HK40006278A - Combination therapy for cancer - Google Patents
Combination therapy for cancer Download PDFInfo
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- HK40006278A HK40006278A HK19129761.3A HK19129761A HK40006278A HK 40006278 A HK40006278 A HK 40006278A HK 19129761 A HK19129761 A HK 19129761A HK 40006278 A HK40006278 A HK 40006278A
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Description
The present invention relates to the field of medicine. The present invention relates to combinations of antibodies against human Epidermal Growth Factor Receptor (EGFR) and antibodies against human programmed cell death 1(PD-1) receptor, such as the combination of nimotuzumab (necitumumab) with pembrolizumab (pembrolizumab), and methods of using the combinations to treat cancer, particularly lung cancer, more particularly non-small cell lung cancer (NSCLC), particularly squamous and non-squamous non-small cell lung cancer (NSCLC).
Overexpression of EGFR has been reported in many human malignancies, including bladder, brain, head and neck, pancreatic, lung, breast, ovarian, colon, prostate and renal cancers. In many of these conditions, overexpression of EGFR is associated or correlated with poor prognosis in patients. Inhibition of the EGFR signaling pathway has been used to treat cancer.
Rituximab (IMC-11F8) is a recombinant human monoclonal antibody that binds to extracellular domain III of human EGFR and blocks the interaction between EGFR and its ligand. Tolituzumab resistance, including its sequences, and methods of making and using the antibodies, including for the treatment of neoplastic diseases, such as solid and non-solid tumors, are disclosed in WO 2005/090407.
The pertuzumab is an active drug component in PORTRAZZA which is approved to be used for treating metastatic squamous NSCLC in combination with gemcitabine and cis-platinum. The INSPIRE trial of pemetrexed and cisplatin with or without rituximab resistance (which was included in NSCLC patients with non-squamous histology) failed to meet the primary endpoint of their overall survival. See Portrazza @ (resistant to xintuzumab) for us and european labels (parts "limit of use" and "warnings and notices", respectively).
The immune system is regulated by a number of inhibitory pathways, collectively referred to as immune checkpoints, which maintain tolerance to self-antigens. One of the mechanisms of cancer tolerance is the ability of tumor cells to co-select immune checkpoint pathways. The adaptive up-regulation of PD-L1 (a ligand for PD-1) reflects the natural physiological process of normal cytoprotection from immune-mediated tissue damage. The most common process in solid tumors (including NSCLC) is used by cancer cells to avoid killing by the immune system.
Binding of PD-1 ligands PD-L1 and PD-L2 to PD-1 receptors expressed on T cells inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors, and signaling through this pathway contributes to the inhibition of active T cell immune surveillance by tumors.
Pembrolizumab is a monoclonal antibody that binds to the human PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby releasing the inhibition of PD-1 pathway-mediated immune responses, including anti-tumor immune responses. WO 2008/156712 discloses pembrolizumab, sequences thereof, and methods of making and using the same, including activities for increasing an immune response through the PD-1 pathway.
Pembrolizumab is an active pharmaceutical ingredient in KEYTRUDA that has been approved by the FDA for the treatment of melanoma, NSCLC and head and neck squamous cell carcinoma in a population of PD-L1 positive patients. More specifically, with respect to NSCLC, Keytruda @ (pembrolizumab) was approved in the united states for "patients with metastatic NSCLC whose tumors expressed PD-L1 (as determined by FDA approved testing) and had disease progression during or after platinum-containing chemotherapy" ("indication of use"). An indication of approved IHC PD-L1 IHC22C3 pharmDx (Keytruda's FDA approved PD-L1 test) provides "a sample should be considered PD-L1 positive if TPS ≧ 50% of the live tumor cells exhibit membrane staining of any intensity. "
Lung cancer ranks among the most common causes of death from cancer in men and women throughout the world. The two major types of lung cancer are small cell lung cancer and NSCLC. NSCLC accounts for approximately 85% or more of lung cancer cases. Treatment may involve surgery, chemotherapy, radiation therapy, biological therapy, targeted therapy, and immunotherapy, as well as selected combinations of these therapies. Immunotherapy has recently become the mainstay of treatment in several solid tumors, including NSCLC, but the efficacy, dosing, sequencing, biomarker/biomarker levels, mutations, and efficacy in different disease states of specific combinations of these agents remains unknown.
Combinations of PD-1 inhibitors and EGFR inhibitors have been discussed. WO2015/176033 discusses nivolumab plus EGFR targetingTyrosine kinase inhibitors(TKI), including erlotinib, for use in the treatment of NSCLC. Rizvi N., JClin Oncol 32:5s, 2014 (suppl; abstr 8022) discusses the results of NCT01454102, which investigated "the safety and response of Nintenbuzumab (anti-PD-1; BMS-936558, ONO-4538) plus erlotinib in patients with epidermal growth factor receptor mutant (EGFR MT) advanced NSCLC (pts). Has in EGFRMutationsIn patients with Erlotinib (EGFR)TKI) NCT01454102 was performed. Bastos, B, et al International Journal of radiation Oncology, Biology, Physics, 2016 (4), 929 discusses the use of Nivorumab plus cetuximab in a proposed phase 1 clinical trial for the treatment of recurrent head and neck cancer.
Unfortunately, cure of NSCLC remains difficult and even treatment options remain limited, with poor prognosis for the patient; treatment of NSCLC remains an unmet clinical need. There is a need for more and different therapies that can prove effective in treating NSCLC.
Presented herein are novel methods of treating squamous and non-squamous NSCLC using a combination of rituximab and pembrolizumab. Presented herein are novel methods of treating squamous and non-squamous NSCLC using a combination of antibody 1 and antibody 2. Accordingly, some aspects of the invention provide antibody 1 for use in simultaneous, separate or sequential combination with antibody 2 in the treatment of non-small cell lung cancer, wherein antibody 1 comprises two heavy chains and two light chains, wherein the heavy chains comprise a Heavy Chain Variable Region (HCVR) having the amino acid sequence of SEQ ID No. 1, and wherein the light chains comprise a Light Chain Variable Region (LCVR) having the amino acid sequence of SEQ ID No. 2, and wherein antibody 2 comprises two heavy chains and two light chains, wherein the heavy chains comprise a HCVR having the amino acid sequence of SEQ ID No. 5, and the light chains comprise a LCVR having the amino acid sequence of SEQ ID No. 6, and wherein antibody 1 is administered at a dose of 400 mg to 800mg, and wherein antibody 2 is administered at a dose of 200 mg.
More specifically, antibody 1 comprises two heavy chains and two light chains comprising a heavy chain having the amino acid sequence of SEQ ID NO. 3 and a light chain having the amino acid sequence of SEQ ID NO. 4, and wherein antibody 2 comprises two heavy chains and two light chains comprising a heavy chain having the amino acid sequence of SEQ ID NO. 7 and a light chain having the amino acid sequence of SEQ ID NO. 8.
More specifically, antibody 1 was administered at a dose of 400 mg. More specifically, antibody 1 was administered at a dose of 600 mg. More specifically, antibody 1 was administered at a dose of 800 mg.
In a preferred aspect, antibody 1 is administered by intravenous infusion. In a preferred aspect, antibody 2 is administered by intravenous infusion.
More specifically, the non-small cell lung cancer is non-squamous. More specifically, the non-small cell lung cancer is squamous.
More specifically, antibody 1 was administered at a dose of 400 mg on days 1 and 8 of each 3-week cycle, and antibody 2 was administered at a dose of 200mg on day 1 of each 3-week cycle. More specifically, antibody 1 was administered at a dose of 600 mg on days 1 and 8 of each 3-week cycle, and antibody 2 was administered at a dose of 200mg on day 1 of each 3-week cycle. More specifically, antibody 1 was administered at a dose of 800mg on days 1 and 8 of each 3-week cycle, and antibody 2 was administered at a dose of 200mg on day 1 of each 3-week cycle.
In a preferred aspect, antibody 1 is administered by intravenous infusion. In a preferred aspect, antibody 2 is administered by intravenous infusion.
More specifically, the non-small cell lung cancer is non-squamous. More specifically, the non-small cell lung cancer is squamous.
More specifically, the invention provides antibodies 1 and 2 for use wherein tumor tissue from the patient has a protein expression level of PD-L1, and wherein expression of PD-L1 is such that less than 50% of the viable tumor cells exhibit partial or complete membrane staining.
More specifically, the invention provides antibody 1 for use in simultaneous, separate or sequential combination with antibody 2 in the treatment of non-small cell lung cancer in a patient, the treatment comprising assaying a sample of tumor tissue of the patient in vitro for the protein expression level of PD-L1, and administering therapeutically effective amounts of antibody 1 and antibody 2 if the expression of PD-L1 is such that less than 50% of the viable tumor cells exhibit partial or complete membrane staining.
More specifically, the invention provides antibody 1 for use in simultaneous, separate or sequential combination with antibody 2 in the treatment of non-small cell lung cancer in a patient, the treatment comprising assaying a sample of tumor tissue of the patient in vitro for the protein expression level of PD-L1, determining the level of PD-L1, and administering therapeutically effective amounts of antibody 1 and antibody 2 if the level of PD-L1 is such that less than 50% of the living tumor cells exhibit partial or complete membrane staining.
