, multiple endocrine neoplasia, multiple myeloma, myelodysplasia syndrome, neuroblastoma, neuroendocrine tumor, papillary thyroid carcinoma, parathyroid tumor, pediatric cancer, peripheral nerve sheath tumor, phaeochromocytoma, pituitary tumor, prostate cancer, posterior uveal melanoma, rare hematologic disorder, rhabdoid tumor, rhabdomysarcoma, sarcoma, soft-tissue sarcoma, squamous cell cancer, synovial sarcoma, mesothelioma, cutaneous squamous cell carcinoma, testicular cancer, thymic carcinoma, thymoma, and thyroid metastatic cancer.

[0617] 6. Use according to any proceeding numbered paragraph, wherein the cancer is a lung cancer, preferably NSCLC.

[0618] 7. Use according to any preceding numbered paragraph, wherein the PD-1 pathway inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, atezolizumab, avelumab, and durvalumab.

[0619] 8. Use according to any preceding numbered paragraph, wherein the PD-1 pathway inhibitor is pembrolizumab.

[0620] 9. Use according to any preceding numbered paragraph, wherein the chemotherapy agent is a combination of two or more chemotherapy agents.

[0621] 10. Use according to any preceding numbered paragraph, wherein the LAG-3 derivative is IMP321, the PD-1 pathway inhibitor is pembrolizumab, the chemotherapy agent comprises a combination of pemetrexed and carboplatin, and the cancer is NSCLC, preferably non-squamous NSCLC.

[0622] 11. Use according to any preceding numbered paragraph, wherein the PD-L1 expression level of the subject is < 50%.

[0623] 12. Use according to numbered paragraph 11 , wherein the PD-L1 expression level of the subject is 1-49%.

[0624] 13. Use according to numbered paragraph 11, wherein the PD-L1 expression level of the subject is < 1%. 14. Use according to any preceding numbered paragraph, wherein the subject is a human. Embodiments of the invention are now described, by way of example only, with reference to the accompanying drawings.

[0625] Example 1 - Active immunotherapy IMP321 in combined therapy with a PD-1 pathway inhibitor and a chemotherapy agent (trial INSIGHT, EudraCT No. 2016-002309-20)

[0626] A clinical study was carried out to investigate the safety and efficacy of the active immunotherapy IMP321 in combination with a PD-1 pathway inhibitor and a chemotherapy agent in patients with various solid tumours including NSCLC. It was planned to enrol 20 patients.

[0627] In particular, patients with non-squamous 1stline metastatic NSCLC were treated with biweekly IMP321 (30 mg s.c.) in parallel with a standard of care combination of pemetrexed (500 mg / m2), carboplatin (ALIC5) and pembrolizumab (200 mg) administered every three weeks, for up to 24 weeks. Thereafter, patients moved to maintenance therapy for a total study duration of up to 52 weeks.

[0628] The maintenance therapy generally consisted of IMP321 (30 mg s.c.) administered either every 2 weeks or every 3 weeks in parallel with pemetrexed (500 mg / m2) and pembrolizumab (200 mg) administered every 3 weeks. Maintenance therapy may alternatively consist of therapy with IMP321 (30 mg) and pembrolizumab (200 mg) only (chemotherapy-free).

[0629] Patients stayed on the study until disease progression, unacceptable toxicity, completion of the maintenance phase or discontinuation for any other reason. Treatment beyond disease progression is an option in the presence of a clinical benefit.

[0630] After the maintenance phase, patients were followed up for 12 months or until disease progression, whichever is earlier.

[0631] Additional radiation therapy is permitted. In case of bone metastases, the administration of bisphosphonates is permitted. Irradiation on target lesions is not allowed.

[0632] As of the end of May 2022, 11 / 20 non-squamous 1stline metastatic NSCLC patients had been enrolled into the trial, thus far. In 8 evaluable patients, there were 4 confirmed partial responses, 3 patients with stable disease, and only 1 patient with disease progression (interim disease control rate in evaluable patients: 87.5%). No additional toxicity was observed from treatment with the triple combination therapy compared to treatment with a combination of pembrolizumab and chemotherapy in historical trials. No adverse events leading to discontinuation from the trial were observed, thus far.

[0633] Single patient case study:

[0634] Bipulmonary metastatic lung carcinoma originating from the right lower lobe

[0635] ECOG = 1

[0636] Adenocarcinoma

[0637] Thyroid transcription factor (TTF) negative

[0638] PD-L1: TPS = 0 (IC 0%)

[0639] No driver mutations

[0640] pT2a, pNO, RO

[0641] Malignancy grade G2

[0642] Ipsilateral pleural dissemination (pM1a)

[0643] Histological confirmation of pulmonary metastasis contralateral (left upper lobe of lung)

[0644] The patient with a more limited prognosis was treated with the triple combination therapy and has since moved to a maintenance phase of therapy with a combination of IMP321 and pembrolizumab only. The patient has stable disease and remains under therapy with an ECOG status = 1.

[0645] CT scans of the thorax region of the patient have shown shrinkage of target tumour lesions in the course of therapy. An example of the shrinkage of a target lesion is shown in Figure 2 where the lesion shrunk from 22.62 mm in diameter to “evaluable but not measurable”. Similarly, Figure 3 illustrates the shrinkage of another target lesion: this one from 35.92 mm in diameter to 25.70 mm. Example 2 - Active immunotherapy IMP321 in combined therapy with a PD-1 pathway inhibitor and a chemotherapy agent (Trial INSIGHT, EudraCT number: 2016-002309-20) -excellent survival data in Non-Small Cell Lung Cancer (NSCLC)

[0646] This example provides an update to the results for the clinical study described in Example 1. The update is based on data available as of 15 October 2024 for 21 patients.

