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1. (WO2018065938) DOSING REGIMEN OF AVELUMAB FOR THE TREATMENT OF CANCER
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DOSING REGIMEN OF AVELUMAB FOR THE TREATMENT OF CANCER

Field

The present invention relates to dosing regimens of avelumab for the treatment of cancer. In particular, the invention relates to improved dosing regimens of avelumab for the treatment of cancer.

Background

The programmed death 1 (PD-1) receptor and PD-1 ligands 1 and 2 (PD-L1 and PD-L2, respectively) play integral roles in immune regulation. Expressed on activated T25 cells, PD-1 is activated by PD-L1 (also known as B7-H1) and PD-L2 expressed by stromal cells, tumor cells, or both, initiating T-cell death and localized immune suppression (Dong et al., Nat Med 1999; 5: 1365-69; Freeman et al. J Exp Med 2000; 192: 1027-34), potentially providing an immune-tolerant environment for tumor development and growth. Conversely, inhibition of this interaction can enhance local T30 cell responses and mediate antitumor activity in nonclinical animal models (Iwai Y, et al.Proc Natl Acad Sci USA 2002; 99: 12293-97).

Avelumab is a fully human mAb of the lgG1 isotype that specifically targets and blocks PD-L1. Avelumab is the International Nonproprietary Name (INN) for the anti-PD-L1 monoclonal antibody MSB0010718C and has been described by its full length heavy and light chain sequences in WO2013079174, where it is referred to as A09-246-2. The glycosylation and truncation of the C-terminal Lysine in its heavy chain is described in WO2017097407. Avelumab has been in clinical development for the treatment of Merkel Cell Carcinoma (MCC), non-small cell lung cancer (NSCLC), urothelial carcinoma (UC), renal cell carcinoma (RCC) and a number of other cancer conditions of a dosing regimen of 10 mg/kg Q2W.

Summary of the Invention

This invention relates to dosing regimens of avelumab for the treatment of cancer. More specifically, the invention relates method of treating cancer in a patient, comprising administering to the patient a dosing regimen that provides a higher mean exposure, as measured by Ctrough or other suitable PK parameters, of avelumab in the patient, than the current dosing regimen of 10mg/kg Q2W that are used in the clinical trials.

In one embodiment, the invention relates to a method of treating a cancer in a patient, comprising administering avelumab to the patient in a dosing regimen of 5-10 mg/Kg Q1 W. In one aspect of this embodiment, the dosing regimen is 5 mg/kg Q1 W, 6 mg/kg Q1W, 7 mg/kg Q1W, 8 mg/kg Q1W, 9 mg/kg Q1W or 10 mg/kg Q1W. More preferably, the dosing regimen is 5 mg/kg Q1W, 8 mg/kg Q1W or 10 mg/kg Q1W. Even more preferably, the dosing regimen is 10 mg/kg Q1W. In another aspect of this embodiment, and in combination with any other aspects of this embodiment, the cancer is selected from the group consisting of MCC, NSCLC, RCC, bladder cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, urothelial carcinoma, breast cancer, adenocarcinoma of the stomach and thymoma. Preferably, the cancer is MCC, NSCLC, RCC, bladder cancer, ovarian cancer, head and neck cancer and gastric cancer. More preferably, the cancer is MSCLC or MCC. In another embodiment, the invention relates to a method of treating a cancer in a patient, comprising administering avelumab to the patient in a dosing regimen of 11-20 mg/kg Q2W. In one aspect of this embodiment, the dosing regimen is 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg/kg Q2W. Preferably, the dosing regimen is 13, 15, 17 or 20 mg/kg Q2W. More preferably, the dosing regimen is 15 or 20 mg/kg Q2W. Even more preferably, the dosing regimen is 20 mg/kg Q2W. In another aspect of this embodiment, and in combination with any other aspects of this embodiment, the cancer is selected from the group consisting of MCC, NSCLC, RCC, bladder cancer, ovarian cancer, head and neck cancer gastric cancer, mesothelioma, urothelial carcinoma, breast cancer, adenocarcinoma of the stomach and thymoma. Preferably, the cancer is MCC, NSCLC, RCC, bladder cancer, ovarian cancer, head and neck cancer gastric cancer. More preferably, the cancer is MSCLC or MCC.

In another embodiment, the invention relates to a method of treating a cancer in a patient, comprising administering avelumab to the patient in a dosing regimen of 15-30mg/kg Q3W. In one aspect of this embodiment, the dosing regimen is, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28 29 or 30 mg/kg Q3W. Preferably, the dosing regimen is 15, 20, 25 or 30 mg/kg Q3W. More preferably, the dosing regimen is 15, 20 or 25mg/kg Q3W. Even more preferably, the dosing regimen is 20mg/kg Q3W. In another aspect of this embodiment, and in combination with any other aspects of this embodiment, the cancer is selected from the group consisting of MCC, NSCLC, RCC, bladder cancer, ovarian cancer, head and neck cancer gastric cancer, mesothelioma, urothelial carcinoma, breast cancer, adenocarcinoma of the stomach and thymoma. Preferably, the cancer is MCC, NSCLC, RCC, bladder cancer, ovarian cancer, head and neck cancer gastric cancer. More preferably, the cancer is MSCLC or MCC.