The invention also provides antibody 2 for simultaneous, separate or sequential use in combination with antibody 1 for the treatment of non-small cell lung cancer, wherein antibody 1 comprises two heavy chains and two light chains, wherein the heavy chains comprise HCVRs having the amino acid sequence of SEQ ID No. 1, and wherein the light chains comprise LCVRs having the amino acid sequence of SEQ ID No. 2, and wherein antibody 2 comprises two heavy chains and two light chains, wherein the heavy chains comprise HCVRs having the amino acid sequence of SEQ ID No. 5, and the light chains comprise LCVRs having the amino acid sequence of SEQ ID No. 6, and wherein antibody 2 is administered at a dose of 200mg, and wherein antibody 1 is administered at a dose of 400 mg to 800 mg.
More specifically, antibody 1 comprises two heavy chains and two light chains comprising a heavy chain having the amino acid sequence of SEQ ID NO. 3 and a light chain having the amino acid sequence of SEQ ID NO. 4, and wherein antibody 2 comprises two heavy chains and two light chains comprising a heavy chain having the amino acid sequence of SEQ ID NO. 7 and a light chain having the amino acid sequence of SEQ ID NO. 8.
More specifically, antibody 1 was administered at a dose of 400 mg. More specifically, antibody 1 was administered at a dose of 600 mg. More specifically, antibody 1 was administered at a dose of 800 mg.
More specifically, antibody 2 was administered at a dose of 200mg on day 1 of each 3-week cycle, and antibody 1 was administered at a dose of 400 mg on days 1 and 8 of each 3-week cycle. More specifically, antibody 2 was administered at a dose of 200mg on day 1 of each 3-week cycle, and antibody 1 was administered at a dose of 600 mg on days 1 and 8 of each 3-week cycle. More specifically, antibody 2 was administered at a dose of 200mg on day 1 of each 3-week cycle, and antibody 1 was administered at a dose of 800mg on days 1 and 8 of each 3-week cycle.
In a preferred aspect, antibody 1 is administered by intravenous infusion. In a preferred aspect, antibody 2 is administered by intravenous infusion.
More specifically, the non-small cell lung cancer is non-squamous. More specifically, the non-small cell lung cancer is squamous.
More specifically, the invention provides the antibody 2 used wherein the tumor tissue from the patient has a protein expression level of PD-L1 if the expression of PD-L1 is such that less than 50% of the living tumor cells show partial or complete membrane staining.
More specifically, the invention provides antibody 2 for use in simultaneous, separate or sequential combination with antibody 1 in the treatment of non-small cell lung cancer in a patient, the treatment comprising assaying a sample of tumor tissue of the patient in vitro for the protein expression level of PD-L1, and administering therapeutically effective amounts of antibody 2 and antibody 1 if the expression of PD-L1 is such that less than 50% of the viable tumor cells exhibit partial or complete membrane staining.
More specifically, the invention provides antibody 2 for use in simultaneous, separate or sequential combination with antibody 1 in the treatment of non-small cell lung cancer in a patient, the treatment comprising assaying a sample of tumor tissue of the patient in vitro for the protein expression level of PD-L1, determining the level of PD-L1, and administering therapeutically effective amounts of antibody 2 and antibody 1 if the level of PD-L1 is such that less than 50% of the living tumor cells exhibit partial or complete membrane staining.
The invention also provides the use of antibody 1 in the manufacture of a medicament for the treatment of non-small cell lung cancer, wherein antibody 1 is administered at a dose of 400 mg to 800mg in simultaneous, separate or sequential combination with antibody 2, wherein antibody 2 is administered at a dose of 200mg, and wherein antibody 1 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 1, and wherein the light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 2, and wherein antibody 2 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 5, and the light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 6.
More specifically, antibody 1 comprises two heavy chains and two light chains comprising a heavy chain having the amino acid sequence of SEQ ID NO. 3 and a light chain having the amino acid sequence of SEQ ID NO. 4, and wherein antibody 2 comprises two heavy chains and two light chains comprising a heavy chain having the amino acid sequence of SEQ ID NO. 7 and a light chain having the amino acid sequence of SEQ ID NO. 8.
More specifically, antibody 1 was administered at a dose of 400 mg. More specifically, antibody 1 was administered at a dose of 600 mg. More specifically, antibody 1 was administered at a dose of 800 mg.
More specifically, antibody 1 was administered at a dose of 400 mg on days 1 and 8 of each 3-week cycle, and antibody 2 was administered at a dose of 200mg on day 1 of each 3-week cycle. More specifically, antibody 1 was administered at a dose of 600 mg on days 1 and 8 of each 3-week cycle, and antibody 2 was administered at a dose of 200mg on day 1 of each 3-week cycle. More specifically, antibody 1 was administered at a dose of 800mg on days 1 and 8 of each 3-week cycle, and antibody 2 was administered at a dose of 200mg on day 1 of each 3-week cycle.
In a preferred aspect, antibody 1 is administered by intravenous infusion. In a preferred aspect, antibody 2 is administered by intravenous infusion.
More specifically, the non-small cell lung cancer is non-squamous. More specifically, the non-small cell lung cancer is squamous.
The invention also provides the use of antibody 2 in the manufacture of a medicament for the treatment of non-small cell lung cancer, wherein antibody 2 is administered at a dose of 200mg in simultaneous, separate or sequential combination with antibody 1, wherein antibody 1 is administered at a dose of 400 mg to 800mg, and wherein antibody 1 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 1, and wherein the light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 2, and wherein antibody 2 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 5, and the light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 6.
More specifically, antibody 1 comprises two heavy chains and two light chains comprising a heavy chain having the amino acid sequence of SEQ ID NO. 3 and a light chain having the amino acid sequence of SEQ ID NO. 4, and wherein antibody 2 comprises two heavy chains and two light chains comprising a heavy chain having the amino acid sequence of SEQ ID NO. 7 and a light chain having the amino acid sequence of SEQ ID NO. 8.
More specifically, antibody 1 was administered at a dose of 400 mg. More specifically, antibody 1 was administered at a dose of 600 mg. More specifically, antibody 1 was administered at a dose of 800 mg.
More specifically, antibody 1 was administered at a dose of 400 mg on days 1 and 8 of each 3-week cycle, and antibody 2 was administered at a dose of 200mg on day 1 of each 3-week cycle. More specifically, antibody 1 was administered at a dose of 600 mg on days 1 and 8 of each 3-week cycle, and antibody 2 was administered at a dose of 200mg on day 1 of each 3-week cycle. More specifically, antibody 1 was administered at a dose of 800mg on days 1 and 8 of each 3-week cycle, and antibody 2 was administered at a dose of 200mg on day 1 of each 3-week cycle.
In a preferred aspect, antibody 1 is administered by intravenous infusion. In a preferred aspect, antibody 2 is administered by intravenous infusion.
More specifically, the non-small cell lung cancer is non-squamous. More specifically, the non-small cell lung cancer is squamous.
The present invention provides a kit for treating non-small cell lung cancer comprising antibody 1 and antibody 2; and wherein antibody 1 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR with the amino acid sequence of SEQ ID No. 1, and wherein the light chains comprise an LCVR with the amino acid sequence of SEQ ID No. 2, and wherein antibody 2 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR with the amino acid sequence of SEQ ID No. 5, and the light chains comprise an LCVR with the amino acid sequence of SEQ ID No. 6, and wherein the amount of antibody 1 is 400 mg to 800mg, and the amount of antibody 2 is 200 mg.
More specifically, antibody 1 comprises two heavy chains and two light chains comprising a heavy chain having the amino acid sequence of SEQ ID NO. 3 and a light chain having the amino acid sequence of SEQ ID NO. 4, and wherein antibody 2 comprises two heavy chains and two light chains comprising a heavy chain having the amino acid sequence of SEQ ID NO. 7 and a light chain having the amino acid sequence of SEQ ID NO. 8.
More specifically, the amount of antibody 1 was 400 mg. More specifically, the amount of antibody 1 was 600 mg. More specifically, the amount of antibody 1 was 800 mg.
In a preferred aspect, antibody 1 is administered by intravenous infusion. In a preferred aspect, antibody 2 is administered by intravenous infusion.
More specifically, the non-small cell lung cancer is non-squamous. More specifically, the non-small cell lung cancer is squamous.
The invention provides a kit for treating non-small cell lung cancer comprising a first container and a second container, the first container containing a pharmaceutical composition comprising antibody 1 and one or more pharmaceutically acceptable carriers, diluents or excipients, and the second container containing a pharmaceutical composition comprising antibody 2 and one or more pharmaceutically acceptable carriers, diluents or excipients, and wherein antibody 1 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 1, and wherein the light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 2, and wherein antibody 2 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 5, and the light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 6, and wherein the amount of antibody 1 is 400 mg to 800mg and the amount of antibody 2 is 200 mg.
