Methods of treating cancer by administering a combination therapy including a neoadjuvant pd-1 inhibitor

Abstract

The present disclosure provides methods for treating, reducing the severity of, inhibiting the growth of a tumor, or inducing necrosis of a tumor, wherein the method includes selecting a patient with cancer (e.g., liver cancer, lung cancer, or head and neck cancer) in need thereof and administering to the patient a neoadjuvant therapy comprising a therapeutically effective amount of a programmed death 1 (PD-1) inhibitor (e.g., cemiplimab or a bioequivalent thereof) in combination with radiation therapy (e.g., SBRT) or an anti-LAG-3 antibody (e.g., fianlimab) followed by surgical resection, and optional administration of a programmed death 1 (PD-1) inhibitor (e.g., cemiplimab or a bioequivalent thereof) as post-surgery adjuvant therapy. In certain embodiments, the cancer is liver cancer, such as hepatocellular carcinoma (HCC).

Description

METHODS OF TREATING CANCER BY ADMINISTERING A COMBINATION THERAPY INCLUDING A NEOADJUVANT PD-1 INHIBITORSEQUENCE LISTING

[0001] The sequence listing of the present application is submitted electronically as an ST.26 formatted xml file with a file name “SeqListl 1694. xml,” creation date of November 8, 2024, and a size of 13,161 bytes. This sequence listing submitted is part of the specification and is hereby incorporated by reference in its entirety. The following sequence has a length that is below the minimum length permitted under ST.26 format: AAS (SEQ ID NO: 7).FIELD

[0002] The present disclosure relates to methods of treating or inhibiting the growth of a tumor, including selecting a patient with cancer in need thereof and administering to the patient a neoadjuvant therapy including a therapeutically effective amount of a programmed death 1 (PD-1) inhibitor (e.g., cemiplimab or a bioequivalent thereof) in combination with radiation or an anti-LAG3 inhibitor, followed by surgical resection, and optionally followed by post-surgery adjuvant administration of a therapeutically effective amount of a PD-1 inhibitor.BACKGROUND

[0003] Non-small cell lung cancer (NSCLC), liver cancer, and head and neck squamous cell carcinoma (HNSCC) are some of the leading causes of cancer deaths worldwide.

[0004] NSCLC causes the most cancer deaths in men and women, and the majority of patients do not achieve significant clinical benefit from the combination of PD-1 / PD-L1 blockade and chemotherapy. Until recently, roughly three-quarters of lung cancer was diagnosed as Stage 4 disease. Computed tomography (CT) screening has increased the number of earlier stage, potentially curable tumors detected. Yet, despite increasingly identifying NSCLC at earlier stages, operable Stage 1-3 lung cancer — which recurs in the majority of patients — has seen few, significant improvements in treatment approaches. Given high rates of recurrence and the paucity of effective treatments, better approaches are needed.

[0005] HNSCC is the sixth most common malignancy worldwide, and the rates of HNSCC have increased steadily since the 1980s, in part due to the rise in human papilloma virus (HPV) infection in the oropharynx, so that currently, roughly half of the cases of HNSCC that occur in the developed world are attributable to HPV infection, while the latter only accounts for 10-20% of cases in the developing world (Torre et al., A Cancer Journal for Clinicians, 2015;65(2):87-108; Chaturvedi et al . , Journal of Clinical Oncology: Official Journal of the American Society of ClinicalOncology, 2008;26(4):612-619; de Martel et al., The Lancet Oncology, 2012;13(6):607-615). Patients with HPV-related disease, across stages, have improved survival outcomes when compared to HPV-negative tumors, which are commonly associated with tobacco and alcohol exposure (Ang, 2010). Early-stage disease is typically treated with surgery and / or radiation, and these patients have a good prognosis, with 5-year overall survival (OS) of 70-90%, but patients with locoregionally advanced disease who often receive chemotherapy in addition to locoregional therapies (surgery and / or radiation) have a dismal 30% 5-year OS, worse still in those with HPV- negative disease (Blanchard et al., Radiother Oncol, 2011 ; 100(1):33-40). Hence, improved treatments for NSCLC are needed.

[0006] Liver cancer, particularly hepatocellular carcinoma (HOC), accounts for the second most cancer deaths in men worldwide (Ferlay et al., Int J Cancer, 2015;136(5):E359-E386), and is the most rapidly rising cause of cancer mortality in the United States, with more than 30,000 new cases per year (Siegel et al., A Cancer Journal for Clinicians, 2013;63(1):11-30; Torre et al., A Cancer Journal for Clinicians, 2015;65(2):87-108). HOC accounts for 75%-85% of primary liver cancer cases, which was the third leading cause of cancer death worldwide in 2020. (Sung et al., CA Cancer J Clin, 2021). The recommended first-line treatment for very early / early-stage HCC is surgery, which includes hepatic resection and transplantation, or radiofrequency ablation (RFA) in patients with preserved liver function, and results have improved with advances in surgical techniques and perioperative care. However, there is a high incidence of postoperative recurrence and cancer-related deaths. (European Association for the Study of the Liver. J Hepatol. 2018;69:182-236; Poon et al., Ann Surg. 2000;232:10-24; Chan et al., Liver Transpl. 2013; 19:411- 419). Negative margins are usually observed at the time of surgical resection; however, it is believed that HCC recurs as a result of residual micrometastases that persist after resection, highlighting the potential benefit of neoadjuvant therapy in improving HCC outcomes. There is no standard recommended treatment in the neoadjuvant setting (European Association for the Study of the Liver. J Hepatol. 2018;69: 182-236; Akateh C et al. World J Gastroenterol 2019;25:3704- 3721). And no neoadjuvant or adjuvant therapies have demonstrated a reduction in risk of recurrence or a proven survival benefits in patients with HCC. While immunotherapy combinations have changed the prognosis of patients with advanced HCC, the majority of patients still perish from this disease.

[0007] HCC typically presents in advanced stages, at which time surgery is not an option. Hence, the usual prognosis for HCC is poor because only 10-20% of hepatocellular carcinomas can be removed completely by surgery. If the cancer cannot be completely removed, the disease is often fatal within three to six months. Additionally, PD-1 and PD-L1 are generallyoverexpressed in HCC, and high PD-L1 expression by tumor cells has been associated with significantly poorer prognosis.

[0008] The treatment of choice for patients with HCC and preserved liver function is surgical resection, with hepatic resection being the accepted treatment of early-stage HCC. However, postsurgical tumor intrahepatic recurrence is common, with early (within 2 years) recurrence being observed in approximately 50% of cases (Franssen et al., Ann Surg, 2014;260(4):650-656; Tabrizian et al., Ann Surg., 2015;261(5):947-955). In fact, the majority of tumors recur despite surgery and no perioperative intervention has demonstrated a survival advantage. Since negative margins are usually observed at the time of surgical resection, it is believed that HCC recurrence occurs as a result of micrometastases that persist after resection. Chemotherapy usually has no role in the management of HCC. Targeted agents such as sorafenib have shown some survival benefit in patients with unresectable disease, but a large international trial of adjuvant sorafenib treatment showed no benefit (Bruix et al., The Lancet Oncology, 2015;16(13):1344-1354). Thus, there remains a significant need for a safe and effective therapy for treating liver cancer, including HCC.SUMMARY

[0009] In one aspect, the disclosed technology relates to a method of treating or inhibiting the growth of a tumor, comprising: (a) selecting a patient with cancer; (b) administering to the patient a therapeutically effective amount of a neoadjuvant programmed death-1 (PD-1) inhibitor, wherein the neoadjuvant PD-1 inhibitor is an antibody that binds specifically to PD-1 and comprises three heavy chain complementarity determining regions (CDRs) (HCDR1 , HCDR2 and HCDR3) contained in a heavy chain variable region (HCVR) of SEQ ID NO: 1 and three light chain CDRs (LCDR1 , LCDR2 and LCDR3) contained in a light chain variable region (LCVR) of SEQ ID NO: 2 in combination with radiation therapy; and (c) after step (b), surgically resecting the cancer tumor. In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the radiation is stereotactic body radiotherapy (SBRT).

[0010] In another aspect, the disclosed technology relates to a method of treating or inhibiting the growth of a tumor, comprising: (a) selecting a patient with cancer; (b) administering to the patient a therapeutically effective amount of a neoadjuvant programmed death-1 (PD-1) inhibitor, wherein the neoadjuvant PD-1 inhibitor is an antibody that binds specifically to PD-1 and comprises three heavy chain complementarity determining regions (CDRs) (HCDR1 , HCDR2 and HCDR3) contained in a heavy chain variable region (HCVR) of SEQ ID NO: 1 and three light chain CDRs (LCDR1 , LCDR2 and LCDR3) contained in a light chain variable region (LCVR) of SEQ ID NO: 2 in combination with an antibody that binds specifically to LAG-3; and (c) after step (b),surgically resecting the cancer tumor. In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the anti-LAG-3 antibody is fianlimab.

[0011] In some embodiments, the administered neoadjuvant anti-PD-1 antibody comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 3; a HCDR2 having an amino acid sequence of SEQ ID NO: 4; a HCDR3 having an amino acid sequence of SEQ ID NO: 5; a LCDR1 having an amino acid sequence of SEQ ID NO: 6; a LCDR2 having an amino acid sequence of SEQ ID NO: 7; and a LCDR3 having an amino acid sequence of SEQ ID NO: 8. In some embodiments, the administered neoadjuvant anti-PD-1 antibody comprises a HCVR comprising an amino acid sequence of SEQ ID NO: 1. In some embodiments, the administered neoadjuvant anti-PD-1 antibody comprises a LCVR comprising an amino acid sequence of SEQ ID NO: 2. In some embodiments, the administered neoadjuvant anti-PD-1 antibody comprises a HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 / 2. In some embodiments, the administered neoadjuvant anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain has an amino acid sequence of SEQ ID NO: 9. In some embodiments, the administered neoadjuvant anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the light chain has an amino acid sequence of SEQ ID NO: 10. In some embodiments, the administered neoadjuvant anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain has an amino acid sequence of SEQ ID NO: 9 and the light chain has an amino acid sequence of SEQ ID NO: 10. In some embodiments, the administered neoadjuvant anti-PD-1 antibody is cemiplimab.

