Combination therapies with PD-L1 antagonists

Abstract

This disclosure describes combination therapies comprising a programmed death ligand 1 (PD-L1) receptor antagonist and another therapeutic agent, and the use of such combination therapies for the treatment of cancer.

Description

Field

[0001] The present invention relates to avelumab for uses in combination with axitnib for the treatment of cancer.Background

[0002] Renal cell carcinoma (RCC) is the most common kidney cancer and constitutes about 3% of all malignant tumors in adults. Until 2005, interferon-alpha (IFN-α) and high-dose interleukin (IL)-2 therapies were the standards of care for patients with advanced RCC (aRCC), albeit with modest efficacy. Since then, development and approval of multiple vascular endothelial growth factor (VEGF) pathway and mammalian target of rapamycin (mTOR) inhibitors have significantly improved the outcomes of aRCC patients. These agents include the VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs) sunitinib, pazopanib, axitinib and sorafenib, the mTOR inhibitors temsirolimus and everolimus, and the anti-VEGF monoclonal antibody bevacizumab.

[0003] However, despite the substantial improvement of patient outcomes with these agents, durable and complete responses in aRCC patients are uncommon; the majority of patients will eventually develop resistance, exhibit disease progression while on therapy, and succumb to death due to metastatic disease.

[0004] 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 T 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-toleraant environment for tumor development and growth. Conversely, inhibition of this interaction can enhance local T-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 IgG1 isotype that specifically targets and blocks PD-L1. Avelumab is the International Nonproprietary Name (INN) for the anti-PD-L1 monoclonal antibody MSB0010718C.

[0005] Axitinib is a VEGF receptor (VEGFR) TKI. The antitumor activity of single-agent axitinib 5 mg twice daily (BID) in previously untreated patients with clear cell aRCC was assessed against sorafenib in a randomized, open-label, Phase 3 trial. Although the study did not demonstrate a statistically significant difference in progression-free survival (PFS) between patients treated with axitinib or sorafenib, axitinib was associated with a longer median PFS (mPFS) time (mPFS of 10.1 months (95% CI 7.2,12.1) with axitinib vs. 6.5 months (95% CI 4.7, 8.3) with sorafenib, stratified hazard ratio 0.77 (95% CI 0.56, 1.05) (D. Cella et al.; "Patient-reported outcomes for axitinib vs sorafenib in metastatic renal cell carcinoma: phase III (AXIS) trial"; Br J Cancer 108:1571-1578 (2013)).

[0006] There is a need for improved therapies for the treatment of cancers. Furthermore, there is a need for therapies having greater efficacy than existing therapies. Preferred combination therapies of the present invention show greater efficacy than treatment with either therapeutic agent alone.Summary

[0007] This invention relates to therapeutic regimens for treatment of renal cell carcinoma (RCC).

[0008] Provided herein are uses of the PD-L1 antagonist avelumab in combination with a VEGFR inhibitor axitinib (N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide) or a pharmaceutically acceptable salt thereof for treating a RCC in a subject. Also provided are above recited uses of inhibiting growth or progression of RCC in a subject who has malignant cells. Also provided are above recited uses of inhibiting metastasis of malignant cells in a subject. Also provided are above recited uses of inducing tumor regression in a subject who has malignant cells.

[0009] In some instances of the above uses, the axitinib can be formulated as a 1 mg tablet, 3 mg tablet, or a 5 mg tablet.

[0010] The invention is defined in the appended claims and concerns "purpose-limited product claims" reflecting the aforementioned usesDetailed DescriptionI. Definitions

[0011] So that the invention may be more readily understood, certain technical and scientific terms are specifically defined below. Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0012] As used herein, including the appended claims, the singular forms of words such as "a," "an," and "the," include their corresponding plural references unless the context clearly dictates otherwise.

[0013] "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, rabbit) and most preferably a human.