In another embodiment, the invention relates to a method of treating a cancer in a patient, comprising administering avelumab to the patient in a dosing regimen of X mg/kg QlW for n weeks followed by Y mg/kg Q2W, wherein X is 5-20, Y is 10-20, n is 6, 12 or 18. In one aspect of this embodiment, n is 12. In another aspect of the embodiment, n is 6. In another aspect of the embodiment, and in combination with any other aspect of this embodiment, X is 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 19, 18, 19 or 20. Preferably, X is 5, 10, 15 or 20. More preferably, X is 5, 10, or 15. Even more preferably, X is 10. In another aspect of the embodiment, and in combination with any other aspect of this embodiment, Y is 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20. Preferably, Y is 10, 15 or 20. More preferably, Y is 10. In another aspect of this embodiment, and in combination with any other aspects of this embodiment, the cancer is selected from the group consisting of MCC, NSCLC, RCC, bladder cancer, ovarian cancer, head and neck cancer gastric cancer, mesothelioma, urothelial carcinoma, breast cancer, adenocarcinoma of the stomach and thymoma. Preferably, the cancer is MCC, NSCLC, RCC, bladder cancer, ovarian cancer, head and neck cancer gastric cancer. More preferably, the cancer is MSCLC or MCC.

In some embodiments, a flat dose can be used in place of the mg/kg dose mentioned above. Correlation between mg/kg dose and the flat dose can be made, e.g., as follows: 5 mg/kg is about 500 mg flat dose; 10 mg/kg is about 800 mg; 1 1 mg/mg is about 900mg; 15 mg/kg is about 1240 mg flat dose; 20 mg is about 1600 mg flat dose and 30 mg/kg is about 2400 mg flat dose. Therefore, in another embodiment of the invention, the aforementioned embodiments based on a mg/kg dosing regimen of avelumab can be replaced with the corresponding flat dosing regimen as described herein.

In other embodiments, the invention relates to a method of treating a cancer in a patient, comprising administering avelumab to the patient a flat dosing regimen of avelumab. In one aspect of the embodiment, the flat dosing regimen is 400-800 mg flat dose Q1W. Preferably, the flat dosing regimen is 400 mg, 450 mg, 500 mg, 550 mg,

600 mg, 650 mg, 700 mg, 750 mg or 800 mg flat dose Q1W. Preferably, the flat dosing regimen is 800 mg flat dose Q1W. In another aspect of this embodiment, the flat dosing regimen is 880 - 1600 mg flat dose Q2W. Preferably the flat dosing regimen is 880 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1 100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg or 1600 mg flat dose Q2W. More preferably, the flat dosing regimen is 1200 mg or 1600 mg flat dose Q2W. In another aspect of this embodiment, the flat dosing regimen is 1200 - 2400 mg flat dose Q3W, preferably 1200 mg Q3W. Preferably, the flat dosing regimen is 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg or 2400 mg flat dose Q3W. More preferably, the dosing regimen is 1200 mg flat dose Q3W. In another aspect of the embodiment, the flat dosing regimen is 400-1600mg QlW for n weeks followed by 800-1600mg Q2W, wherein n is 6, 12 or 18. Preferably, the flat dosing regimen is 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1050 mg, 1 100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg or 1600 mg QlW for n weeks followed by 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1 100 mg, 1 150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg or 1600 mg Q2W. More preferably, the dosing regimen is 800 mg flat dose QlW for n weeks followed by 800mg flat dose Q2W. Even more preferably, n is 12. In another aspect of this embodiment, the flat dosing regimen is 400-800 mg flat dose Q2W. Preferably, the flat dosing regimen is 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg 750 mg or 800 mg flat dose Q2W. More preferably, the flat dosing regimen is 800 mg flat dose Q2W. In another aspect of this embodiment, and in combination with any other aspects of this embodiment not inconsistent, the cancer is selected from the group consisting of MCC, NSCLC, RCC, bladder cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, urothelial carcinoma, breast cancer, adenocarcinoma of the stomach and thymoma. Preferably, the cancer is MCC, NSCLC, RCC, bladder cancer, ovarian cancer, head and neck cancer gastric cancer. More preferably, the cancer is NSCLC or MCC.

In another embodiment, the invention is directed to a method of treating a cancer comprising administering to the patient avelumab in a dosing regimen as described in any of the proceeding embodiments, wherein the patient has a TPS of PD-L1 expression of 1 % and above, 5% and above, 10% and above, 20% and above, 30% and above, 40% and above, 50% and above, 60% and above, 70% and above, 80% and above 95% and above, or 95% and above. Preferably, the TPS of PD-L1 expression is 20% and above. More preferably, the TPS of PD-L1 expression is 50% and above.

In another embodiment, the invention is directed to a method of treating a cancer in a patient, comprising administering avelumab to the patient in a dosing regimen selected from the group consisting of 800 mg Q1W for 12 weeks followed by 800 mg Q2W, 10 mg/kg QlW for 12 weeks followed by 10 mg/kg Q2W and 1200 mg Q3W, and wherein the tumor proportion score of PD-L1 expression is 5% and above, 20% and above, 50% and above or 80% and above. Preferably, tumor proportion score of PD-L1 expression is 20% and above. More preferably, the TPS of PD-L1 expression is 50% and above. In one aspect of this embodiment and the cancer is selected from NSCLC, urothelial cancer, RCC, ovarian cancer, head and neck cancer gastric cancer. More preferably, the cancer is NSCLC.

In another embodiment, the invention is directed to a method of treating a cancer comprising administering to the patient avelumab in a dosing regimen as described in any of the proceeding embodiments, further comprising administering to the patient at least one of a second anti-cancer treatment. In an aspect of this embodiment, the method further comprising administering one or two of a second anti-cancer treatment. Preferably, the second anti-cancer treatment is selected from the group consisting of a VEGFR antagonist, an anti-4-1 BB antibody an anti-OX-40 antibody, an anti-MCSF antibody, an anti-PTK-7 antibody based antibody drug conjugate (ADC) wherein the drug payload is an antineoplastic agent, an ID01 antagonist, an ALK antagonist, an anti-cancer vaccine, a radio therapy and a standard of care treatment of cancers of the relevant tumor type. Preferably, the VEGFR antagonist is axitinib, the anti-4-1 BB antibody is PF0582566, the antiOX-40 antibody is PF4518600, the anti-MCSF antibody is PF-0360324, the ALK antagonist is crizotinib or lorlatinib (PF-06463922) and the anti-PTK7 antibody based ADC is PF-06647020.