[0012] In some embodiments, the administered neoadjuvant PD-1 inhibitor is an anti-PD- 1 antibody comprising a HCVR with 90%, 95%, 97%, or 98% sequence identity to SEQ ID NO: 1. In some embodiments, the administered neoadjuvant PD-1 inhibitor is an anti-PD-1 antibody comprising a LCVR with 90%, 95%, 97%, or 98% sequence identity to SEQ ID NO: 2. In some embodiments, the administered neoadjuvant PD-1 inhibitor is an anti-PD-1 antibody comprising a HCVR with 90%, 95%, 97%, or 98% sequence identity to SEQ ID NO: 1 , and a LCVR with 90%, 95%, 97%, or 98% sequence identity to SEQ ID NO: 2.

[0013] In some embodiments, the method further comprises: (d) after step (c), administering to the patient a therapeutically effective amount of an adjuvant programmed death-1 (PD-1) inhibitor, wherein the adjuvant PD-1 inhibitor is an antibody that binds specifically to PD-1 and comprises three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained in a heavy chain variable region (HCVR) of SEQ ID NO: 1 and three light chain CDRs (LCDR1 , LCDR2 and LCDR3) contained in a light chain variable region (LCVR) of SEQ ID NO: 2. In some embodiments, the administered adjuvant anti-PD-1 antibody comprises HCDR1 having an amino acid sequence of SEQ ID NO: 3; HCDR2 having an amino acid sequence of SEQID NO: 4; HCDR3 having an amino acid sequence of SEQ ID NO: 5; LCDR1 having an amino acid sequence of SEQ ID NO: 6; LCDR2 having an amino acid sequence of SEQ ID NO: 7; and LCDR3 having an amino acid sequence of SEQ ID NO: 8. In some embodiments, the administered adjuvant anti-PD-1 antibody comprises a HCVR comprising an amino acid sequence of SEQ ID NO: 1.In some embodiments, the administered adjuvant anti-PD-1 antibody comprises a LCVR comprising an amino acid sequence of SEQ ID NO: 2. In some embodiments, the administered adjuvant anti- PD-1 antibody comprises a HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 / 2. In some embodiments, the administered adjuvant anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain has an amino acid sequence of SEQ ID NO: 9. In some embodiments, the administered adjuvant anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the light chain has an amino acid sequence of SEQ ID NO: 10. In some embodiments, the administered adjuvant anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain has an amino acid sequence of SEQ ID NO: 9 and the light chain has an amino acid sequence of SEQ ID NO: 10. In some embodiments, the administered adjuvant PD-1 inhibitor is an anti-PD-1 antibody comprising a HCVR with 90%, 95%, 97%, or 98% sequence identity to SEQ ID NO: 1. In some embodiments, the administered adjuvant PD-1 inhibitor is an anti-PD-1 antibody comprising a LCVR with 90%, 95%, 97%, or 98% sequence identity to SEQ ID NO: 2. In some embodiments, the administered adjuvant PD-1 inhibitor is an anti-PD-1 antibody comprising a HCVR with 90%, 95%, 97%, or 98% sequence identity to SEQ ID NO: 1, and a LCVR with 90%, 95%, 97%, or 98% sequence identity to SEQ ID NO: 2.

[0014] In some embodiments, the method further comprises administering to the patient an additional therapeutic agent or therapy selected from one or more of: an anti-viral therapy, photodynamic therapy, a programmed death ligand 1 (PD-L1) inhibitor, a lymphocyte activation gene 3 (LAG3) inhibitor, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, a glucocorticoid-induced tumor necrosis factor receptor (GITR) agonist, a T-cell immunoglobulin and mucin containing -3 (TIM3) inhibitor, a B- and T-lymphocyte attenuator (BTLA) inhibitor, a T-cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor, a CD38 inhibitor, a CD47 inhibitor, an antagonist of another T-cell co-inhibitor or ligand, a CD20 inhibitor, an indoleamine-2,3- dioxygenase (IDO) inhibitor, a CD28 activator, a vascular endothelial growth factor (VEGF) antagonist, an angiopoietin-2 (Ang2) inhibitor, a transforming growth factor beta (TGFp) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an agonist to a co-stimulatory receptor, an antibody to a tumor-specific antigen, a vaccine, an adjuvant to increase antigen presentation, an oncolytic virus, a cytotoxin, a chemotherapeutic agent, platinum-based chemotherapy, a tyrosine kinase inhibitor, an IL-6R inhibitor, an IL-4R inhibitor, an IL-10 inhibitor, a cytokine, an antibody drug conjugate (ADC), chimeric antigen receptor T cells, an anti-inflammatory drug, and a dietarysupplement.

[0015] In some embodiments, the neoadjuvant PD-1 inhibitor is administered as one or more doses, wherein each dose is administered every two weeks, three weeks, four weeks, five weeks or six weeks. In some embodiments, the neoadjuvant PD-1 inhibitor is administered as two or more doses, wherein each dose is administered every three weeks. In some embodiments, the neoadjuvant PD-1 inhibitor is administered at a dose of 5 mg to 1000 mg. In some embodiments, the neoadjuvant PD-1 inhibitor is administered at a dose of 200 mg, 250 mg, 350 mg, 400 mg, 500 mg, 600 mg, 750 mg, 800 mg, or 1000 mg. In some embodiments, the neoadjuvant PD-1 inhibitor is administered at a dose of 1 mg / kg to 20 mg / kg of the patient’s body weight. In some embodiments, the neoadjuvant PD-1 inhibitor is administered at a dose of 1 mg / kg, 3 mg / kg or 10 mg / kg of the patient’s body weight. In some embodiments, the neoadjuvant PD-1 inhibitor and / or the adjuvant PD-1 inhibitor is administered intravenously, or subcutaneously.

[0016] In some embodiments, the radiation therapy is administered prior to the PD-1 inhibitor. In some embodiments, the radiation therapy is SBRT. In some embodiments, the radiation therapy is low-dose SBRT. In some embodiments, the radiation therapy is administered one week prior to the PD-1 inhibitor.DETAILED DESCRIPTION

[0017] It is to be understood that the present disclosure is not limited to the particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, and that the scope of the present disclosure will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, preferred methods and materials are now described. All publications mentioned herein are hereby incorporated by reference in their entirety unless otherwise stated.Methods of Treating or Inhibiting Growth of Cancer

[0018] The present disclosure includes methods for treating or inhibiting the growth of a tumor comprising selecting a patient with cancer, such as liver cancer, lung cancer, or head and neck cancer, and administering to the patient in need thereof a PD-1 inhibitor (e.g., cemiplimab or a bioequivalent thereof), wherein the PD-1 inhibitor is administered in combination with neoadjuvant radiation (e.g., stereotactic body radiation therapy (SBRT)) or an anti-LAG-3 antibody (e.g.,fianlimab or a bioequivalent thereof) prior to treating the patient with surgery (e.g., hepatic resection). In certain embodiments, the disclosed methods further include administering to the subject a PD-1 inhibitor (e.g., cemplimab or a bioequivalent thereof) as an adjuvant therapy after completion of surgery for treating the cancer (e.g., liver cancer, lung cancer, or head and neck cancer). In certain embodiments, the disclosed methods include administering to a subject in need thereof a combination of a PD-1 inhibitor (e.g., cemplimab or a bioequivalent thereof) and radiation as a neoadjuvant treatment prior to planned surgery for treating cancer (e.g., liver cancer, lung cancer, or head and neck cancer), and subsequently administering to the patient a PD-1 inhibitor as adjuvant therapy post-surgery. In certain embodiments, the disclosed methods include administering to a subject in need thereof a combination of a PD-1 inhibitor (e.g., cemplimab or a bioequivalent thereof) and an anti-LAG-3 antibody as a neoadjuvant treatment prior to planned surgery for treating cancer (e.g., liver cancer, lung cancer, or head and neck cancer), and subsequently administering to the patient a PD-1 inhibitor as adjuvant therapy post-surgery. In certain embodiments, the neoadjuvant radiation therapy is administered prior to the administration of the PD-1 inhibitor. For example, the radiation therapy may be administered one day, two days, three days, four days, five days, six days, one week or more prior to the PD-1 inhibitor.

[0019] As used herein, “liver cancer” refers to cancer of the liver, such as hepatocellular carcinoma, fibrolamellar carcinoma, cholangiocarcinoma, angiosarcoma, and hepatoblastoma. In some embodiments, the liver cancer is hepatocellular carcinoma (HCC). In some embodiments, the liver cancer is resectable and recurrent. In some embodiments, the liver cancer is metastatic. In some embodiments, the patient is a surgical candidate for resection of the liver cancer tumor. In some embodiments, the patient has liver cancer for which the intent of surgery would be curative.

[0020] As used herein, “lung cancer” refers to cancer of the lung, such as non-small cell lung cancer (NSCLC) (e.g., advanced NSCLC, stage 111 B, stage I IIC, or stage IV squamous or non- squamous NSCLC, adenocarcinoma, squamous cell carcinoma, or large cell carcinoma), adenosquamous carcinoma, and sarcomatoid carcinoma. In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the lung cancer is squamous non-small cell lung cancer. In some embodiments, the lung cancer is non-squamous non-small cell lung cancer. In some embodiments, the lung cancer is locally advanced, recurrent or metastatic lung cancer.

[0021] As used herein, the term “head and neck cancer” refers to cancer of the mouth, sinuses, nose or throat - e.g., head and neck squamous cell carcinoma (HNSCC).

[0022] As used herein, the terms “treating”, “treat”, or the like, mean to alleviate or reduce the severity of at least one symptom or indication, to eliminate the causation of symptoms either on a temporary or permanent basis, to delay or inhibit tumor growth, to reduce tumor cell load or tumor burden, to promote tumor regression, to cause tumor shrinkage, necrosis and / ordisappearance, to prevent tumor recurrence, to prevent or inhibit metastasis, to inhibit metastatic tumor growth, to eliminate the need for surgery, and / or to increase duration of survival of the subject. In many embodiments, the terms “tumor”, “lesion,” “tumor lesion,” “cancer,” and “malignancy” are used interchangeably and refer to one or more cancerous growths.