[0014] 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 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., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. 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.II. GENERAL METHODS

[0015] Standard methods in molecular biology are described Sambrook, Fritsch and Maniatis (1982 & 1989 2nd Edition, 2001 3rd Edition) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Sambrook and Russell (2001) Molecular Cloning, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Wu (1993) Recombinant DNA, Vol. 217, Academic Press, San Diego, CA). Standard methods also appear in Ausbel, et al. (2001) Current Protocols in Molecular Biology, Vols.1-4, John Wiley and Sons, Inc. New York, NY, which describes cloning in bacterial cells and DNA mutagenesis (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), glycoconjugates and protein expression (Vol. 3), and bioinformatics (Vol. 4).

[0016] Methods for protein purification including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization are described (Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 1, John Wiley and Sons, Inc., New York). Chemical analysis, chemical modification, post-translational modification, production of fusion proteins, glycosylation of proteins are described (see, e.g., Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 2, John Wiley and Sons, Inc., New York; Ausubel, et al. (2001) Current Protocols in Molecular Biology, Vol. 3, John Wiley and Sons, Inc., NY, NY, pp. 16.0.5-16.22.17; Sigma-Aldrich, Co. (2001) Products for Life Science Research, St. Louis, MO; pp. 45-89; Amersham Pharmacia Biotech (2001) BioDirectory, Piscataway, N.J., pp. 384-391). Production, purification, and fragmentation of polyclonal and monoclonal antibodies are described (Coligan, et al. (2001) Current Protcols in Immunology, Vol. 1, John Wiley and Sons, Inc., New York; Harlow and Lane (1999) Using Antibodies, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Harlow and Lane, supra). Standard techniques for characterizing ligand / receptor interactions are available (see, e.g., Coligan, et al. (2001) Current Protocols in Immunology, Vol. 4, John Wiley, Inc., New York).

[0017] Monoclonal, polyclonal, and humanized antibodies can be prepared (see, e.g., Sheperd and Dean (eds.) (2000) Monoclonal Antibodies, Oxford Univ. Press, New York, NY; Kontermann and Dubel (eds.) (2001) Antibody Engineering, Springer-Verlag, New York; Harlow and Lane (1988) Antibodies A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp. 139-243; Carpenter, et al. (2000) J. Immunol. 165:6205; He, et al. (1998) J. Immunol. 160:1029; Tang et al. (1999) J. Biol. Chem. 274:27371-27378; Baca et al. (1997) J. Biol. Chem. 272:10678-10684; Chothia et al. (1989) Nature 342:877-883; Foote and Winter (1992) J. Mol. Biol. 224:487-499; U.S. Pat. No. 6,329,511).

[0018] An alternative to humanization is to use human antibody libraries displayed on phage or human antibody libraries in transgenic mice (Vaughan et al. (1996) Nature Biotechnol. 14:309-314; Barbas (1995) Nature Medicine 1:837-839; Mendez et al. (1997) Nature Genetics 15:146-156; Hoogenboom and Chames (2000) Immunol. Today 21:371-377; Barbas et al. (2001) Phage Display: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; Kay et al. (1996) Phage Display of Peptides and Proteins: A Laboratory Manual, Academic Press, San Diego, CA; de Bruin et al. (1999) Nature Biotechnol. 17:397-399).

[0019] Purification of antigen is not necessary for the generation of antibodies. Animals can be immunized with cells bearing the antigen of interest. Splenocytes can then be isolated from the immunized animals, and the splenocytes can fused with a myeloma cell line to produce a hybridoma (see, e.g., Meyaard et al. (1997) Immunity 7:283-290; Wright et al. (2000) Immunity 13:233-242; Preston et al., supra; Kaithamana et al. (1999) J. Immunol. 163:5157-5164).