[0647] This trial is a multi-centre study being run as the third arm of the ongoing Phase I INSIGHT trial described in Example 1. The study is evaluating a triple combination therapy in front line non-small cell lung cancer (NSCLC) patients consisting of eftilagimod alpha (efti) administered subcutaneously in conjunction with an existing approved standard-of-care combination of anti-PD-1 therapy (pembrolizumab) and doublet chemotherapy (carboplatin and pemetrexed) delivered intravenously. The trial assess the safety, tolerability, and initial efficacy of the combination.

[0648] The use of immune checkpoint inhibitor (ICI) agents in the form of checkpoint inhibitors as monotherapies has led to great strides in the management of many diseases. However, durable responses have been seen in only -20% of treated patients with most solid malignancies. Eftilagimod alpha plus ICI therapy was assessed to be safe and well tolerated with no new safety signals reported so far in clinical trials. Also, first signals of therapeutic efficacy were detectable. Combination of an APC activator, like eftilagimod alpha, with ICI may increase efficacy and is fundamentally different from the currently most applied approach utilizing two immune checkpoint inhibitory (ICI) antibodies (i.e., anti-LAG-3 plus anti-PD-1 monoclonal antibodies).

[0649] Apoptotic cell death induced by tumor destruction, for example by chemotherapy, leads to a beneficial immune-adjuvant effect in patients. Eftilagimod alpha is a recombinant soluble LAG-3lg fusion protein that binds to MHC class II molecules and mediates antigen-presenting cell (APC) activation followed by CD8 T-cell activation. Eftilagimod alpha given after chemotherapy or immunotherapy / targeted therapy induces APCs to mature and transport apoptotic tumor cell antigenic debris to the lymph nodes for presentation to the T cells. The activation of the dendritic cell network and T cell recruitment at the tumor site with eftilagimod alpha may lead to stronger anti-tumor CD8 T cell responses than observed with immunotherapy alone. The combination of chemotherapy with active immunotherapy (chemo-immunotherapy) induces amplification of natural pre-existing T-cell responses specific for any known or unknown tumor antigen and the recruitment and amplification of new tumor-specific T-cell responses resulting from the use of cytotoxic drugs. Patients with late stage carcinomas and with an unmet medical need receiving the current standard of care have the chance to benefit from the adjunctive therapy of eftilagimod alpha.

[0650] In the trial, patients are treated with the Standard-of-Care (SoC) chemotherapy and / or immunotherapy / targeted therapy for their tumor entity along with subcutaneous injections of eftilagimod alpha. Patients with solid tumors treated with SoC chemotherapy and / or immunotherapy / targeted therapy in first or second line (additional radiation therapy permitted) receive concomitant subcutaneous (s.c.) injections with eftilagimod alpha (30 mg) injected on a biweekly schedule in parallel to the chemotherapy and / or immunotherapy / targeted therapy for up to 24 weeks (induction phase).

[0651] Patients proceed to a maintenance phase in which eftilagimod alpha (30 mg) is injected s.c. every 2 or 3 weeks (dependent on the maintenance schedule of the SoC) for a total study treatment duration of up to 52 weeks (combination with Standard-of-Care chemotherapy and / or immunotherapy / targeted therapy is allowed).

[0652] A patient stays on treatment until disease progression, unacceptable toxicity, completion of the maintenance phase or discontinuation for any other reason. For SoC regimen in which treatment beyond disease progression is an option (e.g. regimen including immune checkpoint inhibitors), treatment beyond radiologic progression is also possible within this trial in the presence of clinical benefit.

[0653] After the maintenance phase, patients are followed-up for 12 months or until disease progression, whichever occurs first. Individual survival follow-up will be performed until the end of the study.

[0654] Additional radiation therapy is permitted. In case of bone metastases, the administration of bisphosphonates is permitted. Irradiation on target lesions is NOT allowed.

[0655] Efficacy endpoints:

[0656] • Objective response according to RECIST v1.1

[0657] • Time to and duration of response according to RECIST v1.1

[0658] • Progression-free survival according to RECIST v1.1

[0659] • Overall survival

[0660] • Biomarker analyses and possible links to antitumor activity RECIST:

[0661] For patients with measurable disease, clinical response evaluation is based on RECIST criteria version 1.1 (Eisenhauer et al., 2009):

[0662] • CR (complete response): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

[0663] • PR (partial response): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

[0664] • SD (stable disease): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

[0665] • PD (progressive disease): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).

[0666] EISENHAUER, E. A., THERASSE, P., BOGAERTS, J., et al. 2009. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer, 45, 228-47.

[0667] Eftilagimod alpha (Efti, IMP321):

[0668] The eftilagimod alpha drug product is a single-use, preservative-free, sterile buffered solution of eftilagimod alpha at a concentration of 25 ± 1.2 mg / mL. Each 2 ml glass vial is filled with 1.36 mL drug product to achieve an extractable volume of 1.2 ml. The vials have to be stored at 2 to 8°C and protected from light.

[0669] Subcutaneous (s.c.) injections of eftilagimod alpha:

[0670] The route of administration for eftilagimod alpha is subcutaneous injection (single anatomical site) in the anterior face of the thigh. The location of the injection site should be rotated with each injection and alternating left and right thighs (if, for example, the first injection is on the left thigh, the subsequent one will be on the right and so on). The injection should be performed slowly in order to avoid discomfort at the site of injection.

[0671] Frequency of administration of eftilagimod alpha is dependent on SoC therapy cycles: In case of weekly therapy cycles eftilagimod alpha administration is performed on the day of each second therapy administration (biweekly); in case of biweekly therapy cycles eftilagimod alpha administration is performed on the day of each therapy administration (biweekly); in case of three-week therapy cycles eftilagimod alpha is injected in a biweekly schedule in parallel to the chemotherapy and / or immunotherapy / targeted therapy administration for up to a maximum of 24 weeks; in case of continuous application of SoC therapy eftilagimod alpha administration is performed biweekly.