More specifically, antibody 1 comprises two heavy chains and two light chains comprising a heavy chain having the amino acid sequence of SEQ ID NO. 3 and a light chain having the amino acid sequence of SEQ ID NO. 4, and wherein antibody 2 comprises two heavy chains and two light chains comprising a heavy chain having the amino acid sequence of SEQ ID NO. 7 and a light chain having the amino acid sequence of SEQ ID NO. 8.
More specifically, the amount of antibody 1 was 400 mg. More specifically, the amount of antibody 1 was 600 mg. More specifically, the amount of antibody 1 was 800 mg.
More specifically, the non-small cell lung cancer is non-squamous. More specifically, the non-small cell lung cancer is squamous.
The invention also provides a kit comprising a first container containing a pharmaceutical composition comprising antibody 1, wherein antibody 1 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 1, and wherein the light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 2, and wherein antibody 1 is formulated with 10mM citrate, 40 mM sodium chloride, 133 mM glycine, 50mM mannitol, 0.01% polysorbate-80 (ph6.0) at a final concentration of 16mg/mL, and a second container containing a pharmaceutical composition comprising antibody 2, wherein antibody 2 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 5, and the light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 6, wherein antibody 2 was formulated with 9.99 mM L-histidine, 0.15 mM polysorbate 80 and 204.68 mM sucrose at a final concentration of 25 mg/mL.
More specifically, the amount of antibody 1 is 400 mg to 800mg, and the amount of antibody 2 is 200 mg. More specifically, the amount of antibody 1 was 400 mg. More specifically, the amount of antibody 1 was 600 mg. More specifically, the amount of antibody 1 was 800 mg.
In a preferred aspect, antibody 1 is administered by intravenous infusion. In a preferred aspect, antibody 2 is administered by intravenous infusion.
More specifically, the non-small cell lung cancer is non-squamous. More specifically, the non-small cell lung cancer is squamous.
Thus, in some aspects, the invention provides methods of treating non-small cell lung cancer in a patient, comprising administering to a patient in need of such treatment an effective amount of antibody 1 in combination with an effective amount of antibody 2, wherein antibody 1 comprises two heavy chains and two light chains, wherein the heavy chains comprise a heavy chain having the amino acid sequence of SEQ ID NO:1 (HCVR), and wherein the light chain comprises a light chain having the amino acid sequence of SEQ ID NO:2 (LCVR), and wherein antibody 2 comprises two heavy chains and two light chains, wherein the heavy chain comprises a light chain having the amino acid sequence of SEQ ID NO:5 in a sequence of an amino acid sequence of HCVR, and wherein the light chain comprises a light chain having the amino acid sequence of SEQ ID NO:6, and a LCVR of the amino acid sequence of, and wherein antibody 1 is administered at a dose of 400 mg to 800mg, and wherein antibody 2 is administered at a dose of 200 mg.
More specifically, antibody 1 comprises two heavy chains and two light chains comprising a heavy chain having the amino acid sequence of SEQ ID NO. 3 and a light chain having the amino acid sequence of SEQ ID NO. 4, and wherein antibody 2 comprises two heavy chains and two light chains comprising a heavy chain having the amino acid sequence of SEQ ID NO. 7 and a light chain having the amino acid sequence of SEQ ID NO. 8.
More specifically, the amount of antibody 1 was 400 mg. More specifically, the amount of antibody 1 was 600 mg. More specifically, the amount of antibody 1 was 800 mg. More specifically, the amount of antibody 2 was 200 mg.
More specifically, antibody 1 was administered at a dose of 400 mg on days 1 and 8 of each 3-week cycle. More specifically, antibody 1 was administered at a dose of 600 mg on days 1 and 8 of each 3-week cycle. More specifically, antibody 1 was administered at a dose of 800mg on days 1 and 8 of each 3-week cycle. More specifically, however, antibody 2 was administered at a dose of 200mg on day 1 of each 3-week cycle.
In a preferred aspect, antibody 1 is administered by intravenous infusion. In a preferred aspect, antibody 2 is administered by intravenous infusion.
More specifically, the non-small cell lung cancer is non-squamous. More specifically, the non-small cell lung cancer is squamous.
Preferably, the combination of antibody 1 and antibody 2 is administered simultaneously, separately or sequentially.
The invention also provides a method of treating non-small cell lung cancer in a patient comprising administering to a patient in need of such treatment an effective amount of antibody 1 in combination with an effective amount of antibody 2, wherein antibody 1 comprises two heavy chains and two light chains, wherein the heavy chains comprise the amino acid sequence of SEQ ID No. 3, and wherein the light chains comprise the amino acid sequence of SEQ ID No. 4, and wherein antibody 2 comprises two heavy chains and two light chains, wherein the heavy chains comprise the amino acid sequence of SEQ ID No. 7, and wherein the light chains comprise the amino acid sequence of SEQ ID No. 8, and wherein antibody 1 is administered at a dose of 400 mg to 800mg, and wherein antibody 2 is administered at a dose of 200 mg.
More specifically, the amount of antibody 1 was 400 mg. More specifically, the amount of antibody 1 was 600 mg. More specifically, the amount of antibody 1 was 800 mg.
More specifically, antibody 1 was administered at a dose of 400 mg on days 1 and 8 of each 3-week cycle. More specifically, antibody 1 was administered at a dose of 600 mg on days 1 and 8 of each 3-week cycle. More specifically, antibody 1 was administered at a dose of 800mg on days 1 and 8 of each 3-week cycle. More specifically, however, antibody 2 was administered at a dose of 200mg on day 1 of each 3-week cycle.
In a preferred aspect, antibody 1 is administered by intravenous infusion. In a preferred aspect, antibody 2 is administered by intravenous infusion.
More specifically, the non-small cell lung cancer is non-squamous. More specifically, the non-small cell lung cancer is squamous.
Preferably, the combination of antibody 1 and antibody 2 is administered simultaneously, separately or sequentially.
More specifically, wherein the tumor tissue from the patient has a protein expression level of PD-L1, and wherein the expression of PD-L1 is such that less than 50% of the viable tumor cells show partial or complete membrane staining.
More specifically, a method of treating non-small cell lung cancer in a patient comprising the steps of: (1) measuring the protein expression level of PD-L1 in a tumor tissue sample taken from the patient, and (2) administering to a patient in need of such treatment an effective amount of antibody 1 in combination with an effective amount of antibody 2 if PD-L1 is expressed such that less than 50% of the viable tumor cells exhibit partial or complete membrane staining.
The invention also provides a method of treating non-small cell lung cancer in a patient comprising administering to the patient a 800mg dose of antibody 1 and a 200mg dose of antibody 2, said antibody 1 comprising two heavy chains and two light chains, wherein said heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 1, and wherein said light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 2, and said antibody 2 comprises two heavy chains and two light chains, wherein said heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 5, and said light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 6, with the proviso that a sample of tumor tissue from the patient contains a protein expression level of PD-L1 that displays partial or complete membrane staining for less than 50% of live tumor cells.
The invention also provides rituximab for simultaneous, separate or sequential use in combination with pembrolizumab in the treatment of non-small cell lung cancer in a patient, wherein the rituximab is administered at a dose of 800mg on days 1 and 8 of each 3-week cycle, and wherein pembrolizumab is administered at a dose of 200mg on day 1 of each 3-week cycle.
The invention also provides pembrolizumab for simultaneous, separate, or sequential use in combination with rituximab in the treatment of non-small cell lung cancer in a patient, wherein pembrolizumab is administered at a dose of 200mg on day 1 of each 3-week cycle, and wherein rituximab is administered at a dose of 800mg on days 1 and 8 of each 3-week cycle.
The invention also provides the use of rituximab in the manufacture of a medicament for the treatment of non-small cell lung cancer, wherein the rituximab is administered at a dose of 800mg in simultaneous, separate or sequential combination with pembrolizumab, wherein pembrolizumab is administered at a dose of 200 mg.
The invention also provides the use of pembrolizumab in the manufacture of a medicament for the treatment of non-small cell lung cancer, wherein pembrolizumab is administered at a dose of 200mg in simultaneous, separate or sequential combination with tolituzumab administered at a dose of 800 mg.
The invention also provides a kit for treating non-small cell lung cancer comprising rituximab and pembrolizumab, wherein the amount of rituximab is 800mg and the amount of pembrolizumab is 200 mg.
The present invention also provides a kit for treating non-small cell lung cancer comprising a first container and a second container, the first container containing a pharmaceutical composition comprising nimotuzumab with one or more pharmaceutically acceptable carriers, diluents, or excipients, and the second container containing a pharmaceutical composition comprising pembrolizumab with one or more pharmaceutically acceptable carriers, diluents, or excipients, and wherein the amount of nimotuzumab is 800mg and the amount of pembrolizumab is 200 mg.