Brief description of the Figures and Drawings

FIG. 1 depicts the Ctrough v. ORR curve of 88 patients in phase III MCC trial.

FIG. 2. depicts the Ctrough v. ORR curve of 156 patients in phase III first line NSCLC patients

FIG. 3 depicts the Ctrough v. ORR curve of 184 patients in phase I, 2nd line NSCLC patients.

FIG. 4A and FIG. 4B depict the density plots showing the distribution of AUCo- 336h ( gh/mL) after 10 mg/kg Q2W and flat 800 mg Q2W dosing using the PK SS model for the entire population (FIG. 4A) and split by quartiles of weight (FIG. 4B)

FIG. 5A and FIG. 5B depict the box and whisker plots showing the AUCo-336h ^gh/mL) after 10 mg/kg Q2W and 800 mg Q2W dosing using the PK SS model for the entire population (FIG.5A) and split by quartiles of weight (FIG. 5B)

FIG. 6 depicts the density plot of mean probability of best overall response (BOR) in simulated studies with metastatic MCC (mMCC) based on the PK CYCLE model, for the 10 mg/kg Q2W and the 800 mg Q2W dose.

FIG. 7 depicts the box and whisker plot of mean probability of BOR in simulated studies with UC for the 10 mg/kg Q2W and 800 mg Q2W.

FIG. 8A and FIG. 8B depict the density plot (FIG.8A) and box and whisker plot (FIG.8B), using the PK CYCLE model, showing the probably of experiencing an immune-related adverse event (irAE) after 10 mg/kg Q2W and 800mg Q2W dose.

FIG. 9A and FIG. 9B depict the density plot (FIG. 9A) and box and whisker plot (FIG. 9B), using the PK SS model, showing the probably of experiencing an irAE after 10 mg/kg Q2W and 800 mg Q2W dose.

Detailed Description of the Invention

As used herein, the terms such as "area under curve" (AUC), Ctrough, Cmax, "best overall response" (BOR), "overall response rate" (ORR), Q1W, Q2W, Q3W have the meaning as they are generally known by one of the ordinary skill in the art.

As used herein, the term "anti-cancer treatment" refers to any standard of care treatment of cancers in any relevant tumor types, or the administration of any single pharmaceutical agent, any fixed dose combinations of two or more single pharmaceutical agents, other than the standard of care treatment of cancer, documented in the state of the art as having or potentially having an effect toward the treatment of cancer or in the relevant tumor types.

As used herein the term "standard of care treatment of cancers" refers to any non-surgical treatment of any particular tumor type that is suggested in the NCCN Guidelines Version 1 2017. For clarity, such standard of care treatment of cancers may be radiation or, the administration of a single pharmaceutical agent, a fixed dose combinations of two or more single pharmaceutical agents or the combination of two or more single pharmaceutical agents, provided that standard of care treatment of cancers does not already contain any PD-1 or PD-L1 antagonist.

As used herein the term "single pharmaceutical agent" means any composition that comprising a single substance as the only active pharmaceutical ingredient in the composition.

As used herein, the term "tumor proportion score" or "TPS" as used herein refers to the percentage of viable tumor cells showing partial or complete membrane staining in an immunohistochemistry test of a sample. "Tumor proportion score of PD-L1 expression" used here in refers to the percentage of viable tumor cells showing partial or complete membrane staining in a PD-L1 expression immunohistochemistry test of a sample. Exemplary samples include, without limitation, a biological sample, a tissue sample, a formalin-fixed paraffin-embedded (FFPE) human tissue sample and a formalin-fixed paraffin-embedded (FFPE) human tumor tissue sample. Exemplary PD-L1 expression immunohistochemistry tests include, without limitation, the PD-L1 IHC 22C3 PharmDx (FDA approved, Daco), Ventana PD-L1 SP263 assay, and the tests described in PCT/EP2017/073712.

"Administration" and "treatment," as it applies to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refers to contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell. "Administration" and "treatment" also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding compound, or by another cell. The term "subject" includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit) and most preferably a human. "Treatment", as used in a clinical setting, is intended for obtaining beneficial or desired clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cells, inhibiting metastasis of neoplastic cells, shrinking or decreasing the size of tumor, remission of a disease (e.g., cancer), decreasing symptoms resulting from a disease (e.g., cancer), increasing the quality of life of those suffering from a disease (e.g., cancer), decreasing the dose of other medications required to treat a disease (e.g., cancer), delaying the progression of a disease (e.g., cancer), curing a disease (e.g., cancer), and/or prolong survival of patients having a disease (e.g., cancer).

An "antibody" is an immunoglobulin molecule capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule. As used herein, the term encompasses not only intact polyclonal or monoclonal antibodies, but also antigen binding fragments thereof (such as Fab, Fab', F(ab')2, Fv), single chain (scFv) and domain antibodies (including, for example, shark and camelid antibodies), and fusion proteins comprising an antibody, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site. An antibody includes an antibody of any class, such as IgG, IgA, or IgM (or sub-class thereof), and the antibody need not be of any particular class. Depending on the antibody amino acid sequence of the constant region of its heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., lgG1 , lgG2, lgG3, lgG4, lgA1 and lgA2. The heavy-chain constant regions that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.