[0020] Antibodies can be conjugated, e.g., to small drug molecules, enzymes, liposomes, polyethylene glycol (PEG). Antibodies are useful for therapeutic, diagnostic, kit or other purposes, and include antibodies coupled, e.g., to dyes, radioisotopes, enzymes, or metals, e.g., colloidal gold (see, e.g., Le Doussal et al. (1991) J. Immunol. 146:169-175; Gibellini et al. (1998) J. Immunol. 160:3891-3898; Hsing and Bishop (1999) J. Immunol. 162:2804-2811; Everts et al. (2002) J. Immunol. 168:883-889).

[0021] Methods for flow cytometry, including fluorescence activated cell sorting (FACS), are available (see, e.g., Owens, et al. (1994) Flow Cytometry Principles for Clinical Laboratory Practice, John Wiley and Sons, Hoboken, NJ; Givan (2001) Flow Cytometry, 2nd ed.; Wiley-Liss, Hoboken, NJ; Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, NJ). Fluorescent reagents suitable for modifying nucleic acids, including nucleic acid primers and probes, polypeptides, and antibodies, for use, e.g., as diagnostic reagents, are available (Molecular Probesy (2003) Catalogue, Molecular Probes, Inc., Eugene, OR; Sigma-Aldrich (2003) Catalogue, St. Louis, MO).

[0022] Standard methods of histology of the immune system are described (see, e.g., Muller-Harmelink (ed.) (1986) Human Thymus: Histopathology and Pathology, Springer Verlag, New York, NY; Hiatt, et al. (2000) Color Atlas of Histology, Lippincott, Williams, and Wilkins, Phila, PA; Louis, et al. (2002) Basic Histology: Text and Atlas, McGraw-Hill, New York, NY).

[0023] Software packages and databases for determining, e.g., antigenic fragments, leader sequences, protein folding, functional domains, glycosylation sites, and sequence alignments, are available (see, e.g., GenBank, Vector NTI ®< Suite (Informax, Inc, Bethesda, MD); GCG Wisconsin Package (Accelrys, Inc., San Diego, CA); DeCypher ®< (TimeLogic Corp., Crystal Bay, Nevada); Menne, et al. (2000) Bioinformatics 16: 741-742; Menne, et al. (2000) Bioinformatics Applications Note 16:741-742; Wren, et al. (2002) Comput. Methods Programs Biomed. 68:177-181; von Heijne (1983) Eur. J. Biochem. 133:17-21; von Heijne (1986) Nucleic Acids Res. 14:4683-4690).III. ExamplesExample 1: Combination Treatment with Avelumab and Axitinib

[0024] This example illustrates a clinical trial study to evaluate safety, efficacy, pharmacokinetics, and pharmacodynamics of avelumab (MSB0010718C) in combination with axitinib (AG-013736) in patients with previously untreated advanced renal cell carcinoma (aRCC).

[0025] This study is an open-label, multi-center, multiple-dose trial designed to estimate the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D) of avelumab (MSB0010718C) in combination with axitinib (AG-013736). Once the MTD of avelumab administered in combination with axitinib is estimated (dose finding portion), the dose expansion phase will be opened to further characterize the combination in term of safety profile, anti-tumor activity, pharmacokinetics, pharmacodynamics and biomarker modulation. Protocol design is set forth in Table 4.

[0026] The Dose Finding Phase will estimate the MTD and RP2D in patients with aRCC with clear cell histology who did not receive prior systemic therapy for advanced disease, using the modified toxicity probability interval (mTPI) method. Dose finding will follow an "Up-and-Down" design, with up to 4 potential dose levels (DL) to be tested, shown in Table 4.