The invention also provides a kit comprising a first container containing a pharmaceutical composition comprising rituximab and wherein the rituximab is formulated with 10mM citrate, 40 mM sodium chloride, 133 mM glycine, 50mM mannitol, 0.01% polysorbate-80 (ph6.0) at a final concentration of 16mg/mL and a second container containing a pharmaceutical composition comprising pembrolizumab wherein pembrolizumab is formulated with 9.99 mM L-histidine, 0.15 mM polysorbate 80 and 204.68 mM sucrose at a final concentration of 25 mg/mL. More specifically, the amount of rituximab is 800mg, and wherein pembrolizumab is 200 mg.
The present invention also provides a method of treating non-small cell lung cancer in a patient comprising administering to a patient in need of such treatment an effective amount of a combination of nimotuzumab with an effective amount of pembrolizumab, wherein nimotuzumab is administered at a dose of 800mg, and wherein pembrolizumab is administered at a dose of 200 mg.
The present invention also provides a method of treating non-small cell lung cancer in a patient comprising administering to a patient in need of such treatment an effective amount of a combination of rituximab and an effective amount of pembrolizumab, wherein the rituximab is administered at a dose of 800mg on days 1 and 8 of each 3-week cycle, and wherein pembrolizumab is administered at a dose of 200mg on day 1 of each 3-week cycle.
The invention also provides for rituximab for simultaneous, separate or sequential use in combination with pembrolizumab in the treatment of non-small cell lung cancer in a patient, the treatment comprising in vitro assaying a sample of the patient's tumor tissue for the protein expression level of PD-L1, and administering therapeutically effective amounts of rituximab and pembrolizumab comprising administering a 800mg dose of rituximab and a 200mg dose of pembrolizumab if the expression of PD-L1 is such that less than 50% of the viable tumor cells exhibit partial or complete membrane staining.
The invention also provides pembrolizumab for simultaneous, separate or sequential use in combination with tolituzumab for treating non-small cell lung cancer in a patient, the treatment comprising assaying a sample of tumor tissue of the patient in vitro for the protein expression level of PD-L1, and administering therapeutically effective amounts of pembrolizumab and tolituzumab, including administering a 800mg dose of tolituzumab and a 200mg dose of pembrolizumab if the expression of PD-L1 is such that less than 50% of the viable tumor cells exhibit partial or complete membrane staining.
The present invention also provides a method of treating non-small cell lung cancer in a patient comprising the steps of: (1) measuring the protein expression level of PD-L1 in a tumor tissue sample taken from the patient, and (2) administering to a patient in need of such treatment an effective amount of a combination of tolituzumab-plus an effective amount of pembrolizumab comprising administering a 800mg dose of tolituzumab-plus a 200mg dose of pembrolizumab if PD-L1 is expressed such that less than 50% of the viable tumor cells exhibit partial or complete membrane staining.
The invention also provides a method of treating non-small cell lung cancer in a patient comprising administering to the patient a dose of 800mg of rituximab and a dose of 200mg of pembrolizumab, with the proviso that a sample of tumor tissue of the patient contains PD-L1 at a protein expression level that less than 50% of the viable tumor cells exhibit partial or complete membrane staining.
An antibody or full length antibody is an immunoglobulin molecule comprising two heavy chains and two light chains interconnected by disulfide bonds. The amino-terminal portion of each chain includes a variable region of about 100-110 amino acids, which is primarily responsible for antigen recognition via the Complementarity Determining Regions (CDRs) contained therein. The carboxy-terminal portion of each chain defines a constant region primarily responsible for effector function.
As used herein, the term "antibody 1" refers to any antibody comprising the amino acid sequence:
heavy chain variable region
Light chain variable region
An antibody having the following heavy and light chain sequences will meet the definition of antibody 1 as used herein:
heavy chain
Light chain
In one aspect of the invention, "rituximab-resistant" refers to any antibody that is rituximab-resistant as defined by the international non-proprietary name (INN) as found in WHO Drug information vol 23, number 3, 2009, pp.253-254. As mentioned above, rituximab is an active pharmaceutical ingredient of Portrazza @. It is also identified as IMC-11F8 and CAS registry number 906805-06-9. Rituximab is an example of antibody 1.
As used herein, the term "antibody 2" refers to any antibody comprising the amino acid sequence:
heavy chain variable region
Light chain variable region
An antibody having the following heavy and light chain sequences will meet the definition of antibody 2 as used herein:
heavy chain
Light chain
In one aspect of the invention, "pembrolizumab" refers to any antibody that is pembrolizumab as defined by the international non-proprietary name (INN) as found in WHO Drug Information vol.28, number 3, 2014, p.407. As mentioned above, pembrolizumab is an active pharmaceutical ingredient in Keytruda ®. It is also identified as MK-3475; SCH-900475; lambrolizumab; lambrolizumab and CAS registry number 1374853-91-4. Pembrolizumab is an example of antibody 2.
As used herein, the terms "treating", "treating" or "treatment" refer to inhibiting, slowing, arresting, reducing or reversing the progression or severity of an existing symptom, disorder, condition, disease or cancer.
As used herein, the term "patient" refers to a mammal, preferably a human.
As used herein, the terms "cancer" and "cancerous" refer to or describe a physiological condition in a patient that is generally characterized by unregulated cell growth. Included in this definition are benign and malignant cancers. Examples of cancer include NSCLC, among others.
The term "kit" as used herein refers to a package comprising at least two separate containers, wherein a first container contains a pharmaceutical composition comprising antibody 1 and a second container contains a pharmaceutical composition comprising antibody 2. The "kit" may further comprise instructions for administering all or part of the contents of these first and second containers to a cancer patient.
A potential advantage of the combination therapy of the present invention is that it is possible to produce significant and/or prolonged anti-cancer effects in patients with an acceptable safety profile, including acceptable tolerability, toxicity and/or adverse events, such that the patients benefit from the overall combination therapy approach. The efficacy of the combination therapy of the invention can be measured by various endpoints commonly used in evaluating cancer treatments, including, but not limited to: tumor regression, tumor weight or size reduction, time to progression, overall survival, progression-free survival, overall response rate, response duration, and quality of life. The therapeutic agent used in the present invention may cause inhibition of metastatic spread without shrinking the primary tumor, or may simply exert a tumor-inhibiting effect. Because the present invention involves the use of unique combinations of antineoplastic agents, various methods of determining the efficacy of any particular combination therapy of the present invention can optionally be employed, including, for example, cell cycle-dependent biomarker measurement/visualization, and measuring response by radiographic imaging.
As used herein, the term Complete Response (CR) is defined as the disappearance of all target lesions. Any pathological lymph node (whether targeted or non-targeted) must be reduced to <10 mm in the minor axis. Tumor marker results must have been normalized.
As used herein, the term Partial Response (PR) is defined as a reduction of at least 30% of the sum of the diameters of the target lesions, the baseline sum diameter being used as a reference.
As used herein, the term disease Progression (PD) is defined as the sum of the target lesion diameters increased by at least 20%, with the smallest sum in the study being used as a reference (including the baseline sum if that is the smallest). In addition to a relative increase of 20%, the sum must also indicate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. For progressive ambiguous findings (e.g., very small and uncertain new lesions; cystic changes or necrosis in existing lesions), treatment may continue until the next scheduled evaluation. If progression is confirmed in the evaluation of the next schedule, the date of progression should be an earlier date in which progression is suspected.
As used herein, the term disease Stability (SD) is defined as neither shrinking enough to comply with PR, increasing nor complying with PD, the minimum sum diameter in the study being used as a reference.
As used herein, the term non-evaluable (NE) is defined as the ability to affect a reliable assessment of the response when an incomplete radiological assessment of the target lesion is performed or there is a change from the baseline measurement method.
As used herein, the term progression-free survival (PFS) is defined as the time from the date of the first dose of any study drug until the date of radiographic recording of PD or death due to any cause (whichever precedes).
As used herein, the term Overall Survival (OS) is defined as the time from the date of the study first dose of any study drug to the date of death for any reason.
As used herein, the term objective response rate is defined as the proportion of patients who achieve the best overall response for PR or CR.
As used herein, the term Disease Control Rate (DCR) is defined as the proportion of patients who achieve the best overall response to SD, PR, or CR.
As used herein, the term overall response rate is based on the best objective response per patient and will be determined for all evaluable patients via the response assessment criteria for solid tumors (RECIST) v 1.1 criteria. The overall response rate (%) will be calculated as the number of patients with the best objective response of CR or PR divided by the number of patients with measurable disease at baseline. The optimal objective response for a given patient will be based on the objective response determined from the obtained data, up to: progression or final evaluable assessment without progression. Patients with no certainty of an objective response, or patients with the best objective response being NE, will be considered non-responders. The overall response rates will be summarized together with the 95% cloner Pearson confidence interval.
As used herein, the term "effective amount" refers to the amount or dose of antibody 1 (including but not limited to rituximab) and the amount or dose of antibody 2 (including but not limited to pembrolizumab) that provides an effective response in a diagnosed or treated patient upon administration of a single or multiple doses to the patient. It is also understood that the combination therapy of the present invention is carried out by administering antibody 1 (including but not limited to rituximab) along with antibody 2 (including but not limited to pembrolizumab) in any manner that provides effective levels of antibody 1 (including but not limited to rituximab) and antibody 2 (including but not limited to pembrolizumab) in vivo.