The term "antigen binding fragment" or "antigen binding portion" of an antibody, as used herein, refers to one or more fragments of an intact antibody that retain the ability to specifically bind to a given antigen (e.g., PD-L1). Antigen binding functions of an antibody can be performed by fragments of an intact antibody. Examples of binding fragments encompassed within the term "antigen binding fragment" of an antibody include Fab; Fab'; F(ab')2; an Fd fragment consisting of the VH and CH1 domains; an Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a

single domain antibody (dAb) fragment (Ward et al., Nature 341 :544-546, 1989), and an isolated complementarity determining region (CDR).

An antibody, an antibody conjugate, or a polypeptide that "preferentially binds" or "specifically binds" (used interchangeably herein) to a target (e.g., PD-L1 protein) is a term well understood in the art, and methods to determine such specific or preferential binding are also well known in the art. A molecule is said to exhibit "specific binding" or "preferential binding" if it reacts or associates more frequently, more rapidly, with greater duration and/or with greater affinity with a particular cell or substance than it does with alternative cells or substances. An antibody "specifically binds" or "preferentially binds" to a target if it binds with greater affinity, avidity, more readily, and/or with greater duration than it binds to other substances. For example, an antibody that specifically or preferentially binds to a PD-L1 epitope is an antibody that binds this epitope with greater affinity, avidity, more readily, and/or with greater duration than it binds to other PD-L1 epitopes or non-PD-L1 epitopes. It is also understood that by reading this definition, for example, an antibody (or moiety or epitope) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. As such, "specific binding" or "preferential binding" does not necessarily require (although it can include) exclusive binding. Generally, but not necessarily, reference to binding means preferential binding.

A "variable region" of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. As known in the art, the variable regions of the heavy and light chain each consist of four framework regions (FR) connected by three complementarity determining regions (CDRs) also known as hypervariable regions. The CDRs in each chain are held together in close proximity by the FRs and, with the CDRs from the other chain, contribute to the formation of the antigen binding site of antibodies. There are at least two techniques for determining CDRs: (1) an approach based on cross-species sequence variability (i.e., Kabat et al. Sequences of Proteins of Immunological Interest, (5th ed., 1991 , National Institutes of Health, Bethesda MD)); and (2) an approach based on crystallographic studies of antigen-antibody complexes (Al-lazikani et al., 1997, J. Molec. Biol. 273:927-948). As used herein, a CDR may refer to CDRs defined by either approach or by a combination of both approaches.

A "CDR" of a variable domain are amino acid residues within the variable region that are identified in accordance with the definitions of the Kabat, Chothia, the accumulation of both Kabat and Chothia, AbM, contact, and/or conformational definitions or any method of CDR determination well known in the art. Antibody CDRs may be identified as the hypervariable regions originally defined by Kabat et al. See, e.g., Kabat et al., 1992, Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, NIH, Washington D.C. The positions of the CDRs may also be identified as the structural loop structures originally described by Chothia and others. See, e.g., Chothia et al., Nature 342:877-883, 1989. Other approaches to CDR identification include the "AbM definition," which is a compromise between Kabat and Chothia and is derived using Oxford Molecular's AbM antibody modeling software (now Accelrys®), or the "contact definition" of CDRs based on observed antigen contacts, set forth in MacCallum et al., J. Mol. Biol., 262:732-745, 1996. In another approach, referred to herein as the "conformational definition" of CDRs, the positions of the CDRs may be identified as the residues that make enthalpic contributions to antigen binding. See, e.g., Makabe et al., Journal of Biological Chemistry, 283: 1 156-1166, 2008. Still other CDR boundary definitions may not strictly follow one of the above approaches, but will nonetheless overlap with at least a portion of the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. As used herein, a CDR may refer to CDRs defined by any approach known in the art, including combinations of approaches. The methods used herein may utilize CDRs defined according to any of these approaches. For any given embodiment containing more than one CDR, the CDRs may be defined in accordance with any of Kabat, Chothia, extended, AbM, contact, and/or conformational definitions.

"Isolated antibody" and "isolated antibody fragment" refers to the purification status and in such context means the named molecule is substantially free of other biological molecules such as nucleic acids, proteins, lipids, carbohydrates, or other material such as cellular debris and growth media. Generally, the term "isolated" is not intended to refer to a complete absence of such material or to an absence of water, buffers, or salts, unless they are present in amounts that substantially interfere with experimental or therapeutic use of the binding compound as described herein.

"Monoclonal antibody" or "mAb" or "Mab", as used herein, refers to a population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts. In contrast, conventional (polyclonal) antibody preparations typically include a multitude of different antibodies having different amino acid sequences in their variable domains, particularly their CDRs, which are often specific for different epitopes. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256: 495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). The "monoclonal antibodies" may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol. Biol. 222: 581-597, for example. See also Presta (2005) J. Allergy Clin. Immunol. 1 16:731.

"Chimeric antibody" refers to an antibody in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in an antibody derived from a particular species (e.g., human) or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in an antibody derived from another species (e.g., mouse) or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.

"Human antibody" refers to an antibody that comprises human immunoglobulin protein sequences only. A human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell. Similarly, "mouse antibody" or "rat antibody" refer to an antibody that comprises only mouse or rat immunoglobulin sequences, respectively.

"Humanized antibody" refers to forms of antibodies that contain sequences from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies contain minimal sequence derived from non-human immunoglobulin. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. The prefix "hum", "hu" or "h" is added to antibody clone designations when necessary to distinguish humanized antibodies from parental rodent antibodies. The humanized forms of rodent antibodies will generally comprise the same CDR sequences of the parental rodent antibodies, although certain amino acid substitutions may be included to increase affinity, increase stability of the humanized antibody, or for other reasons.

Avelumab entered phase 1 clinical trial in early 2013 and has since then advanced to phase 3 trials in several different tumor types such as MCC, NSCLC, RCC, gastric cancer, ovarian cancer and bladder cancer. The dosing regimen in these trials was 10 mg/kg Q2W. Provided herein are improved dosing regimens for avelumab which could achieve a better overall response rate than the current 10mg/kg Q2W dosing regimen.

