Administration of PD-1 inhibitors for treating skin cancer

Abstract

To provide methods for treating or inhibiting the growth of a tumor in a patient with a skin cancer.SOLUTION: The present invention relates to a method comprising administering to a patient a therapeutically effective amount of a programmed death 1 (PD-1) inhibitor. In certain embodiments, the method comprises administering to a patient a therapeutically effective amount of a PD-1 inhibitor as adjuvant therapy after the patient has completed surgery and, optionally, radiation therapy for skin cancer, such as CSCC, and is at high risk of disease recurrence. In certain embodiments, the method comprises administering to a skin cancer patient a therapeutically effective amount of a PD-1 inhibitor as neoadjuvant therapy prior to planned surgery for skin cancer. In certain embodiments, the method comprises administering to a skin cancer patient a therapeutically effective amount of a PD-1 inhibitor as neoadjuvant therapy prior to planned surgery for skin cancer and, subsequently, administering a PD-1 inhibitor as adjuvant therapy after such surgery.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure relates to a method for treating or inhibiting tumor growth, which includes selecting a patient with skin cancer and administering to the patient a therapeutically effective amount of a programmed death 1 (PD-1) inhibitor.

Background Art

[0002] Skin cancer is the most common cancer in the United States (Non-Patent Document 1). An estimated 5.4 million cases of non-melanoma skin cancer, including basal cell carcinoma and squamous cell carcinoma, were diagnosed in the United States in 2012 (Non-Patent Document 2). Cutaneous squamous cell carcinoma (CSCC) is the second most common malignancy in the United States after basal cell carcinoma (BCC) (Non-Patent Document 3). Prolonged sun exposure is the dominant risk factor for non-melanoma skin cancer.

[0003] CSCC is a malignant proliferation of epithelial keratinocytes accompanied by dermal invasion and is distinguished from non-invasive precursor lesions such as actinic keratosis (Non-Patent Document 4). The worldwide incidence varies widely, with Australia having the highest incidence and some parts of Africa having the lowest incidence (Non-Patent Document 5). The exact incidence of CSCC is unknown because it is not included in most cancer registries. However, according to estimates that do not include patients with only non-invasive precursor lesions, the incidence of CSCC has been increasing in recent decades (Non-Patent Document 5) (Non-Patent Document 6) (Non-Patent Document 7).

[0004] Risk factors for CSCC include UV exposure, advanced age, and immunosuppression (Non-Patent Document 8; Non-Patent Document 9). The majority of individuals diagnosed with CSCC or BCC have a very good prognosis, but CSCC has a tendency for aggressive recurrence compared to BCC. Furthermore, individuals diagnosed with CSCC have a higher mortality rate compared to age-matched controls, unlike those diagnosed with BCC (Non-Patent Document 10).

[0005] Surgical resection is the most important item in the clinical management of CSCC or BCC. The first goal is complete excision of the cancer, and an acceptable cosmetic outcome is the second goal. Poor prognosis of CSCC Factors associated with it include tumor size > 2 cm, tumor depth > 2 mm, perineural invasion, host immunosuppression, and recurrent lesions. However, among patients who develop progressive CSCC, including both locally advanced and metastatic CSCC, there are those who are not candidates for surgery. Among such patients, some can receive postoperative radiotherapy or chemotherapy, but these may not be attractive options due to concerns about safety and tolerance.

[0006] Field cancerization, defined as multiple cancerous lesions at UV-exposed sites, is a feature of many CSCC patients. Furthermore, recurrent CSCC increases the risk of subsequent recurrence. In a single-institution retrospective study of 212 patients, recurrent CSCC was twice as likely to recur again after excision surgery compared to primary CSCC (Non-Patent Document 11). Multiple surgeries over time can damage appearance and lead to postoperative fatigue, i.e., physical and emotional debilitation resulting from successive surgical procedures. Additionally, CSCC in secondary sites of the head and neck, such as the ear, cheek, and lip, was associated with a worse clinical outcome (Non-Patent Document 12; Non-Patent Document 11; Non-Patent Document 13).

[0007] The most common clinical subtype of BCC is nodular BCC. Rare clinical subtypes are superficial, morphoeic (fibrotic), and fibroepithelial. Most patients are cured by surgery, but a small number of patients experience recurrent lesions or develop locally advanced or metastatic disease that is inoperable. The recognition of the oncogenic role of the G protein-coupled receptor Smoothened (SMO) in BCC led to the development of vismodegib and sonidegib, orally administrable inhibitors of SMO, generally referred to as hedgehog inhibitors (HHIs). In addition to the harmful side effects of HHIs, it was found that subsequent treatment with another HHI (sonidegib) does not result in tumor inhibition for patients treated with HHI (vismodegib) (Non-Patent Document 14).

[0008] Accordingly, there remains a need to provide a safe and effective therapy for skin cancer, such as CSCC and BCC, particularly skin cancer that recurs despite previous surgery.

[0009] Furthermore, only a small number of CSCC patients are considered to have high-risk CSCC when evaluated using several factors including the cancer progression classification using Non-Patent Document 15, immune status, lymphatic invasion, degree of lymph node metastasis, presence of extracapsular extension invasion, and treatment history. In cases of high-risk cases, postoperative radiotherapy is recommended (Non-Patent Documents 16) (Non-Patent Document 17). However, high-risk patients may relapse with local regional recurrence or distant metastasis (Non-Patent Document 18). Accordingly, there remains an unaddressed need to reduce the risk of CSCC recurrence, particularly in high-risk patients.

Prior Art Documents

Non-Patent Documents

[0010]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non - Patent Document 8

Non - Patent Document 9

Non - Patent Document 10

Non - Patent Document 11

Non - Patent Document 12

Non - Patent Document 13

Non - Patent Document 14

Non - Patent Document 15

Non - Patent Document 16

Non - Patent Document 17

Non - Patent Document 18

Summary of the Invention

Means for Solving the Problems

[0011] In one aspect, the disclosed technology is a method of treating or inhibiting tumor growth, comprising: (a) selecting a patient with skin cancer in whom surgery and / or radiotherapy for treating the skin cancer has been completed; and (b) subsequently administering to the patient an adjuvant treatment comprising a therapeutically effective amount of a programmed death 1 (PD-1) inhibitor. In one embodiment, the method of treating or inhibiting tumor growth comprises: (a) selecting a patient with skin cancer in whom surgery for treating the skin cancer and optionally postoperative radiotherapy has been completed; and (b) subsequently administering to the patient an adjuvant treatment comprising a therapeutically effective amount of a programmed death 1 (PD-1) inhibitor. In one embodiment, the skin cancer is cutaneous squamous cell carcinoma (CSCC), basal cell carcinoma (BCC), Merkel cell carcinoma or melanoma. In another embodiment, the skin cancer is CSCC. In another embodiment, the patient is at high risk of recurrence of CSCC. In one embodiment, the patient has metastatic disease and has undergone resection surgery. In another embodiment, the patient has at least one of the following high-risk features: nodular disease with extracapsular extension and at least one nodule >20 mm; in-transit metastasis (ITM); T4 lesion; perineural invasion (PNI); and recurrent CSCC + at least one of the following additional features: disease of ≧N2b associated with the recurrent lesion; nominal ≧T3; and a recurrent lesion with a diameter of ≧20 mm.

[0012] In another embodiment, the therapeutically effective amount comprises 5 mg to 500 mg of the PD-1 inhibitor. In another embodiment, the therapeutically effective amount comprises 350 mg of the PD-1 inhibitor. In another embodiment, the PD-1 inhibitor is administered intravenously or intraperitoneally. In another embodiment, the PD-1 inhibitor is administered intravenously. In another embodiment, step (b) is performed 2 to 6 weeks after completion of surgery and / or radiotherapy. In one embodiment, one or more doses of the PD-1 inhibitor The agent is administered as adjuvant therapy, and each dose is administered 2 to 12 weeks after the immediately preceding dose. In another embodiment, the PD-1 inhibitor is administered as adjuvant therapy according to the dosing regimens disclosed herein. In another embodiment, administration of the PD-1 inhibitor leads to a reduction in the risk of recurrence of subsequent skin cancer or results in no occurrence of recurrence of subsequent skin cancer. In another embodiment, administration of the PD-1 inhibitor leads to an incidence of recurrence of subsequent skin cancer that is at least about 10% lower compared to patients after completion of surgery and radiation therapy without adjuvant skin cancer treatment. In another embodiment, the method further comprises administering a second therapeutic agent selected from a chemotherapeutic agent, a corticosteroid, an anti-inflammatory agent, and / or combinations thereof.

[0013] In another embodiment, the PD-1 inhibitor is selected from the group consisting of an anti-PD-1 antibody or an antigen-binding fragment thereof, an anti-PD-L1 antibody or an antigen-binding fragment thereof, and an anti-PD-L2 antibody or an antigen-binding fragment thereof. In another embodiment, the PD-1 inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof comprising three complementarity-determining regions (CDRs) (HCDR1, HCDR2, and HCDR3) of the heavy-chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and three CDRs (LCDR1, LCDR2, and LCDR3) of the light-chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. In another embodiment, HCDR1 has the amino acid sequence of SEQ ID NO: 3; HCDR2 has the amino acid sequence of SEQ ID NO: 4; HCDR3 has the amino acid sequence of SEQ ID NO: 5; LCDR1 has the amino acid sequence of SEQ ID NO: 6; LCDR2 has the amino acid sequence of SEQ ID NO: 7; and LCDR3 has the amino acid sequence of SEQ ID NO: 8. In another embodiment, the anti-PD-1 antibody or an antigen-binding fragment thereof comprises the HCVR / LCVR sequence pair of SEQ ID NO: 1 / 2. In another embodiment, the anti-PD-1 antibody comprises a heavy chain and a light chain, and the heavy chain has the amino acid sequence of SEQ ID NO: 9. In another embodiment, the anti-PD-1 antibody comprises a heavy chain and a light chain, and the light chain has the amino acid sequence of SEQ ID NO: 10. In another embodiment, the anti-PD-1 antibody comprises a heavy chain and a light chain, the heavy chain has the amino acid sequence of SEQ ID NO: 9, and the light chain has the amino acid sequence of SEQ ID NO: 10.

[0014] In another embodiment, the PD-1 inhibitor is semiprimab or a biological equivalent thereof. In another embodiment, the PD-1 inhibitor is an anti-PD-1 antibody selected from the group consisting of semiprimab, nivolumab, pembrolizumab, pidilizumab, MEDI0608, BI 754091, PF-06801591, spartalizumab, camrelizumab, JNJ-63723283, and MCLA-134. In another embodiment, the PD-1 inhibitor is an anti-PD-L1 antibody selected from the group consisting of H1H8314N, avelumab, atezolizumab, durvalumab, MDX-1105, LY3300054, FAZ053, STI-1014, CX-072, KN035, and CK-301.

[0015] In another aspect, the disclosed technology relates to a pharmaceutical composition comprising a therapeutically effective amount of a programmed death 1 (PD-1) inhibitor for use in the adjuvant treatment of skin cancer after the completion of surgery and optionally postoperative radiation therapy. In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof comprising three complementarity-determining regions (CDRs) (HCDR1, HCDR2, and HCDR3) of a heavy-chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and three CDRs (LCDR1, LCDR2, and LCDR3) of a light-chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. In another embodiment, HCDR1 has the amino acid sequence of SEQ ID NO: 3; HCDR2 has the amino acid sequence of SEQ ID NO: 4; HCDR3 has the amino acid sequence of SEQ ID NO: 5; LCDR1 has the amino acid sequence of SEQ ID NO: 6; LCDR2 has the amino acid sequence of SEQ ID NO: 7; and LCDR3 has the amino acid sequence of SEQ ID NO: 8. In another embodiment, the anti-PD-1 antibody or an antigen-binding fragment thereof comprises the HCVR / LCVR sequence pair of SEQ ID NO: 1 / 2. In another embodiment, the pharmaceutical composition comprises 5 mg to 500 mg of the PD-1 inhibitor. In another embodiment, the pharmaceutical composition comprises 350 mg of the PD-1 inhibitor. In another embodiment, the skin cancer is CSCC.

[0016] In another aspect, the disclosed technology is a method of treating or inhibiting tumor growth comprising: (a) selecting a patient with skin cancer for whom surgical removal is planned; and (b) administering to the patient a neoadjuvant treatment comprising a therapeutically effective amount of a programmed death 1 (PD-1) inhibitor prior to surgical removal. In one embodiment, the skin cancer is cutaneous squamous cell carcinoma (CSCC), basal cell carcinoma (BCC), Merkel cell carcinoma or melanoma. In another embodiment, the skin cancer is CSCC. In another embodiment, the patient is at high risk of recurrence of CSCC. In another embodiment, the patient has at least one of the following high-risk components: nodular disease with extracapsular extension and at least one nodule >20 mm; in-transit metastasis (ITM); T4 lesion; perineural invasion (PNI); and recurrent CSCC + at least one of the following additional components: disease of ≧N2b associated with the recurrent lesion; nominal ≧T3; and recurrent lesion with a diameter of ≧20 mm. In another embodiment, the patient has stage II to stage IV skin cancer and the patient is a candidate for surgery. In one embodiment, a patient with a resectable tumor has an increased risk of recurrence and / or an increased risk of damage to appearance or loss of function.

[0017] In another embodiment, the therapeutically effective amount comprises 5 mg to 500 mg of a PD-1 inhibitor administered as neoadjuvant. In another embodiment, the therapeutically effective amount comprises 350 mg of a PD-1 inhibitor administered as neoadjuvant. In one embodiment, one or more doses of a PD-1 inhibitor are administered as neoadjuvant therapy, and each dose is administered 2 to 12 weeks after the immediately preceding dose. In another embodiment, the method further comprises (c) surgically removing the skin cancer following neoadjuvant therapy. In another embodiment, the method further comprises administering to the patient an adjuvant therapy comprising a therapeutically effective amount of a PD-1 inhibitor after step (c), and the adjuvant PD-1 inhibitor may be the same as or different from the neoadjuvant PD-1 inhibitor. In another embodiment, the adjuvant therapy comprises administering one or more doses of a PD-1 inhibitor, and each dose comprises 5 mg to 500 mg of a PD-1 inhibitor. In another embodiment, each dose of the adjuvant therapy comprises 350 mg of a PD-1 inhibitor. In one embodiment, each dose of the adjuvant therapy is administered 2 to 12 weeks after the immediately preceding dose. In another embodiment, the PD-1 inhibitor is administered intravenously or intraperitoneally. In another embodiment, the PD-1 inhibitor is administered intravenously.

[0018] In another embodiment, administration of the PD-1 inhibitor leads to a reduction in the risk of recurrence of subsequent skin cancer or results in no occurrence of recurrence of subsequent skin cancer. In another embodiment, administration of the PD-1 inhibitor leads to an incidence rate of recurrence of subsequent skin cancer that is at least about 10% lower compared to patients after completion of surgery and radiotherapy without adjuvant skin cancer treatment. In another embodiment, the method further comprises administering a second therapeutic agent selected from chemotherapeutic agents, corticosteroids, anti-inflammatory agents, and / or combinations thereof. In another embodiment, the PD-1 inhibitor is selected from the group consisting of an anti-PD-1 antibody or an antigen-binding fragment thereof, an anti-PD-L1 antibody or an antigen-binding fragment thereof, and an anti-PD-L2 antibody or an antigen-binding fragment thereof.

[0019] In another embodiment, the PD-1 inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof that includes three complementarity-determining regions (CDRs) (HCDR1, HCDR2, and HCDR3) of the heavy-chain variable region (HCVR) that includes the amino acid sequence of SEQ ID NO: 1 and three CDRs (LCDR1, LCDR2, and LCDR3) of the light-chain variable region (LCVR) that includes the amino acid sequence of SEQ ID NO: 2. In another embodiment, HCDR1 has the amino acid sequence of SEQ ID NO: 3; HCDR2 has the amino acid sequence of SEQ ID NO: 4; HCDR3 has the amino acid sequence of SEQ ID NO: 5; LCDR1 has the amino acid sequence of SEQ ID NO: 6; LCDR2 has the amino acid sequence of SEQ ID NO: 7; LCDR3 has the amino acid sequence of SEQ ID NO: 8. In another embodiment the anti-PD-1 antibody or an antigen-binding fragment thereof includes the HCVR / LCVR sequence pair of SEQ ID NO: 1 / 2. In another embodiment, the anti-PD-1 antibody includes a heavy chain and a light chain, and the heavy chain has the amino acid sequence of SEQ ID NO: 9. In another embodiment, the anti-PD-1 antibody includes a heavy chain and a light chain, and the light chain has the amino acid sequence of SEQ ID NO: 10. In another embodiment, the anti-PD-1 antibody includes a heavy chain and a light chain, the heavy chain has the amino acid sequence of SEQ ID NO: 9, and the light chain has the amino acid sequence of SEQ ID NO: 10.

[0020] In another embodiment, the PD-1 inhibitor is semiprimab or a biological equivalent thereof. In another embodiment, the PD-1 inhibitor is an anti-PD-1 antibody selected from the group consisting of semiprimab, nivolumab, pembrolizumab, pidilizumab, MEDI0608, BI 754048, PF-06371548, spartalizumab, camrelizumab, JNJ-63313240, and MCLA-134. In another embodiment, the PD-1 inhibitor is an anti-PD-L1 antibody selected from the group consisting of H1H8314N, avelumab, atezolizumab, durvalumab, MDX-1105, LY3300054, FAZ053, STI-1014, CX-031, KN035, and CK-301.

[0021] In another aspect, the disclosed technology relates to a pharmaceutical composition comprising a therapeutically effective amount of a programmed death 1 (PD-1) inhibitor for use in neoadjuvant therapy prior to a planned surgery for treating skin cancer. In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof comprising three complementarity-determining regions (CDRs) (HCDR1, HCDR2, and HCDR3) of a heavy-chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and three CDRs (LCDR1, LCDR2, and LCDR3) of a light-chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. In another embodiment, HCDR1 has the amino acid sequence of SEQ ID NO: 3; HCDR2 has the amino acid sequence of SEQ ID NO: 4; HCDR3 has the amino acid sequence of SEQ ID NO: 5; LCDR1 has the amino acid sequence of SEQ ID NO: 6; LCDR2 has the amino acid sequence of SEQ ID NO: 7; LCDR3 has the amino acid sequence of SEQ ID NO: 8. In another embodiment, the anti-PD-1 antibody or an antigen-binding fragment thereof comprises the HCVR / LCVR sequence pair of SEQ ID NO: 1 / 2. In another embodiment, the pharmaceutical composition comprises 5 mg to 500 mg of the PD-1 inhibitor. In another embodiment, the pharmaceutical composition comprises 350 mg of the PD-1 inhibitor. In another embodiment, the skin cancer is CSCC.

[0022] As used herein, "PD-1 inhibitor" can refer to at least one of a neoadjuvant PD-1 inhibitor and an adjuvant PD-1 inhibitor.

Brief Description of the Drawings

[0023]

Figure 1

Figure 2

Modes for Carrying Out the Invention

[0024] It should be understood that the present disclosure is not limited to the specific methods and experimental conditions described, as such methods and conditions may vary. It should also be understood that the terms used herein are for the purpose of describing only particular embodiments and are not intended to be limiting, and that the scope of the present disclosure is limited only by the appended claims.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed invention pertains. As used herein, the term "about," when used in connection with a specific recited numerical value, means that the value may vary by up to 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0026] Any methods and materials similar or equivalent to those described herein can be used in the practice of the present disclosure, but the preferred methods and materials are described below.