An effective amount can be readily determined by one skilled in the art by using known techniques and by observing results obtained under similar circumstances. In determining an effective amount for a patient, the attending diagnostician considers a number of factors, including but not limited to: the species of the patient; its size, age and overall health; the particular disease or condition involved; the degree or involvement or severity of the disease or disorder; the response of the individual patient; the specific compound administered; a mode of administration; bioavailability characteristics of the administered preparation; a selected dosage regimen; the medicines are used in a combined way; and other related circumstances.
As used herein, the term "effective response" to a patient being treated with a combination of agents or "responsiveness" of a patient and similar phrases, refers to a clinical or therapeutic benefit imparted to a patient upon co-administration of antibody 2 (including but not limited to pembrolizumab) and antibody 1 (including but not limited to rituximab). Such benefits include any one or more of the following: extended survival (including OS and PFS); results in objective responses (including CR or PR); or improving signs or symptoms of cancer, etc.
Antibody 1 (including but not limited to rituximab) is generally effective within the dosage range of the combination of the invention. For example, the dose per 21-day cycle generally falls within the following ranges: the 2-day dose of the cycle is about 400 to 800mg, preferably about 400 to 800mg on days 1 and 8 of each 21-day cycle, more preferably about 600 to 800mg on days 1 and 8 of each 21-day cycle, and most preferably about 800mg on days 1 and 8 of each 21-day cycle. Antibody 2 (including but not limited to pembrolizumab) is generally effective within the dosage range of the combination of the invention. For example, the dose per 21-day cycle typically falls within the range of about 1 mg/kg to about 3 mg/kg as an intravenous infusion over 30 minutes, more preferably about 2 mg/kg as an intravenous infusion over 30 minutes. Alternatively, the dose per 21-day cycle typically falls within the range of about 100 mg to about 300 mg as an intravenous infusion over 30 minutes, more preferably about 200mg as an intravenous infusion over 30 minutes.
The dosage regimen may be adjusted or tailored for patient safety to provide the best desired response (e.g., therapeutic response). For intravenous administration ofi.vA dosing schedule for non-intravenous administration, local or systemic, or a combination thereof typically ranges from a single bolus dose or continuous infusion to multiple administrations per day (e.g., every 4-6 hours), or as indicated by the treating physician and the patient's condition. As used herein, intravenous infusion and intravenous injection are used interchangeably.
The phrase "in combination with" as used herein refers to the simultaneous administration of antibody 1 and antibody 2. The phrase "in combination with" as used herein also refers to the sequential administration of antibody 1 and antibody 2 in any order. The phrase "in combination with" as used herein also refers to administering antibody 1 and antibody 2 in any combination thereof. Antibody 2 can be administered prior to administration of antibody 1. Antibody 2 can be administered simultaneously with administration of antibody 1. Antibody 2 can be administered after antibody 1. Antibody 2 can be administered prior to, concurrently with, or after administration of antibody 1, or in some combination thereof.
In the case where antibody 1 is administered at repeated intervals (e.g., during a standard course of treatment), antibody 2 may be administered prior to each administration of antibody 1. In the case where antibody 1 is administered at repeated intervals (e.g., during a standard course of treatment), antibody 2 may be administered simultaneously with each administration of antibody 1. In the case where antibody 1 is administered at repeated intervals (e.g., during a standard course of treatment), antibody 2 may be administered after each administration of antibody 1. In the case where antibody 1 is administered at repeated intervals (e.g., during the course of standard therapy), antibody 2 may be administered prior to, concurrently with, or after each administration of antibody 1, or in some combination thereof. In the case where antibody 1 is administered at repeated intervals (e.g., during a standard course of treatment), antibody 2 may be administered at different intervals relative to therapy with antibody 1. In the case where antibody 1 is administered at repeated intervals (e.g., during the course of standard therapy), antibody 2 may be administered at a single or series dose before, during, any time or after the course of therapy with antibody 1. In the case where antibody 1 is administered at repeated intervals (e.g., during the course of standard therapy), antibody 2 may be administered at a single dose before, during, or after the course of therapy with antibody 1. In the case where antibody 1 is administered at repeated intervals (e.g., during a standard course of treatment), antibody 2 may be administered at a single dose prior to the course of treatment with antibody 1. In the case where antibody 1 is administered at repeated intervals (e.g., during the course of standard therapy), antibody 2 may be administered at a single dose at any time during the course of therapy with antibody 1. In the case where antibody 1 is administered at repeated intervals (e.g., during the course of standard therapy), antibody 2 may be administered at a single dose following the course of therapy with antibody 1. In the case where antibody 1 is administered at repeated intervals (e.g., during a standard course of treatment), antibody 2 may be administered in a series of doses prior to the course of treatment with antibody 1. In the case where antibody 1 is administered at repeated intervals (e.g., during the course of standard therapy), antibody 2 may be administered in a series of doses following the course of therapy with antibody 1. In the case where antibody 1 is administered at repeated intervals (e.g., during the course of standard therapy), antibody 2 may be administered in a series of doses following the course of therapy with antibody 1.
The present invention contemplates the use of PD-1 ligands, more specifically PD-L1, as biomarkers for cancer patients who respond to treatment when the cancer has PD-1 expression. The present invention further contemplates methods of predicting successful treatment of a patient with a combination of antibody 1 and antibody 2 by measuring the level of PD-L1 in the tumor tissue of the patient.
One aspect of the invention is a method of treating non-small cell lung cancer in a patient, comprising the steps of: (1) measuring the level of PD-L1 in a tumor tissue sample taken from the patient, and (2) administering to a patient in need of such treatment an effective amount of antibody 1 in combination with an effective amount of antibody 2 if the PD-L1 level is such that less than 50% of the viable tumor cells exhibit partial or complete membrane staining.
The present invention also contemplates a method for determining whether a subject with cancer is a candidate for a combination of antibody 1 and antibody 2, comprising: (1) determining ex vivo or in vitro the protein expression level of PD-L1 in a tumor tissue sample of the subject; and (2) wherein less than 50% of the viable tumor cells having a PD-L1 level exhibit partial or complete membrane staining, indicating that the subject is a candidate for the combination.
The present invention also contemplates a therapeutic regimen for treating non-small cell lung cancer comprising: a) selecting a patient having non-small cell lung cancer and having a protein expression level of PD-L1 that is less than 50% that shows partial or complete membrane staining of viable tumor cells, and b) administering to the patient a dose of 800mg of antibody 1 on days 1 and 8 of each 3-week cycle and a dose of 200mg of antibody 2 on day 1 of each 3-week cycle to the patient, the antibody 1 comprising two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID NO:1, and wherein the light chains comprise an LCVR having the amino acid sequence of SEQ ID NO:2, and the antibody 2 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID NO:5, and the light chains comprise an LCVR having the amino acid sequence of SEQ ID NO: 6.
The present invention contemplates a method of treating non-small cell lung cancer in a patient comprising administering to said patient a 800mg dose of antibody 1 and a 200mg dose of antibody 2, said antibody 1 comprising two heavy chains and two light chains, wherein said heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 1, and wherein said light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 2, and said antibody 2 comprises two heavy chains and two light chains, wherein said heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 5, and said light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 6, with the proviso that a sample of tumor tissue from the patient contains a protein expression level of PD-L1 that exhibits partial or complete membrane staining for less than 50% of live tumor cells.
The invention also contemplates an in vitro method of selecting a patient having non-small cell lung cancer for treatment with an 800mg dose of antibody 1 and a 200mg dose of antibody 2, said antibody 1 comprising two heavy chains and two light chains, wherein said heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 1, and wherein said light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 2, and said antibody 2 comprises two heavy chains and two light chains, wherein said heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 5, and said light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 6, said method comprising testing the protein expression level of PD-L1 in a tumor tissue sample from the patient, wherein if the protein expression level of PD-L1 is such that less than 50% of the live tumor cells exhibit partial or complete membrane staining, the patient is selected.
The invention also contemplates a method of identifying a patient having non-small cell lung cancer eligible for treatment with a 800mg dose of antibody 1 and a 200mg dose of antibody 2, said antibody 1 comprising two heavy chains and two light chains, wherein said heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 1, and wherein said light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 2, and said antibody 2 comprises two heavy chains and two light chains, wherein said heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 5, and said light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 6, said method comprising testing a tumor tissue sample from the patient for protein expression levels of PD-L1, wherein if the protein expression level of PD-L1 is such that less than 50% of the live tumor cells exhibit partial or complete membrane staining, the patient is eligible for treatment with the combination of antibody 1 and antibody 2.