[0672] Results

[0673] The survival data from the triple combination therapy in patients irrespective of PD-L1 expression with a minimum follow-up of 22 months (N=21) at data cut-off (15 October 2024) shows:

[0674]

[0675] These results compare favourably to the 22.0-month median OS, 9.0-month median PFS, and 24-month OS rate of 45.5% from a registrational trial of anti-PD-1 and doublet chemotherapy in non-squamous 1L NSCLC regardless of PD-L1 expression.1Notably, this trial has just -10% of patients with high PD-L1 expression (-19% of the 21 patients with mature survival data have high PD-L1 expression), who typically respond better to anti-PD-1 therapy, versus -32% in the registrational trial of anti-PD-1 and doublet chemotherapy.

[0676] Data from all evaluable patients to date (N=40) demonstrates significant improvement of Overall Response Rate (ORR) according to RECIST 1.1 across all levels of PD-L1 expression compared to historical control2:

[0677] • 75.0% ORR versus 62.1% ORR in patients with high PD-L1 expression (TPS >50%) • 58.8% ORR versus 49.2% ORR in patients with low PD-L1 expression (TPS 1-49%) • 47.4% ORR versus 32.3% ORR in patients with negative PD-L1 expression (TPS <1%)

[0678] In this all-comer PD-L1 trial, the 55.0% ORR and 87.5% Disease Control Rate (DCR) are from the following breakdown of patients by PD-L1 expression: TPS >50% (N=4), TPS 1-49% (N=17), and TPS <1% (N=19). As compared to the general 1L NSCLC patient population of which each of these PD-L1 levels represents roughly one-third, INSIGHT is biased towards low and negative PD-L1 (TPS <50%) patients who are typically less responsive to anti-PD-1 therapy. In these patients with low and negative PD-L1 expression (N=36), the triple combination achieved a 52.8% ORR and 86.1% DCR. Of note, all 19 patients in the expansion cohort have TPS <50% and several with stable disease have potential to become responders.

[0679] Safety continues to be favourable for efti in combination with pembrolizumab and chemotherapy, with no new safety signals.

[0680] Conclusions

[0681] This trial evaluates eftilagimod alpha (efti) in combination with a PD-1 pathway inhibitor (pembrolizumab, KEYTRUDA®) and chemotherapy (the most widely used immunotherapychemo combination today). The results provide positive data for first-line treatment of metastatic non-squamous non-small cell lung cancer (1L NSCLC) patients. In particular:

[0682] • Mature data in patients with a minimum follow-up of 22 months (N=21) shows excellent results, well above historical controls and exceeding expectations

[0683] • Median Overall Survival is 32.9 months, with median Progression-Free Survival reaching 12.7 months, and a 24-month Overall Survival rate of 81.0%

[0684] • Data from all evaluable patients to date (N=40) demonstrates significant improvement of Overall Response Rate compared to historical controls

[0685] • Safety continues to be favourable with no new safety signals

[0686] The strength of these mature survival results coupled with a favourable safety profile in first-line treatment of patients with non-squamous NSCLC, the vast majority of whom have negative or low PD-L1 expression, is very encouraging. This data provides evidence for a beneficial effect from the addition of efti, a unique MHC Class II agonist, to the standard-of-care combination of pembrolizumab and chemotherapy which has revolutionised the treatment landscape in lung cancer.

[0687] 7, 2Journal of Clinical Oncology 202038:14, 1505-1517, Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer

[0688]

[0689] combination

[0690]

[0691] This example describes a protocol for treatment of a cancer using a triple combination therapy of the invention.

[0692] In an induction phase, a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, is administered to a patient every two weeks, and a PD-1 pathway inhibitor, and a chemotherapy agent are administered every three weeks, preferably for up to 12 weeks (4 cycles of three weeks), or preferably for up to 24 weeks (8 cycles of three weeks).

[0693] In a maintenance phase the patient is administered with the LAG-3 protein, or derivative, every two or three weeks, and the PD-1 pathway inhibitor and a chemotherapy agent every three weeks, preferably for up to 93 weeks (~ 2 years total treatment duration).

[0694] Optionally the chemotherapy agent for the induction phase is two different chemotherapy agents, for example pemetrexed and a platinum chemotherapy agent (such as pemetrexed and carboplatin, or pemetrexed and cisplatin), or a taxane and a platinum chemotherapy agent (such as paclitaxel and carboplatin, or nab-paclitaxel and carboplatin).

[0695] Optionally the chemotherapy agent for the maintenance phase is a single chemotherapy agent, for example pemetrexed.

[0696] In an alternative maintenance phase the patient is administered with the LAG-3 protein, or derivative, every two or three weeks, and the PD-1 pathway inhibitor is administered without a chemotherapy agent (i.e. a chemotherapy-free maintenance phase) every three weeks, preferably for up to 93 weeks (~ 2 years total treatment duration).

[0697] More detailed examples of this are set out below:

[0698] Efti + SoC (pembro + chemo):

[0699] 1)

[0700] Efti:

[0701] 30 mg of eftilagimod alpha is administered to a subject suffering from a cancer once every two weeks subcutaneously for the first 6 months, and thereafter once every three weeks for up to 24 months in total; and

[0702] SoC: • Pembrolizumab - 200 mg pembrolizumab is administered every 3 weeks intravenously for up to approximately 24 months; and

[0703] • Platinum doublet chemotherapy:

[0704] o Carboplatin AUC 5 or 6 in combination with paclitaxel 175 mg / m2or 200mg / m2every three weeks, or

[0705] o Cisplatin 75mg / m2or carboplatin AUC 5 or 6 in combination with pemetrexed 500mg / m2. After the initial 4 cycles, 500mg / m2pemetrexed is administered every 3 weeks.

