Methods of treating skin cancer by administering a pd-1 inhibitor

Abstract

The present invention provides methods for treating, reducing the severity, or inhibiting the growth of cancer (e.g., skin cancer). The methods of the present invention comprise administering to a subject in need thereof a therapeutically effective amount of a programmed death 1 (PD-1) antagonist (e.g., an anti-PD-1 antibody). In certain embodiments, the skin cancer is cutaneous squamous cell carcinoma or basal cell carcinoma.

1 . A method of treating or inhibiting the growth of a tumor comprising:
 (a) selecting a patient with basal cell carcinoma (BCC); and   (b) administering to the patient a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds PD-1; wherein the antibody or antigen-binding fragment thereof comprises the three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2.   
     
     
         2 - 30 . (canceled) 
     
     
         31 . The method of  claim 1 , wherein the BCC is metastatic, unresectable and/or locally advanced. 
     
     
         32 . The method of  claim 1 , wherein the patient was previously treated with at least one anti-cancer therapy. 
     
     
         33 . The method of  claim 32 , wherein the anti-cancer therapy is selected from surgery, radiation, chemotherapy, a hedgehog pathway inhibitor, and another anti-PD-1 antibody. 
     
     
         34 . The method of  claim 1 , wherein the BCC has progressed after prior treatment with, or the patient is intolerant to, a hedgehog pathway inhibitor. 
     
     
         35 . The method of  claim 34 , wherein the hedgehog pathway inhibitor is selected from vismodegib and sonedegib. 
     
     
         36 . The method of  claim 1 , wherein the BCC is inoperable or the patient is not amenable to curative surgery, radiation, or treatment with a hedgehog pathway inhibitor. 
     
     
         37 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof is administered in one or more doses, wherein each dose is administered 0.5 to 4 weeks after the immediately preceding dose. 
     
     
         38 . The method of  claim 37 , wherein each dose is administered 2 weeks after the immediately preceding dose. 
     
     
         39 . The method of  claim 37 , wherein each dose is administered 3 weeks after the immediately preceding dose. 
     
     
         40 . The method of any one of  claims 37 , wherein each dose comprises 1, 3, or 10 mg/kg of patient's body weight. 
     
     
         41 . The method of  claim 40 , wherein each dose comprises 3 mg/kg of the patient's body weight. 
     
     
         42 . The method of  claim 37 , wherein each dose comprises 50-600 mg of the antibody or antigen-binding fragment thereof. 
     
     
         43 . The method of  claim 42 , wherein each dose comprises 200, 250, or 350 mg of the antibody or antigen-binding fragment thereof 
     
     
         44 . The method of  claim 1 , wherein the patient is resistant or inadequately responsive to, or relapsed after prior therapy. 
     
     
         45 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof is administered as a monotherapy. 
     
     
         46 . The method of  claim 1 , wherein the administration leads to at least one effect selected from inhibition of tumor growth, tumor regression, reduction in the size of a tumor, reduction in tumor cell number, delay in tumor growth, abscopal effect, inhibition of tumor metastasis, reduction in metastatic lesions over time, reduced use of chemotherapeutic or cytotoxic agents, reduction in tumor burden, increase in progression-free survival, increase in overall survival, complete response, partial response, and stable disease. 
     
     
         47 . The method of  claim 1 , further comprising administering to the patient an additional therapeutic agent or therapy selected from a hedgehog pathway inhibitor, surgery, radiation, a chemotherapeutic agent, a cancer vaccine, a programmed death ligand 1 (PD-L1) inhibitor, a lymphocyte activation gene 3 (LAG3) inhibitor, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, an anti-glucocorticoid-induced tumor necrosis factor receptor (GITR) antibody, a T-cell immunoglobulin and mucin-domain containing-3 (TIM3) inhibitor, a B- and T-lymphocyte attenuator (BTLA) inhibitor, a T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor, a CD47 inhibitor, an indoleamine-2,3-dioxygenase (IDO) inhibitor, a bispecific anti-CD 3 / a nti-CD20 antibody, a vascular endothelial growth factor (VEGF) antagonist, an angiopoietin-2 (Ang2) inhibitor, a transforming growth factor beta (TGF(3) inhibitor, a CD38 inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, granulocyte-macrophage colony-stimulating factor (GM-CSF), cyclophosphamide, an antibody to a tumor-specific antigen, Bacillus Calmette-Guerin vaccine, a cytotoxin, an interleukin 6 receptor (IL-6R) inhibitor, an interleukin 4 receptor (IL-4R) inhibitor, an IL-10 inhibitor, IL-2, IL-7, IL-21, IL-15, an antibody-drug conjugate, an anti-inflammatory drug, and a dietary supplement. 
     
     
         48 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof is administered intravenously, subcutaneously, or intraperitoneally. 
     
     
         49 . The method of  claim 1 , wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. 
     
     
         50 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1 and the LCVR comprising the amino acid sequence of SEQ ID NO: 2. 
     
     
         51 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a HCVR with 90% sequence identity to SEQ ID NO: 1. 
     
     
         52 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a LCVR with 90% sequence identity to SEQ ID NO: 2. 
     
     
         53 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a HCVR with 90% sequence identity to SEQ ID NO: 1 and a LCVR with 90% sequence identity to SEQ ID NO: 2. 
     
     
         54 . The method of  claim 1 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. 
     
     
         55 . A method of treating or inhibiting the growth of a tumor comprising:
 (a) selecting a patient with locally advanced basal cell carcinoma (BCC) or metastatic BCC, wherein the patient was previously treated with a hedgehog pathway inhibitor or is not amenable to treatment with a hedgehog pathway inhibitor; and   (b) administering to the patient a dose of 350 mg of an antibody that specifically binds PD-1, wherein the dose is administered intravenously every three weeks; wherein the antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) comprising the amino acid sequence of SEQ ID NO: 2.   
     
     
         56 . The method of  claim 55 , wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. 
     
     
         57 . The method of  claim 55 , wherein the antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1 and a LCVR comprising the amino acid sequence of SEQ ID NO: 2. 
     
     
         58 . The method of  claim 55 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.