The PD-L1 expression levels may be measured in various methods, including qualitative immunohistochemical assays, such as concomitant diagnosis by FDA approved for keyru da (pembrolizumab), PD-L1 IHC22C3 pharmDx. IHC PD-L1 IHC22C3 pharmDx was indicated as an adjunct to identifying NSCLC patients for treatment with KEYTRUDA (pembrolizumab). "PD-L1 IHC22C3 pharmDx is a qualitative immunohistochemical assay using monoclonal mouse Anti-PD-L1, Clone 22C3, intended for detection of PD-L1protein in formalin fixed, paraffin embedded (FFPE) non-small cell lung cancer (NSCLC) tissues using the EnVision FLEX visualization system on Autostainer Link 48 (PD-L1 IHC22C3 pharmDx a qualitative immunological tissue using monoclonal antibody PD-L1, Clone 22C3 embedded for the detection of the PD-L1protein in the tissue of the monoclonal antibody PD-L1, purified-labeled (FFPE) non-small cell lung cancer (NSCLC) tissue. PD-L1protein expression (PD-L1 protein expression expressed by determined by using Tumor Proportion Score (TPS), which is the percentage of viable tumor cells showing partial or complete membrane staining, white is the percentage of viable cells or complete membrane staining). "(IHC PD-L1 IHC22C3 pharmDx, approach Order Letter for PMA P150013, 2 November 2015.)
The following examples and results of clinical studies further illustrate the present invention.
The following clinical study design further illustrates the present invention, but should not be construed as limiting the scope of the invention in any way.
For example, rituximab or antibody 1 may be prepared according to the disclosure in WO 2005/090407. For example, pembrolizumab or antibody 2 may be prepared according to the disclosure in WO 2008/156712.
Study of combinations of rituximab and pembrolizumab on patients with stage IV NSCLC
Design of clinical study
An open label, single-cohort, multicenter phase 1b study (hereinafter "study") that studies the efficacy, safety and tolerability of a combination of tolituzumab ozogamicin and pembrolizumab in-65 patients with stage IV NSCLC, including squamous and non-squamous NSCLC. See NCT02451930 available on clinicalters. The study consisted of several parts, including:
● part A: in patients with stage IV NSCLC, increasing doses of tolituzumab (600 mg and 800mg IV) on days 1 and 8 every 3 weeks (Q3W) were administered in combination with pembrolizumab (200 mg IV) on day 1Q 3W.
● part B: an expanded cohort of combinations of the dose of rituximab identified in part a with a fixed pembrolizumab regimen of Q3W (200 mg IV) on day 1 in patients with stage IV NSCLC.
Approximately 54 patients were enrolled in section B and approximately equally divided between patients with squamous and non-squamous histology.
Patients will be treated until PD, toxicity needs to be stopped, protocol noncompliance or consent withdrawn. Patients who continue study therapy at study completion may continue to receive study therapy for a continued entry period until they meet the stopping criteria. Study completion is expected approximately 6-12 months after the last patient has been enrolled.
The primary qualifying criteria include: progression after 1 platinum-based chemotherapy; ECOG PS 0-1; no prior treatment with anti-PD-1, -PD-L1, or-PD-L2 agents; and no symptomatic brain metastases.
PD-L1 and EGFR status will be evaluated in archived tissue samples. The PD-L1 expression levels were measured using a companion diagnosis approved by the FDA for KEYTRUDA (Pimex) PD-L1 IHC22C3 pharmDx.
A PD-L1 negative status is assigned to the patient when PD-L1protein is expressed such that less than 1% of the viable tumor cells show partial or complete membrane staining as determined by using the Tumor Proportion Score (TPS). A low positive status of PD-L1 is assigned to the patient when 1-49% of the live tumor cells expressing the PD-L1protein show partial or complete membrane staining as determined by using the Tumor Proportion Score (TPS). A high positive state of PD-L1 is assigned to a patient when PD-L1protein is expressed such that more than 50% of the viable tumor cells show partial or complete membrane staining as determined by using the Tumor Proportion Score (TPS).
Object of study
The primary objective of part a of this study was to study the safety and tolerability of pembrolizumab 200mg Q3W in patients with stage IV NSCLC (all histologies) when combined with tolituzumab therapy administered at doses of 600 mg and 800mg on days 1 and 8 of the 21-day cycle, as measured by the number of patients with DLT during cycle 1; and the main objective of part B is to assess the efficacy of the combination of rituximab with pembrolizumab in terms of ORR by RECIST1.1 in patients with stage IV NSCLC with squamous and non-squamous histology.
Secondary goals of the study included: for part a: (i) study safety profiles, as assessed by important clinical and laboratory events for the combination of rituximab and pembrolizumab; (ii) determining ORR (by RECIST 1.1); (iii) determining the PK of rituximab-resistant in the presence of pembrolizumab; (iv) determining the immunogenicity of the rituximab-resistant in the presence of pembrolizumab; for part B: (v) demonstrating the feasibility of combining rituximab with pembrolizumab at the recommended dose by: (1) study safety profiles as assessed by clinical and laboratory important events, and determine Disease Control Rate (DCR), duration of response (DOR), and PFS by RECIST1.1, and OS; (2) determining the PK of rituximab-resistant in the presence of pembrolizumab; and (3) determining the immunogenicity of the rituximab in the presence of pembrolizumab. The association of potential biomarkers with clinical outcome can also be evaluated.
Test drugs:
nixituzumab is a sterile, preservative-free I.V. infusate supplied at a final concentration of 16mg/mL (800 mg/50 mL) contained in disposable vials in a formulation of 10mM citrate, 40 mM sodium chloride, 133 mM glycine, 50mM mannitol, 0.01% polysorbate- (TWEEN) -80, pH 6.0.
Pembrolizumab is a sterile, preservative-free, white to off-white lyophilized powder in a disposable vial. Each vial was reconstituted and diluted for intravenous infusion. Each 2 mL of reconstitution solution contained 50 mg pembrolizumab and was formulated in L-histidine (3.1 mg), polysorbate 80 (0.4 mg), and sucrose (140 mg). Hydrochloric acid/sodium hydroxide may be included to adjust the pH to 5.5.
The research results are as follows:
part A was completed without dose-limiting toxicity (9 patients; 2 squamous, 7 non-squamous). Part B (extended study) was started with 800mg of tolituzumab-resistant in 2015 at 12 months.
The clinical features of patients are typical of those with advanced non-small cell lung cancer; of note, slightly more than expected patients without PD-L1 expression (50% without expression). Notably, 7/34 (21%) patients were never smokers and 3/34 (9%) patients were treated with EGFR TKI as the first-line therapy, indicating the presence of EGFR mutations. Historically, these patients have responded poorly to PD-1-directed antibodies.
Based on the six mid-month efficacy analysis, also the primary outcome analysis of the non-squamous NSCLC cohort, data from all lesions (confirmed and not confirmed) of 34 patients (7 non-squamous patients from section a and 27 non-squamous patients from section B) demonstrated an objective response rate of 29% for patients receiving a combination of tolituzumab and pembrolizumab, and a disease control rate of 68%. The median PFS was 6.9 months (with 95% confidence interval [ CI ] 2.7-NR) and the 6-month PFS rate was 55% (95% CI 36-71). The best overall reaction shows: 0 CR, 10 PR (29%), 12 SD (38%), 7 PD (21%) and 4 were not evaluated (12%) due to no baseline post-scan.
Thus, the 6-month interim results indicate that the combination of rituximab-resistant with pembrolizumab provides an ORR and PFS that are improved over the historical single agent activity of pembrolizumab seen in the Keynote 001 study (KN001) (Garon E et al, N Engl J Med 2015;372: 2018-28). The combination of tolituzumab and pembrolizumab demonstrates a numerical benefit compared to pembrolizumab based on historical data when compared to median PFS and 6-month PFS rate of pembrolizumab alone as seen in the KN001 study.
Based on PD-L1 status, the overall response rate was 18.0% in 17 PD-L1 negative patients, 60% in 5 PD-L1 low positive patients, and 40% in 5 PD-L1 high positive patients, compared to 9%, 15%, and 41% for the same class in KN001, respectively. When patients who did not smoke and who received prior EGFR TKI were excluded, ORR was 38%, which included a response rate of 25% in PD-L1 non-expressing patients, a response rate of 75% in PD-L1 low expressing patients and a response rate of 50% in PD-L1 high expressing patients.
Thus, less than 50% of PD-L1 expression compared to pembrolizumab indicates an improved potency response to the combination of cetuximab and pembrolizumab.
The safety profile of the combination corresponds to the individual profiles of the two drugs, where there is no additive toxicity.
Data cutoff of 2016, 2, 11 and a month
18 patients (neci 600 mg n =3, 800mg n =15) were eligible for inclusion. The patients were 44.4% female with a median age of 66.5 years [ range 48-76], and adenocarcinoma histology 77.8%. All patients experienced Adverse Events (AE) that occurred after ≥ 1 treatment, of which ≥ 1 was associated with study treatment (Table 1). 4 severe AEs occurred in 3 (16.7%) patients (all respiratory and mediastinal); none are treatment related. No cessation or death was due to AE. AEs occurring at >15% frequency are listed in the table below. 4 (22.2%) patients experienced 8 grades >2 AE: acute respiratory failure, hypokalemia, hypophosphatemia, infusion-related reactions, pulmonary embolism, elevated γ -glutamyl transferase (1 patient at a time) and dyspnea (2 patients).