[0023] As used herein, the term “recurrent” refers to a frequent or repeated diagnosis of liver cancer, lung cancer, or head and neck cancer in a patient or a frequent or repeated occurrence of individual tumors, such as primary tumors and / or new tumors that may represent recurrence of a prior tumor. In certain embodiments, administration of the PD-1 inhibitor inhibits the recurrence of a liver cancer, lung cancer, or head and neck cancer tumor in the patient.

[0024] As used herein, the expression “a subject in need thereof” means a human or non-human mammal that exhibits one or more symptoms or indications of liver cancer, lung cancer, or head and neck cancer), and / or who has been diagnosed with liver cancer, lung cancer, or head and neck cancer, and who needs treatment for the same. In many embodiments, the terms “subject” and “patient” are used interchangeably. The expression includes subjects with primary, established, or recurrent tumors (advanced malignancies). In specific embodiments, the expression includes human subjects that have and / or need treatment for recurrent but not metastatic liver cancer, lung cancer, or head and neck cancer. In certain embodiments, the expression includes patients with a solid tumor that is resistant to or refractory to or is inadequately controlled by prior therapy (e.g., surgery or treatment with an anti-cancer agent other than cemiplimab or a bioequivalent thereof). In certain embodiments, the expression includes subjects with liver cancer, lung cancer, or head and neck cancer who are candidates for curative surgery.

[0025] In certain embodiments, the methods of the present disclosure are used for treating a subject with a solid tumor. As used herein, the term “solid tumor” refers to an abnormal mass of tissue that usually does not contain cysts or liquid areas. Solid tumors may be benign (not cancer) or malignant (cancer). For the purposes of the present disclosure, the term “solid tumor” means malignant solid tumors. The term includes different types of solid tumors named for the cell types that form them, viz. sarcomas, carcinomas and blastomas.

[0026] In certain embodiments, the disclosed methods include administering a therapeutically effective amount of a PD-1 inhibitor (e.g., cemplimab or a bioequivalent thereof) in combination with an additional therapeutic agent or therapy. The additional therapeutic agent or therapy may be administered for increasing anti-tumor efficacy, for reducing toxic effects of one or more therapies and / or for reducing the dosage of one or more therapies. In various embodiments, the additional therapeutic agent or therapy may include one or more of: an anti-viral therapy (e.g., cidofovir), photodynamic therapy, a programmed death ligand 1 (PD-L1) inhibitor (e.g., an anti-PD- L1 antibody as disclosed in US 2015 / 0203580 or atezolizumab), a lymphocyte activation gene 3(LAG3) inhibitor (e.g., an anti-LAG3 antibody), a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor (e.g., ipilimumab), a glucocorticoid-induced tumor necrosis factor receptor (GITR) agonist (e.g., an anti-GITR antibody), a T-cell immunoglobulin and mucin containing -3 (TIM3) inhibitor, a B- and T-lymphocyte attenuator (BTLA) inhibitor, a T-cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor, a CD38 inhibitor, a CD47 inhibitor, an antagonist of another T-cell co-inhibitor or ligand (e.g., an antibody to CD-28, 2B4, LY108, LAIR1 , ICOS, CD160 or VISTA), a CD20 inhibitor (e.g., an anti-CD20 antibody, or a bispecific CD3 / CD20 antibody), an indoleamine- 2,3-dioxygenase (IDO) inhibitor, a CD28 activator, a vascular endothelial growth factor (VEGF) antagonist (e.g., a “VEGF-Trap” such as aflibercept or other VEGF-inhibiting fusion protein as set forth in US 7087411 , or an anti-VEGF antibody or antigen binding fragment thereof (e.g., bevacizumab, or ranibizumab) or a small molecule kinase inhibitor of VEGF receptor (e.g., sunitinib, sorafenib, pazopanib, or ramucirumab)), an angiopoietin-2 (Ang2) inhibitor, a transforming growth factor beta (TGFp) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor (e.g., erlotinib, cetuximab), an agonist to a co-stimulatory receptor (e.g., an agonist to CD28, 4-1 BB, or 0X40), an antibody to a tumor-specific antigen (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), a vaccine (e.g., Bacillus Calmette-Guerin or a cancer vaccine), an adjuvant to increase antigen presentation (e.g., granulocyte-macrophage colony-stimulating factor), an oncolytic virus, a cytotoxin, a chemotherapeutic agent (e.g., pemetrexed, dacarbazine, temozolomide, cyclophosphamide, docetaxel, doxorubicin, daunorubicin, cisplatin, carboplatin, gemcitabine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, topotecan, irinotecan, vinorelbine, and vincristine), platinum-based chemotherapy (e.g., platinum-doublet chemotherapy), a tyrosine kinase inhibitor (e.g., lenvatinib, regorafenib, and cabozantinib), an IL-6R inhibitor, an IL-4R inhibitor, an IL-10 inhibitor, a cytokine such as IL-2, IL-7, IL-12, IL-21 , and IL-15, an antibody drug conjugate (ADC) (e.g., anti-CD19-DM4 ADC, and anti-DS6-DM4 ADC), chimeric antigen receptor T cells (e.g., CD19-targeted T cells), an anti-inflammatory drug such as a corticosteroid, a nonsteroidal anti-inflammatory drug (NSAID), and a dietary supplement such as an antioxidant.

[0027] As used herein, the term “anti-viral therapy” refers to any agent, drug or therapy used to treat, prevent, or ameliorate a viral infection in a host subject, including but not limited to: zidovudine, lamivudine, abacavir, ribavirin, lopinavir, efavirenz, cobicistat, tenofovir, rilpivirine, analgesics, corticosteroids, and combinations thereof. In the context of the present disclosure, chronic viral infections include those caused by viruses, including but not limited to: human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV).

[0028] In certain embodiments, administering to a subject with liver cancer radiation therapy (e.g., SBRT) followed by a therapeutically effective amount of a PD-1 inhibitor (e.g.,cemplimab or a bioequivalent thereof) leads to increased inhibition of tumor growth - e.g., greater tumor regression in the treated subject. In certain embodiments, administering to a subject with liver cancer a therapeutically effective amount of a PD-1 inhibitor (e.g., cemplimab or a bioequivalent thereof) leads to necrosis of the resected tumor, e.g., more than 50% necrosis, more than 60% necrosis, more than 70% necrosis, or more than 80% necrosis. In certain embodiments, administering to a subject with liver cancer radiation therapy (e.g., SBRT) followed by a therapeutically effective amount of a PD-1 inhibitor (e.g., cemplimab or a bioequivalent thereof) leads to increased tumor regression, tumor shrinkage and / or disappearance.

[0029] In certain embodiments, the administration of radiation therapy (e.g., SBRT) in combination with a PD-1 inhibitor leads to one or more of: (i) delay to surgery, e.g., surgery more than 28 days after the end of the cycle of the last dose of neoadjuvant PD-1 inhibitor (e.g., cemplimab or a bioequivalent thereof); (ii) delay in tumor growth and development, e.g., tumor growth may be delayed by about 3 days, more than 3 days, about 7 days, more than 7 days, more than 15 days, more than 1 month, more than 3 months, more than 6 months, more than 1 year, more than 2 years, or more than 3 years in the treated subject, as compared to an untreated subject or a subject treated with surgical resection alone; (iii) increased disease-free survival (DFS) from date of surgery until recurrence of tumor or death, as compared to an untreated subject or a subject treated with surgical resection alone; and (iv) improved overall response rate, complete response, or partial response, as compared to an untreated subject or a subject treated with surgical resection alone. In certain embodiments, administering to a subject with liver cancer radiation therapy followed by a therapeutically effective amount of a PD-1 inhibitor (e.g., cemplimab or a bioequivalent thereof) prevents tumor recurrence and / or increases duration of survival of the subject, e.g., increases duration of survival by more than 15 days, more than 1 month, more than 3 months, more than 6 months, more than 12 months, more than 18 months, more than 24 months, more than 36 months, or more than 48 months as compared to an untreated subject or a subject treated with surgical resection alone. In certain embodiments, administering to a subject with lung cancer or head and neck cancer radiation therapy followed by a therapeutically effective amount of a PD-1 inhibitor (e.g., cemplimab or a bioequivalent thereof) prevents tumor recurrence and / or increases duration of survival of the subject, e.g., increases duration of survival by more than 15 days, more than 1 month, more than 3 months, more than 6 months, more than 12 months, more than 18 months, more than 24 months, more than 36 months, or more than 48 months as compared to an untreated subject or a subject treated with surgical resection alone.

[0030] In certain embodiments, administering to a subject with liver cancer radiation therapy in combination with a therapeutically effective amount of a PD-1 inhibitor (e.g., cemplimab or a bioequivalent thereof) leads to increased overall survival (OS) or progression-free survival(PFS) of the subject as compared to a subject treated with surgical resection alone. In certain embodiments, the radiation therapy is adminsitere prior to the PD-1 inhibitor. In certain embodiments, the PFS is increased by at least one 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 treated with surgical resection alone. In certain embodiments, the OS is increased by at least one 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 treated with surgical resection alone.

[0031] In certain embodiments, administering to a subject with lung cancer or head and neck cancer radiation therapy followed by a therapeutically effective amount of a PD-1 inhibitor (e.g., cemplimab or a bioequivalent thereof) leads to increased overall survival (OS) or progression- free survival (PFS) of the subject as compared to a subject treated with surgical resection alone. In certain embodiments, the PFS is increased by at least one 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 treated with surgical resection alone. In certain embodiments, the OS is increased by at least one 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 treated with surgical resection alone.PD-1 Inhibitors

[0032] The methods disclosed herein include administering a therapeutically effective amount of a PD-1 inhibitor, wherein the PD-1 inhibitor is cemiplimab (also known as REGN2810; LIBTAYO®) or a bioequivalent thereof. As used herein, the term “bioequivalent” refers to anti-PD-1 antibodies or PD-1-binding proteins or fragments thereof that are pharmaceutical equivalents or pharmaceutical alternatives whose rate and / or extent of absorption do not show a significant difference with that of cemiplimab when administered at the same molar dose under similar experimental conditions, either single dose or multiple dose. In the context of the present disclosure, the term “bioequivalent” includes antigen-binding proteins that bind to PD-1 and do not have clinically meaningful differences with cemiplimab with respect to safety, purity and / or potency.