[0027] The Dose Finding Phase will lead to the identification of an Expansion Test Dose for avelumab in combination with axitinib in patients with aRCC who did not receive prior systemic therapy for their advanced disease. The Expansion Test Dose will either be the MTD (i.e., the highest dose of avelumab and axitinib associated with the occurrence of DLTs in <33% of patients) or the RP2D, i.e., the highest tested dose that is declared safe and tolerable by the investigators and sponsor. Once the Expansion Test Dose is identified, the Dose Expansion Phase will be opened, and avelumab in combination with axitinib will be evaluated in up to approximately 20-40 patients with previously untreated aRCC. Table 4Arms Assigned Interventions Dose finding phase Group 1:avelumab 10 mg / kg IV Q2W; axitinib 5 mg oral BIDGroup 2: avelumab 5 mg / kg IV Q2W; axitinib 5 mg oral BIDGroup 3: avelumab 10 mg / kg IV Q2W; axitinib 3 mg oral BIDGroup 4: avelumab 5 mg / kg IV Q2W; axitinib 3 mg oral BIDDose expansion phase Group 1:avelumab 10 mg / kg IV Q2W; axitinib 5 mg oral BIDGroup 2: avelumab 5 mg / kg IV Q2W; axitinib 5 mg oral BIDGroup 3: avelumab 10 mg / kg IV Q2W; axitinib 3 mg oral BIDGroup 4: avelumab 5 mg / kg IV Q2W; axitinib 3 mg oral BID

[0028] Inclusion Criteria: Histologically or cytologically confirmed advanced RCC with clear cell component. Primary tumor resected. Mandatory archival formalin fixed, paraffin embedded (FFPE) tumor tissue block from primary tumor resection specimen (all patients). For Extension Cohort only, mandatory de novo tumor biopsy from a locally recurrent or metastatic lesion unless obtained from a procedure performed within 6 months of study entry and if the patient has received no intervening systemic anti-cancer treatment. At least one measureable lesion as defined by RECIST version 1.1. Age ≥18 years. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Adequate bone marrow function, renal and liver functions.

[0029] The number of patients to be enrolled in the Dose Finding Phase will depend on the observed safety profile, and the number of tested dose levels. Up to approximately 55 patients (including Dose Finding Phase and Dose Expansion Phase) are projected to be enrolled in the study.

[0030] Study Treatment: Axitinib will be given orally (PO) twice daily (BID), with or without food, on a continuous dosing schedule. Avelumab will be given as a 1-hour intravenous infusion (IV) every two weeks (Q2W). In all patients, treatment with study drugs may continue until confirmed disease progression, patient refusal, patient lost to follow up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first.

[0031] In order to mitigate avelumab infusion-related reactions, a premedication regimen of 25 to 50 mg IV or oral equivalent diphenhydramine and 650 mg IV or oral equivalent acetaminophen / paracetamol (as per local practice) may be administered approximately 30 to 60 minutes prior to each dose of avelumab. This may be modified based on local treatment standards and guidelines, as appropriate.

[0032] Tumor Assessment: Anti-tumor activity will be assessed by radiological tumor assessments at 6-week intervals, using RECIST version 1.1. Complete and partial responses will be be confirmed on repeated imaging at least at 4 weeks after initial documentation. After 1 year from enrollment in the study, tumor assessments should be conducted less frequently, i.e., at 12-week intervals. In addition, radiological tumor assessments will also be conducted whenever disease progression is suspected (e.g., symptomatic deterioration), and at the time of End of Treatment / Withdrawal (if not done in the previous 6 weeks). If radiologic imaging shows progressive disease (PD), tumor assessment should be repeated at least ≥4 weeks later in order to confirm PD.

[0033] Brain Computerized Tomography (CT) or Magnetic Resonance Imaging (MRI) scans are required at baseline and when there is a suspected brain metastasis. Bone scan (bone scintigraphy) or 18fluorodeoxyglucose-positron emission tomography / CT(18FDG-PET / CT) are required at baseline, then every 16 weeks only if bone metastases are present at baseline. Otherwise, bone imaging is required only if new bone metastases are suspected. Bone imaging is also required at the time of confirmation of CR for patients who have bone metastases.