The combination of tolituzumab and pembrolizumab appears to be tolerable. The safety profile corresponds to the individual profiles of the two drugs, where there is no additive toxicity.
Additional clinical disclosure
This phase 1b, multicenter, single-panel study resistant to both rituximab and pembrolizumab examined safety, efficacy, and tolerability in pre-treated patients with stage IV NSCLC (NCT 02451930). PDL1 (negative, weakly positive, strongly positive if <1%, 1-49%, ≧ 50% of tumor cells were stained, respectively) was retrospectively centrally assessed using the IHC22C3 pharmDx assay. Increasing doses of rituximab 600-800 mg IV (every 3 weeks [ Q3W ] day 1 and day 8) were administered together with a fixed dose of pembrolizumab (200 mg IV) of Q3W on day 1 (part A). A determined dose of tolituzumab from part a (part B) was used in the expanded cohort. The objective of the study in part a was to determine dose-limiting toxicity (DLT) and to evaluate tolerability and Overall Response Rate (ORR) by RECIST 1.1.
Part a of the study was completed (increasing dose of rituximab in combination with standard dose of pembrolizumab) without dose-limiting toxicity (DLT); the combination is tolerable. No additive, new or unexpected Adverse Events (AEs) were seen, and the safety results corresponded to those for each drug.
Part B the main objective was to assess ORR by RECIST1.1 of resistant rituximab when combined with pembrolizumab in patients with stage IV NSCLC who had progressed following 1 platinum-based chemotherapy regimen.
Part B secondary objectives were to determine Disease Control Rate (DCR), duration of response (DoR) and Progression Free Survival (PFS) (by RECIST 1.1), safety and OS; immunogenicity and Pharmacokinetics (PK) of rituximab-resistant (in the presence of pembrolizumab).
A total of 64 patients (part a and part B) with squamous (n =30) and non-squamous (n = 34) histology were enrolled. Results for 64 patients were reported. Patient demographics and characteristics are shown in table 2. Efficacy results by PDL1 status and histology are also shown in table 2. PDL1 (negative, weakly positive, strongly positive if <1%, 1-49%, ≧ 50% of tumor cells were stained, respectively) was retrospectively centrally assessed using the IHC22C3 pharmDx assay.
Tumor response was assessed according to RECIST1.1 radiology. Initial tumor imaging was performed within 21 days of the first dose treatment; subsequent image evaluations were then performed every 6 weeks.
The null hypothesis was based on the hypothesis that ORR was 20% and the replacement response rate of the combination treatment to ORR was 35%, the sample size of 54 evaluable patients (27 squamous and 27 non-squamous) in section B provided a statistical efficacy of 83%, with a nominal unilateral α level of 0.10.
The baseline characteristics and efficacy results for both overall and by histology are provided in table 2.
The results indicate a modest activity of this combination in NSCLC patient populations with a relatively high proportion of PDL1 negative tumors.
In all evaluable patients, regardless of histology or PDL1 status: ORR (confirmed) 23.4% (95% CI, 13.8% -35.7%); DCR (validated) 64.1% (95% CI, 51.1% -75.7%); mPFS 4.1 mo (95% CI, 2.4-6.9); and an OS rate of 74.7% (95% CI, 61.5% -83.9%) at 6 months.
ORR was similar in squamous and non-squamous histology (20.0% vs 26.5%, respectively). However, PFS was better in the non-squamous group than in the squamous group (mPFS was 6.9 mo vs 2.8 mo, respectively).
Efficacy appears to correlate with the PDL1 status of strong positive, weak positive and negative, respectively: ORR 40.0%, 25.0%, and 12.5%; and mPFS 7.6 mo, 5.4 mo and 2.7 mo.
ECOG PS, eastern tumor cooperative group performance status; PDL1, programmed death ligand 1; ORR, overall response rate; mPFS, median progression-free survival; OS, overall survival; CI, confidence interval; NR, not reached; m, month.
The safety profile of the combination corresponds to the individual profiles of the two therapeutic components and no additive effect was seen.>Adverse events occurring after treatment in 10% of patients are shown in table 3. A summary of safety is shown in table 4. While most patients experience any grade of treatment-related ae (TRAE), less than 10% experience at least 1 grade 3 or higher of TRAE.
aThe denominator is adjusted for female patients only.
bGrade 5 respiratory tract infections twice.
The results indicate the activity of the combination of rituximab and pembrolizumab in a pre-treated NSCLC patient population with a relatively high proportion of PDL1 negative patients. The safety profile corresponds to the individual profiles of the two drugs, where there is no additive toxicity. The combination of PD 1 and EGFR blockade may be a therapeutic strategy that extends the duration of the therapeutic response and delays resistance development in a biomarker-selected population.
Sequence of
< SEQ ID NO:1; PRT1; Artificial sequence >
Variable region of heavy chain of anti-Xituzumab
< SEQ ID NO:2; PRT1; Artificial sequence >
Variable region of light chain of anti-Xituzumab
< SEQ ID NO:3; PRT1; Artificial sequence >
Heavy chain of anti-rituximab
< SEQ ID NO:4; PRT1; Artificial sequence >
Light chain of rituximab-resistant
< SEQ ID NO:5; PRT1; Artificial sequence >
Pemumab heavy chain variable region
< SEQ ID NO:6; PRT1; Artificial sequence >
Pemumab light chain variable region
< SEQ ID NO:7; PRT1; Artificial sequence >
Heavy chain of pembrolizumab
< SEQ ID NO:8; PRT1; Artificial sequence >
Light chain of pembrolizumab
Sequence listing
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1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
Asp Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asp Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Val Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Val Ser Ile Phe Gly Val Gly Thr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Leu Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210>4
<211>214
<212>PRT
<213> Artificial sequence
<220>
<223> synthetic peptide
<400>4
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 7580
Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Tyr Gly Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Ala Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210>5
<211>120
<212>PRT
<213> Artificial sequence
<220>
<223> synthetic peptide
<400>5
Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln
100 105110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210>6
<211>111
<212>PRT
<213> Artificial sequence
<220>
<223> synthetic peptide
<400>6
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser
20 25 30
Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ser Arg
8590 95
Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210>7
<211>447
<212>PRT
<213> Artificial sequence
<220>
<223> synthetic peptide
<400>7
Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp IleAla Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210>8
<211>218
<212>PRT
<213> Artificial sequence
<220>
<223> synthetic peptide
<400>8
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser
20 25 30
Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ser Arg
85 90 95
Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
Claims (45)
1. Antibody 1 for simultaneous, separate or sequential use in combination with antibody 2 in the treatment of non-small cell lung cancer in a patient, wherein antibody 1 comprises two heavy chains and two light chains, wherein the heavy chains comprise a Heavy Chain Variable Region (HCVR) having the amino acid sequence of SEQ ID NO:1, and wherein the light chains comprise a Light Chain Variable Region (LCVR) having the amino acid sequence of SEQ ID NO:2, and wherein antibody 2 comprises two heavy chains and two light chains, wherein the heavy chains comprise a HCVR having the amino acid sequence of SEQ ID NO:5, and the light chains comprise a LCVR having the amino acid sequence of SEQ ID NO:6, and wherein antibody 1 is administered at a dose of 400 mg to 800mg, and wherein antibody 2 is administered at a dose of 200 mg.
2. Antibody 1 for use according to claim 1, wherein antibody 1 is administered at a dose of 800 mg.
3. Antibody 1 for use according to any one of claims 1 to 2, wherein antibody 1 is administered at a dose of 800mg on day 1 and day 8 of each 3-week cycle.
4. Antibody 1 for use according to any one of claims 1 to 3, wherein antibody 2 is administered at a dose of 200mg on day 1 of each 3-week cycle.
5. Antibody 1 for use according to any one of claims 1 to 4, wherein the non-small cell lung cancer is non-squamous.
6. Antibody 1 for use according to any one of claims 1 to 4, wherein the non-small cell lung cancer is squamous.
7. Antibody 1 for use according to any one of claims 1 to 6, wherein the tumor tissue from the patient has a protein expression level of PD-L1, and wherein the expression of PD-L1 is such that less than 50% of the living tumor cells show partial or complete membrane staining.
8. Antibody 2 for simultaneous, separate or sequential use in combination with antibody 1 in the treatment of non-small cell lung cancer in a patient, wherein antibody 1 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 1, and wherein the light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 2, and wherein antibody 2 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 5, and the light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 6, and wherein antibody 2 is administered at a dose of 200mg, and wherein antibody 1 is administered at a dose of 400 mg to 800 mg.
9. Antibody 2 for use according to claim 8, wherein antibody 1 is administered at a dose of 800 mg.
10. Antibody 2 for use according to any one of claims 8 to 9, wherein antibody 2 is administered at a dose of 200mg on day 1 of each 3-week cycle, and wherein antibody 1 is administered at a dose of 800mg on days 1 and 8 of each 3-week cycle.