[0033] The term "antibody," as used herein, is intended to refer to immunoglobulin molecules comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds (i.e., "full antibody molecules"), as well as multimers thereof {e.g. IgM) or antigen-binding fragments thereof. Each heavy chain is comprised of a heavy chain variable region (“HCVR” or “VH”) and a heavy chain constant region (comprised of domains CH1 , CH2 and CH3). Each light chain is comprised of a light chain variable region (“LCVR or “VL”) and a light chain constant region (CL). The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1 , CDR1, FR2, CDR2, FR3, CDR3, FR4. In certain embodiments, the FRs of the antibody (or antigen binding fragment thereof) may be identical to the human germline sequences or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs. The term “antibody,” as used herein, also includes antigen-binding fragments of full antibody molecules.

[0034] As used herein, the terms “antigen-binding fragment” of an antibody, “antigenbinding portion” of an antibody, and the like, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and / or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and / or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.

[0035] Non-limiting examples of antigen-binding fragments include: (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 the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigen-binding fragment," as used herein.

[0036] An antigen-binding fragment of an antibody will typically comprise at least one variable domain. The variable domain may be of any size or amino acid composition and will generally comprise at least one CDR which is adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a VHdomain associated with a VLdomain, the V andLdomains may be situated relative to one another in any suitable arrangement. For example, the variable region may be dimeric and contain VH-VH, VH-VL or VL-VL dimers. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric VH or VL domain.

[0037] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting, exemplary configurations of variable and constant domains that may be found within an antigenbinding fragment of an antibody of the present disclosure include: (i) VH-CH1 ; (ii) VH-CH2; (iii) VH- CH3; (iv) VH-CH1-CH2; (V) VH-CH1-CH2-CH3; (vi) VH-CH2-CH3; (vii) VH-CL; (viii) VL-CH1; (ix) VL-CH2; (x) V -CH3; (xi) -CH1-CH2; (xii) VL-CH1-CH2-CH3; (xiii) -CH2-CH3; and (xiv) V -CL. In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region. A hinge region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Moreover, an antigenbinding fragment of an antibody of the present disclosure may comprise a homo-dimer or heterodimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with one another and / or with one or more monomericHor VLdomain (e.g., by disulfide bond(s)).

[0038] The antibodies used in the methods disclosed herein may be human antibodies. As used herein, the term “human antibody” refers to antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the present disclosure may nonetheless include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3. However, the term “human antibody,” as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0039] The antibodies used in the methods disclosed herein may be recombinant human antibodies. As used herein, the term “recombinant human antibody” includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described furtherbelow), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) or antibodies prepared, expressed, created 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. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VHand V regions of the recombinant antibodies are sequences that, while derived from and related to human germline VHand V sequences, may not naturally exist within the human antibody germline repertoire in vivo.

[0040] According to certain embodiments, the PD-1 inhibitor is an anti-PD-1 antibody (e.g., cemiplimab) comprising three heavy chain complementarity determining regions (HCDRs) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and three light chain complementarity determining regions (LCDRs) 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 (e.g., cemiplimab) comprises three HCDRs (HCDR1 , HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. In certain embodiments, the anti-PD-1 antibody (e.g., cemiplimab) comprises an HCVR comprising SEQ ID NO: 1 and an LCVR comprising SEQ ID NO: 2. In certain embodiments, the anti-PD-1 antibody (e.g., cemiplimab) comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.

[0041] According to certain embodiments, a bioequivalent of cemiplimab is an anti-PD-1 antibody comprising a HCVR having 90%, 95%, 97% or 98% sequence identity to SEQ ID NO: 1. According to certain embodiments, a bioequivalent of cemiplimab is an anti-PD-1 antibody comprising a LCVR having 90%, 95%, 97% or 98% sequence identity to SEQ ID NO: 2. According to certain embodiments, a bioequivalent of cemiplimab is an anti-PD-1 antibody comprising a HCVR having 90%, 95%, 97% or 98% sequence identity to SEQ ID NO: 1 , and a LCVR having 90%, 95%, 97% or 98% sequence identity to SEQ ID NO: 2. Sequence identity may be measured by methods known in the art (e.g., GAP, BESTFIT, and BLAST).

[0042] According to certain embodiments, a bioequivalent of cemiplimab is an anti-PD-1antibody comprising a HCVR comprising an amino acid sequence of SEQ ID NO: 1 having no more than 5 amino acid substitutions. According to certain embodiments, a bioequivalent of cemiplimab is an anti-PD-1 antibody comprising a LCVR comprising an amino acid sequence of SEQ ID NO: 2 having no more than 2 amino acid substitutions. According to certain embodiments, a bioequivalent of cemiplimab is an anti-PD-1 antibody comprising a HCVR comprising an amino acid sequence of SEQ ID NO: 1 having no more than 5 amino acid substitutions, and a LCVR comprising an amino acid sequence of SEQ ID NO: 2 having no more than 2 amino acid substitutions.Radiation Therapy

[0043] In some embodiments, the radiation therapy is Stereotactic Body Radiation Therapy (SBRT). SBRT refers to high-precision radiotherapy utilized to focus a radical radiation dose to a tumor part in an in vitro irradiation mode to destroy tumor cell tissues and prevent cancer cells from propagating. As the radiation is strong, the treatment is mainly performed on small and isolated lesions of a tumor. One difference between SBRT and common radiotherapy is that the SBRT is more accurate in positioning and stronger in a single dose. In some embodiments, the radiation therapy (e.g., SBRT) is administered as part of a neoadjuvant therapy for treating or inhibiting the growth of a tumor prior to surgical resection of the tumor. In certain embodiments, the neoadjuvant radiation therapy (e.g., SBRT) is administered prior to the PD-1 inhibitor. For example, the neoadjuvant radiation therapy is administered one day, two days, three days, four days, five days, six days, one week, or more prior to the PD-1 inhibitor.

[0044] In certain embodiments, the radiation therapy disclosed herein is administered in one or more doses. In certain embodiments, each dose of radiation therapy comprises 2 - 100 Gray (Gy), such as 5 Gy, 8 Gy, 10 Gy, 20 Gy, 30 Gy, 40 Gy, 50 Gy, 60 Gy, 70 Gy, 80 Gy, 90 Gy, 100 Gy, 2-10 Gy, or 5-8 Gy. In certain embodiments, the radiation therapy is hypofractionated radiation therapy. In certain embodiments, the radiation therapy comprises 2 - 12 fractions, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 fractions.Combination Therapies

[0045] In general, the methods of the present disclosure include administering a neoadjuvant therapy including a therapeutically effective amount of a PD-1 inhibitor (e.g., cemiplimab) in combination with radiation (e.g., SBRT) or an anti-LAG-3 antibody (e.g., fianlimab) prior to surgery. As used herein, the expression “in combination with” means that a first disclosed neoadjuvant therapy is administered before, after, or concurrently with a second disclosed neoadjuvant therapy. This expression includes sequential or concurrent administration of the neoadjuvant therapies.

[0046] In some embodiments, when the first neoadjuvant therapy is administered “before” the second neoadjuvant therapy, the first neoadjuvant therapy may be administered more than 12 weeks, about 12 weeks, about 11 weeks, about 10 weeks, about 9 weeks, about 8 weeks, about 7 weeks, about 6 weeks, about 5 weeks, about 4 weeks, about 3 weeks, about 2 weeks, about 1 week, about 150 hours, about 100 hours, about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, or about 30 minutes prior to the administration of the second neoadjuvant therapy .

[0047] In some embodiments, when the first neoadjuvant therapy is administered “after” the second neoadjuvant therapy, the first neoadjuvant therapy may be administered about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 5 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, or more than 12 weeks after the administration of the second neoadjuvant therapy.

[0048] As used herein, "concurrent" administration means that the first and second neoadjuvant therapies are administered to the subject in a single dosage form (e.g., co-formulated, as appropriate) or in separate dosage forms administered to the subject within about 30 minutes or less of each other (i.e. , before, after, or at the same time), such as about 15 minutes or less, or about 5 minutes or less. If administered in separate dosage forms, each dosage form may be administered via the same route (e.g., both administered intravenously, subcutaneously, etc.); or, alternatively, each dosage form may be administered via a different route. In any event, administering the neoadjuvant therapies in a single dosage from, in separate dosage forms by the same route, or in separate dosage forms by different routes are all considered "concurrent” administration" for purposes of the present disclosure. As used herein, “sequential” administration means that each dose of a selected neoadjuvant therapy is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks, or months).Pharmaceutical Compositions and Administration

[0049] The present disclosure provides therapeutic pharmaceutical compositions comprising the PD-1 inhibitors disclosed herein. Such pharmaceutical compositions may be formulated with suitable pharmaceutically acceptable carriers, excipients, buffers, and other agents that provide suitable transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al., "Compendium of excipients for parenteral formulations" PDA, J Pharm Sci Technol 52:238-311 (1998).

[0050] The dose of PD-1 inhibitor (e.g., anti-PD-1 antibody) may vary depending upon the age and the size of a subject to be administered, target disease, conditions, route of administration, and the like. When a PD-1 inhibitor of the present disclosure is used for treating or inhibiting the growth of liver cancer, lung cancer, or head and neck cancer, it may be advantageous to administer the PD-1 inhibitor at a single dose of about 0.1 to about 100 mg / kg body weight. Depending on the severity of the condition, the frequency and the duration of the treatment can be adjusted. In certain embodiments, the PD-1 inhibitor of the present disclosure can be administered as an initial dose of at least about 0.1 mg to about 800 mg, about 1 to about 1000 mg, about 1 to about 800 mg, about 5 to about 500 mg, or about 10 to about 400 mg. In certain embodiments, the initial dose may be followed by administration of a second or a plurality of subsequent doses of the PD-1 inhibitor in an amount that can be approximately the same or less than that of the initial dose, wherein the subsequent doses are separated by at least 1 day to 3 days; at least one week, at least 2 weeks; at least 3 weeks; at least 4 weeks; at least 5 weeks; at least 6 weeks; at least 7 weeks; at least 8 weeks; at least 9 weeks; at least 10 weeks; at least 12 weeks; or at least 14 weeks.