[0027] Methods for treating or inhibiting tumor growth The present disclosure includes a method for treating or inhibiting the growth of skin cancer, the method comprising selecting a patient with skin cancer and administering to the patient a therapeutically effective amount of a PD-1 inhibitor (e.g., an antibody or an antigen-binding fragment thereof that specifically binds to PD-1, PD-L1, and / or PD-L2, or any other "PD-1 inhibitor" described herein). In the present disclosure, references to anti-PD-1 antibodies in particular are provided to exemplify representative PD-1 inhibitors and do not limit the scope of the present disclosure. In one embodiment, the PD-1 inhibitor is administered prior to treating the patient with surgery and / or radiation therapy. In certain embodiments, the method includes administering a PD-1 inhibitor as adjuvant therapy to subjects in need thereof after completion of surgery and optionally radiation therapy for treating skin cancer, e.g., postoperative radiation therapy. In certain embodiments, the method includes administering a PD-1 inhibitor as neoadjuvant therapy to subjects in need thereof prior to a planned surgery for treating skin cancer, and the method can further include subsequently administering a PD-1 inhibitor to the patient as adjuvant therapy after surgery for treating skin cancer, if appropriate.

[0028] In certain embodiments, the present disclosure includes a method for treating or inhibiting the growth of skin cancer, the method comprising: (a) selecting a patient with skin cancer, wherein the patient has at least one of the following high-risk features: nodular disease with extracapsular extension and at least one nodule >20 mm; in-transit metastasis (ITM); T4 lesion; perineural invasion (PNI); and recurrent CSCC + at least one of the following additional features: disease of ≧N2b associated with the recurrent lesion; nominal ≧T3; and recurrent lesion with a diameter of ≧20 mm; and (b) administering to the patient in need thereof a therapeutically effective amount of a PD-1 inhibitor as adjuvant or neoadjuvant therapy.

[0029] As used herein, the terms "treating", "treat", etc. mean to delay or inhibit tumor growth, to reduce tumor cell burden or tumor mass, to promote tumor regression, to cause tumor shrinkage, necrosis and / or disappearance, to prevent tumor recurrence, to prevent or inhibit metastasis, to inhibit metastatic tumor growth, to obviate the need for surgery, and / or to extend the survival period of a subject, in order to eliminate the cause of a symptom, at least temporarily or permanently, and / or to reduce or alleviate the severity of one or more symptoms or signs. In many embodiments, the terms "tumor", "lesion", "tumor lesion", "cancer" and "malignant lesion" are used interchangeably and refer to one or more growths.

[0030] In some embodiments, the skin cancer is cutaneous squamous cell carcinoma (CSCC), basal cell carcinoma (BCC), Merkel cell carcinoma or melanoma. In some embodiments, the skin cancer is squamous cell carcinoma of the head and neck. In some embodiments, the skin cancer is advanced CSCC. In some embodiments, the skin cancer is metastatic, resectable, unresectable, recurrent, or locally advanced. In some embodiments, the skin cancer is CSCC, including but not limited to metastatic CSCC, locally advanced CSCC, resectable CSCC, unresectable CSCC or recurrent CSCC. In one embodiment, the skin cancer is resectable recurrent CSCC.

[0031] As used herein, the term "recurrent" refers to the frequent or repeated diagnosis of a patient's skin cancer (e.g., CSCC), or the frequent or repeated occurrence of new tumor lesions that may indicate recurrence of an individual tumor lesion, e.g., a primary tumor lesion and / or previous tumor lesions.

[0032] As used herein, the term "recurrence" is defined as the appearance of one or more new cutaneous cancer (e.g., CSCC) lesions, local, regional or distant. In many cases, new skin lesions due to field cancerization from long-term UV-mediated skin damage are new primary tumors (Christensen, F1000Res, 7, 2018). For CSCC, local or regional (locoregional) recurrence is defined by any of the following sites of disease recurrence: (a) for HN CSCC, recurrence in nodal or soft tissue above the clavicle; (b) for non-HN CSCC, recurrence within the first draining nodal basin of the excised tumor (or related soft tissue within the first draining nodal basin); (c) in-transit metastases defined as skin or subcutaneous metastases >2 cm from the primary lesion but not beyond the regional nodal basin. Distant recurrence is defined by any of the following sites of disease recurrence: (a) for HN CSCC, nodal recurrence below the clavicle; (d) for non-HN CSCC, recurrence beyond the first draining nodal basin of the excised tumor bed. Recurrence in two nodal basins is considered distant recurrence even if adjacent (i.e., two mediastinal nodal basins, two pelvic nodal basins); (e) recurrence in non-nodal tissue (including but not limited to lung, liver, bone, brain); (f) epidermotropic metastases defined as distant lesions in the dermis without epithelial involvement.

[0033] As used herein, the expression "subjects in need thereof" or "patients in need thereof" means a human or non-human mammal that exhibits one or more symptoms or signs of skin cancer and / or has been diagnosed with skin cancer, including solid tumors, and is in need of treatment for skin cancer. In many embodiments, the terms "subject" and "patient" are used interchangeably. This expression includes subjects having primary, established, or recurrent tumor lesions. In certain embodiments, this expression includes human subjects having solid tumors and / or in need of treatment for solid tumors. This expression also includes subjects having primary or metastatic tumors (advanced malignancies). In certain embodiments, this expression includes patients having solid tumors that are resistant or refractory to previous therapies (e.g., treatment with surgery or anticancer agents such as carboplatin or docetaxel) or are inadequately controlled by previous therapies. In certain embodiments, this expression includes patients having tumor lesions that have been treated (e.g., surgically removed) in one or more lines of previous therapy but have subsequently recurred. In certain embodiments, this expression includes subjects having tumor lesions of skin cancer who are not candidates for curative surgery or curative radiation or for whom conventional anticancer therapy is not a viable option, for example, due to toxic side effects. In other embodiments, this expression includes subjects having tumor lesions of skin cancer for which surgical removal is planned. In other embodiments, this expression includes subjects at high risk of recurrence due to a history of postoperative recurrence.

[0034] In certain embodiments, the methods of the disclosure are used in subjects having solid tumors. As used herein, the term "solid tumor" refers to an abnormal tumor of tissue that does not typically include cysts or liquid regions. Solid tumors can be benign (non-cancerous) or malignant (cancerous). In the present disclosure, the term "solid tumor" means a malignant solid tumor. The term includes different types of solid tumors named after the cell type that forms them, namely, sarcomas, carcinomas, and lymphomas. In certain embodiments, the term "solid tumor" includes more than one tumor lesion located separately from each other, e.g., two or more, five or more, ten or more, fifteen or more, twenty or more, twenty-five or more lesions, in a subject in need of treatment. In certain embodiments, more than one lesion are located distally from each other.

[0035] In certain embodiments, the disclosed methods include administering a therapeutically effective amount of a PD-1 inhibitor (e.g., an anti-PD-1 antibody) in combination with an anti-tumor therapy. As used herein, the phrase "in combination with" means that the PD-1 inhibitor is administered before, after, or simultaneously with the anti-tumor therapy. Anti-tumor therapies include, but are not limited to, conventional anti-tumor therapies such as chemotherapy, radiation, surgery, or those described elsewhere herein. In one embodiment, the anti-tumor therapy includes surgery. In one embodiment, the PD-1 inhibitor is administered as neoadjuvant therapy before surgery and / or radiation therapy. In another embodiment, the PD-1 inhibitor (e.g., an anti-PD-1 antibody) is administered as adjuvant therapy after surgery, after radiation therapy, or after surgery and postoperative radiation therapy. In certain embodiments, the PD-1 inhibitor (e.g., an anti-PD-1 antibody) is administered after surgery and optionally postoperative radiation therapy. In certain embodiments, the disclosed methods include administering a therapeutically effective amount of a PD-1 inhibitor (e.g., an anti-PD-1 antibody) in combination with an anti-tumor therapy. As used herein, the phrase "in combination with" means that the PD-1 inhibitor is administered before, after, or simultaneously with the anti-tumor therapy. Anti-tumor therapies include, but are not limited to, conventional anti-tumor therapies such as chemotherapy, radiation, surgery, or those described elsewhere herein. In one embodiment, the anti-tumor therapy includes surgery. In one embodiment, the PD-1 inhibitor is administered as neoadjuvant therapy before surgery and / or radiation therapy. In another embodiment, the PD-1 inhibitor (e.g., an anti-PD-1 antibody) is administered as adjuvant therapy after surgery, after radiation therapy, or after surgery and postoperative radiation therapy. In certain embodiments, the PD-1 inhibitor (e.g., an anti-PD-1 antibody) is administered after surgery and optionally postoperative radiation therapy.

[0036] In certain embodiments, the methods of the disclosure include: (a) selecting a patient with skin cancer, wherein the skin cancer is selected from CSCC, BCC, Merkel cell carcinoma, or melanoma, and the patient has one of the following high-risk profiles: nodular disease with extracapsular extension and at least one nodule >20 mm; in-transit metastasis (ITM); T4 lesion; perineural invasion (PNI); and recurrent CSCC + at least one of the following additional profiles: disease ≧N2b associated with the recurrent lesion; nominal ≧T3; and recurrent lesion with a diameter ≧20 mm); and (b) administering a therapeutically effective amount of a PD-1 inhibitor (e.g., an anti-PD-1 antibody) to the patients in need thereof. In some embodiments, the patient has a progressive solid tumor, such as CSCC. In certain embodiments, the progressive solid tumor is painless or aggressive. In one embodiment, the patient has previously received surgery and / or radiation for treating the skin cancer. In some embodiments, the methods of the disclosure include selecting a high-risk CSCC patient with a high risk of recurrence of CSCC based on a patient showing one of the following high-risk profiles: nodular disease with extracapsular extension and at least one nodule >20 mm; in-transit metastasis (ITM); T4 lesion; perineural invasion (PNI); and recurrent CSCC + at least one of the following additional profiles: disease ≧N2b associated with the recurrent lesion; nominal ≧T3; and recurrent lesion with a diameter ≧20 mm (optionally the patient has undergone excision surgery).

[0037] In certain embodiments, the subject is not responsive to previous therapy or surgery, or has relapsed after previous therapy or surgery (e.g., has experienced a recurrent lesion). In certain embodiments, the PD-1 inhibitor (e.g., an anti-PD-1 antibody) is administered intravenously or intraperitoneally to the subject. In some embodiments, the subject has a high-risk tumor profile, such as a high-risk nodular disease, a T4 tumor, perineural invasion, in-transit metastasis, or CSCC with a history of recurrence + at least one other risk factor.

[0038] As used herein, the expression "high risk" with respect to recurrence of CSCC or disease recurrence in CSCC patients refers to at least one of the following factors: (a) extracapsular extension (ECE) in a surgical pathology report and nodular disease with at least one nodule >20 mm (ECE is defined as extension into the surrounding connective tissue through the lymph node capsule, with or without an associated stromal reaction, including, for example, invasion of the skin and infiltration of the muscular system / infiltration into adjacent structures in a clinical examination); (b) in transit metastasis (ITM) defined as skin or subcutaneous metastasis >2 cm from the primary lesion but not exceeding the regional lymph node basin (Leitenberger et al., J Am Acad Dermatol, 75(5):1022-31, 2016); (c) T4 lesions, including HN lesions (AJCC, 2017) and non-HN lesions (UICC, 2015); (d) perineural invasion (PNI) defined as clinical and / or radiological involvement of a specified nerve (UICC, Manual of Clinical Oncology, 9th Edition, 2015) (e) recurrent CSCC defined as CSCC occurring within the area of a previously excised tumor + at least one of the following additional components (AJCC, 2017): (i) disease of ≧N2b associated with the recurrent lesion, (ii) a recurrent lesion of nominal ≧T3 (diameter ≧4 cm of the recurrent lesion, or superficial erosion, or invasion >6 mm when measured from the granular layer of the normal adjacent epithelium), or (iii) a recurrent lesion with a poorly differentiated histologic appearance and a diameter of ≧20 mm (the recurrent tumor must be recorded as being within the area of the previously excised CSCC, as measured by the radius measurement of the longest radius of the final abnormality, measured from the presumed center of the original surgical wound).

[0039] According to certain embodiments, the method of the present disclosure involves administering to a subject, intravenously or intraperitoneally, a therapeutically effective amount of a PD-1 inhibitor (e.g., an anti-PD-1 antibody) in combination with a further therapeutic agent, treatment regimen or treatment procedure. The further therapeutic agent, treatment regimen or treatment procedure can be administered to enhance the anti-tumor efficacy, to reduce the toxic effects of one or more therapies, and / or to reduce the dosage of one or more therapies.In various embodiments, additional therapeutic agents, regimens or procedures can include one or more of the following: chemotherapy, cyclophosphamide, surgery, cancer vaccines, programmed death ligand 1 (PD-L1) inhibitors (e.g., anti-PD-L1 antibodies), lymphocyte activation gene 3 (LAG3) inhibitors (e.g., anti-LAG3 antibodies), cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors (e.g., ipilimumab), glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists (e.g., anti-GITR antibodies), T cell immunoglobulin and mucin-containing-3 (TIM3) inhibitors, B and T lymphocyte attenuator (BTLA) inhibitors, T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitors, CA28 activators, 4-1BB agonists, CD38 inhibitors, CD47 inhibitors, indoleamine-2,3-dioxygenase (IDO) inhibitors, vascular endothelial growth factor (VEGF) antagonists, angiopoietin-2 (Ang2) inhibitors, anti-CD3 antibodies, transforming growth factor β (TGFβ) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, antibodies against tumor-specific antigens [e.g., CA9, CA125, melanoma-associated antigen 3 (MAGE3), carcinoembryonic antigen (CEA), vimentin, tumor-M2-PK, prostate-specific antigen (PSA), mucin-1, MART-1 and CA19-9], anti-CD3 / anti-CD20 bispecific antibodies, vaccines (e.g., Bacillus Calmette-Guerin), granulocyte-macrophage colony-stimulating factor, cytotoxins, chemotherapeutic agents, IL-6R inhibitors, IL-4R inhibitors, IL-10 inhibitors, cytokines, e.g., IL-2, IL-7, IL-21 and IL-15, anti-inflammatory agents, e.g., corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), and dietary supplements, e.g., antioxidants. In certain embodiments, PD-1 inhibitors (e.g., anti-PD-1 antibodies) can be administered in combination with therapies including chemotherapeutic agents and / or surgery.

[0040] In certain embodiments, administering a PD-1 inhibitor (e.g., an anti-PD-1 antibody) as adjuvant therapy to a subject having skin cancer after surgery and optionally radiation therapy, e.g., after completion of postoperative radiation therapy, leads to complete disappearance of all evidence of tumor cells (“complete response”), leads to at least a 30% or greater decrease in tumor cells or tumor size (“partial response”), or leads to complete or partial disappearance of lesions including tumor cells / new measurable lesions. Tumor reduction can be measured by any method known in the art, e.g., by x-ray, positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), cytodiagnosis, histodiagnosis, or molecular genetic analysis.

[0041] In certain embodiments, administering a PD-1 inhibitor (e.g., an anti-PD-1 antibody) as adjuvant therapy to a subject having skin cancer after surgery and optionally radiation therapy, e.g., after completion of postoperative radiation therapy, leads to an extension of overall survival (OS) or progression-free survival (PFS) of the subject as compared to a subject receiving “standard of care” (SOC) therapy (e.g., chemotherapy, surgery, or radiation). In certain embodiments, the PFS increases by at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 1 year, at least 2 years, or at least 3 years as compared to a subject receiving any one or more SOC therapies. In certain embodiments, the OS increases by at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 1 year, at least 2 years, or at least 3 years as compared to a subject receiving any one or more SOC therapies.

[0042] In certain embodiments, administration of a therapeutically effective amount of a PD-1 inhibitor (e.g., an anti-PD-1 antibody) to a subject having skin cancer as adjuvant therapy after completion of surgery and optionally postoperative radiation therapy (where the subject is at high risk of recurrence) leads to a reduction in the risk of subsequent recurrence of skin cancer or results in no recurrence of skin cancer. In certain embodiments, administration of a therapeutically effective amount of a PD-1 inhibitor (e.g., an anti-PD-1 antibody) to a CSCC patient after completion of surgery and / or radiation therapy for treating skin cancer leads to a reduction in the risk of subsequent recurrence of CSCC or results in no recurrence of CSCC. In certain embodiments of the disclosed methods, administration of a therapeutically effective amount of a PD-1 inhibitor (e.g., an anti-PD-1 antibody) to a CSCC patient after completion of surgery and radiation therapy for treating skin cancer results in no recurrence of CSCC for at least 6 months or at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 years or more after administration of the adjuvant PD-1 inhibitor.

[0043] In certain embodiments, administration of a therapeutically effective amount of a PD-1 inhibitor (e.g., an anti-PD-1 antibody) to a skin cancer patient after completion of surgery and radiation therapy for treating skin cancer leads to an incidence of subsequent recurrence of CSCC that is at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90% lower compared to patients treated with surgery and radiation therapy without adjuvant skin cancer treatment.

[0044] In certain embodiments, administering a PD-1 inhibitor (e.g., an anti-PD-1 antibody) as neoadjuvant therapy to a subject having skin cancer prior to a planned surgery for treating the skin cancer, and optionally subsequently administering the PD-1 inhibitor to the patient as adjuvant therapy after the surgery for treating the skin cancer, leads to complete disappearance of all evidence of tumor cells ("complete response"), leads to at least a 30% or greater decrease in tumor cells or tumor size ("partial response"), or leads to complete or partial disappearance of lesions including tumor cells / new measurable lesions. Tumor reduction can be measured by any method known in the art, such as by x-ray, positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), cytodiagnosis, histodiagnosis, or molecular genetic analysis.

[0045] In certain embodiments, administering a PD-1 inhibitor (e.g., an anti-PD-1 antibody) as neoadjuvant therapy to a subject having skin cancer prior to a planned surgery for treating the skin cancer, and optionally subsequently administering the PD-1 inhibitor to the patient as adjuvant therapy after the surgery for treating the skin cancer, leads to an extension of overall survival (OS) or progression-free survival (PFS) of the subject as compared to subjects receiving "standard of care" (SOC) therapy (e.g., chemotherapy, surgery, or radiation). In certain embodiments, the PFS is at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 increases by at least 1 month, at least 11 months, at least 1 year, at least 2 years or at least 3 years. In certain embodiments, the OS increases by at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 1 year, at least 2 years or at least 3 years compared to a subject to whom any one or more SOC therapies are administered.

[0046] In certain embodiments, administration of a therapeutically effective amount of a PD-1 inhibitor (e.g., an anti-PD-1 antibody) to a subject having skin cancer as neoadjuvant therapy prior to a planned surgery leads to a reduction in the risk of subsequent recurrence of skin cancer or results in no occurrence of recurrence of skin cancer. In certain embodiments, administration of a therapeutically effective amount of a PD-1 inhibitor (e.g., an anti-PD-1 antibody) to a CSCC patient prior to surgical removal of a skin cancer lesion for treating the skin cancer leads to a reduction in the risk of subsequent recurrence of CSCC or results in no occurrence of recurrence of CSCC. In certain embodiments of the disclosed methods, administration of a therapeutically effective amount of a PD-1 inhibitor (e.g., an anti-PD-1 antibody) to a CSCC patient as neoadjuvant therapy prior to a planned surgery for treating skin cancer results in no occurrence of recurrence of CSCC for at least 6 months or for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 years or more after the surgery.

[0047] In certain embodiments, administration of a therapeutically effective amount of a PD-1 inhibitor (e.g., an anti-PD-1 antibody) to a skin cancer patient as neoadjuvant therapy prior to a planned surgery for treating skin cancer leads to an incidence of subsequent recurrence of CSCC that is at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90% lower compared to patients treated with surgery without neoadjuvant skin cancer therapy.