[0034] Pharmacokinetic / Immunogenicity Assessments: PK / immunogenicity sampling will be collected. To understand the PK effects of avelumab on axitinib, a 7-day lead-in period with single-agent axitinib will be included prior to Cycle 1 in all patients in the Dose Finding Phase and in at least 8 patients in the Dose Expansion Phase of the study. Since avelumab has a long half-life (3-5 days), it would not be feasible to run a lead-in to study the PK of avelumab alone. Therefore, the effect of axitinib on avelumab will be evaluated by comparing avelumab trough concentrations at steady state in the presence of axitinib with those reported for avelumab alone in prior studies.

[0035] Biomarker Assessments: A key objective of the biomarker analyses that will be performed in this study is to investigate biomarkers that are potentially predictive of treatment benefit with the combination of avelumab and axitinib. In addition, biomarker studies of tumor and blood biospecimens will be carried out to help further understand the mechanism of action of the avelumab in combination with axitinib, as well as potential mechanisms of resistance.

[0036] Tumor biospecimens from archived tissue samples and metastatic lesions will be used to analyze candidate DNA, RNA, or protein markers, or a relevant signature of markers, for their ability to identify those patients who are most likely to benefit from treatment with the study drugs. Markers that may be analyzed include, but not be limited to, PD-L1 expression tumor-infiltrating CD8+ T lymphocytes, and T-cell receptor gene sequence quantitation. Optional tumor biopsies obtained upon disease progression will be used to investigate acquired mechanisms of resistance. Only core needle or excisional biopsies, or resection specimen are suitable.

[0037] Peripheral Blood: Specimens will be retained as whole blood, serum, and plasma in a biobank for exploratory biomarker assessments, unless prohibited by local regulation or by decision of the Institutional Review Board or Ethics Committee. Samples may be used to identify or characterize cells, DNA, RNA, or protein markers known or suspected to be of relevance to the mechanisms of action, or the development of resistance to avelumab used in combination with axitinib. These include biomarkers that may aid in the identification of those patients who might preferentially benefit from treatment with avelumab in combination with axitinib, including but not limited to biomarkers related to anti-tumor immune response or target modulation, such as soluble VEGF-A, IL-8, IFNγ and / or tissue FoxP3, PD-1, PD-L2. Biospecimens should be obtained pre-dose and at the same time as PK samples whenever possible.Example 2: Combination Treatment with Axitinib and Avelumab Versus Sunitinib

[0038] This example illustrates a clinical trial study to evaluate safety and efficacy of avelumab (MSB0010718C) in combination with axitinib (AG-013736) and to demonstrate the superiority of this combination versus standard-of-care sunitinib monotherapy in the first-line treatment of patients with advanced RCC (aRCC). Sunitinib malate (SUTENT ®< ) is an oral multitargeted TKI of stem cell receptor factor (KIT), platelet derived growth factor-receptors (PDGFRs), VEGFRs, glial cell-line neurotrophic factor receptor (RET), and FMS-like tyrosine kinase 3 (FLT3), and colony stimulating factor receptor Type 1 (CSR-1R) approved multinationally for the treatment of aRCC, imatinib-resistant or intolerant gastrointestinal stromal tumor (GIST), and unresectable, well-differentiated metastatic pancreatic neuroendocrine tumors (NET).

[0039] The study is a Phase 3, randomized, multination, multicenter, open-label, parallel 2-arm study in which approximately 465 patients are planned to be randomized to receive avelumab in combination with axitinib or sunitinib monotherapy: Arm A: avelumab in combination with axitinib; Arm B: sunitinib. Patients will be stratified according to ECOG performance status (0 versus 1) and LDH (>1.5 ULN vs. ≤1.5 ULN). In arm A (avelumab in combination with axitinib), avelumab will be given as a 1 hour intravenous infusion (IV) every 2 weeks in a 6-week cycle. Axitinib will be given orally (PO) twice daily (BID), with or without food, on a continuous dosing schedule.