[0051] Various delivery systems are known and can be used to administer the pharmaceutical composition of the disclosure, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor mediated endocytosis (see, e.g., Wu et al. (1987) J. Biol. Chem. 262:4429-4432). Methods of introduction include, but are not limited to, intradermal, transdermal, intramuscular, intravenous, subcutaneous, intranasal, epidural and oral routes. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. The pharmaceutical composition can be also delivered in a vesicle, in particular a liposome (see, e.g., Langer (1990) Science 249:1527-1533).

[0052] The use of nanoparticles to deliver the PD-1 inhibitor of the present disclosure is also contemplated herein. Antibody-conjugated nanoparticles may be used both for therapeutic and diagnostic applications. Antibody-conjugated nanoparticles and methods of preparation and use are described in detail by Arruebo et al., 2009, “Antibody-conjugated nanoparticles for biomedical applications,” J. Nanomat., Vol. 2009, Article ID 439389, 24 pages. Nanoparticles may bedeveloped and conjugated to antibodies contained in pharmaceutical compositions to target cells. Nanoparticles for drug delivery have also been described in, for example, US 8257740 or US 8246995.

[0053] In certain situations, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump may be used. In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in proximity of the composition’s target, thus requiring only a fraction of the systemic dose.

[0054] The injectable preparations may include dosage forms for intravenous, subcutaneous, intracranial, and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by methods publicly known.

[0055] A pharmaceutical composition of the present disclosure can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, with respect to subcutaneous delivery, a pen delivery device readily has applications in delivering a pharmaceutical composition of the present disclosure. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0056] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc. The amount of the antibody contained is generally about 5 to about 1000 mg per dosage form in a unit dose, such as about 5 to about 600 mg, about 5 to about 350 mg, or about 10 to about 300 mg.

[0057] In certain embodiments, the present disclosure provides a pharmaceutical composition or formulation comprising a therapeutic amount of a PD-1 inhibitor (e.g., cemplimab or a bioequivalent thereof) and a pharmaceutically acceptable carrier. Non-limiting examples of pharmaceutical compositions comprising an anti-PD-1 antibody provided herein that can be used in the context of the present disclosure are disclosed in US 2019 / 0040137.

[0058] The present disclosure also provides kits comprising a PD-1 inhibitor (e.g., cemplimab or a bioequivalent thereof) for therapeutic uses as described herein. Kits typicallyinclude a label indicating the intended use of the contents of the kit and instructions for use. As used herein, the term “label” includes any writing, or recorded material supplied on, in or with the kit, or which otherwise accompanies the kit. Accordingly, this disclosure provides a kit for treating a patient afflicted with liver cancer, lung cancer, or head and neck cancer, the kit comprising: (a) a therapeutically effective dosage of a PD-1 inhibitor (e.g., cemplimab or a bioequivalent thereof); and (b) instructions for using the PD-1 inhibitor in any of the methods disclosed herein.Administration Regimens

[0059] In certain embodiments, the methods disclosed herein include administering to the tumor of a subject in need thereof a therapeutically effective amount of a PD-1 inhibitor (e.g., cemiplimab or a bioequivalent thereof) in multiple doses, e.g., as part of a specific therapeutic dosing regimen. For example, the therapeutic dosing regimen may comprise administering one or more doses of a PD-1 inhibitor to the subject at a frequency of about once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, once a month, once every two months, once every three months, once every four months, twice a day, twice every two days, twice every three days, twice every four days, twice every five days, twice every six days, twice a week, twice every two weeks, twice every three weeks, twice every four weeks, twice every five weeks, twice every six weeks, twice every eight weeks, twice every twelve weeks, twice a month, twice every two months, twice every three months, twice every four months, three times a day, three times every two days, three times every three days, three times every four days, three times every five days, three times every six days, three times a week, three times every two weeks, three times every three weeks, three times every four weeks, three times every five weeks, three times every six weeks, three times every eight weeks, three times every twelve weeks, three times a month, three times every two months, three times every three months, three times every four months or less frequently or as needed so long as a therapeutic response is achieved. In one embodiment, one or more doses of the PD-1 inhibitor are administered as a neoadjuvant once every three weeks. In one embodiment, one or more doses of the PD-1 inhibitor are administered as a post-surgery adjuvant once every three weeks.

[0060] In certain embodiments, the one or more doses are administered in at least one treatment cycle - e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 treatment cycles. The methods, according to this aspect, comprise administering to a subject in need thereof at least one neoadjuvant treatment cycle, and optionally at least one adjuvant treatment cycle, each 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., cemplimab or abioequivalent thereof). 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 of the patient’s body weight. In certain embodiments, each dose comprises 5 - 1000 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, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 mg or more of the PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is administered in 2 neoadjuvant treatment cycles. In some embodiments, the PD-inhibitor is further administered in 8 post-surgery adjuvant treatment cycles. In some embodiments, neoadjuvant treatment comprises 2 treatment cycles, each cycle comprising 1 dose (e.g., 350 mg Q3W) of the PD-1 inhibitor. In some embodiments, adjuvant treatment comprises 8 treatment cycles, each cycle comprising 1 dose (e.g., 350 mg Q3W) of the PD-1 inhibitor.Dosage

[0061] The amount of PD-1 inhibitor (e.g., cemiplimab or a bioequivalent thereof) administered to a subject according to the methods disclosed herein is, generally, a therapeutically effective amount. As used herein, the term "therapeutically effective amount" means an amount of a PD-1 inhibitor administered as a neoadjuvant prior to planned surgery for treating liver cancer, lung cancer, or head and neck cancer that results in one or more of: (a) inhibition of tumor growth, or an increase in tumor necrosis, tumor shrinkage and / or tumor disappearance; (b) a reduction in the severity or duration of a symptom or an indication of the cancer - e.g., a tumor lesion; (c) delay in tumor growth and development; (d) inhibition of tumor metastasis; (e) prevention of recurrence of tumor growth; (f) increase in survival of a subject with the cancer; and / or (g) delay of surgery, each as compared to an untreated subject or a subject treated with surgical resection alone.

[0062] In certain embodiments, a therapeutically effective amount of the PD-1 inhibitor (e.g., cemplimab or a bioequivalent thereof) can be from about 0.05 mg to about 1000 mg, from about 1 mg to about 800 mg, from about 5 mg to about 600 mg, from about 10 mg to about 550 mg, from about 50 mg to about 400 mg, from about 75 mg to about 350 mg, or from about 100 mg to about 300 mg of the antibody. For example, in various embodiments, the amount of the PD-1 inhibitor is about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, 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, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, or about 1000 mg.

[0063] The amount of a PD-1 inhibitor (e.g., cemplimab or a bioequivalent thereof) contained within an individual dose may be expressed in terms of milligrams of antibody per kilogram of subject body weight ( / .e., mg / kg). In certain embodiments, the PD-1 inhibitor used in the methods disclosed herein may be administered to a subject at a dose of about 0.0001 to about 100 mg / kg of subject body weight. In certain embodiments, an anti-PD-1 antibody may be administered at dose of about 0.1 mg / kg to about 20 mg / kg of a patient’s body weight. In certain embodiments, the methods of the present disclosure comprise administration of a PD-1 inhibitor (e.g., an anti-PD- 1 antibody) at a dose of about 1 mg / kg to 3 mg / kg, 1 mg / kg to 5 mg / kg, 1 mg / kg to 10 mg / kg, 1 mg / kg, 3 mg / kg, 5 mg / kg, or 10 mg / kg of a patient’s body weight.

[0064] In certain embodiments, an individual dose amount of a PD-1 inhibitor (e.g., cemplimab or a bioequivalent thereof) administered to a patient may be less than a therapeutically effective amount, i.e., a subtherapeutic dose. For example, if the therapeutically effective amount of a PD-1 inhibitor comprises 3 mg / kg, a subtherapeutic dose comprises an amount less than 3 mg / kg, e.g., 2 mg / kg, 1.5 mg / kg, 1 mg / kg, 0.5 mg / kg or 0.3 mg / kg. As defined herein, a “subtherapeutic dose” refers to an amount of the PD-1 inhibitor that does not lead to a therapeutic effect by itself. However, in certain embodiments, multiple subtherapeutic doses of a PD-1 inhibitor are administered to collectively achieve a therapeutic effect in the subject.

[0065] In certain embodiments, each dose comprises 0.1 - 10 mg / kg (e.g., 0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg) of PD-1 inhibitor (e.g., cemplimab or a bioequivalent thereof) based on the subject’s body weight. In certain other embodiments, each dose comprises 5 to 600 mg of the PD-1 inhibitor, e.g., 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 45 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg of the PD-1 inhibitor.

[0066] In one embodiment, a therapeutically effective amount of PD-1 inhibitor (e.g., cemiplimab or a bioequivalent thereof) is 350 mg intravenously administered as neoadjuvant treatment in combination with neoadjuvant radiation therapy prior to planned surgery for livercancer, lung cancer, or head and neck cancer. In some embodiments, another therapeutically effective amount of PD-1 inhibitor (e.g., cemiplimab or a bioequivalent thereof) is 350 mg intravenously administered as an adjuvant treatment after surgery.EXAMPLES

[0067] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the present disclosure and are not intended to limit the scope of what the inventors regard as their invention. Likewise, the disclosure is not limited to any particular preferred embodiments described herein. Indeed, modifications and variations of the embodiments may be apparent to those skilled in the art upon reading this specification and can be made without departing from its spirit and scope. Efforts have been made to ensure accuracy with respect to numbers used e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Centigrade, room temperature is about 25°C, and pressure is at or near atmospheric.Example 1 : Clinical Trial of Neoadjuvant Cemiplimab for the Treatment of Resectable NSCLC, HCC, and HNSCC

[0068] This study is a phase 2a, multi-cohort study of neoadjuvant cemiplimab for the treatment of resectable non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), and head and neck squamous cell carcinoma (HNSCC), and neoadjuvant cemiplimab with or without chemotherapy for NSCLC.