[0048] PD-1 inhibitor The methods disclosed herein include administering a therapeutically effective amount of a PD-1 inhibitor. As used herein, "PD-1 inhibitor" refers to any molecule that can inhibit, block, suppress, or prevent the activity or expression of PD-1. In some embodiments, the PD-1 inhibitor can be an antibody, small molecule compound, nucleic acid, polypeptide, or a functional fragment or variant thereof. Non-limiting examples of suitable PD-1 inhibitor antibodies include anti-PD-1 antibodies and antigen-binding fragments thereof, anti-PD-L1 antibodies and antigen-binding fragments thereof, and anti-PD-L2 antibodies and antigen-binding fragments thereof. Other non-limiting examples of suitable PD-1 inhibitors include RNAi molecules, such as anti-PD-1 RNAi molecules, anti-PD-L1 RNAi, and anti-PD-L2 RNAi, antisense molecules, such as anti-PD-1 antisense RNA, anti-PD-L1 antisense RNA, and anti-PD-L2 antisense RNA, and dominant negative proteins, such as dominant negative PD-1 protein, dominant negative PD-L1 protein, and dominant negative PD-L2 protein. Some examples of the foregoing PD-1 inhibitors are described, for example, in US9308236, US10011656, and US20170290808, and that portion thereof that identifies the PD-1 inhibitor is incorporated herein by reference.

[0049] As used herein, the term "antibody" refers to an immunoglobulin molecule and multimers thereof (e.g., IgM) that contain four polypeptide chains interconnected by disulfide bonds, i.e., two heavy (H) chains and two light (L) chains. In a typical antibody, each heavy chain contains a heavy chain variable region (HCVR or V H omitted herein) and a heavy chain constant region. The heavy chain constant region contains three domains, i.e., C H 1, C H 2, and C H 3. Each light chain contains a light chain variable region (LCVR or V L omitted herein) and a light chain constant region. The light chain constant region contains one domain (C L 1). VH and V L The region can be further subdivided into hypervariable regions called complementarity determining regions (CDRs), in which more conserved regions, called framework regions (FRs), are interspersed. Each V H and V L is composed of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments of the invention, the FRs of the anti-IL-4R antibody (or antigen-binding portion thereof) may be identical to the human germline, or may be naturally or artificially modified. Amino acid consensus sequences can be defined based on side-by-side analysis of two or more CDRs. As used herein, the term "antibody" includes antigen-binding fragments of complete antibody molecules.

[0050] As used herein, terms such as "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, etc. include any naturally occurring, enzymatically obtained, synthetic or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen and forms a complex. Antigen-binding fragments of an antibody can be generated, for example, from a complete antibody molecule using any suitable standard technique, including protein digestion or recombinant genetic engineering techniques involving manipulation and expression of DNA encoding the variable and optionally constant domains of the antibody. Such DNA is known and / or readily available, for example, from commercial suppliers, DNA libraries (including, for example, phage antibody libraries), or can be synthesized. The DNA can be sequenced and manipulated chemically or using molecular biological techniques, for example, to arrange one or more variable and / or constant domains in an appropriate configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.

[0051] Non-limiting examples of antigen-binding fragments include the following: (i) Fab fragments; (ii) F(ab’)2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable regions of an antibody (e.g., isolated complementarity-determining regions (CDRs), such as CDR3 peptides), or constrained FR3-CDR3-FR4 peptides. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetra-bodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains are also included within the expression “antigen-binding fragment” as used herein.

[0052] An antigen-binding fragment of an antibody typically includes at least one variable domain. The variable domain can be of any size or amino acid composition and generally includes at least one CDR adjacent to or in-frame with one or more framework sequences. The V L domain bound to the V H domain in an antigen-binding fragment having a V H and V L domain can be positioned relative to each other in any suitable arrangement. For example, the variable regions can be dimeric and can include V H -V H V H -V L or V L -V L dimers. Alternatively, an antigen-binding fragment of an antibody can include a monomeric V H or V L domain.

[0053] In certain embodiments, an antigen-binding fragment of an antibody can include at least one variable domain covalently attached to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that can be found within the antigen-binding fragments of the antibodies of the present disclosure include the following: (i) V H -C H 1; (ii) V H -C H 2; (iii) V H -C H 3; (iv) V H -C H 1-C H 2; (v) V H -C H 1-C H 2-C H 3; (vi) V H -C H 2-C H 3; (vii) V H -C L ; (viii) V L -C H 1; (ix) V L -C H 2; (x) V L -C H 3; (xi) V L -C H 1-C H 2; (xii) V L -C H 1-C H 2-C H 3; (xiii) V L -C H 2-C H 3; and (xiv) V L -C LIn any configuration of the variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be directly linked to each other or may be linked by a full or partial hinge or linker region. The hinge region can consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that provide a flexible or semi-flexible bond between adjacent variable and / or constant domains in a single polypeptide molecule. Further, the antigen-binding fragments of the antibodies of the present disclosure can be non-covalently associated with each other and / or with one or more monomeric V H or V L domains (e.g., by disulfide bonds) to include homodimers or heterodimers (or other multimers) of any of the variable and constant domain configurations listed above.

[0054] The antibodies used in the methods disclosed herein may be human antibodies. As used herein, the term "human antibody" refers to an antibody having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibodies of the present disclosure can include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by in vitro random or site-directed mutagenesis or by somatic mutations in vivo), for example, in CDRs, particularly CDR3. However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been transplanted into human framework sequences.

[0055] The antibodies used in the methods disclosed herein may be recombinant human antibodies. As used herein, the term "recombinant human antibody" refers to any human antibody prepared, expressed, made, or isolated by recombinant means, such as an antibody expressed using a recombinant expression vector transfected into a host cell (described further below), an antibody isolated from a recombinant combinatorial human antibody library (described further below), an antibody isolated from an animal that is transgenic for human immunoglobulin genes (e.g., a mouse) [see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295], or an antibody prepared, expressed, made, or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, if an animal that is transgenic for human Ig sequences is used, in vivo somatic mutagenesis), and thus the amino acid sequences of the V H and V L regions of the recombinant antibody are related to, but may not naturally occur in the human antibody germline repertoire in vivo, sequences that are derived from the human germline V H and V L sequences.

[0056] Anti-PD-1 antibodies and antigen-binding fragments thereof In some embodiments, the PD-1 inhibitor used in the methods disclosed herein is an antibody or an antigen-binding fragment thereof that specifically binds to PD-1. Terms such as "specifically binds" mean that the antibody or an antigen-binding fragment thereof forms a relatively stable complex with the antigen under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, as used in the present disclosure, an antibody that "specifically binds" to PD-1 binds to PD-1 or a portion thereof with a K of less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about D 2 nM, less than about 1 nM or less than about 0.5 nM as measured by surface plasmon resonance assay. However, an isolated antibody that specifically binds to human PD-1 may have cross-reactivity to other antigens, such as PD-1 molecules from other (non-human) species.

[0057] According to certain exemplary embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity determining region (CDR) comprising the amino acid sequence of any of the anti-PD-1 antibodies described in U.S. Patent No. 9,987,500, which is incorporated herein by reference in its entirety. In certain exemplary embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof that can be used in the present disclosure comprises a heavy chain complementarity determining region (HCDR) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain complementarity determining region (LCDR) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. According to certain embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), 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. In yet other embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises an HCVR comprising SEQ ID NO: 1 and an LCVR comprising SEQ ID NO: 2. In certain embodiments, the methods of the present disclosure comprise the use of an anti-PD-1 antibody, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-PD-1 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 10. An exemplary antibody comprising 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 is a fully human anti-PD-1 antibody known as cemiplimab (also known as REGN2810, LIBTAYO®).

[0058] According to certain exemplary embodiments, the methods of the present disclosure include the use of REGN2810 or a biological equivalent thereof. As used herein, the term "biological equivalent" refers to a pharmaceutical equivalent or alternative of an anti-PD-1 antibody, a PD-1 binding protein, or a fragment thereof, which, when administered in a single or multiple doses at the same molar dose under similar experimental conditions, does not show a significant difference in the rate and / or extent of absorption from that of a reference antibody (e.g., REGN2810). In the present disclosure, the term "biological equivalent" includes an antigen-binding protein that binds to PD-1 and has no clinically meaningful difference from REGN2810 with respect to safety, purity, and / or efficacy.

[0059] According to certain embodiments of the present disclosure, an anti-human PD-1 or an antigen-binding fragment thereof comprises a HCVR having 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 1.

[0060] According to certain embodiments of the present disclosure, an anti-human PD-1 or an antigen-binding fragment thereof comprises a LCVR having 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 2.

[0061] According to certain embodiments of the present disclosure, an anti-human PD-1 or an antigen-binding fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1 and having no more than five amino acid substitutions. According to certain embodiments of the present disclosure, an anti-human PD-1 or an antigen-binding fragment thereof comprises a LCVR comprising the amino acid sequence of SEQ ID NO: 2 and having no more than two amino acid substitutions.

[0062] Sequence identity can be measured by methods known in the art (e.g., GAP, BESTFIT, and BL AST).

[0063] The present disclosure also includes the use of anti-PD-1 antibodies in methods for treating skin cancer, wherein the anti-PD-1 antibodies comprise variants of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein that have one or more conservative amino acid substitutions. For example, the present disclosure includes the use of anti-PD-1 antibodies having HCVR, LCVR, and / or CDR amino acid sequences having, for example, 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. conservative amino acid substitutions relative to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein.

[0064] Other anti-PD-1 antibodies that can be used in the methods of the present disclosure include, for example, nivolumab, pembrolizumab, MEDI0608, pidilizumab, BI 754091, spartalizumab (also known as PDR001), camrelizumab (also known as SHR-1210), JNJ-63723283, MCLA-134, antibodies known in the art, or those described in U.S. Patent Nos. 6,808,710, 7,488,802, 8,008,449, 8,168,757, 8,354,509, 8,609,089, 8,686,119, 8,779,105, 8,900,587, and 9,987,500, and Patent Publications WO2006 / 121168, WO2009 / 114335. All portions of the aforementioned publications that identify anti-PD-1 antibodies are hereby incorporated herein by reference.

[0065] The anti-PD-1 antibodies used in the methods of the present disclosure can have pH-dependent binding properties. For example, an anti-PD-1 antibody for use in the methods of the present disclosure can exhibit a reduction in binding to PD-1 at acidic pH as compared to neutral pH. Alternatively, the anti-PD-1 antibodies of the present invention can exhibit an enhancement in binding to its antigen at acidic pH as compared to neutral pH. The expression "acidic pH" includes pH values of less than about 6.2, such as about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0 or less. As used herein, the expression "neutral pH" means a pH of from about 7.0 to about 7.4. The expression "neutral pH" includes pH values of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35 and 7.4.

[0066] In certain cases, "reduction in binding to PD-1 at acidic pH as compared to neutral pH" is represented in terms of the ratio of the K D value for antibody binding to PD-1 at acidic pH to the K D value for antibody binding to PD-1 at neutral pH (or vice versa). For example, an antibody or an antigen-binding fragment thereof can be considered to exhibit "reduction in binding to PD-1 at acidic pH as compared to neutral pH" in the present disclosure if the antibody or an antigen-binding fragment thereof exhibits an acidic / neutral K D ratio of about 3.0 or more. In certain exemplary embodiments, the acidic / neutral K D ratio for an antibody or an antigen-binding fragment of the present disclosure can be about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0 or more.

[0067] Antibodies having pH-dependent binding characteristics can be obtained, for example, by screening a population of antibodies for reduced (or enhanced) binding to a particular antigen at acidic pH compared to neutral pH. Further, modification of the antigen-binding domain at the amino acid level can result in antibodies having pH-dependent properties. For example, by substituting one or more amino acids in the antigen-binding domain (e.g., within a CDR) with histidine residues, an antibody can be obtained that has reduced antigen binding at acidic pH compared to neutral pH. This specific As used in this specification, the expression "acidic pH" means a pH of 6.0 or less.

[0068] Anti-PD-L1 antibodies and antigen-binding fragments thereof In some embodiments, the PD-1 inhibitor used in the methods disclosed herein is an antibody or an antigen-binding fragment thereof that specifically binds to PD-L1. For example, as used in this disclosure, an antibody that "specifically binds" to PD-L1 has a K -8 of about 1 × 10 D (e.g., the smaller the K D , the stronger the binding) and binds to PD-L1 or a portion thereof. A "high-affinity" anti-PD-L1 antibody has a K -8 of at least 10 -9 M, preferably 10 -10 M, more preferably 10 -11 M, even more preferably 10 -12 M, and even more preferably 10 D as measured by surface plasmon resonance, e.g., BIACORE™, or solution affinity ELISA, and refers to an mAb having binding affinity for PD-L1. However, an isolated antibody that specifically binds to human PD-L1 may have cross-reactivity to other antigens, e.g., PD-L1 molecules from other (non-human) species.

[0069] According to certain exemplary embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity determining region (CDR) comprising the amino acid sequence of any of the anti-PD-L1 antibodies described in U.S. Patent No. 9,938,345, which is incorporated herein by reference in its entirety. In certain exemplary embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof that can be used in the present disclosure comprises a heavy chain complementarity determining region (HCDR) of the heavy chain variable region (HCVR) and a light chain complementarity determining region (LCDR) of the light chain variable region (LCVR), and the HCVR and LCVR comprise the amino acid sequence of the anti-PD-L1 antibody designated H1H8314N in U.S. Patent No. 9,938,345. According to certain embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), and HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequence of the anti-PD-L1 antibody designated H1H8314N in U.S. Patent No. 9,938,345. In still other embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises an HCVR and an LCVR comprising the amino acid sequence of the anti-PD-L1 antibody designated H1H8314N in U.S. Patent No. 9,938,345.

[0070] According to certain embodiments of the present disclosure, the anti-human PD-L1 or antigen-binding fragment thereof comprises an LCVR having 90%, 95%, 98% or 99% sequence identity to the LCVR amino acid sequence of the anti-PD-L1 antibody designated H2M8314N in U.S. Patent No. 9,938,345.

[0071] According to certain embodiments of the present disclosure, an anti-human PD-L1 or an antigen-binding fragment thereof comprises a HCVR comprising the amino acid sequence of an anti-PD-L1 antibody designated H1H8314N in U.S. Patent No. 9,938,345, having five or fewer amino acid substitutions. According to certain embodiments of the present disclosure, an anti-human PD-L1 or an antigen-binding fragment thereof comprises a LCVR comprising the amino acid sequence of an anti-PD-L1 antibody designated H1H8314N in U.S. Patent No. 9,938,345, having two or fewer amino acid substitutions.

[0072] Sequence identity can be measured by methods known in the art (e.g., GAP, BESTFIT, and BLAST).

[0073] The present disclosure also includes the use of an anti-PD-L1 antibody in a method for treating skin cancer, wherein the anti-PD-L1 antibody is a variant of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein, having one or more conservative amino acid substitutions. For example, the present disclosure includes the use of an anti-PD-L1 antibody having a HCVR, LCVR, and / or CDR amino acid sequence having, for example, 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. conservative amino acid substitutions relative to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein.

[0074] Other anti-PD-L1 antibodies that can be used in the methods of the present disclosure include, for example, MDX-1105, atezolizumab (TECENTRIQ™), durvalumab (IMFINZI™), avelumab (BAVENCIO™), LY3300054, FAZ053, STI-1014, CX-072, KN035 (Zhang et al., Cell Discovery, 3, 170004 (March 2017)), CK-301 (Gorelik et al., American Association for Cancer The Research Annual Meeting (AACR), April 4, 2016, Abstract 4606), and other anti-PD-L1 antibodies known in the art, or those described in patent publications US7943743, US8217149, US9402899, US9624298, US9938345, WO2007 / 005874, WO2010 / 077634, WO2013 / 181452, WO2013 / 181634, WO2016 / 149201, WO2017 / 034916, or EP3177649. All portions of the aforementioned publications that identify anti-PD-L1 antibodies are hereby incorporated by reference into this specification.

[0075] Pharmaceutical Compositions and Administration The PD-1 inhibitors disclosed herein can be included within a pharmaceutical composition that can be formulated with a suitable carrier, excipient, buffer, and other agents that provide for appropriate transit, delivery, tolerability, etc. Numerous suitable formulations can be found in the formulary known to all pharmacists: Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (e.g., LIPOFECTIN (trademark)), DNA conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, emulsion carbowaxes (polyethylene glycols of various molecular weights), semi-solid gels, and carbowax-containing semi-solid mixtures. See also Powell et al., “Compendium of excipients for parenteral formulations” PDA, J Pharm Sci Technol 52:238~311 (1998).

[0076] A variety of delivery systems are known and can be used to administer the pharmaceutical compositions of the present invention, for example, encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis. See, for example, Wu et al., J. Biol. Chem. 262:4429-32 (1987).

[0077] The pharmaceutical composition containing the PD-1 inhibitor disclosed herein is suitable for intravenous administration or intraperitoneal administration.

[0078] Injectable formulations of the pharmaceutical composition can be prepared by known methods. For example, an injectable formulation can be prepared by dissolving, suspending, or emulsifying the above antibody or its salt in a sterilized aqueous medium or an oily medium conventionally used for injection. Examples of the aqueous medium for injection include physiological saline, isotonic solutions containing glucose and other adjuvants, and these can be used in combination with suitable solubilizers such as alcohols (e.g., ethanol), polyalcohols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. Examples of the oily medium include sesame oil, soybean oil, etc., and these can be used in combination with solubilizers such as benzyl benzoate, benzyl alcohol, etc. The injectable formulation thus prepared is preferably filled in a suitable injection ampoule. In some embodiments, the injectable formulation may be in the form of an injection solution containing a concentrate of the PD-1 inhibitor and one or more solvents (e.g., distilled water, saline, etc.).

[0079] In certain embodiments, the present disclosure provides a pharmaceutical composition or formulation comprising a therapeutically effective amount of a PD-1 inhibitor (e.g., an anti-PD-1 antibody) and a pharmaceutically acceptable carrier. In certain embodiments, the present disclosure provides a PD-1 inhibitor (e.g., an anti-PD-1 antibody) formulated in a pharmaceutical composition suitable for administration by intravenous injection.

[0080] Exemplary pharmaceutical compositions containing anti-PD-1 antibodies that can be used in the present disclosure are disclosed, for example, in US2019 / 0040137.

[0081] Dosing regimen In certain embodiments, the methods disclosed herein include administering, for example, as part of a particular therapeutic dosing regimen, a therapeutically effective amount of a PD-1 inhibitor (e.g., an anti-PD-1 antibody) in multiple doses to the tumor of a subject in need thereof. For example, suitable therapeutic dosing regimens can be, as long as a therapeutic response is achieved, about once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once a month, once every 2 months, once every 3 months, once every 4 months, twice a day, twice every 2 days, twice every 3 days, twice every 4 days, twice every 5 days, twice every 6 days, twice a week, twice every 2 weeks, twice every 3 weeks, twice every 4 weeks, twice every 5 weeks, twice every 6 weeks, twice every 8 weeks, twice every 12 weeks, twice a month, twice every 2 months, twice every 3 months, twice every 4 months, three times a day, three times every 2 days, three times every 3 days, three times every 4 days, three times every 5 days, three times every 6 days, three times a week, three times every 2 weeks, three times every 3 weeks, three times every 4 weeks, three times every 5 weeks, three times every 6 weeks, three times every 8 weeks, three times every 12 weeks, three times a month, three times every 2 months, three times every 3 months, three times every 4 months, or at a lower frequency, or as needed, administering one or more doses of a PD-1 inhibitor to the subject. In one embodiment, one or more doses of an anti-PD-1 antibody are administered once a week.