[0706] 2)

[0707] Efti:

[0708] 30 mg of eftilagimod alpha is administered to a subject suffering from a cancer once every two weeks subcutaneously for the first 6 months, and thereafter once every three weeks for up to approximately 24 months in total; and

[0709] SoC:

[0710] • Pembrolizumab - 200 mg pembrolizumab is administered every 3 weeks intravenously for up to approximately 24 months; and

[0711] • Platinum doublet chemotherapy:

[0712] o Carboplatin AUC 5 or 6 in combination with paclitaxel 175 mg / m2or 200mg / m2, or nab-paclitaxel 100 mg / m2, every three weeks for at least 4 cycles, or

[0713] o Cisplatin 75mg / m2or carboplatin AUC 5 or 6 in combination with pemetrexed 500mg / m2every three weeks for at least an initial 4 cycles. After the at least initial 4 cycles, 500mg / m2pemetrexed is administered every 3 weeks.

[0714] 3)

[0715] Efti:

[0716] 30 mg of eftilagimod alpha is administered to a subject suffering from a cancer once every two weeks subcutaneously in parallel with:

[0717] SoC:

[0718] • pemetrexed (500 mg / m2);

[0719] • carboplatin (AUC5); and

[0720] • pembrolizumab (200 mg)

[0721] administered intravenously every 3 weeks, for example for 12 weeks up to 24 weeks. Thereafter, the subject is administered maintenance therapy, for example for a total duration of up to 52 weeks or up to 105 weeks, comprising:

[0722] 30 mg of eftilagimod alpha administered either every 2 weeks or every 3 weeks in parallel with:

[0723] pembrolizumab (200 mg) alone, or a combination of:

[0724] • pemetrexed (500 mg / m2); and

[0725] • pembrolizumab (200 mg);

[0726] administered intravenously every 3 weeks.

[0727] Detailed SoC examples:

[0728] i) During the first four 3-week cycles, either pembrolizumab 200 mg is administered intravenously on day 1 of each cycle with carboplatin (area under the concentration-time curve, 6 mg / mL / min) and either paclitaxel (200 mg / m2on day 1 of each cycle) or nab-paclitaxel (100 mg / m2on day 1, 8, and 15 of each cycle). After the first four cycles, patients continue to receive pembrolizumab every 3 weeks, with treatment continuing until a total of 35 cycles of pembrolizumab are completed or if any of the following occurr: (1) documented disease progression, (2) withdrawal of consent, (2) unacceptable toxicity, or (2) investigator decision to withdraw the patient (Paz-Ares, et al., A Randomized, Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407, Journal of Thoracic Oncology Vol. 15 No. 10: 1657-69); or

[0729] ii) Pembrolizumab 200 mg is administered every 3 weeks (for up to 35 cycles, ~2 years) plus four cycles of pemetrexed (500 mg / m2) and investigators’ choice of cisplatin (75 mg / m2) or carboplatin (area under the curve 5 mg min / ml) every 3 weeks, followed by pemetrexed until progression (Rodriguez-Abreu et al., Annals of Oncology, Volume 32, Issue 7, 2021, 881-895, Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189). 4 - Treatment of metastatic non-; non-small cell

[0730]

[0731] cancer

[0732]

[0733] using triple combination therapy (Trial INSIGHT, EudraCT number: 2016-002309-20; NCT03252938; IKF-S614)

[0734] This example provides an update to the results for the clinical study described in Examples 1 and 2. The update is based on data available as of September 2025.

[0735] This example describes treatment of metastatic NSCLC patients using a triple combination therapy according to an embodiment of the invention - eftilagimod alpha (soluble LAG-3 protein) combined with 1st line chemo-immunotherapy in metastatic non-squamous non-small cell lung cancer (NSCLC) - Updates from INSIGHT-003 (IKF-s614). Initial overall response rate (ORR) and disease control rate (DCR) data are presented from the full cohort of patients (51 evaluable patients) - see Table 3 below.

[0736]

[0737] Stratum C of the INSIGHT multicenter platform trial evaluates eftilagimod alpha (efti) combined with standard of care (SOC) 1st line chemo-immunotherapy (CIT) in metastatic non-squamous (NSQ) NSCLC patients (pts). Efti is an MHC class II agonist (soluble LAG-3 protein) activating antigen-presenting (APCs) cells followed by T-cell (CD4 / CD8) activation. Efti aims to enhance efficacy of IC. We hereby report the initial results from the full cohort of 54 pts.

[0738] Figure 10 shows the mechanism of action of efti. Efti is a soluble LAG-3 protein (LAG-3 domains fused to human IgG backbone). Activating APCs with efti leads to a broader immune response, including an increase in activated T cells (CD4 / CD8) to fight cancer.

[0739] Methods

[0740] Patients with 1st line advanced or metastatic NSCLC adenocarcinomas (non-squamous) receive carboplatin AUC5 I pemetrexed 500 mg / m21 pembrolizumab 200 mg q3w 4 cycles followed by maintenance pembrolizumab q3w and optional pemetrexed 500 mg / m2q3w combined with s.c. efti (30 mg) (q2w for 24 weeks; thereafter q3w till week 52; SOC thereafter). Imaging: q8w. Primary endpoint: feasibility (safety I tolerability). Secondary endpoints include ORR*, PFS* and OS.

[0741] * Per RECIST 1.1.

[0742] Figure 11 shows the study design. Results

[0743] From August 2021 until December 2024, 54 patients were enrolled and received treatment. Data cut-off was September 2025.

[0744] Baseline characteristics are reported in Table 1. Overview of Adverse- Events is shown in Table 2. Efficacy results for the evaluable population (pts with >1 evaluable post-baseline scan; N=51) are presented in table 3.

[0745] Table 1: Baseline Characteristics

[0746] <

[0747] >

[0748]

[0749] Table 2: Safety Overview

[0750]

[0751] AE: Adverse Event

[0752] TRAE: Treatment Related Adverse Event

[0753] *No Grade 5 AE was considered treatment-related

[0754] Table 3: Efficacy Overview by PD-L1 status

[0755] < > <

[0756]

[0757] DCR* % | 90.2 | 86.4 | 92.0 | 100.0 |_89.4 |

[0758] * Per RECIST 1.1.