[0069] Cemiplimab is a fully human monoclonal anti-PD-1 antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 9 and a light chain having the amino acid sequence of SEQ ID NO: 10; an HCVR / LCVR amino acid sequence pair comprising SEQ ID NOs: 1 / 2; and heavy and light chain CDR sequences comprising SEQ ID NOs: 3-8, as described herein. See also US 9987500. Fianlimab (REGN3767) s a fully human, hinge-stabilized lgG4 monoclonal antibody (mAb) that binds with high affinity to lymphocyte activation gene-3 (LAG-3) and blocks this pathway of inhibitory T-cell signaling (Burova et al 2019, Mol. Cancer Then; US 10,358,495).

[0070] Open-label cemiplimab will be supplied as a liquid in sterile, single-use vials that will display the product lot number on the label. Each vial will contain cemiplimab at a concentration of 50 mg / mL. Open-label fianlimab will be supplied in single-use vials. Fianlimab (REGN3767) and cemiplimab (REGN2810) vials will display the product lot number on the label. Fianlimab andcemiplimab will be refrigerated at the site at a temperature of 2°C to 8°C, and refrigerator temperature will be logged daily.

[0071] Objectives: The primary objective of the study is to evaluate the clinical activity of neoadjuvant cemiplimab therapy (with or without chemotherapy, stereotactic body radiation therapy (SBRT), or fianlimab) in patients with resectable NSCLC, HCC, and HNSCC lesions, as measured by pathological evaluations of resected tumors: Cohorts A1 , A2, A3 (NSCLC): to evaluate major pathologic response (MPR); Cohort B, B2, B3 (HCC): to evaluate significant tumor necrosis (STN); Cohort C (HNSCC): to evaluate major treatment effect (MTE). Other objectives of the study include: to assess the anti-tumor activity of neoadjuvant and adjuvant cemiplimab therapy (with or without chemotherapy, SBRT, or fianlimab) as defined by cohort specific treatment criteria; to determine the safety and tolerability of neoadjuvant and adjuvant cemiplimab therapy (with or without chemotherapy, SBRT or fianlimab) including delay to surgery; and to assess the change in tumorinfiltrating CD8 T-cell density and to explore the correlation to the pathological response to therapy.

[0072] In cohort B2, neoadjuvant SBRT will be performed prior to administration of cemiplimab. In HCC, SBRT is effective with 3-year local control rates of approximately 90%, but the 3-year progression free survival is approximately 40% primarily due to out of field progression from micrometastatic disease (Takeda, 2016). It is expected that the addition of cemiplimab following SBRT will mitigate out of field progression via enhancement of a systemic anti-tumor immune response. Tumors treated with radiation release neoantigens, danger-associated molecular patterns and cytokines which may facilitate generation of cell mediated immunity, including tumor specific cytotoxic lymphocytes that mediate anti-tumor effects on both irradiated and non-irradiated lesions (Ngwa, 2018). However, incidences of abscopal responses with radiation alone are historically anecdotal, which may relate to multiple factors that contribute to suppression of an effective systemic anti-tumor response, including radiation-induced upregulation of PD-L1 (Abuodeh, 2016; Deng, 2014). Immune checkpoint blockade may counteract this upregulation, facilitating a sustained adaptive immune response to both the primary tumor and metastatic lesions. This is supported by preclinical data which has demonstrated that PD-1 blockade following radiotherapy mediates a potent and durable anti-tumor and abscopal response associated with an increase in intra-tumoral density of polyfunctional CD8 T cells (Wei, 2021). Notably, sequencing of PD-1 blockade following radiation was found to be a key factor to induction of abscopal responses, which were not observed when PD-1 blockade was administered prior to radiation. Administration of anti-PD-1 antibodies prior to radiation abrogated the systemic immune response due to increased radiosensitivity of intra-tumoral CD8+ T cells following PD-1 blockade. Thus, in cohort B2, SBRT will be administered prior to cemiplimab in order to maximize the potential synergy of thiscombination therapy. A dosing regimen of 8 Gy X 3 fractions (below the upper limit set by Vanpouille-Box et al.) was selected for cohort B2.

[0073] In cohort B3, the activity of the combination of fianlimab and cemiplimab as neoadjuvant and adjuvant therapy in patients with resectable HCC will be evaluated, with the goal of improving response rates. Clinical and correlative results from this cohort can be compared with observations in cohorts B and B2.

[0074] LAG-3 is detected in tumor infiltrating lymphocytes (TIL) of untreated HCC at higher levels than that of surrounding normal liver (Guo, 2020). Increased expression of LAG. -3 in HCC is associated with increased relapse after hepatectomy. Furthermore, the liver is an immune tolerant organ primed for LAG-3 immune suppression due to high expression of LAG-3 ligand, fibrogen-like protein 1 (FGL-1), which is also detected at high levels in HCC (Guo, 2020). Data for cohort B has demonstrated that administration of cemiplimab is associated with upregulation of immune checkpoint proteins, including PD-1 and LAG-3 in a proportion of patients with HCC and it is expected that the combination of fianlimab and cemiplimab will broaden and deepen the response when used as neoadjuvant therapy and further decrease relapse rates when used in the adjuvant setting (Marron, 2022).

[0075] One of the exploratory objectives of this trial is to create dynamic cellular and molecular profiles of the effect of cemiplimab with or without fianlimab, to characterize the effect of PD-1 blockade (and chemotherapy for the NSCLC cohorts, and LAG-3 blockade in HCC cohort B3) on the TME in responders and non-responders. This will allow for evaluation of mechanisms of response, non-response, and / or relapse. These dynamic cellular and molecular profiles will include longitudinal analyses of the tumor and its microenvironment across two transitional stages: after neoadjuvant treatment, and upon recurrence in patients who relapse. An array of high-dimensional assays will be utilized to characterize tumor, stromal, and immune components of tumors at the radiologic (organ), tissue, cellular, genomic, transcriptomic, and protein levels, with emphasis on single-cell data. The resulting datasets from analysis of resected tumors, biopsies, and blood taken during the trial will be assembled in a multidimensional framework to allow questioning of markers in relation to clinical features and mechanistic changes; this information will aid in rational clinical trial design moving forward, specifically rational combinatorial approaches.

[0076] Study Endpoints: The primary endpoint of this study is the clinical efficacy of neoadjuvant therapy in patients with resectable NSCLC, HCC, and HNSCC lesions, as defined below:• Cohort A1, A2, and A3 (NSCLC): MPR at time of surgery is the primary endpoint for the NSCLC cohort. MPR defined as <10% viable tumor within resection, at time of surgery is the primary endpoint for the NSCLC cohort.• Cohort B, B2, B3 (HCC): STN at time of surgery is the primary endpoint for the HCC cohorts. STN defined as >70% necrosis of the tumor, based on pathologic analysis of gross tumor resection, at time of surgery is the primary endpoint for the HCC cohorts.• Cohort C (HNSCC): MTE at time of surgery is the primary endpoint for the HNSCC cohort. MTE defined as tumor necrosis and / or giant cell / histiocytic reaction to keratinous debris in >70% of the pre-treatment tumor area, at time of surgery is the primary endpoint for the HNSCC cohort.

[0077] The secondary endpoints are:• Delay to surgery is defined as surgery >28 days following the end of the second cycle of cohort specific neoadjuvant therapy• Event-free survival (EFS) defined as the time from the first study treatment to the date of disease progression that precluded definitive surgery, or recurrence of tumor after successful surgery, or death from any cause.• Disease-free survival (DFS) defined as the time from date of surgery until recurrence of tumor or death from any cause after successful surgery and recovery• ORR defined as the percent of patients with a CR or PR documented by the Investigator per RECIST 1.1 (Eisenhauer 2009), where confirmation of CR or PR is not required. Patients who are not evaluable for response will be considered as non-responders• OS defined as the time from the first study treatment and date of death for any reason• OS rate at 12 months, 18, 24, 36, 48, and 60 months• The incidence of TEAEs (including perioperative complications), imAEs, SAEs, deaths, laboratory abnormalities (Grade 3 or higher per Common Terminology Criteria for Adverse Events [CTCAE V5.0])• Change in tumor-infiltrating CD8 T-cell density, defined as the change from baseline to the time of surgery

[0078] Demographic and Baseline Characteristics: Baseline characteristics will include standard demography (e.g., age, race, weight, height, etc.), disease characteristics including medical history, and medication history for each patient.

[0079] Efficacy Variables: The efficacy variables include pathological evaluation of resected tumors:• For NSCLC: MPR defined as <10% viable tumor within resection. MPR is a surrogate for clinical benefit developed and validated with previous NSCLC, neoadjuvant chemotherapy studies (Hellman, 2014) (Pataer, 2012).• For HCC: STN defined as >70% necrosis of the tumor, based on pathologic analysis of gross tumor resection. Tumor necrosis of >70% of tumor has been shown in HCC to correlate with clinical outcome (Allard, 2015).• For HNSCC: MTE is defined as tumor necrosis and / or giant cell / histiocytic reaction to keratinous debris in >70% of the pre-treatment tumor area.

[0080] Study Design: Eligible patients with a known diagnosis of resectable NSCLC, HCC, or HNSCC will be enrolled in the following cohorts.

[0081] Cohort A1 : Cohort A1 will enroll approximately 21 NSCLC patients to receive cemiplimab 350 mg every 3 weeks (Q3W) X 2 cycles in the neoadjuvant setting, followed by adjuvant therapy with 8 cycles of cemiplimab therapy along with 4 cycles of standard platinum- doublet chemotherapy.

[0082] Cohort A2: Cohort A2 will enroll approximately 21 NSCLC patients to receive 2 cycles of neoadjuvant and 2 cycles of adjuvant combination platinum-doublet chemotherapyimmunotherapy (cemiplimab 350 mg Q3W), followed by 6 additional cycles of cemiplimab monotherapy. All patients will receive a total of 4 cycles of split standard platinum-doublet chemotherapy, 2 in the neoadjuvant setting and 2 following surgery.

[0083] Cohort A3: Prior to PA3, cohort A3 was planned to enroll approximately 10 NSCLC patients to receive 2 cycles of neoadjuvant platinum-doublet chemotherapy, 2 additional cycles of adjuvant combination platinum-doublet chemotherapy-immunotherapy (cemiplimab 350 mg Q3W) followed by 6 additional cycles of adjuvant cemiplimab. All patients received a total of 4 cycles of split, standard platinum-doublet chemotherapy, 2 in the neoadjuvant setting and 2 following surgery.