[0082] In certain embodiments, one or more doses are administered in at least one treatment cycle. The methods according to this aspect include administering at least one treatment cycle comprising administration of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses of a PD-1 inhibitor (e.g., an anti-PD-1 antibody) to a subject in need thereof. In one embodiment, the treatment cycle comprises 3 doses of the PD-1 inhibitor. In one embodiment, the treatment cycle comprises 12 doses of the PD-1 inhibitor. In one embodiment, the treatment cycle comprises 24 doses of the PD-1 inhibitor. In one embodiment, the treatment cycle comprises 3 doses of the PD-1 inhibitor, and each dose is administered 2 weeks after the immediately preceding dose. In one embodiment, the treatment cycle comprises 10 doses of the PD-1 inhibitor, and each dose is administered 1 week after the immediately preceding dose. In one embodiment, the treatment cycle comprises 12 doses of the PD-1 inhibitor, and each dose is administered 1 week after the immediately preceding dose.

[0083] In one embodiment, all doses administered in a treatment cycle contain the same amount of the PD-1 inhibitor. In another embodiment, the treatment cycle comprises administration of at least 2 doses containing different amounts of the PD-1 inhibitor. In one embodiment, the first dose of the treatment cycle contains a greater amount of the PD-1 inhibitor than subsequent doses of the treatment cycle. In one embodiment, the first dose of the treatment cycle contains a lesser amount of the PD-1 inhibitor than subsequent doses of the treatment cycle.

[0084] In one embodiment, all doses of the treatment cycle are administered using the same route of administration. In another embodiment, the doses of the treatment cycle are administered using different routes of administration, including two or more routes of administration.

[0085] In one embodiment, the treatment cycle is repeated. In some embodiments, the treatment cycle is repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more times.

[0086] In certain embodiments, a dose of the PD-1 inhibitor is administered to the subject in a single session or patient visit.

[0087] As used herein, the terms "first," "second," "third," etc. refer to the chronological order of administration. Thus, a "first dose" is the dose administered at the beginning of a treatment regimen (also referred to as the "baseline dose"); a "second dose" is the dose administered after the first dose; and a "third dose" is the dose administered after the second dose. The first, second, and third doses can all contain the same amount of a PD-1 inhibitor (anti-PD-1 antibody). However, in certain embodiments, the amounts contained in the first, second, and / or third doses are different from each other (e.g., adjusted up or down as appropriate) during the course of treatment. In certain embodiments, one or more (e.g., 1, 2, 3, 4, or 5) doses are administered as a "loading dose" at the beginning of a treatment regimen, followed by subsequent doses administered at a lower frequency (e.g., a "maintenance dose"). For example, an anti-PD-1 antibody can be administered to a cancer patient at a loading dose of about 1 mg / kg to about 3 mg / kg based on the patient's weight, followed by one or more maintenance doses of about 0.1 mg / kg to about 20 mg / kg.

[0088] In an exemplary embodiment of the present disclosure, each second and / or third dose is administered 1 / 2 to 4 or more weeks (e.g., 1 / 2, 1, 1 1 / 2, 2, 2 1 / 2, 3, 3 1 / 2, 4, or more weeks) after the immediately preceding dose. As used herein, the phrase "immediately preceding dose" means the dose of an anti-PD-1 antibody that is administered to a subject prior to the administration of the next dose in the order of multiple administrations, without intervening doses.

[0089] Similarly, a "first treatment cycle" is a treatment cycle performed at the beginning of a treatment regimen; a "second treatment cycle" is a treatment cycle performed after the first treatment cycle; and a "third treatment cycle" is a treatment cycle performed after the second treatment cycle. In the present disclosure, the treatment cycles may be the same as or different from each other.

[0090] Dosage In certain embodiments, each dose of the PD-1 inhibitor comprises 0.1, 1, 0.3, 3, 4, 5, 6, 7, 8, 9 or 10 mg / kg based on the patient's body weight. In certain embodiments, each dose comprises 5-500 mg of the PD-1 inhibitor, for example, 5, 10, 15, 20, 25, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 mg or more of the PD-1 inhibitor. In one embodiment, the PD-1 inhibitor is REGN2810 (semiplimab).

[0091] The amount of the PD-1 inhibitor administered to a subject (e.g., intravenously or intraperitoneally) according to the methods disclosed herein is generally a therapeutically effective amount. As used herein, the term "therapeutically effective amount" means an amount of the PD-1 inhibitor that results in one or more of the following: (a) reduction in the severity or duration of symptoms or signs of skin cancer, e.g., tumor lesions; (b ) inhibition of tumor growth, or increased tumor necrosis, tumor shrinkage and / or tumor disappearance; (c) delay in the growth and development of tumors; (d) inhibition of tumor metastasis; (e) prevention of recurrence of tumor growth; and / or (f) increase in the survival of a subject having cancer.

[0092] In the case of a PD-1 inhibitor (e.g., an anti-PD-1 antibody), the therapeutically effective amount can be about 5 mg to about 500 mg, about 10 mg to about 450 mg, about 50 mg to about 400 mg, about 75 mg to about 350 mg, or about 100 mg to about 300 mg of the antibody. For example, in various embodiments, the amount of the PD-1 inhibitor is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg of the PD-1 inhibitor.

[0093] In one embodiment, according to certain methods disclosed herein, after surgery and optionally postoperative radiotherapy, a therapeutically effective amount of 350 mg of a PD-1 inhibitor (e.g., an anti-PD-1 antibody) can be administered intravenously as adjuvant therapy. In another embodiment, according to certain methods disclosed herein, a therapeutically effective amount of 350 mg of a PD-1 inhibitor (e.g., an anti-PD-1 antibody) can be administered intravenously as neoadjuvant therapy prior to a planned surgery for treating skin cancer.

[0094] The amount of the PD-1 inhibitor contained in each dose can be expressed in units of milligrams of antibody per kilogram of the subject's body weight (i.e., mg / kg). In certain embodiments, the PD-1 inhibitor used in the methods disclosed herein can be administered to a subject at a dose of about 0.0001 to about 100 mg / kg based on the subject's body weight. In certain embodiments, the anti-PD-1 antibody can be administered at a dose of about 0.1 mg / kg to about 20 mg / kg based on the patient's body weight. In certain embodiments, the methods of the present disclosure include administering a PD-1 inhibitor (e.g., an anti-PD-1 antibody) at a dose of about 1 mg / kg, 3 mg / kg, 5 mg / kg, or 10 mg / kg based on the patient's body weight.

[0095] In certain embodiments, the individual dose of the PD-1 inhibitor (e.g., an anti-PD-1 antibody) administered to a patient (e.g., intravenously or intraperitoneally) can be less than a therapeutically effective amount, i.e., a dose less than the therapeutic amount. For example, if the therapeutically effective amount of the PD-1 inhibitor includes 3 mg / kg, a dose less than the therapeutic amount includes an amount less than 3 mg / kg, such as 2 mg / kg, 1.5 mg / kg, 1 mg / kg, 0.5 mg / kg, or 0.3 mg / kg. As defined herein, a "dose less than the therapeutic amount" refers to an amount of the PD-1 inhibitor that does not itself cause a therapeutic effect. However, in certain embodiments, a plurality of doses of the PD-1 inhibitor less than the therapeutic amount are administered to collectively achieve a therapeutic effect in a subject.

[0096] In certain embodiments, each dose includes 0.1 to 10 mg / kg (e.g., 0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg) based on the subject's body weight. In certain other embodiments, each dose includes 5 to 600 mg of the PD-1 inhibitor (e.g., an anti-PD-1 antibody), such as 5 mg, 10 mg, 15 mg, 20 mg, 25 0 mg, 300 mg, 350 mg, 400 mg, or 500 mg of the PD-1 inhibitor.

Examples

[0097] The disclosed technology is described next using the following examples. The use of these and other examples anywhere in this specification is for illustration only and in no way limits the scope and meaning of the invention or any of the exemplified forms. Similarly, the invention is not limited to any particular preferred embodiment described herein. Indeed, modifications and variations of the invention may become apparent to those skilled in the art upon reading this specification and can be made without departing from the spirit and scope thereof. Accordingly, the invention should be limited only by the terms of the claims along with the full scope of equivalents to which the claims are entitled. Further, while efforts have been made to ensure the accuracy of the numbers used (e.g., amounts, temperatures, etc.), some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure.

Example

[0098] A clinical trial comparing anti-PD-1 antibody versus placebo as adjuvant therapy for CSCC patients after surgery and radiotherapy This study is a randomized, placebo-controlled, double-blind, multi-center, phase 3 study comparing anti-PD-1 antibody versus placebo as adjuvant therapy for CSCC patients who have completed surgery and postoperative radiotherapy (RT) and have a composition associated with a high risk of recurrent disease. The study population includes CSCC patients who have completed surgery and postoperative RT and have a high-risk composition on surgical pathology. See Figure 1.

[0099] The exemplary anti-PD-1 antibody used in this study is REGN2810 (cemiplimab, or also known as H4H7798N disclosed in US9987500), which is a fully human monoclonal anti-PD-1 antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10; an HCVR / LCVR amino acid sequence pair comprising SEQ ID NO: 1 / 2; and heavy and light chain CDR sequences comprising SEQ ID NOs: 3-8.

[0100] Study Objectives The first objective of the study is to compare disease-free survival (DFS) between patients with high-risk CSCC treated with adjuvant REGN2810 and those treated with placebo after surgery and RT.

[0101] The second objectives of the study include: (1) comparing overall survival (OS) between patients with high-risk CSCC treated with adjuvant REGN2810 and those treated with placebo after surgery and RT; (2) comparing the effect of adjuvant REGN2810 with that of placebo on freedom from local regional recurrence (FFLRR) in patients after surgery and RT; (3) comparing the effect of adjuvant REGN2810 with that of placebo on freedom from distant recurrence (FFDR) in patients after surgery and RT; (4) comparing the effect of adjuvant REGN2810 with that of placebo on the cumulative incidence of second primary CSCC tumors (SPT) after surgery and RT; and (5) evaluating the safety of adjuvant REGN2810 and that of placebo in patients with high-risk CSCC after surgery and RT.

[0102] Study duration The duration of the first part of the study (double-blind treatment period) is up to 48 weeks. The duration of the second part of the study (open-label REGN2810 treatment period) is up to 96 weeks.

[0103] Study population Randomize approximately 412 patients into two treatment groups of approximately 206 patients each . The target patient population consists of adult patients with high-risk CSCC who have undergone surgical resection followed by RT. Prior to registration and randomization for the study, postoperative radiation therapy (PORT) is given following complete macroscopic resection of high-risk CSCC in the head and neck (HN) and non-HN sites according to the following inclusion criteria.

[0104] Inclusion criteria: To be eligible for inclusion in the study, patients must meet the following criteria: (1) at least 18 years of age (21 years of age in Japan only); (2) patients with resection of pathologically confirmed CSCC by macroscopic gross resection of all diseases (primary CSCC lesions only, or primary CSCC with lymph node metastasis, or CSCC nodular metastases with previously treated known primary CSCC lesions within the efferent lymph node echelon); (3) high-risk CSCC defined by at least one of the following: (a) extracapsular extension (ECE) in the surgical pathology report and nodular disease with at least one nodule >20 mm (ECE is defined as extension into the surrounding connective tissue through the lymph node capsule, with or without associated stromal reaction).Macroscopic evidence of ECE (defined as invasion of the skin, infiltration of the musculature / fixation to adjacent structures on clinical examination) is a high enough threshold to classify these as ECE positive (AJCC, 2017)); (b) in-transit metastases (ITM), defined as cutaneous or subcutaneous metastases >2 cm from the primary lesion but not beyond the regional lymph node basin (Leitenberger et al., J Am Acad Dermatol, 75(5):1022-31, 2016); (c) T4 lesions, including HN lesions (AJCC, 2017) and non-HN lesions (UICC, 2015); (d) perineural invasion (PNI), defined as clinical and / or radiological involvement of a specified nerve (UICC, Manual of Clinical (e) recurrent CSCC, defined as CSCC arising within a previously resected area of ​​tumor, with at least one of the following additional constructs (AJCC, 2017): (i) ≥N2b disease associated with the recurrent lesion, (ii) nominal ≥T3 (recurrent lesion ≥4 cm in diameter or minimal bone erosion or >6 mm deep invasion as measured from the granular layer of normal adjacent epithelium), or (iii) recurrent lesion with poorly differentiated histology and ≥20 mm in diameter (the recurrent tumor must be documented to be within a previously resected area of ​​CSCC by a radial measurement of the longest radius of the final abnormality measured from the estimated center of the original surgical wound); (4) completion of postoperative RT with curative intent within 2–6 weeks of randomization.Patients must receive a minimum biological equivalent dose of 60 Gy for the primary head and neck site and 50 Gy for non-head and neck primary sites, in 2 Gy (EQD2) fractions to the previous gross disease sites; (5) Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 1; (6) Adequate liver function: a. Total bilirubin ≤ 1.5 × upper limit of normal (ULN), b. Transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) ≤ 3 × ULN, c. Alkaline phosphatase (ALP) ≤ 2.5 × ULN; (7) Adequate renal function: Serum creatinine ≤ 1.5 × ULN or estimated creatinine clearance (CrCl) > 30 mL / min by the Cockcroft and Gault method; (8) Adequate bone marrow function: a. Hemoglobin ≥ 9.0 g / dL, b. Absolute neutrophil count (ANC) ≥ 1.0 × 10 9 / L, c. Platelet count ≥ 75 × 10 9 / L; (9) If specified by the guidelines of the health authorities and institutions, informed consent signed by the study patient or legally acceptable representative must be provided; (10) All toxicities from radiotherapy, except for taste abnormalities, fatigue, dry mouth, trismus, alopecia, fibrosis, or edema in the irradiated area, must have resolved to grade 1 or less; (11) Ability to attend the clinic and comply with study-related procedures; and (12) Ability to understand and complete study-related questionnaires.

[0105] Exclusion criteria: Patients who meet any of the following criteria will be excluded from the study: (1) Squamous cell carcinoma (SCC) occurring in non-skin sites (e.g., dry red lips [cheilitis], oral cavity, oropharynx, paranasal sinuses, larynx, hypopharynx, nasopharynx, salivary glands, nasal mucosa, anogenital region, or metastatic SCC nodules of unknown primary); (2) Tumors with negligible risk of metastasis or death, such as appropriately treated basal cell carcinoma (BCC) of the skin, cervical intraepithelial neoplasia, or non-invasive ductal carcinoma of the breast, or low-risk early-stage prostate adenocarcinoma (T1-T2 where the management plan is active surveillance; aExcluding prostate adenocarcinoma with biochemical recurrence (D’Amico et al., JAMA, 294(4):440 - 47, 2005) (Pham et al., J Urol, 196(2):392 - 98, 2016) with N0M0 and Gleason score ≤6 and prostate - specific antigen (PSA) ≤10 ng / mL, or if the management plan is active surveillance and the reported PSA doubling time >12 months, synchronous malignant lesions other than localized CSCC and / or a history of malignant lesions other than localized CSCC within 3 years from the date of randomization; (3) patients with hematologic malignancies (e.g., chronic lymphocytic leukemia [CLL]); (4) patients with a history of distant - metastatic CSCC (visceral or distant nodules) unless the disease - free interval is at least 3 years (regional lymph node metastases of the disease in the drained lymph node basin excised and irradiated before registration will not be excluded by exclusion criterion 2); (5) evidence of ongoing or recent (within 5 years from the date of randomization) severe autoimmune diseases requiring treatment with systemic immunosuppressive therapy that may suggest a risk of immune - related adverse events (irAE). The following are not excluded: vitiligo requiring only hormone replacement, resolved childhood asthma, type 1 diabetes, residual hypothyroidism, or psoriasis not requiring systemic treatment; (6) having participated in a study of an investigational drug or investigational device within 4 weeks or 5 half - lives (whichever is longer) from the date of randomization. However, patients who have received treatment in a study involving an investigational immunotherapy PET reagent or are enrolled in such a study are not excluded; (7) having received a live vaccine within 28 days from the date of randomization; (8) having previously received systemic anti - cancer immunotherapy for CSCC. Examples of immunomodulatory agents include, but are not limited to, CTLA - 4, 4 - 1BB (CD137) or OX - 40 blockers, therapeutic vaccines, anti - PD - 1 / PD - L1 or PI3Kδ inhibitors; 9) immunosuppressive corticosteroid administration within 4 weeks before the first dose of REGN2810 / placebo (prednisone >10 mg per day or equivalent) (Note: Patients requiring a short - course of steroids (e.g., for prophylaxis for image evaluation due to hypersensitivity to contrast agents) are not excluded).People taking steroids for physiological replacement (i.e., adrenal insufficiency) are not excluded); (10) Having received treatment with an approved anti-cancer systemic therapy within 4 weeks from the randomization date, or not having recovered from any acute toxicity yet, except for changes by clinical tests described in Inclusion Criteria 6, 7, and 8 (i.e., ≤ Grade 1 or baseline) (Note: Patients receiving bisphosphonate or denosumab are not excluded); (11) Previous allogeneic or autologous stem cell transplantation; (12) Patients who have permanently discontinued anti-cancer immunomodulatory therapy due to drug-related toxicity; (13) Encephalitis, meningitis, or uncontrolled seizures in the year before screening / registration; (14) Patients having had a myocardial infarction within 6 months before the randomization date; (15) Any infection requiring hospitalization and / or intravenous antibiotic therapy within 2 weeks of the randomization date; (16) Active tuberculosis; (17) Uncontrolled infection due to human immunodeficiency virus (HIV), hepatitis B or C virus (HBV or HCV) infection; or diagnosis of immunodeficiency. (Note: · Patients with known HIV infection with controlled infection (undetectable viral load (HIV RNA PCR) and CD4 count over 350, either spontaneously or on a stable anti-viral regimen) are permitted. Patients with controlled HIV infection will be monitored according to the local standard. · Patients will be tested for HBV and HCV at the time of screening. · Patients with HBV (hepatitis B surface antigen positive; HepBsAg+) with controlled infection (serum HBV DNA PCR below the detection limit and receiving anti-viral therapy for HBV) are permitted. Patients with controlled infection must receive regular monitoring of HBV DNA. Patients must continue anti-viral therapy for at least 6 months after the last dose of the investigational study drug. · HCV antibody positive. Patients who are (HCV Ab+) and have controlled infection (undetectable HCV RNA by PCR, either spontaneously or in response to a previous course of successful anti-HCV therapy) are eligible; (18) a history of immune-related interstitial pneumonia within the past 5 years; (19) a history of interstitial lung disease (e.g., idiopathic pulmonary fibrosis, organizing pneumonia) or active non-infectious interstitial pneumonia requiring immunosuppressive doses of glucocorticoids to assist in management. A history of radiation-induced interstitial pneumonia in the irradiated area is only permitted if the interstitial pneumonia resolved ≥6 months before the randomization date; (20) a history of a recorded allergic or anaphylactic reaction due to antibody therapy; (21) known hypersensitivity or allergy to any of the excipients in the REGN2810 drug product; (22) patients with a history of solid organ transplantation (patients with a previous corneal transplant are not excluded); (23) any medical comorbidity, physical examination finding, or metabolic dysfunction, or an abnormality in clinical tests that, in the opinion of the study responsible physician, renders the patient ineligible to participate in the clinical trial due to a high safety risk and / or the potential to affect the interpretation of the study results; (24) known psychiatric or substance use disorders that would prevent participation with the requirements of the study; (25) members of the study team at the clinical site or their immediate family members; (26) women who have a positive serum β-human chorionic gonadotropin (HCG) pregnancy test at screening / baseline visit. If positive, pregnancy must be excluded by ultrasound in the patient for the patient to be eligible; (27) women who are breastfeeding; (28) women of childbearing potential (WOCBP) or sexually active men who are unwilling to practice highly effective contraception for at least 180 days from before the first dose of study therapy, during the study, and from the last dose. Highly effective contraceptive measures include the following: a. Stable use of combined (estrogen- and progestogen-containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) related to suppression of ovulation with ≥2 menstrual cycles initiated before screening; b. Intrauterine contraceptive device (IUD); intrauterine hormonal-releasing system (IUS); c. Bilateral tubal ligation; d. Vasectomized partner; and / or e. Sexual abstinence.WOCBP is defined as women who have had one episode of menstruation and have not yet reached menopause or have become surgically infertile, as follows. Menopause is defined as at least 12 consecutive months without any episode of menstruation (not hormonally induced). Postmenopausal women must be amenorrheic for at least 12 months because the possibility of childbirth is not considered. Pregnancy testing and contraception are not required for women who have had a hysterectomy, bilateral oophorectomy, or tubal ligation recorded. Sexual abstinence is considered a very effective method only if it is defined as refraining from heterosexual intercourse for the entire period of the risks associated with the study treatment. Periodic abstinence (calendar method, symptothermal method, postovulatory method), coitus interruptus (withdrawal), spermicides only, and lactational amenorrhea method (LAM) are unacceptable contraceptive methods. Female and male condoms should not be used together.