[0759] Figure 12 shows a case study of a patient with PR

[0760] • TTF1 pos. Adeno-Ca, G3

[0761] • PD-L1 TPS 0%, no actionable genetic alterations

[0762] • ECOG PS 1

[0763] • cT1c pN2 cM1c (PLE, LYM, OSS, HEP, PUL), stage IVb

[0764] • Partial Response after treatment cycle 3, maintained until planned end of treatment (week 52)

[0765] Figure 13 shows the best change in tumor size by RECIST 1.1. 44 of 51 patients (86.3%) experienced tumor shrinkage.

[0766] Summary & Conclusion

[0767] >■ Eftilagimod alpha combined with SOC (carboplatin / pemetrexed / pembrolizumab) in NSQ 1st line NSCLC led to encouraging ORR (unconf. 62.7% & conf. 58.8%) overall.

[0768] >■ More importantly ORR was comparable among TPS strata with conf. ORR of 54.5% on TPS < 1%; 60% in TPS 1-49% and 75% in TPS > 50%, respectively.

[0769] >■ Efti does not increase toxicity of the chemo-immunotherapy SOC.

[0770] >■ This combination is feasible and safe to administer, showing very encouraging ORR especially in pts with TPS score <1% and TPS 1-49%, where the unmet medical need is high. Phase 3 study TACTI-004 is underway (NCT06726265). les of treatments for NSCLC with non-

[0771]

[0772] and

[0773]

[0774] Examples of different treatment schedules according to embodiments of the invention for NSCLC patients with non-squamous and squamous histology are described below.

[0775] Non-squamous NSCLC:

[0776] Cisplatin (for example, 75 mg / m2) or carboplatin (for example, AUC 5 or 6) + pemetrexed (for example, 500 mg / m2) Q3W for 3 months, then maintenance pemetrexed Q3W.

[0777] Pembrolizumab (for example, 200 mg), for example administered as intravenous infusion (for example, 30 min), Q3W for up to 2 years.

[0778] Eftilagimod alpha (efti) (for example, 30 mg), for example injected subcutaneously, Q2Wfor 6 months, then Q3W for up to 2 years.

[0779] Squamous NSCLC:

[0780] Carboplatin (for example, AUC 5 or 6) + paclitaxel (for example, 175 or 200 mg / m2) Q3Wfor 3 months.

[0781] Pembrolizumab (for example, 200 mg), for example administered as intravenous infusion (for example, 30 min), Q3W for up to 2 years.

[0782] Eftilagimod alpha (efti) (for example, 30 mg), for example injected subcutaneously, Q2Wfor 6 months, then Q3W for up to 2 years.

[0783] Examples of these different treatment schedules are illustrated in Figure 14. The embodiments according to the invention include administration of efti rather than placebo.

Claims

Claims1. A LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, for use in improving overall survival (OS) of a subject with a cancer.

2. A LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, for use in improving overall survival (OS) of a subject with a cancer, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

3. A LAG-3 protein, or a derivative, for use according to claim 1 or 2, for use in improving overall survival (OS) of a subject with a cancer compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

4. A LAG-3 protein, or a derivative, for use according to any of claims 1 to 3, for use in improving median OS of the subject.

5. A LAG-3 protein, or a derivative, for use according to claim 4, for use in improving median OS of the subject to at least 30 months.

6. A LAG-3 protein, or a derivative, for use according to claim 4 or 5, for use in improving median OS of the subject by at least 6 months, preferably by at least 9 months, more preferably by at least 10 months, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

7. A LAG-3 protein, or a derivative, for use according to any of claims 1 to 3, for use in improving 24-month OS rate of the subject.

8. A LAG-3 protein, or a derivative, for use according to claim 7, for use in improving 24-month OS rate of the subject to at least 50%, preferably to at least 60%, more preferably to at least 70%, more preferably to at least 80%.

9. A LAG-3 protein, or a derivative, for use according to claim 7 or 8, for use in improving 24-month OS rate of the subject by at least 20%, preferably by at least 30%, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

10. A LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, for use in improving overall response rate (ORR) of a subject with a cancer.

11. A LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, for use in improving overall response rate (ORR) of a subject with a cancer, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

12. A LAG-3 protein, or a derivative, for use according to claim 10 or 11, for use in improving overall response rate (ORR) of a subject with a cancer compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

13. A LAG-3 protein, or derivative, for use according to any of claims 10 to 12, for use in improving overall response rate (ORR) of the subject to: at least 40% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 50% where the subject has low PD-L1 expression (TPS 1-49%); or at least 65% where the subject has high PD-L1 expression (TPS >50%).

14. A LAG-3 protein, or derivative, for use according to any of claims 10 to 12, for use in improving overall response rate (ORR) of the subject to: at least 50% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 55% where the subject has low PD-L1 expression (TPS 1-49%); at least 70% where the subject has high PD-L1 expression (TPS >50%); or at least 50% where the subject has low or negative PD-L1 expression (TPS <50%).

15. A LAG-3 protein, or derivative, for use according to any of claims 10 to 14, for use in improving overall response rate (ORR) of the subject by at least 9% compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway105inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

16. A LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, for use in improving disease control rate (DCR) of a subject with a cancer.

17. A LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, for use in improving disease control rate (DCR) of a subject with a cancer, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.

18. A LAG-3 protein, or a derivative, for use according to claim 16 or 17, for use in improving disease control rate (DCR) of a subject with a cancer compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

19. A LAG-3 protein, or derivative, for use according to any of claims 16 to 18, for use in improving disease control rate (DCR) of the subject to at least 80%.