[0084] Cohort B: Cohort B will enroll approximately 21 HCC patients to receive neoadjuvant cemiplimab 350 mg Q3WX 2 cycles before surgery. In the adjuvant setting, patients will be administered 8 cycles of cemiplimab Q3W.

[0085] Cohort B2: Cohort B2 will enroll approximately 21 HCC patients to receive neoadjuvant SBRT 8 Gy X 3 fractions over 1 week, followed by cemiplimab 350 mg Q3W for 2 cycles before surgery. In the adjuvant setting, patients will be administered 8 cycles of cemiplimab 350 mg IV Q3W.

[0086] Cohort B3: Cohort B3 will enroll approximately 21 HCC patient to receive neoadjuvant cemiplimab 350 mg Q3W and fianlimab 1600 mg X 2 cycles before surgery. In the adjuvant setting, patients will be administered 8 cycles of cemiplimab plus fianlimab Q3W.

[0087] Cohort C: Cohort C was planned to enroll approximately 21 HNSCC patients to receive neoadjuvant cemiplimab 350 mg Q3WX 2 cycles before surgery. Following surgery, patients received standard adjuvant chemotherapy and / or radiation. After the standard adjuvant therapy, patients received 8 cycles of adjuvant cemiplimab Q3W treatment.

[0088] Neoadjuvant Therapy: Patients enrolled into cohorts A1, A2, and B will receive 2 doses of cemiplimab 350 mg IV Q3W before surgery. Patients will be observed for 1 hour followingadministration of cemiplimab, with vital signs monitored at the initiation of the infusion and completion of the infusion. The target administration is 2 doses, dosed 21 days apart before the time of surgery. Patients in cohort A2 will receive platinum-doublet chemotherapy the same day as cemiplimab is administered. Patients enrolled into cohort B2 will receive SBRT 8 Gy X 3 fractions over 1 week, followed by cemiplimab 350 mg Q3Wfor 2 cycles. Patients in cohort B3 will receive 2 doses of cemiplimab 350 mg Q3W IV combined with 2 doses fianlimab 1600 mg Q3W IV before surgery. Patients in cohort A3 received standard platinum-doublet on the Q3W dosing schedule without neoadjuvant cemiplimab. Patients enrolled into cohort C received 2 doses of cemiplimab 350 mg IV Q3W before surgery. Patients were observed for 1 hour following administration of cemiplimab, with vital signs monitored at the initiation of the infusion and completion of the infusion. The target administration was 2 doses, dosed 21 days apart before the time of surgery.

[0089] Neoadjuvant Therapy for NSCLC Cohort: Given the recent studies in which combination chemo-immunotherapy has demonstrated survival advantage over chemotherapy alone, as well as survival rates higher than that seen in PD-1 blockade monotherapy trials, current study will have cohorts assessing the effect of both immunotherapy (cohort A1) and chemoimmunotherapy in the neoadjuvant setting (cohort A2).

[0090] All patients enrolling in cohort A2 will receive a total of 4 cycles of split, standard chemotherapy, 2 in the neoadjuvant setting and 2 following surgery. Cohort A2 will receive 2 cycles of neoadjuvant and 2 cycles of adjuvant combination chemo-immunotherapy, followed by 6 additional cycles of cemiplimab monotherapy. Depending on the comorbidities and organ function of the patient, the Investigator may opt to give carboplatin in lieu of cisplatin, and / or nab-paclitaxel in lieu of paclitaxel, if it is in the best interest of the patient, as is standard clinical practice.

[0091] All patients enrolled in cohort A3 also received a total of 4 cycles of split, standard chemotherapy as described above. Cohort A3 was planned to enroll only approximately 10 patients to allow for comparison of the exploratory endpoints; this cohort received standard therapy during the neoadjuvant period, and as such was not powered to be evaluable for the primary endpoint. This cohort was planned to smaller to enrich for allotment of patients to the experimental arms. Cohort A3 received only neoadjuvant chemotherapy, but this group received 2 additional cycles of adjuvant chemotherapy alongside 8 cycles of adjuvant cemiplimab following surgery (to ensure potential benefit over standard of care for all trial patients).

[0092] Neoadjuvant Therapy for HCC Cohort B2: Patients enrolled into cohort B2 will receive SBRT 8 Gy X 3 fractions over 1 week, followed by cemiplimab 350 mg Q3W for 2 cycles. The timing of the delivery of the 3 fractions of SBRT within the 1 week period will be at the discretion of the treating physician. Cemiplimab administration should begin at least 24 hours after the last fraction is completed.

[0093] Neoadjuvant Therapy for HCC in Cohort B3: Patients in cohort B3 will receive fianlimab 1600 mg IV combined with cemiplimab 350 mg IV Q3Wfor 2 cycles before surgery. The sequence of study drug administration will be fianlimab first followed by cemiplimab on the same day. Vital signs will be monitored at the initiation of fianlimab infusion, the initiation of cemiplimab infusion, and at the end of cemiplimab infusion. Patients will be observed for 1 hour following administration of cemiplimab.

[0094] Surgery After Neoadjuvant Therapy: The study design calls for 2 doses of cemiplimab and / or platinum-doublet chemotherapy or fianlimab (cohort B3) to be administered during the neoadjuvant period 21 days apart. Surgery should generally be scheduled for 4-6 weeks following the first dose of neoadjuvant cemiplimab for all cohorts. If a patient’s tumor morbidity does not allow for delayed surgery long enough to receive their second dose of cemiplimab alone with or fianlimab (cohort B3), they may proceed to surgery as early as 14 days following their first dose of cemiplimab alone or with fianlimab (cohort B3) (applied to chemotherapy for cohort A3 prior to activation of PA3). For patients who receive 2 cycles of planned cemiplimab alone or with fianlimab, surgery should occur at least 1 day after the second dose of cemiplimab, and for patients receiving chemotherapy, upon blood-count recovery from the most recent cycle of chemotherapy. Given the relatively small benefit derived from neoadj uvant / adjuvant chemotherapy alone in patients with NSCLC, and the high likelihood of recurrence in these patients and in HCC patients who will receive no adjuvant chemotherapy or radiation, all NSCLC and HCC patients will be given 8 additional cycles of cemiplimab alone or in combination with fianlimab (cohort B3), Q3W, following recovery from surgery. All HNSCC patients will receive the same 8 additional cycles of cemiplimab following completion of standard-of-care radiation with or without chemotherapy (in this disease there is currently minimal data to support the combination of immunotherapy and radiation, and hence the adjuvant cemiplimab will be initiated after radiation).

[0095] Adjuvant Therapy: Patients in cohorts A1, A2, B, and B2 will receive 8 cycles of adjuvant cemiplimab 350 mg IV Q3W, following recovery from surgery. Patients in cohort B3 will receive 8 cycles of adjuvant fianlimab 1600 mg IV Q3W combined with cemiplimab 350 mg IV Q3W, following recovery from surgery.

[0096] Patients will be followed with regular surveillance regardless of whether they receive standard or experimental adjuvant therapy. Patients with incomplete surgical resection will not receive adjuvant therapy with cemiplimab alone or with fianlimab and will be managed per standard of care for their residual disease. Patients with tumor recurrence during the adjuvant therapy phase will discontinue further cemiplimab (and fianlimab in cohort B3) and will be managed per standard of care for their recurrent disease.

[0097] Patients enrolled in cohort A3 received 8 cycles of adjuvant cemiplimab 350 mg IV Q3W, following recovery from surgery, and patients in cohort C received 8 cycles of adjuvant cemiplimab, Q3W, following completion of standard-of-care adjuvant radiation with or without chemotherapy. Patients were followed as described above.

[0098] Adjuvant Therapy for NSCLC Cohort: All NSCLC patients will receive 8 additional cycles of cemiplimab in the adjuvant setting upon recovery from surgery. Cohort A1 will receive 4 cycles of standard, platinum-doublet chemotherapy with the first 4 of the 8 additional cycles of cemiplimab. Cohort A2 will receive 2 additional cycles of platinum-doublet chemotherapy with the first 2 of these 8 additional cycles of cemiplimab. The first dose of combination chemotherapy and cemiplimab will be scheduled at within 8 weeks following the surgery, and adjuvant therapy will be given on a standard Q3W schedule; however, scheduling changes are permitted at the discretion of the treating physician. If a patient is found to have EGFR exon 19 deletions or exon 21 L858R mutation following enrollment prior to the adjuvant period, cemiplimab will not be administered in the adjuvant setting and the patient will be offered standard of care therapy.

[0099] Cohort A3 received 2 additional cycles of platinum-doublet chemotherapy with the first 2 of these 8 additional cycles of cemiplimab. The first dose of combination chemotherapy and cemiplimab was to be scheduled at within 8 weeks following the surgery, and adjuvant therapy was to be given on a standard Q3W schedule; however, scheduling changes were permitted at the discretion of the treating physician.

[0100] Adjuvant Therapy for HCC Cohort: Given the dearth of adjuvant or neoadjuvant options for HCC patients, and the high likelihood of recurrence, all patients in cohorts B and B2 will be given 8 additional cycles of cemiplimab, infused Q3W. The first dose will be scheduled within 8 weeks following the surgery.

[0101] For patients in cohort B3, patients will receive 8 cycles of adjuvant fianlimab 1600 mg IV Q3W combined with cemiplimab 350 mg IV Q3W, following recovery from surgery. Patients receiving the combination will be administered fianlimab followed by cemiplimab administered the same day.

[0102] Adjuvant Therapy for HNSCC Cohort: Following surgery, patients will receive standard adjuvant radiation with or without chemotherapy as per standard of care (SOC). Given the paucity of data of combined chemotherapy or radiotherapy and PD-1 blockade in HNSCC patients, no cemiplimab will be given during SOC adjuvant therapy; however, these patients will receive 8 cycles of adjuvant cemiplimab following completion of standard adjuvant therapy. The first dose of cemiplimab will be administered within 8 weeks following SOC adjuvant therapy.