[0106] Study variables The primary endpoint of this study is DFS, defined as the time from randomization to the first recorded disease recurrence (local, regional, and / or distant) or death from any cause. For patients without tumor recurrence or death, DFS will be censored at the date of the last disease evaluation. The estimated time frame for DFS assessment is up to approximately 54 months.

[0107] The secondary endpoints of this include: · Overall survival, defined as the time from randomization to the date of death. Patients who have not died will be censored at the last known date, considered to be alive. The estimated time frame for OS assessment is up to approximately 78 months; · Freedom from local regional recurrence (FFLRR), defined as the time from randomization to the date of the first local regional recurrence (LRR). Patients who die without a prior LRR will be censored at the date of death. For patients without an LRR or death, FFLRR assessment will be censored at the last disease date. The estimated time frame for FFLRR assessment is up to approximately 54 months; · Disease-free survival (DFS) defined as the time from randomization to the date of the first distant recurrence (DR). Patients who die without a prior DR will be censored at the date of death. For patients without a DR or death, DFS will be censored at the date of the last disease assessment. The estimated time frame for DFS assessment is up to approximately 54 months; · Cumulative incidence of SPT for each patient from randomization to the occurrence of the first major endpoint event or the end of the study. The estimated time frame for assessment of cumulative incidence of SPT is up to approximately 54 months; · Incidence and severity of treatment-emergent adverse events (TEAEs), deaths, and safety measured by abnormal laboratory tests. The estimated time frame for safety assessment is up to approximately 78 months.

[0108] Pharmacokinetic (PK) variables are the REGN2810 concentrations at each time point. Samples for this study will be collected using a sparse sampling schedule (e.g., collecting only 1 blood sample for drug concentration measurement at any single clinic visit).

[0109] Study Design This is a randomized, double-blind, placebo-controlled Phase 3 trial evaluating REGN2810 as adjuvant therapy for patients with CSCC who have completed surgery and postoperative RT and have a composition associated with a high risk of recurrent disease. The study population will consist of patients who have completed surgery and postoperative RT for CSCC and have at least 1 factor that increases the risk of CSCC recurrence. Patients will be randomized 1:1 to REGN2810 350 mg vs placebo every 3 weeks (Q3W) for up to 48 weeks. The primary endpoint is disease-free survival (DFS). For patients who experience disease recurrence documented during the study, there will be options for subsequent REGN2810 therapy after the first recurrence. Figure 1 provides a flowchart of the overall study outline.

[0110] REGN2810 is supplied as a liquid in sterile disposable vials. Each vial contains REGN2810 at a concentration of 50 mg / mL. The placebo is prepared using the same formulation as that used for REGN2810 without the addition of an active substance. The placebo is supplied as a liquid in sterile disposable vials. REGN2810 350 mg or placebo is administered every 3 weeks (±10 minutes) as a 30-minute IV infusion in an outpatient setting.

[0111] The study consists of two parts. Part 1 (blinded) includes a screening period up to 28 days prior to randomization, a treatment period up to 48 weeks, and a follow-up period. During the treatment period (up to 48 weeks), patients receive an imaging evaluation for tumor recurrence at the end of each 12-week cycle during the approximately 1-year (48-week) planned treatment period. Patients receive post-treatment follow-up until disease recurrence or the end of the study. Part 1 of the study supports the primary endpoint. Part 2 (unblinded) includes optional REGN2810 treatment for patients in the placebo arm who experience disease recurrence, and optional subsequent treatment with REGN2810 for patients in the REGN2810 arm who experience disease recurrence ≥3 months after completing the 48-week planned REGN2810 treatment.

[0112] Study Part 1 (blinded): Patients can begin screening once surgery and postoperative RT for CSCC are completed. Patients who meet the eligibility criteria and demonstrate high-risk features on surgical pathology of the resected tumor sample are randomized 1:1 to receive REGN2810 350 mg or placebo intravenously (IV). The first dose of REGN2810 or placebo is administered within 5 days of randomization, which is between 2 and 6 weeks after completion of RT. REGN2810 or placebo is administered IV every 3 weeks (Q3W) for up to 48 weeks or until unacceptable toxicity, disease recurrence, death, or withdrawal of consent. Prior to each REGN2810 or placebo treatment, patients are evaluated at the clinic. Cycle length It is 12 weeks (Q3W schedule, 4 treatments per cycle). The follow-up period starts after the patient discontinues treatment for any reason, either the completion of the planned 48-week treatment period or the premature discontinuation of treatment for any other reason.

[0113] DFS is the primary endpoint of Part 1. For patients with high-risk CSCC, patterns of failure include local regional recurrence, distant recurrence, local regional and distant recurrence, or death (Porceddu et al., J Clin Oncol, 36(13):1275 - 83, 2018). DFS was chosen as the primary endpoint of the study because it encompasses all of these patterns of failure.

[0114] To evaluate the efficacy of adjuvant REGN2810 in patients at high risk of disease recurrence, REGN2810 is compared with placebo in a 1:1 randomization. Since the current standard of care after RT is surveillance, placebo is a suitable control arm to compare with REGN2810 to enable the evaluation of the efficacy of REGN2810 as an adjuvant treatment after surgery and RT.

[0115] Study Part 2 (open-label): Optional REGN2810 treatment for patients in the placebo arm who experience disease recurrence and optional subsequent treatment with REGN2810 for patients in the REGN2810 arm who experience disease recurrence ≥3 months after completion of the planned 48-week REGN2810 treatment. Patients can be treated up to 96 weeks.

[0116] Patients assigned to the placebo group in Part 1 are eligible to receive open-label subsequent REGN2810 therapy in Part 2 of the study if they meet the following criteria to demonstrate disease recurrence: (i) have documentation of disease recurrence; (ii) provide a separate consent form for subsequent REGN2810 therapy; (iii) have not discontinued placebo treatment due to unacceptable toxicity (if a patient discontinued study treatment due to unacceptable toxicity and then was found to have been on placebo for the purpose of blinding, such patients would have met the criteria for permanent discontinuation of study treatment and thus would not have the opportunity to receive REGN2810 in Part 2); and (iv) repeat screening procedures continue to meet the study eligibility criteria (except for the selected eligibility criteria).

[0117] Patients assigned to the REGN2810 group in Part 1 are also eligible to receive open-label subsequent REGN2810 therapy in Part 2 of the study if they meet the following criteria to demonstrate disease recurrence: (i) documentation of disease recurrence at least 3 months (90 days ± 3 days) after completion of the planned 48-week REGN2810 treatment (even if one or more doses of the planned REGN2810 treatment were missed during the 48-week treatment period); (ii) provide a separate consent form for subsequent REGN2810 treatment in Part 2; (iii) previous REGN2810 was not discontinued due to unacceptable toxicity; and (iv) repeat screening procedures continue to meet the study eligibility criteria (except for the selected eligibility criteria).

[0118] Patients eligible for subsequent REGN2810 therapy in Part 2 of the study can receive REGN2810 350 mg Q3W up to 96 weeks (Part 2), or until disease progression, unacceptable toxicity, withdrawal of consent, death, or loss to follow-up.

[0119] The severity of AE (including the examination findings classified as AE) will be staged using the NCI-CTCAE staging system (NCI-CTCAE v5). Adverse events not listed in NCI-CTCAE v5 will be staged according to the scale described in Table 1.

[0120] Concomitant Medication Application and Procedures Prohibited Medication Application and Procedures: During the participation in this study, unless otherwise specified, patients are not allowed to receive any of the following from the time of informed consent until the end of the follow-up period: (a) Standard or investigational agents for the treatment of tumors other than REGN2810 and placebo; (b) Agents that block the PD-1 / PD-L1 pathway (except for patients assigned to receive REGN2810 in this study); (c) Radiation therapy; and (d) Live vaccines for at least 3 months from the final dose of the study drug.

[0121] Permitted Medication Application and Procedures: Under the following conditions, the following medication applications and procedures are permitted: (a) Any medication application required to treat AE and / or irAE, including systemic corticosteroids; (b) Systemic corticosteroids for physiological replacement (even if > 10 mg / day of prednisone equivalent); (c) Short-term courses of corticosteroids for the prevention or treatment of non-autoimmune conditions; (d) Bisphosphonates and denosumab; (e) Systemic corticosteroids at physiological replacement doses, even if > 10 mg / day of prednisone equivalent; (f) Oral contraceptives, hormone replacement therapy or other maintenance therapies can be continued; (g) Acetaminophen at a dose ≤ 2 g / day; (h) Surgical resection of non-index lesions when clinically indicated, and (i) Other medication applications and procedures may be permitted individually. Since this is an adjuvant study, surgery is not planned. However, if surgery for any urgent medical problem is clinically indicated for an individual patient, this is permitted.

[0122] Procedures and Assessments The screening / baseline procedures include: coagulation tests, serum β-HCG assay, brain imaging (computed tomography [CT] or magnetic resonance imaging [MRI]), and screening for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV).

[0123] The efficacy procedures include: radiological image evaluation for tumor recurrence. Computed tomography imaging of the chest, abdomen, and pelvis is required for each image evaluation. Obtain head and neck images for patients with resected HN lesions. Tumor biopsy is performed when it is possible to obtain pathological (histological or cytological) evidence of recurrent disease or SPT. For recurrent lesions, evaluate the pattern of failure, and recurrence is defined as ≥1 lesion that can be categorized as local, regional, or distant recurrence.

[0124] The safety procedures include: obtaining adverse events (AE), physical examination (complete or limited), weight, 12-lead electrocardiogram (ECG), vital sign evaluation, and comparison of the safety and tolerability of REGN2810 and placebo, evaluated by clinical tests including hematology, blood chemistry, and urine tests.

[0125] PK / drug concentration: Collect PK samples for the evaluation of the serum concentration of REGN2810.

[0126] Results Administration of REGN2810 as adjuvant therapy for CSCC patients who have completed surgery and postoperative RT and are at high risk of recurrence is expected to lead to a reduction in the risk of subsequent disease recurrence or to eliminate the occurrence of subsequent disease recurrence. Adjuvant REGN2810 therapy administered to high-risk CSCC patients after surgery and RT is also expected to improve disease management.

Example

[0127] Clinical trial of an anti-PD-1 antibody administered as neoadjuvant therapy for cutaneous squamous cell carcinoma (CSCC) stages II to IV (M0) This study is a phase 2 single-arm, non-blind, multi-center study in patients with stage II to IV (M0) CSCC who are candidates for surgery but have an increased risk of recurrence and / or risk of damage to appearance or functional deficit.

[0128] The exemplary anti-PD-1 antibody used in this study is REGN2810 (also known as cemiplimab or H4H7798N disclosed in US9987500), which is a fully human monoclonal anti-PD-1 antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10; an HCVR / LCVR amino acid sequence pair comprising SEQ ID NO: 1 / 2; and CDR sequences of the heavy and light chains comprising SEQ ID NOs: 3-8.

[0129] Study objectives The first objective of the study is to evaluate the efficacy of neoadjuvant therapy with REGN2810, measured by the pathologic complete response (pCR) rate per independent central pathology review.

[0130] The second objectives of the study include: (1) To evaluate the efficacy of neoadjuvant REGN2810 against measures of disease response, including (a) the major pathologic response (mPR) rate per independent central pathology review, (b) the pCR rate and mPR rate per local pathology review, and (c) the objective response rate (ORR) prior to surgery according to local assessment using RECIST 1.1; (2) To evaluate the efficacy of neoadjuvant REGN2810 against event-free survival (EFS), disease-free survival (DFS), and overall survival (OS); (3) To evaluate the safety profile of neoadjuvant REGN2810; (4) To evaluate changes in the surgical plan (resection and reconstruction procedures) from screening to final surgery according to both the review of the principal investigator of the trial and the review of a separate surgical expert; and (5) To evaluate changes in the postoperative management plan (radiation, chemoradiation, or observation) from screening to postoperative pathology review according to both the review of the principal investigator of the trial and the review of a separate surgical expert.

[0131] The exploratory objectives of this study include: (1) To explore the discovery of baseline tumor markers for association with treatment response, peripheral and tumor measures related to the mechanism of action of REGN2810, and other potential predictive markers of efficacy or safety; (2) To explain patterns of failure (local vs. distant) in patients who experience disease recurrence; (3) To evaluate the impact on cost due to changes in the surgical plan during the screening period compared to the actual surgical procedures performed; (4) To evaluate the impact on cost due to changes in the postoperative management plan during the screening period compared to actual postoperative management; (5) To evaluate the immunogenicity of REGN2810; and (6) To evaluate health-related quality of life in patients with CSCC who receive neoadjuvant REGN2810.

[0132] Study duration The duration of the first part of the study (pre-operative treatment period) is up to 12 weeks. The duration of the second part of the study (optional post-operative treatment period) is up to 48 weeks. The follow-up period is up to 3 years. Patients will be followed until disease recurrence or the end of the study (whichever comes first).

[0133] Study population Approximately 76 patients will be enrolled. The target population consists of adult patients with stage III to IV (M0) CSCC of the head / neck, extremities, or trunk, and patients with stage II CSCC selected for surgery will be recommended in standard care.

[0134] Inclusion criteria: Patients must meet the following criteria to be eligible for inclusion in the study: (1) at least 18 years old; (2) stage II to IV (M0) CSCC that would be recommended for surgery in standard care. For stage II patients, the lesion must be ≥ 3 cm in greatest diameter (Note: Tumor staging is defined according to the 8th edition of the AJCC (Amin MB, American Joint Committee on C, American Cancer S. AJCC cancer staging manual. 8th edition Springer International Publishing; 2017) for HN tumors and the 9th edition of the UICC (O’Sullivan B, Union for International Cancer C. UICC manual of clinical oncology. 9th edition John Wiley & Sons, Ltd; 2015) for non-HN tumors); (3) at least one measurable lesion by RECIST 1.1; (4) an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (5) (a) hemoglobin > 9.0 g / dL; (b) absolute neutrophil count (ANC) > 1.5 × 10 9 / L; (c) platelet count > 75 × 10 9 / L; (d) Sufficient organ and bone marrow function as recorded by serum creatinine < 1.5 times the upper limit of normal (ULN) or estimated creatinine clearance (CrCl) > 30 mL / min; (e) Sufficient liver function (total bilirubin < 1.5 × ULN; both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 × ULN; alkaline phosphatase (ALP) < 2.5 × ULN) (Note: For patients with Gilbert's syndrome, total bilirubin ≤ 3 × ULN. Gilbert's syndrome must be appropriately recorded in the medical history); (6) Ability to visit the clinic and proceed with study-related procedures; (7) Ability to provide informed consent, duly signed by the study patient or legally acceptable representative; and (8) Ability to understand and complete study-related questionnaires.

[0135] Exclusion Criteria: Patients who meet any of the following criteria will be excluded from the study: (1) Solid malignant lesions within 5 years of the planned enrollment date, or hematological malignancies (including chronic lymphocytic leukemia [CLL] at any point) (Note: Patients with non-melanoma skin cancer receiving potentially curative therapy, or cervical intraepithelial neoplasia, or prostate intraepithelial neoplasia with undetectable prostate-specific antigen, or any other tumor being treated, will not be excluded if the patient has been in complete remission for at least 2 years prior to enrollment and no further therapy is required during the study period); (2) Metastatic disease (M1), visceral and / or distant nodules; (3) Prior radiotherapy for CSCC; (4) Patients with a condition requiring corticosteroid therapy (>10 mg prednisone / day or equivalent) within 14 days of the first dose of the study drug (Note: Physiological replacement doses are permitted even if >10 mg prednisone / day or equivalent, provided they are not administered for immunosuppressive purposes. Inhaled or topical steroids are permitted provided they are not for the treatment of autoimmune disorders); (5) Patients with active, known, or suspected autoimmune diseases that required systemic therapy within 5 years of the planned enrollment date (Note: Vitiligo requiring only hormonal replacement, type I diabetes, and endocrine diseases (including hypothyroidism due to autoimmune thyroiditis), resolved childhood asthma, or psoriasis not requiring systemic treatment are permitted); (6) History of interstitial lung disease (e.g., idiopathic pulmonary fibrosis, organizing pneumonia) or active non-infectious interstitial pneumonia requiring immunosuppressive doses of glucocorticoids to assist management; (7) Uncontrolled infection due to human immunodeficiency virus (HIV), hepatitis B or C virus (HBV or HCV) infection; or diagnosis of immunodeficiency (Note: (a) Patients will be tested for HIV, HBV, and HCV at screening; (b) Infections that are controlled (either spontaneously or with a stable antiviral regimen, undetectable viral load [measured via polymerase chain reaction] for HIV Patients with known HIV infection (RNA and more than 350 CD4 counts) are permitted. For patients with controlled HIV infection, monitoring will be performed according to the local standard; (c) Patients with hepatitis B (HBsAg+) who have controlled infection (serum hepatitis B virus DNA measured via polymerase chain reaction below the detection limit and who are receiving antiviral therapy for hepatitis B) are permitted. Patients with controlled infection must undergo regular monitoring of HBV DNA. Patients must continue antiviral therapy for at least 6 months after the last dose of the investigational study drug; (d) Patients who are hepatitis C virus antibody positive (HCV Ab+) and have controlled infection (HCV RNA undetectable by polymerase chain reaction, either spontaneously or in response to a previous successful course of anti-HCV therapy) are permitted; (8) Active tuberculosis; (9) Myocardial infarction within 6 months of registration; (10) Any medical comorbidity, physical examination findings or metabolic dysfunction, or clinical examination abnormalities that, in the opinion of the responsible investigator of the trial, render the patient ineligible to participate in the clinical trial due to a high risk to safety and / or the potential to affect the interpretation of the results of the study; (11) Recorded allergic or acute hypersensitivity reactions due to antibody therapy; (12) Previous treatment with anti-cancer systemic therapy within the past 3 years prior to the planned registration date; (13) Any previous treatment with anti-PD1 / PD-L1 agents; (14) Participation in a study of an investigational drug or device within 4 weeks of registration; (15) Women who are positive for serum human chorionic gonadotropin HCG pregnancy test at screening / baseline visit. Women who are breastfeeding are also excluded; (16) Women of childbearing potential (as defined below) and sexually active men who are not willing to use highly effective contraception before the first dose of the study therapy, during the study, and for at least 6 months after the last dose.Highly effective contraceptive methods include the following: (a) consistent use of combined (estrogen- and progestogen-containing) hormonal contraceptive methods (oral, intravaginal, transdermal) or progestogen-only hormonal contraceptive methods (oral, injectable, implantable) related to suppression of ovulation initiated for two or more menstrual cycles prior to screening; (b) intrauterine contraceptive devices (IUDs); intrauterine hormone-releasing systems (IUSs); (c) bilateral tubal ligation; (d) a vasectomized partner (provided that the vasectomized male partner is the sole sexual partner of a woman of childbearing potential (WOCBP) study participant and that the vasectomized partner has received a medical evaluation of the surgical success of the procedure); and / or (e) sexual abstinence (as defined below); (17) receipt of live vaccine within 28 days of registration; (18) previous allogeneic or autologous stem cell transplantation; (19) recipients of solid organ transplants (other than corneal transplants); (20) diagnosis of squamous cell carcinoma of unknown (or occult) primary origin; (21) patients admitted to a facility based on an order issued by either a judicial or administrative authority; and (22) members of the clinical site research team or their blood relatives, unless pre-approved by the study sponsor.