20. A LAG-3 protein, or derivative, for use according to any of claims 16 to 19, for use in improving disease control rate (DCR) of the subject to at least 80% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 85% where the subject has low PD-L1 expression (TPS 1-49%); at least 90% where the subject has high PD-L1 expression (TPS >50%); or at least 80% where the subject has low or negative PD-L1 expression (TPS <50%).

21. A LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent, for use in improving progression-free survival (PFS) of a subject with a cancer.

22. A LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules, for use in improving progression-free survival (PFS) of a subject with a cancer, wherein the LAG-3 protein or derivative thereof is to be administered simultaneously or sequentially with a programmed cell death protein-1 (PD-1) pathway inhibitor and a chemotherapy agent.10623. A LAG-3 protein, or a derivative, for use according to claim 21 or 22, for use in improving progression-free survival (PFS) of a subject with a cancer compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

24. A LAG-3 protein, or a derivative, for use according to any of claims 21 to 23, for use in improving median PFS of the subject.

25. A LAG-3 protein, or a derivative, for use according to claim 24, for use in improving median PFS of the subject to at least 12 months.

26. A LAG-3 protein, or a derivative, for use according to claim 24 or 25, for use in improving median PFS of the subject by at least one month, preferably by at least 2 months, more preferably by at least 3 months, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

27. A LAG-3 protein, or a derivative for use according to any preceding claim, wherein the LAG-3 protein, or derivative, is to be administered every two weeks, and the PD-1 pathway inhibitor, and the chemotherapy agent are to be administered every three weeks, preferably up to 12 weeks.

28. A LAG-3 protein, or a derivative for use according to any preceding claim, wherein the chemotherapy agent is a combination of two or more chemotherapy agents.

29. A LAG-3 protein, or a derivative for use according to any preceding claim, wherein the LAG-3 derivative is efti (IMP321), the PD-1 pathway inhibitor is pembrolizumab, and the chemotherapy agent comprises a combination of pemetrexed and carboplatin.

30. A LAG-3 protein, or a derivative for use according to any of claims 1 to 29, wherein the subject is to be administered a maintenance therapy after treatment with the LAG-3 protein, or derivative, the PD-1 pathway inhibitor, and the chemotherapy agent, wherein the maintenance therapy comprises administration of the subject with the LAG-3 protein, or derivative, every two or three weeks, and the PD-1 pathway inhibitor and optionally a chemotherapy agent every three weeks, preferably up to 93 weeks.10731. A LAG-3 protein, or a derivative for use according to claim 30, wherein the maintenance therapy comprises administration of the subject with the LAG-3 protein, or derivative, every two or three weeks, and the PD-1 pathway inhibitor and a chemotherapy agent every three weeks, preferably up to 93 weeks, wherein the chemotherapy agent is a single chemotherapy agent.

32. A LAG-3 protein, or a derivative for use according to claim 31, wherein the single chemotherapy agent is pemetrexed.

33. A LAG-3 protein, or a derivative for use according to any preceding claim, wherein the derivative of LAG-3 protein comprises an amino acid sequence that has at least 70% amino acid identity with domain D1, and optionally domain D2, of LAG-3 protein, preferably human LAG-3 protein.

34. A LAG-3 protein, or a derivative for use according to any preceding claim, wherein the derivative of LAG-3 protein comprises an amino acid sequence that has at least 70% amino acid identity with domains D1 , D2 and D3, and optionally domain D4, of LAG-3 protein, preferably human LAG-3 protein.

35. A LAG-3 protein, or a derivative for use according to any preceding claim, wherein the cancer is selected from the group consisting of breast cancer, skin cancer, lung cancer (NSCLC or SCLC), ovarian cancer, renal cancer (for example renal cell carcinoma), colon cancer, rectal cancer, colorectal cancer, anal cancer, small intestine cancer, gastrointestinal stromal tumours, gastric cancer, esophageal cancer, pancreatic cancer, bladder cancer, urothelial cancer, liver cancer, melanoma (for example, metastatic malignant melanoma), prostate cancer (for example hormone refractory prostate adenocarcinoma), head and neck cancer (for example, head and neck squamous cell carcinoma), cervical cancer, endometrial cancer, uterine cancer, thyroid cancer, glioblastoma, glioma, leukemia, lymphoma (for example, a B cell lymphoma or Hodgkin lymphoma), adrenal gland cancer, AIDS-associated cancer, alveolar soft part sarcoma, astrocytic tumor, bone cancer, brain and spinal cord cancer, metastatic brain tumor, carotid body tumor, chondrosarcoma, chordoma, cutaneous benign fibrous histiocytoma, desmoplastic small round cell tumor, ependymoma, Ewing's tumor, extraskeletal myxoid chondrosarcoma, fibrogenesis imperfecta ossium, fibrous dysplasia of the bone, gallbladder or bile duct cancer, gestational trophoblastic disease, germ cell tumor, haematological malignancy, hepatocellular carcinoma, islet cell tumor, Kaposi's sarcoma, kidney cancer, lipoma / benign lipomatous tumor, liposarcoma / malignant lipomatous tumor, medulloblastoma, meningioma, Merkel cell carcinoma, multiple endocrine108neoplasia, multiple myeloma, myelodysplasia syndrome, neuroblastoma, neuroendocrine tumor, papillary thyroid carcinoma, parathyroid tumor, pediatric cancer, peripheral nerve sheath tumor, phaeochromocytoma, pituitary tumor, prostate cancer, posterior uveal melanoma, rare hematologic disorder, rhabdoid tumor, rhabdomysarcoma, sarcoma, soft-tissue sarcoma, squamous cell cancer, synovial sarcoma, mesothelioma, cutaneous squamous cell carcinoma, testicular cancer, thymic carcinoma, thymoma, and thyroid metastatic cancer.