[0040] Treatment with study drugs may continue until confirmed disease progression, patient refusal, patient lost to follow up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes first. Axitinib treatment may be adjusted by dosing interruption with or without dose reduction. Intrapatient axitinib dose escalation may occur if the intrapatient escalation criteria are met.

[0041] Study Treatment: Axitinib will be given orally twice daily PO on a continuous daily dosing schedule. Avelumab will be given as a 1 hour intravenous infusion every 2 weeks in a 6-week cycle. Sunitinib will be given orally 50 mg taken once daily, on a schedule 4 weeks on treatment followed by 2 weeks off (Schedule 4 / 2). Patients who develop disease progression on study treatment but are otherwise continuing to derive clinical benefit from study treatment will be eligible to continue with avelumab combined with axitinib, or single-agent avelumab, or single-agent axitinib, or single-agent sunitinib provided that the treating physician has determined that the benefit / risk for doing so is favorable.

[0042] Tumor Assessments: Anti-tumor activity will be assessed by radiological tumor assessments and will be based on RECIST guidelines version 1.1 for primary and secondary endpoints and on immune-related RECIST (irRECIST) guidelines for exploratory endpoints. Tumor assessments will be performed every 6 weeks (Q6W) up to 1 year from first dose therapy; thereafter, tumor assessments will be performed every 2 cycles. In addition, radiological tumor assessments will also be conducted whenever disease progression is suspected (e.g., symptomatic deterioration), at the time of the End of Treatment / Withdrawal visit (if not done in the previous 6 weeks), and during the Short term Follow-up period (at the 90-day visit only); subsequent tumor assessments during the Long term Follow-up period can be collected in absence of withdrawal of consent, regardless of initiation of subsequent anti-cancer therapies.

[0043] Tumor assessments will include all known or suspected disease sites. Imaging may include chest, abdomen, and pelvis CT or MRI scans; brain CT or MRI scans (required at baseline and when suspected brain metastasis) and bone scans or 18FDG PET (required at baseline then every 16 weeks only if bone metastases are present at baseline). Otherwise, bone imaging is required only if new bone metastasis are suspected and at the time of confirmation of complete response for patients who have bone metastases. The CT scans should be performed with contrast agents unless contraindicated for medical reasons. The same imaging technique used to characterize each identified and reported lesion at baseline will be employed in the following tumor assessments. Antitumor activity will be assessed through radiological tumor assessments conducted at baseline, at 6 weeks after the first dose of therapy, then every 6 weeks up to 1 year from the first dose of therapy and every 12 weeks thereafter, (if not done in the previous 6 weeks), and during the Short term Follow-up period (at the 90-day visit only); subsequent tumor assessments during the Long term Follow-up period can be collected in absence of withdrawal of consent, regardless of initiation of subsequent anti-cancer therapies. Further imaging assessments may be performed at any time if clinically indicated (e.g., suspected PD, symptomatic deterioration, etc.). Assessment of response will be made using RECIST version 1.1 and as per immune-related response criteria (irRC) (Nishino 2013). All radiographic images will be collected and may be objectively verified by a BICR independent third-party core imaging laboratory.

[0044] Primary Endpoint: Progression-Free Survival (PFS) as assessed by Blinded Independent Central Review (BICR) per RECIST v1.1. Secondary Endpoints: Overall Survival (OS); objective tumor response rate (OR), as assessed by BICR per RECIST version 1.1.; disease Control (DC), as assessed by BICR per RECIST version 1.1.; time to event: time to response (TTR), Duration of Response (DR); adverse Events (AEs) as characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v.4.03), timing, seriousness, and relationship to study therapy; Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v.4.03), and timing; PK parameters including trough concentrations (Ctrough) of avelumab and trough concentrations (Ctrough) and maximum concentrations (Cmax) of axitinib; tumor tissue biomarker status (i.e., positive or negative; based on for example, PD-L1 expression and / or quantitation of tumor infiltrating CD8+ T lymphocytes as assessed by immunohistochemistry); measures of clinical outcome (PFS, OS, OR, DCR, DR and TTR) in biomarker-positive and biomarker-negative sub-groups; anti-drug antibodies (ADAs; neutralizing antibodies) of avelumab when in combination with axitinib; patient-Reported Outcomes (PRO): FACT-Kidney Symptom Index (FKSI-19), EuroQol 5 Dimension (EQ 5D).Example 3: Phase 1b dose-finding study of avelumab (MSB0010718C; anti-PD-L1) + axitinib in treatment-naïve patients with advanced renal cell carcinoma