Table 1 below provides the sequences of the anti-PD-L1 antibody avelumab for use in the treatment method, medicaments and uses of the present invention. Avelumab is described in International Patent Publication No. WO2013/079174, the disclosure of which is hereby incorporated by references in its entirety.

Table 1. Anti-human-PD-L1 antibody Avelumab Sequences

Heavy chain SYIMM (SEQ ID NO:1)

CDR1 (CDRH1)

Heavy chain SIYPSGGITFY (SEQ ID NO:2)

CDR2 (CDRH2)

Heavy chain I KLGTVTTVDY (SEQ ID NO: 3)

CDR3 (CDRH3)

Light chain TGTSSDVGGYNYVS (SEQ ID NO:4)

CDR1 (CDRL1)

Light chain DVSNRPS (SEQ ID NO:5)

CDR2 (CDRL2)

Light chain SSYTSSSTRV (SEQ ID NO:6)

CDR3 (CDRL3)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVR

Heavy chain

QAPGKGLEWVSSIYPSGGITFYADKGRFTISRDNSKNTL

variable region

YLQM N S LRA EDTA VYYCA R I KLGTVTTVDYWGQGTLVT

(VR)

VSS (SEQ ID NO:7)

QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWY QQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTI

Light chain VR

SGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVL (SEQ

ID NO: 8)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVR

QAPGKGLEWVSSIYPSGGITFYADTVKGRFTISRDNSKN

TLYLQMNSLRAE DTA VYYCA R I KLGT VTT V D YWG QGT LV

TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE

PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS

SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC

Heavy chain

PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH

EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVL

TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE

PQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESN

GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV

FSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:9)

QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWY QQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTI SGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVLGQPKA

Light chain

NPTVTLFPPSSEELQANKATLVCLISDFYP G A VT V A WKA DGSPVKAG VETTKPSKQSN N KYAASSYLSLTPEQWKSH RSYSCQVTH EGSTVEKTVAPTECS (SEQ ID NO: 10)

Examples

General methods for Examples 1-3: a population pharmacokinetic (PK) model was used to estimate individual exposure metrics using individual pharmacokinetic parameters for patients with MCC and NSCLC. The influence of exposure metrics (Ctrough,) on response was explored via logistic regression and was applied to model the relationships between exposure and the overall response rate (ORR). In the figures for each example, the heavy dot on each vertical bar represents a summary statistic of the observed data, divided into quartiles. The X axis for each quartile represents the mean Ctrough of the patients in each of the quartiles and the Y axis represents the probability of response for the individual quartile and it is corresponding 95% confidence interval. The curved thin line represents the logisitic regression model fit, about all the observed data along with the 95% prediction interval about the regression (shaded red area).

Example 1. Ctrough and ORR correlation of 88 patients in a phase 3 MCC trial.

88 patients participated in a phase 3 MCC trial with the avelumab dosing of 10 mg/kg Q2W over one hour of IV infusion. Patients were divided into four quartiles based on the Cthrough value of patients, with 22 patients in each quartile. The Ctrough value of each patient was calculated based on the existing model and the actual serum concentration of avelumab tested for each patient at various points during the trial. As shown in FIG. 1 , the four quartiles of patients were represented by the four vertical bars in the figure. The Ctrough value of each quartile is represented by the mean Ctrough value of the quartile. The heavy dot on each vertical bar represents the probability of overall response rate for the group.

A positive correlation between Ctr0ugh and ORR was observed (FIG. 1). Patients of the upper 4th quartile have a probability of ORR of about 60% (FIG.1 ). A mean Ctrough of around 44-50 ug/mL correlates to a probability of ORR of 50-60% (FIG. 1).

Example 2. Ctrough and ORR correlation of 156 patients in phase 3 first line NSCLC trial.

156 patients participated in a phase 3 first line NSCLC trial with the avelumab dosing of 10mg/kg Q2W over one hour of IV infusion. Patients were divided into four quartiles based on the Cthrough value of patients, with 39 patients in each quartile. The Ctrough number of each patient was calculated based on the existing model and the actual serum concentration of avelumab tested for each patient at various points during the trial. As shown in FIG. 2, the four quartiles of patients were represented by the four vertical bars in the figure. The Ctr0ugh value of each quartile is represented by the mean Ctrough value of the quartile. The heavy dot on each vertical bar represents the probability of overall response rate for the group.

A positive correlation between Ctrough and ORR was observed (FIG. 2). Patients of the upper 4th quartile have a probability of ORR of about 35% (FIG. 2). A mean Ctrough of around 44-54 ug/mL correlates to a probability of ORR of 35-50% (FIG 2).

Example 3. Ctrough and ORR correlation of 184 patients in phase 1 b second line NSCLC trial.

184 patients participated in a phase 1 b second line NSCLC trial with the avelumab dosing of 10 mg/kg Q2W over one hour of IV infusion. Patients were divided into four quartiles based on the Cthrough value of patients, with 46 patients in each quartile. The Ctrough number of each patient was calculated based on the existing model and the actual serum concentration of avelumab tested for each patient at various points during the trial. As shown in FIG. 3, the four quartiles of patients were represented by the four vertical bars in the figure. The Ctrough value of each quartile is represented by the mean Ctrough value of the quartile. The heavy dot on each vertical bar represents the probability of overall response rate for the group.

A positive correlation between Ctrough and ORR was observed. Patients of the upper 4th quartile have a probability of ORR of about 31 % (FIG. 3). A mean Ctrough of around 60-85 ug/mL correlates to a probability of ORR of 35-50% (FIG. 3).