36. A LAG-3 protein, or a derivative for use according to any preceding claim, wherein the cancer is a lung cancer.

37. A LAG-3 protein, or a derivative for use according to any preceding claim, wherein the cancer is a NSCLC.

38. A LAG-3 protein, or a derivative for use according to claim 37, wherein the cancer is a non-squamous NSCLC.

39. A LAG-3 protein, or a derivative for use according to any of claims 1 to 28, wherein the LAG-3 derivative is efti (IMP321), the PD-1 pathway inhibitor is pembrolizumab, and the chemotherapy agent comprises a combination of carboplatin and paclitaxel or nab-paclitaxel.

40. A LAG-3 protein, or a derivative for use according to claim 39, wherein the subject is to be administered a maintenance therapy after treatment with the LAG-3 protein, or derivative, the PD-1 pathway inhibitor, and the chemotherapy agent, wherein the maintenance therapy comprises administration of the subject with the LAG-3 protein, or derivative, every two or three weeks, and the PD-1 pathway inhibitor every three weeks, preferably up to 93 weeks.

41. A LAG-3 protein, or a derivative for use according to claim 39 or 40, wherein the cancer is squamous NSCLC.

42. A LAG-3 protein, or a derivative for use according to any of claims 1 to 38, wherein the PD-1 pathway inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, atezolizumab, avelumab, and durvalumab.

43. A LAG-3 protein, or a derivative for use according to any of claims 1 to 38, or 42, wherein the PD-1 pathway inhibitor is pembrolizumab.10944. A LAG-3 protein, or a derivative for use according to any preceding claim, wherein the PD-L1 expression level of the subject is < 50%.

45. A LAG-3 protein, or a derivative for use according to claim 44, wherein the PD-L1 expression level of the subject is 1-49%.

46. A LAG-3 protein, or a derivative for use according to claim 44, wherein the PD-L1 expression level of the subject is < 1%.

47. A LAG-3 protein, or a derivative for use according to any preceding claim, wherein the subject is a human.

48. A method of improving overall survival (OS) of a subject with a cancer, which comprises administering to the subject an effective amount of: (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; (b) a programmed cell death protein-1 (PD-1) pathway inhibitor; and (c) a chemotherapy agent.

49. A method according to claim 48, wherein the method improves overall survival (OS) of the subject compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

50. A method according to claim 48 or 49 which improves median OS of the subject.

51. A method according to claim 50 which improves median OS of the subject to at least 30 months.

52. A method according to claim 50 or 51, which improves median OS of the subject by at least 6 months, preferably by at least 9 months, more preferably by at least 10 months, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

53. A method according to claim 48 or 49 which improves 24-month OS rate of the subject.11054. A method according to claim 53, which improves 24-month OS rate of the subject to at least 50%, preferably to at least 60%, more preferably to at least 70%, more preferably to at least 80%.

55. A method according to claim 53 or 54, which improves 24-month OS rate of the subject by at least 20%, preferably by at least 30%, compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

56. A method of improving overall response rate (ORR) of a subject with a cancer, which comprises administering to the subject an effective amount of: (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; (b) a programmed cell death protein-1 (PD-1) pathway inhibitor; and (c) a chemotherapy agent.

57. A method according to claim 56, wherein the method improves overall response rate (ORR) of the subject compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

58. A method according to claim 56 or 57, which improves overall response rate (ORR) of the subject to: at least 40% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 50% where the subject has low PD-L1 expression (TPS 1-49%); or at least 65% where the subject has high PD-L1 expression (TPS >50%).

59. A method according to any of claims 56 to 58, which improves overall response rate (ORR) of the subject to: at least 50% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 55% where the subject has low PD-L1 expression (TPS 1-49%); at least 70% where the subject has high PD-L1 expression (TPS >50%); or at least 50% where the subject has low or negative PD-L1 expression (TPS <50%).

60. A method according to any of claims 56 to 59, which improves overall response rate (ORR) of the subject by at least 9% compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.Ill61. A method of improving disease control rate (DCR) of a subject with a cancer, which comprises administering to the subject an effective amount of: (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; (b) a programmed cell death protein-1 (PD-1) pathway inhibitor; and (c) a chemotherapy agent.

62. A method according to claim 61, wherein the method improves disease control rate (DCR) of the subject compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

63. A method according to claim 61 or 62 which improves disease control rate (DCR) of the subject to at least 80%.

64. A method according to any of claims 61 to 63 which improves disease control rate (DCR) of the subject to at least 80% where the subject has negative PD-L1 expression (Tumor Proportion Score, TPS <1%); at least 85% where the subject has low PD-L1 expression (TPS 1-49%); at least 90% where the subject has high PD-L1 expression (TPS >50%); or at least 80% where the subject has low or negative PD-L1 expression (TPS <50%).

65. A method of improving progression-free survival (PFS) of a subject with a cancer, which comprises administering to the subject an effective amount of: (a) a LAG-3 protein, or a derivative thereof that is able to bind to MHC class II molecules; (b) a programmed cell death protein-1 (PD-1) pathway inhibitor; and (c) a chemotherapy agent.

66. A method according to claim 65, which improves progression-free survival (PFS) of a subject with a cancer compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

67. A method according to claim 65 or 66, which improves median PFS of the subject.

68. A method according to claim 67, which improves median PFS of the subject to at least 12 months.

69. A method according to claim 67 or 68, which improves median PFS of the subject by at least one month, preferably by at least 2 months, more preferably by at least 3 months,112compared to treatment of a subject with the cancer with: (i) the LAG-3 protein, or derivative, and the PD-1 pathway inhibitor alone; (ii) the LAG-3 protein, or derivative, and the chemotherapy agent alone; or (iii) the PD-1 pathway inhibitor and the chemotherapy agent alone.

70. A method according to any of claims 48 to 69, wherein the LAG-3 protein, or derivative, the programmed cell death protein- 1 (PD-1) pathway inhibitor; and the chemotherapy agent, are administered simultaneously or sequentially.