[0136] A woman of childbearing potential is defined as a woman who is capable of becoming pregnant after menarche and until she becomes postmenopausal (as defined below), unless she is permanently infertile. Permanent infertility methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. The postmenopausal state is defined as the absence of menses for 12 months without another medical cause. High follicle-stimulating hormone (FSH) levels in the postmenopausal range can be used to confirm the postmenopausal state in women not using hormonal contraceptive methods or hormone replacement therapy. However, a single FSH measurement is insufficient to determine the occurrence of the postmenopausal state if amenorrhea has been present for 12 months. The above definitions follow the guidance of the Clinical Trial Facilitation Group (CTFG). Pregnancy testing and contraception are not required for women with a recorded hysterectomy or tubal ligation.

[0137] Sexual abstinence is considered a very effective method only if defined as refraining from heterosexual intercourse during the entire period of the risks associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial as well as the patient's preferred and usual lifestyle. Regular abstinence (calendar method, symptothermal method, post-ovulation method), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are unacceptable contraceptive methods. Female and male condoms should not be used together.

[0138] Study variables For the endpoints measuring pCR, mPR, and ORR (Part 1 of the study), patients are evaluated at surgery (12 weeks). Event-free survival (EFS) and OS are evaluated from the first dose of neoadjuvant REGN2810 until the completion of follow-up. Disease-free survival (DFS) is evaluated from surgery until the completion of follow-up. The EFS, DFS, and OS evaluations continue until all enrolled patients, which is approximately a total duration of 4 years and 3 months, complete the follow-up.

[0139] The primary endpoints of this study include: the pCR rate evaluated by independent central pathology review.

[0140] The secondary endpoints of this study include: (1) the mPR rate evaluated by independent central pathology review; (2) the pCR rate and mPR rate evaluated by local pathology review; (3) the ORR before surgery as evaluated by the treating investigator using RECIST 1.1; (4) event-free survival (EFS); (5) disease-free survival (DFS); (6) overall survival (OS); (7) safety and tolerability measured by the incidence of adverse events (AE), serious adverse events (SAE), death, and abnormal laboratory tests; (8) changes in the surgical plan during screening compared to the actual surgery after neoadjuvant REGN2810; and (9) changes in the postoperative management plan during screening compared to the actual postoperative management.

[0141] The exploratory variables of this study include the following: (1) patterns of failure in patients with local, regional, or distant disease recurrence measured by descriptive statistics; (2) changes in estimated costs due to changes in the surgical plan during the screening period compared to the actual surgical procedures performed after neoadjuvant REGN2810; (3) changes in estimated costs due to changes in the postoperative management plan during the screening period compared to the actual postoperative management; (4) the incidence of ADA against REGN2810; and (5) health-related quality of life evaluated using the EORTC QLQ-C30.

[0142] Pharmacokinetic (PK) variables include the serum concentration of REGN2810 over time.

[0143] Immunogenicity variables include anti-drug antibody (ADA) status, titer, and time point / visit.

[0144] Safety variables include (1) vital signs; (2) physical examination results; (3) electrocardiogram (ECG) results; (4) clinical laboratory results; (5) adverse events (AE); and (6) immune-related adverse events (irAE).

[0145] Pathological complete response (pCR) is defined as the absence of viable cancer cells in the surgical pathology sample.

[0146] Major pathological response (mPR) is defined as ≤10% viable cancer cells in the surgical pathology sample in patients who have not achieved pCR.

[0147] Objective response rate (ORR) is evaluated by the investigator in charge of the clinical trial using RECIST 1.1 (Eur J Cancer 2009;45(2):228-47).

[0148] Event-free survival (EFS) is defined as the time from the first dose of neoadjuvant REGN2810 to any of the following events: progression of disease precluding surgery, inability to undergo a complete resection (R0 or R1), disease recurrence (local, regional, or distant) in patients who have undergone a complete resection (R0 or R1), or death from any cause.

[0149] Disease-free survival (DFS) is defined as the time from surgery to the first recurrence (local, regional, or distant) or death from any cause in patients who are disease-free (R0 or R1 resection) at the completion of surgery.

[0150] Overall survival (OS) is measured as the time from the first dose of neoadjuvant REGN2810 to death from any cause.

[0151] Study Design This is a single-arm, open-label, multi-center, phase 2 study of patients with stage II to IV (M0) CSCC who are candidates for surgery but have an increased risk of recurrence and / or an increased risk of disfigurement or functional impairment.

[0152] This study consists of two parts:

[0153] Part 1 (Neoadjuvant): A screening period of up to 28 days, a treatment period of up to 12 weeks, and surgery after treatment for up to 12 weeks. Part 1 of the study supports the primary endpoint.

[0154] Part 2 (Adjuvant): Optional post-surgical REGN2810 treatment for up to 48 weeks (or radiation therapy or observation only at the discretion of the treating investigator).

[0155] After Part 2 of the study, patients will be followed for a period of up to 3 years. Figure 2 provides a flow diagram of the overall study outline.

[0156] REGN2810 is supplied as a sterilized liquid in a disposable glass vial. Each vial contains REGN2810 at a concentration of 50 mg / mL. 350 mg of REGN2810 is administered as an IV infusion over 30 minutes (±10 minutes) every 3 weeks (Q3W) up to 12 weeks (up to 4 doses) prior to the first part of the surgery and (optionally) up to 48 weeks (up to 16 doses) after the second part of the surgery.

[0157] Part 1 of the study: Patients with stage II to IV (M0) CSCC with a planned surgery and meeting the eligibility criteria will receive 350 mg of REGN2810 intravenously (IV) every 3 weeks (Q3W) up to 12 weeks (up to 4 doses) or until unacceptable toxicity, disease progression, or withdrawal of consent. Patients will be evaluated at the clinic prior to each dose and will receive tumor response imaging evaluations prior to receiving the 3rd dose of REGN2810 (day 43 ± 3) and prior to surgery (day 85). The surgery window is from day 75 to day 100. If a patient meets the criteria for discontinuing REGN2810 during the 12-week neoadjuvant period, the treating physician may transfer the patient to surgery earlier. Following surgical tumor resection, the primary endpoint (pCR rate) will be evaluated by an independent central pathology review committee.

[0158] Part 2 of the study: Patients will have the option to receive adjuvant REGN2810 treatment (350 mg IV Q3W) following surgery up to 48 weeks (up to 16 doses) or until unacceptable toxicity, disease recurrence, or withdrawal of consent. The first dose of adjuvant treatment will be administered 3 weeks (±3 days) after the end of part 1 of the treatment (EOT1). The principal investigator At the discretion of the investigator, the patient may instead receive adjuvant radiation therapy (concurrent or subsequent REGN2810 treatment is not permitted) or enter a period of observation only. During the second part of the study, patients are evaluated at the clinic every 15 weeks. Patients receiving adjuvant REGN2810 will receive a full evaluation as described in the event schedule, while patients not receiving adjuvant REGN2810 will only receive imaging evaluations according to the parallel schedule.

[0159] Follow-up: Follow-up will begin after the patient has completed Part 1 and the second part of the study without disease progression (before surgery) or disease recurrence (after surgery). Patients will be evaluated at the clinic for up to an additional 3 years.

[0160] Concomitant Medication Use and Procedures Prohibited Medication Use and Procedures: While participating in this study (excluding the survival follow-up), unless otherwise specified below, patients may not receive any of the following medication uses from the time of informed consent until the end of the follow-up period: (1) standard or investigational agents (other than REGN281) for the treatment of tumors; and (2) live vaccines for at least 3 months from the final dose of the study drug.

[0161] Permitted Drug Applications and Procedures: The following drug applications and procedures will be permitted under the following conditions: (1) Any drug application required to treat AE and / or irAE, including systemic corticosteroids; (2) Systemic corticosteroids for physiological replacement (even if > 10 mg / day of prednisone equivalent); (3) Short-term courses of corticosteroids for the prevention or treatment of non-autoimmune conditions; (4) Oral contraceptives, hormone replacement therapy, or other maintenance therapies can be continued; (5) Acetaminophen at a dose ≤ 2 g / day; (5) Surgical excision of premalignant or basal cell carcinoma (BCC) lesions; and (6) Other drug applications and procedures may be individually permitted by the study responsible physician and in consultation with the study sponsor. Radiation therapy (with concurrent anti-cancer cytotoxic chemotherapy and / or epidermal growth factor receptor-directed therapy) is permitted at the discretion of the study responsible physician in the adjuvant part of the study. Such patients will be followed for disease recurrence but will not receive further REGN2810 in the study.

[0162] Procedures and Assessments The screening / baseline procedures include: Screening for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV), height measurement, serum β-human chorionic gonadotropin (HCG) test (for women of childbearing potential).

[0163] The efficacy procedures include: (1) Evaluation of surgically resected tumors for pathological response; (2) Radiological imaging evaluation for tumor response as well as disease recurrence (adjuvant part of the study and follow-up) (adjuvant part of the neoadjuvant study); (3) Images of externally visible lesions supplemented with digital medical photographs; (4) Biopsy of tumors to obtain histological or cytological evidence of disease recurrence or evidence of a second primary tumor (SPT); and (5) Evaluation of patterns of failure for recurrent lesions. Recurrence is defined as ≥ 1 lesion that can be categorized as local, regional, or distant recurrence.

[0164] Safety procedures include: obtaining adverse events (AE), physical examinations (complete or limited), weight assessment, recording of 12-lead electrocardiogram (ECG), vital sign assessment, and clinical tests including hematology, blood chemistry, and urine tests.

[0165] Clinical test procedures include the following: (1) Blood chemistry: sodium, potassium, chloride, carbon dioxide (bicarbonate), calcium, glucose (fasting or non-fasting), al bumin, protein (serum), creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin); Hematology: hemoglobin, white blood cells, platelet count, neutrophils, lymphocytes); (3) Urine test: pH, specific gravity, ketones, glucose, blood, spot urine protein; and (4) Other clinical tests: (a) HBV, HCV, HIV tests; (b) Pregnancy test: serum β-HCG or urine β-HCG; (c) Thyroid stimulating hormone (TSH) with reverse T3 and free T4; and (d) Coagulation by measurement of INR and aPTT.

[0166] Results For Phase 1 of the study, administration of REGN2810 as neoadjuvant therapy prior to surgery is expected to result in a significant pathologic complete response (pCR) rate in patients with CSCC.

[0167] For Phase 2 of the study, administration of REGN2810 as adjuvant therapy for CSCC patients in whom surgery and postoperative RT have been completed and who are at high risk of recurrence is expected to lead to a reduction in the risk of subsequent disease recurrence or to eliminate the occurrence of subsequent disease recurrence. Adjuvant REGN2810 therapy administered to high-risk CSCC patients after surgery and RT is also expected to improve disease management.

Example

[0168] Clinical trial of an anti-PD-1 antibody administered to patients with metastatic or unresectable progressive cutaneous squamous cell carcinoma (CSCC) This study is a phase 2 non-randomized 5-arm pivotal trial for patients with progressive CSCC.

[0169] The exemplary anti-PD-1 antibody used in this study is REGN2810 (also known as cemiplimab or H4H7798N disclosed in US9987500), which is a fully human monoclonal anti-PD-1 antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10; an HCVR / LCVR amino acid sequence pair comprising SEQ ID NO: 1 / 2; and CDR sequences of the heavy and light chains comprising SEQ ID NOs: 3-8.

[0170] Study groups Group 1 consists of patients with metastatic (nodular or distant) CSCC treated with REGN2810 (3 mg / kg / dose, IV, once every 2 weeks).

[0171] Group 2 consists of patients with unresectable locally advanced CSCC treated with REGN2810 (3 mg / kg / dose, IV, once every 2 weeks).

[0172] Group 3 consists of patients with metastatic (nodular or distant) CSCC treated with REGN2810 (350 mg / dose, IV, once every 3 weeks).

[0173] Group 4 consists of patients with progressive CSCC [metastatic (nodular or distal) or unresectable locally advanced] treated with REGN2810 (600 mg / dose, IV, once every 4 weeks).

[0174] Group 5 consists of patients with progressive CSCC (metastatic or locally advanced) treated with REGN2810 (438 mg / dose, SC) and then with REGN2810 (350 mg / dose, IV, once every 3 weeks) 3 weeks later.

[0175] Table 3 provides an overview of the disease stages for the five study groups.

[0176]

Table 1

[0177] Study Objectives The first objective of this study for Groups 1 - 4 includes the following: to estimate the clinical utility (overall response rate by central review) of REGN2810 monotherapy in patients with metastatic (nodular or distant) CSCC or unresectable CSCC. The objectives of this study for Group 5 include the following: (1) to measure the concentration of REGN2810 in serum after subcutaneous (SC) administration to evaluate the subcutaneous bioavailability of REGN2810, and (2) to evaluate the safety, tolerability, and PK of a single dose of subcutaneous REGN2810.

[0178] The second objective of the study includes the following: (1) to estimate the objective response rate (ORR) according to the review of the principal investigators of the clinical trial; (2) to estimate the duration of response, progression-free survival (PFS), and overall survival (OS) by the review of the central and principal investigators of the clinical trial; (3) to estimate the complete response (CR) rate by central review; (4) to evaluate the safety and tolerability of REGN2810; (5) to evaluate the pharmacokinetics (PK) of REGN2810; (6) to evaluate the immunogenicity of REGN2810; and (7) to evaluate the impact of REGN2810 on quality of life using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30, see Young et al., European Journal of Cancer, 1999, 35(13):1773 - 82).

[0179] The second objective of the study for Group 4 further includes the following: using the EORTC criteria, 18Evaluate ORR according to F-fluorodeoxyglucose positron emission tomography ( 18 F-FDG-PET).

[0180] Additional research objectives for Groups 2 and 4 include the following: (1) Evaluate the pharmacodynamic effects of REGN2810 in tumor biopsies obtained at baseline, during treatment, and at progression in CSCC patients treated with REGN2810; (2) The number and distribution of tumor-infiltrating lymphocytes (TILs) (CD8 + T cells, CD4 + T cells, regulatory T cells, and other subtypes tolerated by the tissue, such as B cells, bone marrow-derived cells, NK cells, etc.); (3) The expression levels (mRNA and / or protein) of programmed death ligand 1 (PD-L1), glucocorticoid-induced TNFR family-related gene (GITR), and lymphocyte activation gene-3 (LAG-3), and possibly other checkpoint modulators; (4) Mutations in known cancer genes and potential tumor neoantigens; and (5) Tumor mutation burden.

[0181] Study Duration The study duration includes a screening period (up to 4 weeks) for all 5 groups. Groups 1 and 2 will each receive treatment for up to 96 weeks. Group 3 will receive treatment for up to 54 weeks. Group 4 will receive treatment for up to 48 weeks. Group 5 will receive treatment for up to 54 weeks. All groups will be eligible for retreatment for up to 2 years.

[0182] All groups will undergo follow-up for approximately up to 1.5 years.

[0183] Study Population The study will include patients who are subjects with metastatic (nodular and / or distant) CSCC (Groups 1 and 3) and inoperable locally advanced CSCC (Group 2). Group 3 for metastatic CSCC will only be opened after enrollment in Group 1 is complete. Groups 4 and 5 will enroll patients with progressive CSCC, a term that includes both metastatic (nodular or distant) CSCC and locally advanced CSCC.

[0184] Inclusion Criteria: To be eligible for inclusion in the study, patients must meet the following criteria: (1) Histologically confirmed diagnosis of invasive CSCC; (a) Regarding the primary tumor site: Patients with squamous cell carcinoma originating from the dry red lip (vermilion border) are not eligible. Patients with a tumor occurring on the cutaneous hairy (non-hairless) lip extending onto the dry red lip (vermilion border) may be eligible after contacting the medical monitor and obtaining permission from the medical monitor. Patients with squamous cell carcinoma originating from the anogenital region (penis, scrotum, and perianal area) are not eligible. Patients with the primary site in the nose are eligible only if the principal investigator can clearly demonstrate that the primary site is skin and not nasal mucosa extending externally to the skin; and (b) Regarding the tumor histology: Patients with a mixed histology (e.g., sarcomatoid, adenoid squamous) will generally not be eligible. Patients with a predominant histology of invasive CSCC with a mixed histology (having only minimal components of the mixed histology) may be eligible after contacting the medical monitor and obtaining permission from the medical monitor; (2) At least one measurable lesion as determined by the study eligibility criteria. If previously irradiated lesions are followed as target lesions, progression should be confirmed by biopsy after radiotherapy. If there is at least one other measurable target lesion, previously irradiated lesions can be followed as non-target lesions; (a) For patients with metastatic (nodular or distant) CSCC (all patients in groups 1 and 3 and patients in groups 4 and 5 with metastatic CSCC): There must be at least one baseline measurable lesion with a maximum diameter of ≥10 mm (1.5 cm for lymph nodes) according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. For patients with metastatic disease not meeting the target lesion criteria according to RECIST 1.1 (e.g., bone-only lesions, perineural disease; see Eisenhauer et al., Eur J Cancer 2009;45:228-247). For externally visible CSCC target lesions, two-dimensional measurements using digital medical photographs can be used (both perpendicular diameters must be ≥10 mm at baseline).Next, the patient will be registered with a plan to measure the externally visible target lesion by photography in 2D measurements; metastatic lesions that are not measurable according to the RECIST 1.1 criteria will be followed up on the scan as non-target lesions; (b) for patients with unresectable locally advanced CSCC (all patients in group 2 and patients in groups 4 and 5 with locally advanced CSCC): if digital medical photographs are continued, there must be at least one measurable baseline lesion with both the longest diameter (LD) and the perpendicular diameter ≥ 10 mm. Lesions that are not measurable for group 2 are defined as any of the following: lesions measurable in 1D, tumors with ill-defined margins, or lesions with a maximum perpendicular diameter < 10 mm. Patients without measurable disease at baseline are not eligible for the study; (3) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 (ECOG PS 1 definition: Vigorous physical activity is restricted, but the patient can walk and perform light or sedentary work, such as light housework and office work. Patients with ECOG PS > 1 are ineligible; (4) ≥ 18 years old;. (5) Liver function; (a) Total bilirubin ≤ 1.5 × upper limit of normal (ULN; in the case of liver metastasis ≤ 3 × ULN). Patients with Gilbert's disease and a total bilirubin up to 3 × ULN may be eligible after contacting and obtaining permission from the medical monitor; (b) Transaminases ≤ 3 × ULN (or ≤ 5.0 × ULN in the case of liver metastasis); and (c) Alkaline phosphatase (ALP) ≤ 2.5 × ULN (or ≤ 5.0 × ULN in the case of liver or bone metastasis). For patients with liver metastasis who wish to be enrolled in Group 1, Group 3, Group 4, or Group 5: If the transaminase levels (AST and / or ALT) are > 3 × but ≤ 5 × ULN, the total bilirubin must be ≤ 1.5 × ULN. If the total bilirubin is > 1.5 × but ≤ 3 × ULN, both transaminases (AST and ALT) must be ≤ 3 × ULN; (6) Renal function: Serum creatinine ≤ 1.5 × ULN or estimated creatinine clearance (CrCl) > 30 mL / min; (7) Bone marrow function: (a) Hemoglobin ≥ 9.0 g / dL; (b) Absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L; and (c) Platelet count ≥ 75 × 10 9 / L; (8) The ability to provide signed informed consent; (9) The ability to follow and proceed with the scheduled hospital visits, treatment plans, clinical examinations, and other research-related procedures; (10) Predicted remaining life > 12 weeks; (11) Patients with locally advanced CSCC: All patients in Group 2 (and patients in Groups 4 and 5 with locally advanced CSCC): In the opinion of a Mohs dermatologic surgeon, head and neck surgeon, or plastic surgeon, surgery should be considered contraindicated. A copy of the surgeon's consultation record from a clinical hospital visit within 60 days of registration must be submitted. Permissible contraindications in the surgeon's record include: (a) CSCC that recurs at the same site after two or more surgical procedures and is considered to have no prospect of curative resection; (b) CSCC with significant local infiltration that prevents complete resection; (c) CSCC in anatomically difficult locations where surgery may result in severe cosmetic damage or functional impairment (e.g., removal of all or part of the facial structure, such as the nose, ear, or eye; or the need for limb amputation); and (d) Other conditions considered to indicate a contraindication to surgery should be discussed with the medical monitor before enrolling the patient; (12) Patients with locally advanced CSCC (all patients in Group 2 and patients in Groups 4 and 5 with locally advanced CSCC): The patient should be considered unsuitable for radiotherapy. In particular, the patient must meet at least one of the following criteria: (a) A patient who has previously received radiotherapy for CSCC and, as a result, in the opinion of a radiation oncologist, further radiotherapy is likely to exceed the threshold of the acceptable cumulative dose. A copy of the radiation oncologist's consultation record from a clinical hospital visit within 60 days of registration must be submitted; (b) The radiation oncologist's determination that such a tumor is unlikely to respond to therapy.A copy of the radiation oncologist's examination record from a clinical visit within 60 days of registration must be submitted; and (c) individualized benefit:risk assessment by the principal investigator of the clinical trial, within 60 days prior to the registration of the proposed study, by a multidisciplinary team (consisting of at least a radiation oncologist and a medical oncologist with expertise in cutaneous malignancies, either a radiation oncologist or a medical oncologist with expertise in cutaneous malignancies, or a dermatologist, or a head and neck surgeon), and the principal investigator's clinical record indicating that radiotherapy was considered contraindicated. Contraindications to radiotherapy acceptable in the principal investigator's record for patients who have not received any previous radiotherapy include: (i) in the opinion of the multidisciplinary team, CSCC in an anatomically difficult location associated with a risk of toxicity where radiotherapy is considered unacceptable in relation to the patient's overall medical condition (e.g., a neck tumor where radiotherapy is thought to result in a potential need for a percutaneous gastrostomy tube). A copy of the principal investigator's examination record demonstrating the multidisciplinary assessment must be submitted; and (ii) other conditions considered to indicate a contraindication to radiotherapy should be discussed with the medical monitor prior to registering the patient; (13) All patients in any group must consent to provide stored or newly obtained tumor material (either formalin-fixed, paraffin-embedded [FFPE] blocks or 10 unstained or stained slides) for central pathology review to confirm the diagnosis of CSCC. This material must be provided to the central laboratory prior to registration. and must be checked in the received state; (14) Only for Group 2 (patients with locally advanced CSCC) and Group 4 (patients with locally advanced CSCC and metastatic CSCC): The patient must consent to undergo biopsy of the CSCC lesion at baseline, i.e., on Day 29 (± 3 business days) of Cycle 1, at the time of tumor progression, and at other times that may be clinically indicated at the discretion of the Investigator; (15) Only for all patients in Group 2 and patients in Groups 4 and 5 with locally advanced CSCC: A record by the Investigator stating that the natural course of the patient's progressive CSCC would be life-threatening within 3 years with the current management options available other than the clinical trial.