Tumor proportion score (TPS) of PD-L1 expression was tested of the tumor tissues collected during the clinical trial. TPS of PD-L1 expression was analyzed together with Cthrough and response rate. Surprising ORRs were observed among the subset of patients with both high exposure any increased PD-L1 expression in the tumor cells. Among the 184 patients, 142 patients evaluated for Ctrough exposure, and 71 patients were in the upper half (top two quartiles). For patients in the upper half (top two quartiles) of the Ctrough exposure, TPS PD-L1 expression cutoff values of 5s 1 %, Ss 5%, 3s 50%, and 80% yielded ORRs of 25.4%, 25.6%, 33.3%, and 42.9%, respectively (Table 2).

Table 2. Avelumab response in 2L NSCLC patients with high exposure and high TPS of

PD-L1


A consistent positive correlation between mean Ctrough and the probability of ORR observed (Examples 1-3). Taking into consideration of the best probability of the

ORR in each Example, which occurs generally in the 4th quartile (Examples 1-3), the correlation of the Ctrough and ORR is expected to continue within reasonable range above the 4th quartile. These data indicate that a mean Ctrough of 44-85 ug/mL correlates with a probability of ORR of 50% in various tumor types.

Example 4. Simulation of Ctrough of various Avelumab dosing regimens.

Table 3 provides a number of dosing regimens for avelumab. The population PK model generated for avelumab based on previous work, was used to simulate the Ctrough of selected dosing regimens, in MCC, SCCLC and in solid tumor types.

Table 3. Avelumab dosing regimens

Proposed dosing regimen Notes

5-10 mg/kg Q1W Dosing range

- 10 mg/kg Q1W Preferred specific dose

- 5 mg/kg Q1W additional Preferred specific

- 8 mg/kg Q1W dose within the range

11-20 mg/kg Q2W Dosing range

- 1 1 mg Q2W Preferred specific dose

- 20 mg/kg Q2W Preferred specific dose

- 13, 15, 17 mg/kg Q2W Additional preferred specific dose

15-30 mg/kg Q3W Range

- 20 mg/kg Q3W Preferred specific doses

- 15, 20, 25,30 mg/kg Q3W Additional Preferred specific dose within the range

5-20 mg/kg QlW for n weeks followed Dosing range

by 10 mg/kg Q2W n is 6 or 12

- 10 mg/kg QlW for 12 weeks Preferred specific dose

followed by 10 mg/kg Q2W

- 5, 15, 20 mg/kg QlW for 6 or Additional Preferred specific 12 weeks followed by 10 mg/kg dose within the range Q2W

500 - 800 mg Q1W Correspond to 5-10 mg/kg

Q1W

900 -1600 mg Q2W Correspond to 1 1-20 mg/kg

Q2W

1250-2400 mg Q3W Correspond to 15-30 mg/kg

Q2W

500-1600 mg Q1 W for n weeks Correspond to 5-20 mg/kg followed by 800 mg Q2W QlW for n weeks followed by

10 mg/kg Q2W

General methods: Pharmacokinetic simulations of the avelumab dosing regimens were performed using the NONMEM version 7.3 software (ICON Development Solutions, Hanover, MD). Two compartment IV model with linear elimination was used as the population PK model. This model is based on over three thousand PK observations from over seven hundred patients who participated in the avelumab clinical trials thus far. To conduct the simulations of the dosing regimen described in above Table 3, a dataset was created with dosing events, dosing amounts, a 1 hour rate of infusion, and covariates included in the population PK model. The steady-state Ctrough concentrations were calculated by removing the first 3 doses and then computing the average Ctrough from the remaining dosing event for the given dose amount. For loading dose schedules, the Ctrough was calculated for the loading portion of the regimen as well as for the continued dosing after the loading period.

Results of the above simulation are shown in the below Tables 4-6.

Table 4 . Summary of median Ctrough for MCC under various dosing regimen

No. Dosing regimen Median Ctrough 95% Ctrough

(ug/mL) prediction interval

(ug/mL)

1 5 mg/kg Q1W 59 29.0-109.8

2 10 mg/kg Q1W 1 16.5 56.3-208.5

3 10 mg/kg/Q2W 38.9 14.7-83.0

11 mg/kg Q2W 43.4 17.6-91.5

20 mg/kg Q2W 77.1 31.1-160.3

10 mg/kgQ3W 18.1 4.5-45.5

15 mg/kg Q3W 27.3 9.5-67.4

20 mg/kg Q3W 36.6 12.3-86.7

25 mg/kg Q3W

30 mg/kg Q3W 53.7 18.4-127.2

5 mg/kg QlW for During During loading:

12 weeks followed Loading: 59.0 29.0-109.8 by 10mg/kgQ2W After loading: After loading:

40.6 15.7-90.2

10 mg/kg QlW for During During loading:

12 weeks followed loading: 116.5 56.3-208.5 by 10 mg/kg Q2W After loading: After loading:

45.3 17.4-100.4

20 mg/kg QlW for During loading During loading:

12 weeks followed 225.8 115.4-430.3 by 10 mg/kg Q2W After loading: After loading:

55.3 17.4-100.4

5 mg/kg QlW for During During loading:

6 weeks followed loading: 55.0 27.6-105.4 by 10 mg/kg Q2W After loading: After loading:

39.4 16.2-88.3

10 mg QlW for 6 During During loading: weeks followed by loading: 110.1 53.6-206.0

10 mg/kg Q2W After loading: After loading:

41.9 17.1-88.3

20 mg QlW for 6 During During loading: weeks followed by loading: 215.7 107.7-382.6

10 mg/kg Q2W After loading: After loading:

46.2 17.9-105.2

The dosing regimens Nos. 1-2, 4-5, 8-16 of Table 4, and ranges within these regimens such as 5-10 mg/kg Q1W, 11 -20 mg/kg Q2W, 20-30 mg/kg Q3W, 5-20 mg/kg Q1W for 6-12 weeks followed by 10 mg/kg Q2W, provide an expected median Ctrough higher than the current 10 mg/kg Q2W dosing regimen (Table 4). From Example 1 , a dosing regimen that provides a mean Ctrough of over 50 ug/mL correlates with a higher probability of ORR in MCC. The data shown in Table 4 for the avelumab dosing regimens 1-2, 10 and 11 -16 indicate that these regimens could advantageously provide a higher expected probability of ORR for MCC.