71. A method according to any of claims 48 to 70, wherein the LAG-3 protein, or derivative, is administered to the subject every two weeks, and the PD-1 pathway inhibitor, and the chemotherapy agent are administered to the subject every three weeks, preferably up to 12 weeks.

72. A method according to any of claims 48 to 71, wherein the chemotherapy agent is a combination of two or more chemotherapy agents.

73. A method according to any of claims 48 to 72, wherein the LAG-3 derivative is efti (IMP321), the PD-1 pathway inhibitor is pembrolizumab, and the chemotherapy agent comprises a combination of pemetrexed and carboplatin.

74. A method according to any of claims 48 to 73, which further comprises administering a maintenance therapy to the subject after treatment with the LAG-3 protein, or derivative, the PD-1 pathway inhibitor, and the chemotherapy agent, wherein the maintenance therapy comprises administration of the subject with the LAG-3 protein, or derivative, every two or three weeks, and the PD-1 pathway inhibitor and optionally a chemotherapy agent every three weeks, preferably up to 93 weeks.

75. A method according to claim 74, wherein the maintenance therapy comprises administration of the subject with the LAG-3 protein, or derivative, every two or three weeks, and the PD-1 pathway inhibitor and a chemotherapy agent every three weeks, preferably up to 93 weeks, wherein the chemotherapy agent is a single chemotherapy agent.

76. A method according to claim 75, wherein the single chemotherapy agent is pemetrexed.

77. A method according to any of claims 48 to 76, wherein the derivative of LAG-3 protein comprises an amino acid sequence that has at least 70% amino acid identity with domain D1, and optionally domain D2, of LAG-3 protein, preferably human LAG-3 protein.

78. A method according to any of claims 48 to 77, wherein the derivative of LAG-3 protein comprises an amino acid sequence that has at least 70% amino acid identity with domains D1, D2 and D3, and optionally domain D4, of LAG-3 protein, preferably human LAG-3 protein.

79. A method according to any of claims 48 to 78, wherein the cancer is selected from the group consisting of breast cancer, skin cancer, lung cancer (NSCLC or SCLC), ovarian cancer, renal cancer (for example renal cell carcinoma), colon cancer, rectal cancer, colorectal cancer, anal cancer, small intestine cancer, gastrointestinal stromal tumours, gastric cancer, esophageal cancer, pancreatic cancer, bladder cancer, urothelial cancer, liver cancer, melanoma (for example, metastatic malignant melanoma), prostate cancer (for example hormone refractory prostate adenocarcinoma), head and neck cancer (for example, head and neck squamous cell carcinoma), cervical cancer, endometrial cancer, uterine cancer, thyroid cancer, glioblastoma, glioma, leukemia, lymphoma (for example, a B cell lymphoma or Hodgkin lymphoma), adrenal gland cancer, AIDS-associated cancer, alveolar soft part sarcoma, astrocytic tumor, bone cancer, brain and spinal cord cancer, metastatic brain tumor, carotid body tumor, chondrosarcoma, chordoma, cutaneous benign fibrous histiocytoma, desmoplastic small round cell tumor, ependymoma, Ewing's tumor, extraskeletal myxoid chondrosarcoma, fibrogenesis imperfecta ossium, fibrous dysplasia of the bone, gallbladder or bile duct cancer, gestational trophoblastic disease, germ cell tumor, haematological malignancy, hepatocellular carcinoma, islet cell tumor, Kaposi's sarcoma, kidney cancer, lipoma / benign lipomatous tumor, liposarcoma / malignant lipomatous tumor, medulloblastoma, meningioma, Merkel cell carcinoma, multiple endocrine neoplasia, multiple myeloma, myelodysplasia syndrome, neuroblastoma, neuroendocrine tumor, papillary thyroid carcinoma, parathyroid tumor, pediatric cancer, peripheral nerve sheath tumor, phaeochromocytoma, pituitary tumor, prostate cancer, posterior uveal melanoma, rare hematologic disorder, rhabdoid tumor, rhabdomysarcoma, sarcoma, soft-tissue sarcoma, squamous cell cancer, synovial sarcoma, mesothelioma, cutaneous squamous cell carcinoma, testicular cancer, thymic carcinoma, thymoma, and thyroid metastatic cancer.

80. A method according to any of claims 48 to 79, wherein the cancer is a lung cancer.

81. A method according to any of claims 48 to 80, wherein the cancer is a NSCLC.

82. A method according to any of claims 48 to 81 , wherein the cancer is a non-squamous NSCLC.

83. A method according to any of claims 48 to 72, wherein the LAG-3 derivative is efti (IMP321), the PD-1 pathway inhibitor is pembrolizumab, and the chemotherapy agent comprises a combination of carboplatin and paclitaxel or nab-paclitaxel.

84. A method according to claim 83, which further comprises administering a maintenance therapy to the subject after treatment with the LAG-3 protein, or derivative, the PD-1 pathway inhibitor, and the chemotherapy agent, wherein the maintenance therapy comprises administration of the subject with the LAG-3 protein, or derivative, every two or three weeks, and the PD-1 pathway inhibitor every three weeks, preferably up to 93 weeks.

85. A method according to claim 83 or 84, wherein the cancer is squamous NSCLC.

86. A method according to any of claims 48 to 82, wherein the PD-1 pathway inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, atezolizumab, avelumab, and durvalumab.

87. A method according to any of claims 48 to 82, or 86, wherein the PD-1 pathway inhibitor is pembrolizumab.

88. A method according to any of claims 48 to 87, wherein the PD-L1 expression level of the subject is < 50%.

89. A method according to any of claims 48 to 88, wherein the PD-L1 expression level of the subject is 1-49%.

90. A method according to any of claims 48 to 88, wherein the PD-L1 expression level of the subject is < 1%.

91. A method according to any of claims 48 to 90, wherein the subject is a human.

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