[0185] Exclusion Criteria: Patients who meet any of the following criteria will be excluded from the study: (1) Evidence of active or recent (within 5 years) severe autoimmune disease requiring treatment with systemic immunosuppressive therapy that may suggest a risk of immune-related adverse events (irAE). The following are not excluded: vitiligo requiring only hormone replacement, resolved childhood asthma, type 1 diabetes, residual hypothyroidism, or psoriasis not requiring systemic treatment; (2) Prior treatment with agents that block the PD-1 / PD-L1 pathway; (3) (a) Less than 4 weeks (28 days) prior to the first dose of REGN2810, or (b) within 90 days prior to the first dose of REGN2810, related to an immune-mediated adverse event that was ≥ grade 1, or (c) prior treatment with other immune-modulating agents related to toxicity that led to discontinuation of the immune-modulating agent. Examples of immune-modulating agents include therapeutic cancer vaccines, cytokine therapies (other than G-CSF and erythropoietin), or agents that target cytotoxic T-lymphocyte antigen 4 (CTLA-4), 4-1BB (CD137), PI 3-K-δ, or OX-40; (4) Untreated brain metastases that can be considered active. (Note: Patients with brain involvement of CSCC due to direct extension of an infiltrative tumor rather than metastasis may be eligible for enrollment after discussion and approval by the medical monitor if they do not require more than 10 mg of prednisone per day); (5) Immunosuppressive corticosteroid administration within 4 weeks prior to the first dose of REGN2810 (> 10 mg of prednisone per day or equivalent).Note: Patients who require a short course of steroids (e.g., for prophylaxis of imaging diagnosis due to allergy to contrast agents) are not excluded; (6) Active infections that require therapy, such as human immunodeficiency virus infection, or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV); (7) History of non-infectious interstitial pneumonia within the past 5 years. If the interstitial pneumonia had a purely infectious etiology, it may be permitted to enroll in the protocol after discussion with the medical monitor; (8) Grade ≥ 3 hypercalcemia at the time of enrollment; (9) Any systemic anti-cancer therapy (chemotherapy, targeted systemic therapy, photodynamic therapy), investigational or standard care (patients receiving bisphosphonates or denosumab are not excluded), planned to be performed within 30 days of the first dose of REGN2810 or during the study period, radiotherapy planned to be performed within 14 days of the first dose of REGN2810 or during the study period. Note: For patients with multiple CSCCs at baseline that are not designated as target lesions by the principal investigator of the clinical trial, treatment of these non-target CSCCs by surgery may be permitted, but should be discussed with the medical monitor prior to any surgical procedure; (10) History of documented allergic or anaphylactic reaction attributable to antibody therapy; (11) Patients with allergy or hypersensitivity to either REGN2810 or any of the excipients should be excluded. In particular, patients with allergy or hypersensitivity to doxycycline or tetracycline due to the presence of the tracer component of REGN2810 are excluded; (12) Breastfeeding; (13) Positive serum pregnancy test (medical if demonstrated by serial measurements and negative ultrasound). Contact the monitor, and false-positive pregnancy tests will not be excluded when permission is obtained from the medical monitor); (14) Tumors with negligible risk of metastasis or death, such as properly treated BCC of the skin, cervical intraepithelial neoplasia, or non-invasive ductal carcinoma of the breast, or low-risk early-stage prostate adenocarcinoma (T1-T2aN0M0 and Gleason score ≤6 and PSA ≤10 ng / mL) with an active surveillance management plan, or prostate adenocarcinoma with biochemical recurrence with a reported PSA doubling time >12 months and an active surveillance management plan (D’Amico 2005, Pham 2016), excluding synchronous malignancies other than CSCC and / or history of malignancies other than CSCC within 3 years from the date of the first planned dose of REGN2810. Patients with hematologic malignancies (e.g., chronic lymphocytic leukemia, CLL) are excluded; (15) Any acute or chronic psychiatric problems that, in the opinion of the study responsible physician, render the patient ineligible to participate; (16) Continued sexual activity in men or women of childbearing potential who are not willing to practice highly effective contraception starting at least 2 menstrual cycles before screening, during the study, and for at least 6 months after the last dose of the study drug. Highly effective contraceptive measures include the following: stable use of combined (estrogen- and progestogen-containing) hormonal contraceptive methods (oral, vaginal, transdermal) or progestogen-only hormonal contraceptive methods (oral, injectable, implantable) related to suppression of ovulation that have been initiated for more than 2 menstrual cycles before screening; intrauterine contraceptive devices; intrauterine hormone-releasing systems; bilateral tubal ligation; vasectomized partner and sexual abstinence. Contraception is not required for men with a documented vasectomy. Postmenopausal women must be amenorrheic for at least 12 months as the possibility of childbirth is not considered.Pregnancy testing and contraception are not required for women with a recorded hysterectomy or tubal ligation; (17) patients with a history of solid organ transplantation (patients with a previous corneal transplant may be permitted to enroll after discussion with and permission from the Medical Monitor); (18) previous treatment with BRAF inhibitors; (19) any medical comorbidity, physical examination findings or metabolic dysfunction, or clinical laboratory abnormalities that, in the opinion of the Investigator, render the patient ineligible for participation in the clinical trial due to a high safety risk and / or potential impact on the interpretation of the study results; (20) inability to undergo any contrast-enhanced radiographic response evaluation. Note regarding imaging options: Patients who cannot undergo CT with iodine contrast (e.g., due to contrast allergy) will not be excluded if their disease can be measured by MRI with gadolinium. Patients who cannot undergo MRI with gadolinium will not be excluded if their disease can be measured by CT scan with contrast. Note regarding Groups 2, 4, and 5 (only patients with locally advanced CSCC): In selected cases, locally advanced CSCC patients (Group 2, 4, or 5) who cannot undergo any contrast-enhanced radiographic imaging method (neither CT with iodine contrast nor MRI with gadolinium) may be eligible after contacting the Medical Monitor and obtaining permission from the Medical Monitor if the patient's disease can be comprehensively evaluated with digital medical photographs.

[0186] Study Variables The primary efficacy endpoints of this study include: ORR by central review during 12 treatment cycles (Groups 1 and 2) or 6 treatment cycles (Groups 3 and 4). The overall response rate will be evaluated separately for patients with metastatic CSCC or patients with unresectable locally advanced CSCC.

[0187] For patients with metastatic disease (Groups 1, 3, and 4), ORR will be determined using RECIST version 1.1 (Eisenhauer, EA et al., Eur J Cancer 2009;45:228~247). In patients in whom all response evaluations are performed by radiological scans according to RECIST 1.1, the determination of an independent radiological response evaluation committee will serve as the central response evaluation. In cases where all metastatic lesions are not measurable by RECIST (e.g., may occur in patients with bone-only metastases), clinical or composite response criteria can be used for patients with externally visible target lesions. For patients with unresectable locally advanced disease (Groups 2 and 4), ORR will be determined using clinical response criteria for externally visible tumors that require two-dimensional measurement according to World Health Organization (WHO) criteria. For patients with both target lesions measurable by clinical response criteria and target lesions measurable by RECIST 1.1, ORR will be determined using composite response criteria. In patients who achieve CR, tumor biopsy will be used in the final determination of complete vs. PR.

[0188] Patients considered not evaluable (NE) by RECIST version 1.1 (Groups 1, 3, and 4) or patients not evaluable by clinical or composite response criteria (Group 2) will be considered not having reached partial response (PR) / complete response (CR) for ORR.

[0189]

[0190] ​The secondary endpoints of this study include the following: (1) ORR for Groups 1 to 5 as evaluated by the principal investigator of the clinical trial: (a) For patients in Groups 1, 3, 4 (in case of metastasis) and Group 5 (in case of metastasis) where all response evaluations are performed by radiological scans according to RECIST 1.1, the term "composite response evaluation" is not applicable. The response evaluation by the principal investigator of the clinical trial for such patients will be RECIST 1.1 evaluation; (b) For patients in Groups 2, 4 (in case of unresectable locally advanced) and Group 5 (in case of unresectable locally advanced) where all response evaluations are performed by photographs according to the Clinical Response Criteria for Externally Visible Tumors, the term "composite response evaluation" is not applicable. The response evaluation by the principal investigator of the clinical trial for such patients will be according to the Clinical Response Criteria for Externally Visible Tumors; (c) For patients where target lesion response evaluations are performed by both scans (according to RECIST 1.1) and photographs (according to the Clinical Response Criteria for Externally Visible Tumors), the response evaluation by the principal investigator of the clinical trial will be according to the composite response criteria; (d) Patients in Group 4 will undergo PET-CT scans at baseline and at 6-month intervals. The response evaluation by the principal investigator of the clinical trial will be according to the EORTC criteria, Young et al., European Journal of Cancer, 1999, Vol. 35, No. 13, 1773-82; (2) Duration of response; (3) PFS; (4) OS; (5) CR rate; (6) Changes in the scores of the outcomes reported by patients on the EORTC QLQ-C30; (7) AE; (8) Serum concentration of REGN2810; and (9) Anti-REGN2810 antibody.

[0191] The exploratory outcome measures for this study include the following: (1) Fold change in mRNA expression of genes expressed in tumor tissue; (2) TIL (CD8 + T cells, CD4 +Percent changes in the numbers of T cells, regulatory T cells, and other tissue - permissive subtypes (e.g., B cells, bone marrow - derived cells, NK cells, etc.), as well as descriptive changes in the distribution of TILs in tumor tissue and stroma; (3) percent changes in the expression levels (mRNA and / or protein) of PD - L1, GITR, and LAG - 3 and perhaps other checkpoint modulators; (4) changes in the number and type of genetic mutations in known cancer genes and potential tumor neoantigens; and (5) changes in tumor mutation burden.

[0192] The serum concentration of REGN2810 will be evaluated at multiple time points throughout the study treatment and follow - up period to analyze PK. Pharmacokinetic variables may include, but are not limited to: (1) C eoi - concentration at the end of infusion (IV); (2) C max - peak concentration (SC); (3) C TROUGH - pre - infusion concentration; (4) t eoi - time of end of infusion; (5) t max - time to peak concentration (SC); (6) AUC 3w - area under the plasma concentration - time curve after the first SC or IV dose; and (7) F - absolute bioavailability after SC dosing.

[0193] The immunogenicity of REGN2810 will be evaluated. Antidrug antibody (ADA) variables include the following ADA status and titers: (1) emerging with treatment - defined as any positive post - dose ADA assay response when the baseline result is negative; (2) boosted with treatment - defined as any post - dose ADA response that is at least 9 - fold compared to the baseline titer level. ; (3) titer value (category of titer value); (4) low (titer < 1,000); (5) medium (1,000 ≤ titer ≤ 10,000); high (titer > 10,000). The relationship between the immunogenicity and PK of REGN2810 can be appropriately evaluated.

[0194] Study design Groups 1 and 2: After the end of the screening period up to 28 days, each patient in Groups 1 and 2 will receive up to 12 treatment cycles of 56 days (8 weeks) each over a total treatment period of up to 96 weeks. Each patient will receive REGN2810 3 mg / kg IV on days 1, 15±3, 29±3, and 43±3 during each treatment cycle. Tumor evaluations will be performed at the end of each treatment cycle. A broad safety assessment will be performed on day 1 of each cycle; a defined safety assessment will be performed at each REGN2810 dosing visit.

[0195] Group 3: This cohort enrolls patients with metastatic CSCC. Group 3 will start enrolling only after the completion of enrollment in Group 1. The dosing regimen is 350 mg IV every 3 weeks up to 54 weeks.

[0196] Group 4: This cohort enrolls patients with progressive CSCC (metastatic [nodular or distant] or locally advanced). Group 4 will start enrolling only after the completion of enrollment in Groups 1 through 3. The dosing regimen is 600 mg IV every 4 weeks up to 48 weeks.

[0197] Group 5: This cohort enrolls patients with progressive CSCC. The regimen is 438 mg SC as a single dose, followed by 350 mg IV every 3 weeks for a total treatment of 54 weeks within 3 weeks. The first 3 patients in Group 5 will be administered over 3 days to monitor injection site reactions (ISRs). If no severe ISRs are observed in the first 3 patients, the remaining cohort can be enrolled without restriction on the enrollment date (i.e., more than 1 patient can start treatment on the same day). If one or more severe ISRs are observed, enrollment will be temporarily suspended. In that situation, continuation of enrollment in Group 5 may be permitted after agreement between all relevant data review and the designated risk management lead in the Medical Monitor and Pharmacovigilance & Risk Management department. Input from the investigator responsible for the care of these patients can also be sought.

[0198] Patients continue REGN2810 until the planned duration of therapy is completed (96 weeks for Groups 1 and 2, 54 weeks for Groups 3 and 5, and 48 weeks for Group 4), or until disease progression, unacceptable toxicity, or withdrawal of consent. (Patients in Group 1 or 2 who experience a CR have the option to discontinue treatment after 48 weeks).

[0199] The dosing regimens for Groups 1 - 5 are summarized in Tables 4 - 7.

[0200] Dose levels can be reduced according to Table 8.

[0201] Groups 1 - 5: Patients who do not experience progressive disease (PD) at the end of the planned treatment period will enter a follow - up period of approximately 6 months. After completion of this follow - up period, patients will then have an evaluation every 4 months and will enter an extended follow - up period of approximately 1 year (Table 9).

[0202] [Table 2]

[0203] [Table 3]

[0204] [Table 4]

[0205] [Table 5]

[0206] [Table 6]

[0207] REGN2810 will be administered in an outpatient setting as an approximately 30-minute (±10 minutes) IV infusion. Longer infusion durations are permitted if interruption is necessary. The doses for Group 1 and Group 2 patients will depend on the individual body weight. The dose of REGN2810 should be adjusted in each cycle for a body weight change of ≧10%. Dose adjustment for a body weight change of <10% will be at the discretion of the principal investigator of the clinical trial.

[0208] REGN2810 will be supplied as a liquid in sterile disposable vials. Each vial of REGN2810 contains a concentration of 25 or 50 mg / mL (for IV infusion) or a concentration of 175 mg / mL (for SC injection).

[0209] Procedures and Assessments The screening procedures include the following: informed consent, genomic sub-study informed consent (optional), inclusion / exclusion, medical history / tumor history, demographics, complete physical examination and ECOG PS, 12-Lead ECG, vital signs and body weight, brain MRI, viral serology, coagulation, urine test, clinical laboratory tests (hematology, blood chemistry, serum HCG ≦72 hours before dosing, urine test, HBV, HCV, HIV), stored tissue for histological confirmation of CSCC, tumor biopsy for Group 2, CT / MRI and / or digital photography, and treatment assignment.

[0210] The efficacy procedures include the following: images (computed tomography [CT] or magnetic resonance imaging [MRI]) and digital medical photographs (for externally visible lesions) to measure tumor volume and to characterize the efficacy profile of the study treatment using response criteria. Additional efficacy procedures include tumor measurement and tumor biopsy.

[0211] The safety procedures include the following: evaluation of vital signs, physical examination, electrocardiogram (ECG), immune safety assays, immunoglobulin levels (IgG, IgM, IgE), adverse event (AE) monitoring, clinical laboratory tests (including pregnancy test for women of childbearing potential).

[0212] The immune safety assay includes the measurement of the titers and patterns of rheumatoid factor (RF), TSH, C-reactive protein (CRP), and antinuclear antibody (ANA). During the course of the study, if an increase of more than 4-fold from the baseline of RF or ANA or abnormal levels of TSH or CRP are observed, the following tests can also be performed: anti-DNA antibody, anti-Sjögren's syndrome antigen (SSA) antibody (Ro), anti-Sjögren's syndrome B antigen (SSB) antibody (La), anti-thyroglobulin antibody, anti-LKM antibody, anti-phospholipid antibody, anti-islet cell antibody, anti-neutrophil cytoplasmic antibody, C3, C4, CH50.

[0213] Clinical examination procedures include the following: hematology, blood chemistry, pregnancy test (for females only), and urine test.

[0214] PK / drug concentration: PK samples will be collected for the evaluation of the serum concentration of REGN2810.