[0045] This example illustrates results from the study described in Example 1 above. Eligible patients have histologically confirmed aRCC with a clear-cell component, primary tumour resection, ≥1 measurable lesion, archival / fresh tumour biopsy, ECOG PS ≤1, no preexisting uncontrolled hypertension, and no prior systemic therapy for aRCC. To determine dose modifications for future cohorts, dose escalation / de-escalation rules that follow the modified toxicity probability interval method were used. Adverse events (AEs) were graded by NCI CTCAE v4. Objective response rates (ORR; RECIST v1.1) were evaluated.

[0046] The starting dose of avelumab 10 mg / kg (1h IV infusion) Q2W + axitinib 5 mg PO BID met MTD criteria. By 05 April 2016, 6 pts (median age 59.5 [range, 45-73]) have been treated with avelumab for a median of 17.0 wks (range, 11.9-21.7) and with axitinib for 16.3 wks (range, 12.7-22.7). One DLT of grade 3 proteinuria occurred. The most common treatment-related (TR) AEs of any grade were dysphonia (n=4), hypertension (n=4), fatigue (n=3), and headache (n=3). Grade 3-4 TRAEs were hypertension (n=2), hand-foot syndrome (n=1), elevated lipase (n=1), and proteinuria (n=1). Confirmed ORR is 83.3% (95% CI: 35.9, 99.6) based on 5 PRs and stable disease in 1 pt.

[0047] The MTD / RP2D for this expansion phase and further studies in aRCC has been confirmed as avelumab 10 mg / kg IV Q2W + axitinib 5 mg PO BID continuously. The regimen has shown preliminary antitumour activity in treatment-naïve pts with aRCC. Enrollment is ongoing in the expansion cohort. These results demonstrate the efficacy and safety of avelumab + axitinib vs current monotherapies for aRCC.

Claims

1. Avelumab for use in a method of treating PD-L1 -expressing renal cell carcinoma (RCC), 2 wherein avelumab is to be administered in combination with axitinib, or a pharmaceutically acceptable salt thereof.

2. Axitinib, or a pharmaceutically acceptable salt thereof, for use in a method of treating PD-L1-expressing renal cell carcinoma (RCC); wherein axitinib, or the pharmaceutically acceptable salt thereof, is to be administered in combination with avelumab.

3. Avelumab for the use of claim 1; or axitinib or the pharmaceutically acceptable salt thereof, for the use of claim 2; wherein (i) avelumab is administered as once every two weeks, preferably as a 1-hr intravenous infusion; and (ii) axitinib, or the pharmaceutically acceptable salt thereof, is administered twice daily on a continuous dosing schedule.

4. Avelumab for the use of claims 1 or 3; or axitinib or the pharmaceutically acceptable salt for the use of claims 2 or 3; wherein (i) avelumab is formulated as a liquid medicament, and (ii) axitinib is formulated as a 1 mg, a 3 mg or a 5 mg tablet.

5. Avelumab for the use of claims 1 or 3 or 4; or axitinib, or the pharmaceutically acceptable salt thereof, for the use of claims 2 or 3 or 4; wherein the RCC is advanced renal cell carcinoma.

6. Avelumab for the use of claim 5; or axitinib, or the pharmaceutically acceptable salt thereof for the use of claim 5, wherein the RCC is previously untreated advanced renal cell carcinoma.