11. Antibody 2 for use according to any one of claims 8 to 10, wherein the non-small cell lung cancer is non-squamous.
12. Antibody 2 for use according to any one of claims 8 to 10, wherein the non-small cell lung cancer is squamous.
13. Antibody 2 for use according to any one of claims 8 to 12, wherein the tumor tissue from the patient has a protein expression level of PD-L1, and wherein the expression of PD-L1 is such that less than 50% of the living tumor cells show partial or complete membrane staining.
14. Use of antibody 1 in the manufacture of a medicament for the treatment of non-small cell lung cancer, wherein antibody 1 is administered at a dose of 400 mg to 800mg in simultaneous, separate or sequential combination with antibody 2, wherein antibody 2 is administered at a dose of 200mg, and wherein antibody 1 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 1, and wherein the light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 2, and wherein antibody 2 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 5, and the light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 6.
15. The use of claim 14, wherein antibody 1 is administered at a dose of 800 mg.
16. The use of any one of claims 14 to 15, wherein the non-small cell lung cancer is non-squamous.
17. The use of any one of claims 14 to 15, wherein the non-small cell lung cancer is squamous.
18. Use of antibody 2 in the manufacture of a medicament for the treatment of non-small cell lung cancer, wherein antibody 2 is administered at a dose of 200mg in simultaneous, separate or sequential combination with antibody 1, wherein antibody 1 is administered at a dose of 400 mg to 800mg, and wherein antibody 1 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 1, and wherein the light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 2, and wherein antibody 2 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 5, and the light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 6.
19. The use of claim 18, wherein antibody 1 is administered at a dose of 800 mg.
20. The use of any one of claims 18 to 19, wherein the non-small cell lung cancer is non-squamous.
21. The use of any one of claims 18 to 19, wherein the non-small cell lung cancer is squamous.
22. A kit for treating non-small cell lung cancer comprising antibody 1 and antibody 2, and wherein antibody 1 comprises two heavy chains and two light chains, wherein the heavy chains comprise a HCVR having the amino acid sequence of SEQ ID NO:1, and wherein the light chains comprise a LCVR having the amino acid sequence of SEQ ID NO:2, and wherein antibody 2 comprises two heavy chains and two light chains, wherein the heavy chains comprise a HCVR having the amino acid sequence of SEQ ID NO:5, and the light chains comprise a LCVR having the amino acid sequence of SEQ ID NO:6, and wherein the amount of antibody 1 is 400 mg to 800mg, and the amount of antibody 2 is 200 mg.
23. The kit of claim 22, wherein the amount of antibody 1 is 800 mg.
24. The kit of any one of claims 22 to 23, wherein the non-small cell lung cancer is non-squamous.
25. The kit of any one of claims 22 to 23, wherein the non-small cell lung cancer is squamous.
26. A kit for treating non-small cell lung cancer comprising a first container and a second container, the first container containing a pharmaceutical composition comprising antibody 1 and one or more pharmaceutically acceptable carriers, diluents or excipients, and the second container containing a pharmaceutical composition comprising antibody 2 and one or more pharmaceutically acceptable carriers, diluents or excipients, and wherein antibody 1 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID NO. 1, and wherein the light chains comprise an LCVR having the amino acid sequence of SEQ ID NO. 2, and wherein antibody 2 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID NO. 5, and the light chains comprise an LCVR having the amino acid sequence of SEQ ID NO. 6, and wherein the amount of antibody 1 is 400 mg to 800mg and the amount of antibody 2 is 200 mg.
27. The kit of claim 26, wherein the amount of antibody 1 is 800 mg.
28. The kit of any one of claims 26 to 27, wherein the non-small cell lung cancer is non-squamous.
29. The kit of any one of claims 26 to 27, wherein the non-small cell lung cancer is squamous.
30. A kit comprising a first container and a second container, the first container containing a pharmaceutical composition comprising antibody 1, wherein antibody 1 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID NO. 1, and wherein the light chains comprise an LCVR having the amino acid sequence of SEQ ID NO. 2, and wherein antibody 1 is formulated with 10mM citrate, 40 mM sodium chloride, 133 mM glycine, 50mM mannitol, 0.01% polysorbate-80, pH6.0 at a final concentration of 16mg/mL, and the second container containing a pharmaceutical composition comprising antibody 2, wherein antibody 2 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID NO. 5 and the light chains comprise an LCVR having the amino acid sequence of SEQ ID NO. 6, wherein antibody 2 was formulated with 9.99 mM L-histidine, 0.15 mM polysorbate 80 and 204.68 mM sucrose at a final concentration of 25 mg/mL.
31. The kit of claim 20, wherein the amount of antibody 1 is 400 mg to 800mg, and wherein the amount of antibody 2 is 200 mg.
32. The kit of any one of claims 30 to 31, wherein the amount of antibody 1 is 800mg, and wherein the amount of antibody 2 is 200 mg.
33. A method of treating non-small cell lung cancer in a patient comprising administering to a patient in need of such treatment an effective amount of antibody 1 in combination with an effective amount of antibody 2, wherein antibody 1 comprises two heavy chains and two light chains, wherein the heavy chains comprise a Heavy Chain Variable Region (HCVR) having the amino acid sequence of SEQ ID NO:1, and wherein the light chains comprise a Light Chain Variable Region (LCVR) having the amino acid sequence of SEQ ID NO:2, and wherein antibody 2 comprises two heavy chains and two light chains, wherein the heavy chains comprise a HCVR having the amino acid sequence of SEQ ID NO:5, and the light chains comprise a LCVR having the amino acid sequence of SEQ ID NO:6, and wherein antibody 1 is administered at a dose of 400 mg to 800mg, and wherein antibody 2 is administered at a dose of 200 mg.
34. A method of treating non-small cell lung cancer in a patient comprising administering to a patient in need of such treatment an effective amount of antibody 1 in combination with an effective amount of antibody 2, wherein antibody 1 comprises two heavy chains and two light chains, wherein the heavy chains comprise the amino acid sequence of SEQ ID No. 3, and wherein the light chains comprise the amino acid sequence of SEQ ID No. 4, and wherein antibody 2 comprises two heavy chains and two light chains, wherein the heavy chains comprise the amino acid sequence of SEQ ID No. 7, and the light chains comprise the amino acid sequence of SEQ ID No. 8, and wherein antibody 1 is administered at a dose of 400 mg to 800mg, and wherein antibody 2 is administered at a dose of 200 mg.
35. The method of claim 33 or 34, wherein the amount of antibody 1 is 800 mg.
36. The method of claim 33 or 34, wherein antibody 1 is administered at a dose of 800mg on days 1 and 8 of each 3-week cycle.
37. The method of claim 33 or 34, wherein antibody 2 is administered at a dose of 200mg on day 1 of each 3-week cycle.
38. The method of claim 33 or 34, wherein the combination of antibody 1 and antibody 2 is administered simultaneously, separately or sequentially.
39. The method of claim 33 or 34, wherein the non-small cell lung cancer is non-squamous.
40. The method of claim 33 or 34, wherein the non-small cell lung cancer is squamous.
41. The method of claim 33 or 34, wherein the tumor tissue from the patient has a protein expression level of PD-L1, and wherein expression of PD-L1 is such that less than 50% of viable tumor cells exhibit partial or complete membrane staining.
42. Antibody 1 for simultaneous, separate or sequential use in combination with antibody 2 in the treatment of non-small cell lung cancer in a patient, the treatment comprising in vitro assaying a sample of the patient's tumor tissue for the protein expression level of PD-L1, and administering therapeutically effective amounts of antibody 1 and antibody 2 according to claims 1-6 if the expression of PD-L1 is such that less than 50% of the viable tumor cells show partial or complete membrane staining.
43. Antibody 2 for simultaneous, separate or sequential use in combination with antibody 1 in the treatment of non-small cell lung cancer in a patient, the treatment comprising in vitro assaying a sample of the patient's tumor tissue for the protein expression level of PD-L1, and administering therapeutically effective amounts of antibody 2 and antibody 1 according to claims 8-12 if the expression of PD-L1 is such that less than 50% of the viable tumor cells show partial or complete membrane staining.
44. A method of treating non-small cell lung cancer in a patient comprising the steps of: (1) measuring the protein expression level of PD-L1 in a tumor tissue sample taken from the patient, and (2) administering to a patient in need of such treatment an effective amount of antibody 1 in combination with an effective amount of antibody 2 according to method claim 33 or 34 if PD-L1 is expressed such that less than 50% of the viable tumor cells show partial or complete membrane staining.
45. A method of treating non-small cell lung cancer in a patient comprising administering to the patient a 800mg dose of antibody 1 and a 200mg dose of antibody 2, said antibody 1 comprising two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 1, and wherein the light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 2, and said antibody 2 comprises two heavy chains and two light chains, wherein the heavy chains comprise an HCVR having the amino acid sequence of SEQ ID No. 5, and the light chains comprise an LCVR having the amino acid sequence of SEQ ID No. 6, with the proviso that a sample of tumor tissue of the patient contains a protein expression level of PD-L1 that less than 50% of live tumor cells exhibit partial or complete membrane staining.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62/399715 | 2016-09-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK40006278A true HK40006278A (en) | 2020-05-22 |
Family
ID=
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