[0215] Anti-drug antibody measurement: Serum samples will be collected for the evaluation of immunogenicity against REGN2810.

[0216] Genomics sub-study measurements include the following: sequencing of candidate genes and surrounding genomic regions or single nucleotide polymorphism studies, whole exome sequencing, whole genome sequencing, and DNA copy number polymorphisms.

[0217] Concurrent drug applications and procedures Prohibited drug applications and procedures. During the participation in this study, patients cannot receive any standard or investigational agents for the treatment of tumors other than REGN2810 as monotherapy. Once the patient has completed the 24-week study treatment, after communication with the sponsor of the trial, local palliative therapy (e.g., radiation therapy) for local control of the tumor will be permitted. Any other drug applications that are considered necessary for the well-being of the patient and are not expected to interfere with the evaluation of the study drug can be given at the discretion of the responsible investigator of the trial.

[0218] Patients who are using systemic corticosteroids at immunosuppressive doses (more than 10 mg of prednisone or equivalent per day) for purposes other than corticosteroid replacement will not be eligible for the study. Patients are recommended to be free of systemic corticosteroids, such as hydrocortisone, prednisone, prednisolone (Solu-Medrol®), or dexamethasone (Decadron®), at any time throughout the study, except in life-threatening emergencies and / or when treating irAEs. Physiological replacement doses of systemic corticosteroids are permitted even if they are > 10 mg / day prednisone equivalent. Short courses of corticosteroids for prophylaxis (e.g., contrast dye allergy) or treatment of non-autoimmune conditions (e.g., delayed hypersensitivity reactions caused by contact allergens) are permitted. Bisphosphonates and denosumab are not prohibited.

[0219] Surgery: For patients with locally advanced target lesions that are considered unresectable at baseline but may become resectable during the course of the study due to tumor response to REGN2810, surgery for curative intent may be permitted, but should be discussed with the medical monitor prior to any surgical procedure. (This statement does not apply to patients in urgent life-threatening situations requiring immediate surgery). Patients with CSCC that is inoperable at baseline and becomes operable with clear margins will be considered to have experienced a PR.

[0220] If a patient develops a new cutaneous lesion during the study that is suspected to be a non-melanoma skin cancer other than CSCC (e.g., BCC), removal of the lesion during the study and continuation of treatment may be permitted after discussion with the medical monitor.

[0221] Radiation Therapy: Radiation therapy is not part of the study regimen. Patients for whom radiation therapy is planned are not eligible. During the course of the study, if a patient develops a symptomatic lesion for which palliative radiation therapy is considered appropriate by the principal investigator of the clinical trial, this is considered PD and generally the patient will be removed from the study. Palliative radiation therapy may be permitted in certain circumstances for patients who have been in the study for at least 24 weeks. Such cases should be discussed with the medical monitor prior to any radiation therapy if the principal investigator of the clinical trial believes that resumption of REGN2810 after radiation exposure would be in the best interest of the patient. Patients will be considered to have experienced disease progression if radiation therapy is initiated and will be followed for OS. and will be followed for OS.

[0222] WHO Criteria for Visible External Tumors Requiring Two-Dimensional Measurements The criteria for judging clinical response of visible external tumors requiring two-dimensional measurements according to the WHO criteria are as follows:

[0223] Complete Response of Visible External Disease (vCR): All target and non-target lesions that are no longer visible, maintained for at least 4 weeks. Documentation of vCR requires confirmation by biopsy of the site of the visible target lesion, with histological confirmation of no residual malignant lesions, according to central pathology review (Appendix 5). In the absence of such histological confirmation, a patient cannot be considered to have experienced vCR and the best response will be partial response.

[0224] Partial Response of Visible External Disease (vPR): A decrease of 50% or more of the sum of the products of the perpendicular longest diameters of the target lesions, maintained for at least 4 weeks (WHO criteria).

[0225] Stable Visible External Disease (vSD): Does not meet the criteria for vCR, vPR, or progressive disease.

[0226] Visible progression of disease (vPD): An increase of ≥ 25% (WHO criteria) in the sum of the products of the perpendicular longest dimensions of target lesions. In rare cases, progression without suspicion of non-target lesions can be recognized as vPD.

[0227] Results Administration of REGN2810 is expected to lead to enhanced tumor regression and improved disease management. Furthermore, administration of REGN2810 is expected to lead to increased safety in patients with CSCC and a reduced or absent incidence of adverse events and / or toxicities. For patients without metastatic CSCC, a reduced likelihood of metastatic CSCC is expected.

[0228] A total of 193 patients (pts) were enrolled (Group 1, n = 59; Group 2, n = 78; Group 3, n = 56). 128 pts had not received previous systemic anti-cancer therapy, and 65 pts had been previously treated. As of October 11, 2019 (data cut-off), the median follow-up duration was 15.7 months (range: 0.6 - 36.1) among all pts; 18.5 months (range: 1.1 - 36.1) for Group 1, 15.5 months (range: 0.8 - 35.0) for Group 2, and 17.3 months (range: 0.6 - 26.3) for Group 3. The ORR per INV was 54.4% (95% CI: 47.1 - 61.6) for all pts; 50.8% (95% CI: 37.5 - 64.1) for Group 1, 56.4% (95% CI: 44.7 - 67.6) for Group 2, and 55.4% (95% CI: 41.5 - 68.7) for Group 3. The ORR per INV was 57.8% (95% CI: 48.8 - 66.5) among treatment-naïve pts and 47.7% (95% CI: 35.1 - 60.5) among previously treated pts. The median duration of response (DOR) was not reached (observed DOR range: 1.8 - 34.2 months). In responsive pts, the estimated DOR at 24 months was 76.0% (95% CI: 64.1 - 84.4). The median OS was not reached. The estimated OS at 24 months was 73.3% (95% CI: 66.1 - 79.2). The most common treatment-emergent adverse events (TEAEs) occurring with any grade were fatigue (34.7%), diarrhea (27.5%), and nausea (23.8%). The most common grade ≥3 TEAEs were hypertension (4.7%) and anemia and cellulitis (each 4.1%).

[0229] For patients with advanced CSCC, semiprimab achieved DOR and survival was superior to that reported with other agents.

[0230] Note that the length of the following sequence is less than the minimum length allowed in ST.26 format: AAS (SEQ ID NO: 7).

Claims

1. 1. A method of treating or inhibiting tumor growth comprising: (a) selecting patients with skin cancer who have completed surgery and / or radiation therapy to treat the skin cancer; and (b) subsequently administering to the patient an adjuvant treatment comprising a therapeutically effective amount of a programmed death 1 (PD-1) inhibitor. The method comprising:

2. 10. The method of claim 1, wherein the patient has completed surgery and optionally post-operative radiation therapy.

3. 3. The method of claim 1 or 2, wherein the skin cancer is cutaneous squamous cell carcinoma (CSCC), basal cell carcinoma (BCC), Merkel cell carcinoma or melanoma.

4. The method of any one of claims 1 to 3, wherein the skin cancer is CSCC.

5. The method of any one of claims 1 to 4, wherein the patient is at high risk of recurrence of CSCC or has suffered at least one incident of recurrence.

6. 6. The method of claim 5, wherein the patient has at least one of the following high-risk features: (a) nodular disease with extracapsular extension and at least one nodule >20 mm; (b) in-transit transfer (ITM); (c) T4 lesion; (d) perineural invasion (PNI); and (e) recurrent CSCC plus at least one of the following additional configurations: (i) ≥N2b disease associated with recurrent lesions; (ii) Nominal ≧T3; and (iii) Recurrent lesions ≥ 20 mm in diameter.

7. The method of any one of claims 1 to 6, wherein the therapeutically effective amount comprises 5 mg to 500 mg of the PD-1 inhibitor.

8. The method of any one of claims 1 to 6, wherein the therapeutically effective amount comprises 350 mg of the PD-1 inhibitor.

9. 9. The method of any one of claims 1 to 8, wherein the PD-1 inhibitor is administered in one or more doses, each dose being administered 2 to 12 weeks, preferably 3 weeks, after the immediately preceding dose.

10. 10. The method of claim 9, wherein each dose contains 5 mg to 500 mg, preferably 350 mg, of the PD-1 inhibitor.

11. The method of any one of claims 1 to 10, wherein the PD-1 inhibitor is administered intravenously.

12. The method according to any one of claims 1 to 11, wherein step (b) is performed 2 to 6 weeks after completion of radiotherapy.

13. 13. The method of any one of claims 1 to 12, wherein administration of a PD-1 inhibitor leads to a reduced risk of subsequent skin cancer recurrence or eliminates the occurrence of subsequent skin cancer recurrence.

14. 13. The method of any one of claims 1-12, wherein administration of the PD-1 inhibitor leads to at least about a 10% lower incidence of subsequent skin cancer recurrence as compared to patients following completion of surgery and radiation therapy without an adjuvant skin cancer treatment.

15. The method of any one of claims 1 to 14, further comprising administering an additional therapeutic agent selected from a chemotherapeutic agent, a corticosteroid, an anti-inflammatory agent and / or combinations thereof.

16. The method of any one of claims 1 to 15, wherein the PD-1 inhibitor is selected from the group consisting of an anti-PD-1 antibody or antigen-binding fragment thereof, an anti-PD-L1 antibody or antigen-binding fragment thereof, and an anti-PD-L2 antibody or antigen-binding fragment thereof.

17. The method of any one of claims 1 to 16, wherein the PD-1 inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof comprising three complementarity determining regions (CDRs) (HCDR1, HCDR2, and HCDR3) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1, and three CDRs (LCDR1, LCDR2, and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

2.

18. The method of claim 17, wherein HCDR1 has the amino acid sequence of SEQ ID NO:3; HCDR2 has the amino acid sequence of SEQ ID NO:4; HCDR3 has the amino acid sequence of SEQ ID NO:5; LCDR1 has the amino acid sequence of SEQ ID NO:6; LCDR2 has the amino acid sequence of SEQ ID NO:7; and LCDR3 has the amino acid sequence of SEQ ID NO:

8.

19. The method of claim 17 or 18, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises the HCVR / LCVR sequence pair of SEQ ID NOs: 1 / 2.

20. The method of any one of claims 17 to 19, wherein the anti-PD-1 antibody comprises a heavy chain and a light chain, and the heavy chain has the amino acid sequence of SEQ ID NO:

9.

21. The method of any one of claims 17 to 19, wherein the anti-PD-1 antibody comprises a heavy chain and a light chain, and the light chain has the amino acid sequence of SEQ ID NO:

10.

22. 20. The method of any one of claims 17 to 19, wherein the anti-PD-1 antibody comprises a heavy chain and a light chain, the heavy chain having the amino acid sequence of SEQ ID NO:9 and the light chain having the amino acid sequence of SEQ ID NO:

10.

23. The method of any one of claims 1 to 16, wherein the PD-1 inhibitor is cemiplimab or a biological equivalent thereof.

24. The method of any one of claims 1 to 16, wherein the PD-1 inhibitor is an anti-PD-1 antibody selected from the group consisting of cemiplimab, nivolumab, pembrolizumab, pidilizumab, MEDI0608, BI 754091, PF-06801591, spartalizumab, camrelizumab, JNJ-63723283, and MCLA-134.

25. The method of any one of claims 1 to 16, wherein the PD-1 inhibitor is an anti-PD-L1 antibody selected from the group consisting of H1H8314N, avelumab, atezolizumab, durvalumab, MDX-1105, LY3300054, FAZ053, STI-1014, CX-072, KN035, and CK-301.

26. A pharmaceutical composition comprising a therapeutically effective amount of a programmed death 1 (PD-1) inhibitor for use in the adjuvant treatment of skin cancer following completion of surgery and post-surgical radiation.

27. The pharmaceutical composition of claim 26, wherein the PD-1 inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof comprising three complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1 and three CDRs (LCDR1, LCDR2 and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

2.

28. The pharmaceutical composition of claim 27, wherein HCDR1 has the amino acid sequence of SEQ ID NO:3; HCDR2 has the amino acid sequence of SEQ ID NO:4; HCDR3 has the amino acid sequence of SEQ ID NO:5; LCDR1 has the amino acid sequence of SEQ ID NO:6; LCDR2 has the amino acid sequence of SEQ ID NO:7; and LCDR3 has the amino acid sequence of SEQ ID NO:

8.

29. 29. The pharmaceutical composition of claim 28, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises the HCVR / LCVR sequence pair of SEQ ID NOs: 1 / 2.

30. 30. The pharmaceutical composition of any one of claims 26 to 29, comprising 5 mg to 500 mg of a PD-1 inhibitor.

31. The pharmaceutical composition of any one of claims 26 to 30, comprising 350 mg of a PD-1 inhibitor.

32. The pharmaceutical composition according to any one of claims 26 to 31, wherein the skin cancer is CSCC.

33. 1. A method of treating or inhibiting tumor growth comprising: (a) selecting patients with skin cancer for which surgical removal is planned; and (b) administering to the patient, prior to surgical removal, a neoadjuvant treatment comprising a therapeutically effective amount of a programmed death 1 (PD-1) inhibitor. The method comprising:

34. 34. The method of claim 33, wherein the skin cancer is cutaneous squamous cell carcinoma (CSCC), basal cell carcinoma (BCC), Merkel cell carcinoma or melanoma.

35. 35. The method of claim 33 or 34, wherein the skin cancer is CSCC.

36. The method of any one of claims 33 to 35, wherein the patient is at high risk of recurrence of CSCC.

37. 37. The method of claim 36, wherein the patient has at least one of the following high-risk configurations: (a) nodular disease with extracapsular extension and at least one nodule >20 mm; (b) in-transit transfer (ITM); (c) T4 lesion; (d) perineural invasion (PNI); and (e) recurrent CSCC plus at least one of the following additional configurations: (i) ≥N2b disease associated with recurrent lesions; (ii) Nominal ≧T3; and (iii) Recurrent lesions ≥ 20 mm in diameter.

38. A therapeutically effective dose is 5 mg to 500 mg of a PD-1 inhibitor administered as a neoadjuvant. The method of any one of claims 33 to 37, comprising:

39. 39. The method of any one of claims 33-38, wherein the therapeutically effective amount comprises 350 mg of the PD-1 inhibitor administered as a neoadjuvant.

40. 39. The method of any one of claims 33 to 38, wherein one or more doses of the PD-1 inhibitor are administered as a neoadjuvant treatment, each dose being administered 2 to 12 weeks, preferably 3 weeks, after the immediately preceding dose.

41. 41. The method of claim 40, wherein each dose comprises 5 mg to 500 mg, preferably 350 mg, of the PD-1 inhibitor.

42. 42. The method of any one of claims 33-41, further comprising (c) surgically removing the skin cancer following the neoadjuvant treatment.

43. 43. The method of claim 42, further comprising administering to the patient an adjuvant therapy comprising a therapeutically effective amount of a PD-1 inhibitor after step (c), wherein the adjuvant PD-1 inhibitor can be the same as or different from the neoadjuvant PD-1 inhibitor.

44. 44. The method of claim 43, wherein the adjuvant treatment comprises administering between 5 mg and 500 mg of the PD-1 inhibitor.

45. 45. The method of claim 43 or 44, wherein the adjuvant treatment comprises administering 350 mg of a PD-1 inhibitor.

46. The method of any one of claims 33 to 42, wherein the PD-1 inhibitor is administered intravenously.

47. 47. The method of any one of claims 33-46, wherein administration of the PD-1 inhibitor leads to a reduced risk of subsequent skin cancer recurrence or eliminates the occurrence of subsequent skin cancer recurrence.

48. 47. The method of any one of claims 33-46, wherein administration of the PD-1 inhibitor leads to at least about a 10% lower incidence of subsequent skin cancer recurrence as compared to patients following completion of surgery and radiation therapy without an adjuvant skin cancer treatment.

49. 47. The method of any one of claims 33 to 46, further comprising administering an additional therapeutic agent selected from a chemotherapeutic agent, a corticosteroid, an anti-inflammatory agent and / or combinations thereof.

50. 50. The method of any one of claims 33 to 49, wherein the PD-1 inhibitor is selected from the group consisting of an anti-PD-1 antibody or an antigen-binding fragment thereof, an anti-PD-L1 antibody or an antigen-binding fragment thereof, and an anti-PD-L2 antibody or an antigen-binding fragment thereof.

51. The method of any one of claims 33 to 50, wherein the PD-1 inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof comprising three complementarity determining regions (CDRs) (HCDR1, HCDR2, and HCDR3) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1, and three CDRs (LCDR1, LCDR2, and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

2.

52. HCDR1 has the amino acid sequence of SEQ ID NO:3; HCDR2 has the amino acid sequence of SEQ ID NO:4; HCDR3 has the amino acid sequence of SEQ ID NO:5; LCDR1 has the amino acid sequence of SEQ ID NO:

6.

52. The method of claim 51 , wherein LCDR2 has the amino acid sequence of SEQ ID NO:7; LCDR3 has the amino acid sequence of SEQ ID NO:

8.

53. The method of claim 51 or 52, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises the HCVR / LCVR sequence pair of SEQ ID NOs: 1 / 2.

54. The method of any one of claims 51 to 53, wherein the anti-PD-1 antibody comprises a heavy chain and a light chain, and the heavy chain has the amino acid sequence of SEQ ID NO:

9.

55. The method of any one of claims 51 to 53, wherein the anti-PD-1 antibody comprises a heavy chain and a light chain, and the light chain has the amino acid sequence of SEQ ID NO:

10.

56. 54. The method of any one of claims 51 to 53, wherein the anti-PD-1 antibody comprises a heavy chain and a light chain, the heavy chain having the amino acid sequence of SEQ ID NO:9 and the light chain having the amino acid sequence of SEQ ID NO:

10.

57. 51. The method of any one of claims 33 to 50, wherein the PD-1 inhibitor is cemiplimab or a biological equivalent thereof.

58. The method of any one of claims 33 to 50, wherein the PD-1 inhibitor is an anti-PD-1 antibody selected from the group consisting of cemiplimab, nivolumab, pembrolizumab, pidilizumab, MEDI0608, BI 754048, PF-06371548, spartalizumab, camrelizumab, JNJ-63313240, and MCLA-134.

59. The method of any one of claims 33 to 50, wherein the PD-1 inhibitor is an anti-PD-L1 antibody selected from the group consisting of H1H8314N, avelumab, atezolizumab, durvalumab, MDX-1105, LY3300054, FAZ053, STI-1014, CX-031, KN035 and CK-301.

60. A pharmaceutical composition comprising a therapeutically effective amount of a programmed death 1 (PD-1) inhibitor for use in neoadjuvant therapy prior to planned surgery to treat skin cancer.

61. The pharmaceutical composition of claim 60, wherein the PD-1 inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof comprising three complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1 and three CDRs (LCDR1, LCDR2 and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

2.

62. The pharmaceutical composition of claim 61, wherein HCDR1 has the amino acid sequence of SEQ ID NO:3; HCDR2 has the amino acid sequence of SEQ ID NO:4; HCDR3 has the amino acid sequence of SEQ ID NO:5; LCDR1 has the amino acid sequence of SEQ ID NO:6; LCDR2 has the amino acid sequence of SEQ ID NO:7; and LCDR3 has the amino acid sequence of SEQ ID NO:

8.

63. The pharmaceutical composition of claim 62, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises the HCVR / LCVR sequence pair of SEQ ID NOs: 1 / 2.

64. 64. The pharmaceutical composition of any one of claims 60 to 63, comprising 5 mg to 500 mg of a PD-1 inhibitor.

65. A pharmaceutical composition according to any one of claims 60 to 63, comprising 350 mg of a PD-1 inhibitor. thing.

66. The pharmaceutical composition of any one of claims 60 to 65, wherein the skin cancer is CSCC.

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