Table 5 Summary of Median Ctrough under various dosing regimen for NSCLC.

No. Dosing regimen Median 95% Ctrough

Ctrough prediction interval

(ug/mL) (ug/mL)

1 5 mg/kg Q1W 42.8 19.4-79.6

2 10 mg/kg Q1W 83.9 39.9-160.2

3 10 mg/kg/Q2W 20.6 4.8-51.2

4 1 1 mg/kg Q2W 22.2 5.8-56.6

5 20 mg/kg Q2W 39.9 11.5-96.3

6 10 mg/kg Q3W 6.3 0.0-20.1

7 15 mg/kg Q3W 9.1 0.2-34.1

8 20 mg/kg Q3W 12.8 0.5-46.7

9 25 mg/kg Q3W 14.2 0.9-54.6

10 30 mg/kg Q3W 17.6 1.8-66.7

1 1 5 mg/kg QlW for During During loading:

12 weeks followed Loading: 42.8 19.4-79.6 by 10 mg/kgQ2W After loading: After loading: 5.2- 20.2 47.5

12 10 mg/kg QlW for During During loading:

12 weeks followed loading: 83.9 39.9-160 by 10 mg/kg Q2W After loading: After loading: 4.8- 20.2 51.5

13 20 mg/kg QlW for During loading During loading:

12 weeks followed 172.9 74.6-342.6

by 10mg/kg Q2W After loading: After loading: 4.6- 20.5 63.9

14 5 mg/kg QlW for During During loading:

6 weeks followed loading: 42.9 19.5-82.1 by 10 mg/kg Q2W After loading: After loading: 5.2- 20.9 51.7

15 10 mg QlW for 6 During During loading:

weeks followed by loading: 86.7 39.0-163 10 mg/kg Q2W After loading: After loading: 5.0- 20.5 52.6

16 20 mg QlW for 6 During During loading:

weeks followed by loading: 163.4 79.3-332.5 10 mg/kg Q2W After loading: After loading:

19.6 4.9-56.4

The dosing regimens Nos. 1-2, 4-5, 10, 11-16 of Table 5, and ranges within these regimens, such as 5-10 mg/kg Q1W, 11-20 mg/kg Q2W, 5-20 mg/kg QlW for 6-12 weeks followed by 10 mg/kg Q2W, provide an expected median Ctrough above the current 10 mg/kg Q2W dosing regimen (Table 5). .Examples 1-3 above demonstrate that the mean Ctrough has a positive correlation with the probability of ORR. In Examples 2 and 3, a mean Ctrough of 44 ug/mL to 85 ug/mL corresponds to about 35% to about 50% probability of ORR, wherein the 4th quartile probability of ORR in Examples 2 and 3 was 35% and 31 % respectively. The data from Table 5 demonstrate that regimens Nos.1-2, 5 and 11-16 provide an expected mean Ctrough of about or over 44 ug/mL and thus could advantageously provide better probability of ORR in NSCLC patients. Other advantageous dosing regimens include, for example, regimens Nos. 2, 12-13 and 15-16, and the ranges within these regimens such as 10 mg - 20 mg/kg Q1W for 6 or 12 weeks followed by 10 mg/kg Q2W, all of which correspond to a median Ctr0ugh of about or more than 85 ug/mL. Other advantageous regimens for NSCLC are those providing a mean Ctr0ugh between 44 ug/mL and 85 ug/ml, i.e. dosing regimen Nos. 1 , 2, 5, 1 1 , 12, 14, 15 of Table 5, and ranges within these regimens such as 5-10 mg/kg Q1W, 5-10mg/kg QlW for 6-12 weeks followed by 10 mg/kg Q2W.

Table 6 Summary of Median Ctrough under various avelumab dosing regimen for all solid tumor types.

No. Dosing regimen Median Ctrough 95% Ctrough

(ug/mL) prediction interval

(ug/mL)

1 5 mg/kg Q1W 43 19.5-84

2 10 mg/kg Q1W 83.6 36.6-160

3 10 mg/kg/Q2W 19.9 4.7-53.3

4 1 1 mg/kg Q2W 22.9 6.4-57.9

5 20 mg/kg Q2W 40.2 11.1-100.5

6 10 mg/kgQ3W 6.3 0.0-33.5

7 15 mg/kg Q3W 9.2 0.0-33.5

8 20 mg/kg Q3W 1 1.6 0.4-41.9

9 25 mg/kg Q3W

10 30 mg/kg Q3W 16.7 1.7-58.2

1 1 5 mg/kg QlW for During During loading:

12 weeks followed Loading: 43.0 19.5-84.5

by 10 mg/kgQ2W After loading: After loading: 4.7- 20.2 53.2

12 10 mg/kg QlW for During During loading:

12 weeks followed loading: 83.6 36.6-160 by 10 mg/kg Q2W After loading: After loading: 4.3- 19.7 51.6

13 20mg/kg QlW for During loading During loading:

12 weeks followed 160.7 73.8-319 by 10 mg/kg Q2W After loading: After loading: 4.2- 19.3 54.9

14 5 mg/kg QlW for During During loading:

6 weeks followed loading: 42.2 19.6-83.7 by 10 mg/kg Q2W After loading: After loading: 5.1- 20.9 51.1

15 10 mg QlW for 6 During During loading:

weeks followed by loading: 83.9 39.6-158 10 mg/kg Q2W After loading: After loading: 5.5- 19.9 48.6

16 20 mg QlW for 6 During During loading:

weeks followed by loading: 163.8 78.0-314 10 mg/kg Q2W After loading: After loading:

19.9 5.3-52.0

Avelumab dosing regimen Nos. 1-2, 4-5, 11-16 in Table 6, and ranges within these regimens such as 5-10 mg/kg Q1W, 1 1-20 mg/kg Q2W, 5-20 mg/kg QlW for 6-12 weeks followed by 10 mg/kg Q2W, provide an expected median Ctrough above the current 10 mg/kg Q2W dosing regimen, and could advantageously provide a better probability of ORR (see, Examples 1-3). From Examples 1-3, a mean Ctrough of 44-85 ug/mL corresponds to about 50% of ORR respectively. Thus, dosing regimens that provide a mean Ctrough of over 44 ug/mL could advantageously provide a higher probability of ORR in patients with solid tumors. As such, dosing regimen 1-2, 5 and 11 -16 shown in Table 6, or ranges therein, such as 5-10 mg/kg Q1W, 5-20 mg/kg QlW for 6 or 12 weeks followed by 10 mg/kg Q2W, are advantageous for treatment of solid tumor types. Other advantageous dosing regimens to treat solid tumor include avelumab dosing regimen Nos. 2, 12-13 and 15-16 and the ranges within these regimens such as 10 mg - 20 mg/kg QlW for 6 or 12 weeks followed by 10 mg/kg Q2W, all of which corresponding to a median Ctrough of about or more than 85ug/ml_. Other advantageous avelumab dosing regimens include dosing regimen Nos. 1-2, 5, 11 -12 and 14-15 shown in Table 6, and ranges within these regimens such as, for example, 5-10 mg/kg Q1W, 5-10 mg/kg QlW for 6 or 12 weeks followed by 10 mg/kg Q2W, all of which correspond to a median Ctrough between about 44 ug/mL and about 85 ug/mL in solid tumors. Exemplary solid tumor types suitable for treatment with the avelumab dosing regimens provided herein include, without limitation, MCC, NSCLC, RCC, bladder cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, urothelial carcinoma, breast cancer, adenocarcinoma of the stomach and thymoma.

Example 5. Modeling of safety and efficacy for the 800 mg Q2W dosing in

comparison with the 10 mg/kg Q2W dosing.

The clinical profile of avelumab has been evaluated from data in more than 1800 subjects in ongoing Phase I, II, and III trials in adult subjects with various solid tumors. The clinical pharmacology results are obtained from 1827 subjects from three studies with PK information available as of June 9, 2016 (studies EMR100070-001 and

EM R 100070-003) and November 20, 2015 (study EM R 100070-002).

Exposure metrics.

Based on the clinical pharmacology results of these more than 1800 subjects mentioned above, 10000 and 4000 simulated subjects were generated using the PK CYCLE model and PK SS model respectively to project the avelumab exposure metrics of AUC, Cthough and Cmax for both the 10 mg/kg Q2W dosing and the 800 mg Q2W dosing. Where PK CYCLE model represents the PK model generated using PK data from the first dose of avelumab and PK SS model represents the PK model generated using PK data after repeated dosing of avelumab. Such projected exposure metrics were then used in the below Exposure-efficacy correlation and Exposure-safety correlation simulation. The distribution plot of such projected avelumab AUC 0-336 are shown in FIG. 4A, FIG. 4B, FIG. 5A and FIG. 5B. The plots depicted in FIG. 4A and FIG. 4B show that the simulated values of AUCo-336 have a close correspondence between the two dosing regimens. The graphs in FIG. 5A and FIG. 5B show that the total variability of avelumab AUCo-336 is lower in the 800 mg Q2W regimen than the 10 mg/kg Q2W regimen.

Exposure - efficacy correlation and Exposure - safety correlation.

A univariate logistic regression model has been developed to describe the exposure - best overall response (BOR) relationship for the n=88 observed subjects with mMCC. The exposure values that were used for developing the logistic regression model were simulated from the PK CYCLE and PK SS models. Four hundred sets of parameter estimates were sampled from the uncertainty distribution of the exposure-BOR logistic regression model. For each of these 400 parameter sets, 2500 subjects were sampled from the mMCC population of the n=10000 subjects simulated based on

the PK CYCLE and PK SS models. The mean predicted probability of response (across the n=2500 simulated subjects) was then obtained for each of the 400 sets of logistic model parameter estimates.

The same procedure was followed for the UC indication, with n=153 observed subjects with UC.

The results are summarized in the graphs shown in FIG.6 and FIG.7. The graph in FIG. 6 shows the probability of BOR in individual simulated patients with mMCC have large overlap between, and are similar for the 10mg/kg Q2W and the 800mg Q2W dosing regimens. The graph in FIG. 7 shows that the mean probability of BOR is very similar between the 10 mg/kg Q2W and 800mg Q2W dosing regimens for the UC with a lower variability for the 800mg Q2W dosing.

Exposure - safety correlation was modelled similarly using the safety variables immune related AE of any grade (irAE) and infusion related reactions (IRR). The results are shown in FIG. 8A, FIG. 8B, FIG. 9A and FIG. 9B. The graphs depicted in FIG. 8A and FIG. 8B show very similar probability of experiencing an irAE between the two dosing regimens. The graphs depicted in FIG. 9A and FIG. 9B show that the 800 mg Q2W dosing regimen tends to have a lower variability comparing to the 10 mg/kg Q2W dosing.