[0103] Follow-Up: During the post-surgical period, patients will be evaluated in surgery follow up every 4 weeks until the initiation of adjuvant therapy to assess for adverse events. All patients should be evaluated for 90 days after their final dose of cemiplimab for adverse events. Imaging in the post-surgical period should be performed at intervals consistent with standard of care from surgery for up to 5 years following surgery. During this 5 year period, the disease status of patients will be assessed every 6 months from surgery, and upon disease recurrence, patients will be monitored for survival every 12 weeks from the date of recurrence. If a patient does not report for in-person study visits at any time during the post-surgical period, they should continue to be followed for survival every 12 weeks from the date of last contact, through chart review or by telephone until death, withdrawal of consent, or the end of the study, whichever occurs earlier.

[0104] Study Stopping Rules: Enrollment into an individual cohort will be stopped should there be >2 delays in surgery related to cemiplimab within a cohort; or an excessive rate of AEs observed within a cohort based on the established safety profile of cemiplimab.

[0105] End of Study Definition: The end of study is defined as the last visit of the last patient, including the long-term follow-up period.

[0106] Selection, Withdrawal, and Replacement of Patients: The patient population includes approximately 73 patients with a known diagnosis of resectable NSCLC, HOC, or HNSCC. The study duration is approximately 5 years.

[0107] Inclusion Criteria: A patient must meet the following criteria to be eligible for inclusion in the study:1. Men and women of age >18 years2. Patient must have a known diagnosis of NSCLC, HCC, or HNSCC. Histological diagnosis of NSCLC and HNSCC is required. Pre-treatment and diagnostic biopsies can be done simultaneously if the imaging clearly supports the required diagnosis (e.g., HCC) in the opinion of the Investigator. a. NSCLC: Patients will have either a nodal involvement or primary tumor >4 cm. b. HCC: Initial diagnosis of HCC may be made using radiographic parameters; however, pre-treatment, core needle biopsies are mandatory for all cohorts. c. HNSCC: Patients will have primary tumor site of oral cavity, oropharynx, larynx, or hypopharynx.3. Patient must be willing and able to provide blood samples (up to 120 mL at certain visits) at the indicated time points .4. Patient must be willing and able to have excisional or core needle biopsies of tumor prior to initiation of cemiplimab (chemotherapy for cohort A3) (goal is up to 4 biopsies, final numberto be determined by the surgeon and radiologist performing the procedure as safe. Patients receiving anti-coagulation or anti-platelet therapy must be candidates for safe interruption of this therapy prior to biopsy as determined by the investigator, and coagulation parameters (aPTT / INR) must have normalized at the time of biopsy to <1 .5 ULN.For HCC lesions, the biopsy must be performed by an interventional radiologist with imaging guidance, and the biopsy needle must first traverse at least 1 cm of normal hepatic parenchyma in order to mitigate potential bleeding complications.5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 . The exception will be patients carrying long-term disability (such as cerebral palsy) where the disability is neither acute nor progressive, and unlikely to significantly affect their response to therapy.6. Patient is determined to be a surgical candidate for resection of their tumor.7. Patient is able to understand and willing to sign a written informed consent as specified by health authorities and institutional guidelines.8. Adequate organ and bone marrow function as defined below in Table 1.9. Willing and able to comply with clinic visits and study-related procedures and requirementsTable 1 : Organ and Marrow Function Definition

[0108] Exclusion Criteria: A patient who meets any of the following criteria will be excluded from the study:1. Patients who have had any systemic anti-cancer therapy or radiotherapy within 6 months prior to entering the study for their current tumor or a different primary tumor2. Patients whose tumor burden, or pace of tumor growth, in the opinion of the Investigator will not permit delaying surgery through 2 doses of neoadjuvant study treatment3. Patients who have participated in a study of an investigational agent or an investigational device within 4 weeks of study therapy or 5 half-lives (whichever is longer)4. Patients who have had major surgery within 14 days prior to initiation of neoadjuvant therapy5. Patients with metastatic disease for whom the intent of surgery would not be curative6. Uncontrolled, intercurrent illness including, but not limited to: ongoing or active infection requiring antibiotics (exception is a brief (<10 days) course of antibiotics to be completed before initiation of treatment), symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness / social situations that would limit compliance with study requirements as determined by the Investigator7. Is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. Patients on chronic steroids (more than 4 weeks at stable dose) equivalent to <10 mg prednisone will not be excluded.8. Has active autoimmune disease that has required systemic treatment in the past 1 year (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic, corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is acceptable.Has a known, additional malignancy that is progressing and / or requires active treatment. Exceptions include patients with: basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy; in situ cervical or anal cancer; prostate cancer on stable dose of hormonal therapy without rising PSA; breast cancer who have been treated with curative intent, who may be on hormonal therapy. Encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent History of interstitial lung disease (e.g., idiopathic pulmonary fibrosis, organizing pneumonia) or active, noninfectious pneumonitis that required immune-suppressive doses of glucocorticoids to assist with management. A history of radiation pneumonitis in the radiation field is permitted as long as pneumonitis resolved >6 months prior to study treatment. Uncontrolled infection with human immunodeficiency virus (HIV), HBV or hepatitis C infection (HCV); or diagnosis of immunodeficiency. a. Patients will be tested for hepatitis C virus (HCV) and hepatitis B virus (HBV) at screening. b. Patients with known HIV infection who have controlled infection (undetectable viral load (HIV RNA PCR) and CD4 count above 350 either spontaneously or on a stable anti-viral regimen) are permitted. For patients with controlled HIV infection, monitoring will be performed per local standards. c. Patients with hepatitis B (HepBsAg+) who have controlled infection (serum HBV DNA PCR that is <100 lU / ml AND receiving anti-viral therapy for hepatitis B) are permitted. Patients with controlled infections must undergo periodic monitoring of HBV DNA. Patients must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study drug. d. Patients who are hepatitis C virus antibody positive (HCV Ab+) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted. Receipt of a live vaccine within 28 days of planned start of study medication Prior allogeneic stem cell transplantation, or autologous stem cell transplantation, unless discussed with and approved by the Sponsor Recipients of organ transplants unless discussed with and approved by the medical monitor Any medical co-morbidity, physical examination finding, or metabolic dysfunction, or clinical laboratory abnormality that, in the opinion of the Investigator, renders the patient unsuitablefor participation in a clinical trial due to high safety risks and / or potential to affect interpretation of results of the study17. Exclusion criterion removed.18. Member of the clinical site study team or his / her immediate family, unless prior approval granted by the Sponsor19. Documented allergic or hypersensitivity response to any protein therapeutics (e.g., recombinant proteins, vaccines, IV immune globulins, monoclonal antibodies, receptor traps, excipients of cemiplimab)20. Known psychiatric or substance abuse disorders that would interfere with fulfilling the requirements of the study21. Women with a positive serum hCG pregnancy test at the screening / baseline visit. If positive, pregnancy must be ruled out by ultrasound for patient to be eligible.22. Breastfeeding women are excluded.23. Women of childbearing potential* or sexually active men** whose partners are WOCBP, who are unwilling to practice highly effective contraception prior to the initial dose / start of the first treatment, during the study, and for at least 6 months after the last dose.Highly effective contraceptive measures for women include: a. Stable use of combined (estrogen and progestogen-containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening b. Intrauterine device (IUD); intrauterine hormone-releasing system (IUS) c. Bilateral tubal ligation d. Vasectomized partner* e. And / or sexual abstinencef, £.WOCBP are defined as women who are fertile following menarche until becoming postmenopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSHmeasurement is insufficient to determine the occurrence of a postmenopausal state. Pregnancy testing and contraception are not required for women with documented hysterectomy.** Male study participants with WOCBP partners are required to use condoms unless they are vasectomized¥or practice sexual abstinence!, !■ t Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. t Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together.¥Vasectomized partner or vasectomized study participant must have received medical assessment of the surgical success.24. NSCLC cohorts only: Patients do not have a history of smoking. History of smoking is defined as smoking >100 cigarettes in a lifetime.25. NSCLC cohorts only: Patients with tumors tested positive for EGFR gene mutations, ALK gene translocations, or ROS1 fusions.

[0109] Study Treatments: Cemiplimab, Chemotherapy, and Radiation Treatments; treatment dosage and administration are described below in Table 2.Table 2: Treatment Regimens

[0110] Patients enrolled into cohorts A1 , A2, B, B2, and C will receive 2 doses of cemiplimab (350 mg Q3W) IV before surgery. The target administration is 2 doses, dosed 21 days apart before the time of surgery. Patients in cohort A2 will receive platinum-doublet chemotherapy the same day as cemiplimab is administered. Patients enrolled into cohort B2 will receive SBRT 8 Gy X 3 fractions over 1 week, followed by cemiplimab 350 mg Q3W for 2 cycles before surgery. Patients in cohort B3 will receive 2 doses of fianlimab 1600 mg followed by cemiplimab 350 mg IV on the same day, dosed 21 days apart before surgery.

[0111] Patients in cohorts B and B2 will receive 8 cycles of adjuvant cemiplimab 350 mg IV Q3W after surgery. Patients in cohort B3 will receive 8 cycles of adjuvant of fianlimab 1600 mg IV followed by cemiplimab 350 mg IV on the same day Q3W after surgery.

[0112] Patients in cohort A3 received standard platinum-doublet on the Q3W dosing schedule and no neoadjuvant cemiplimab (for details see Section 6.1), and patients in cohort C received standard-of-care radiotherapy with or without chemotherapy prior to receiving cemiplimab.

[0113] Concomitant Medications and Procedures: Any procedure performed or treatment administered of both prescription medications or over-the-counter preparations from the time of informed consent until 90 days after the last study treatment will be considered concomitant treatment. This includes medications and other therapies for which administration started since the ICF had been signed and before the first dose of the study, and which will continue during the study, as well as any therapies started in the follow-up period to treat a study-drug-related AE. All concomitant treatments must be recorded in the study case report form (CRF) with the generic name, dose, dose unit, frequency, indication, and start / stop date, as appropriate.

[0114] Prohibited Medications and Procedures: While participating in this study, a patient may not receive any standard or investigational agent for treatment of a tumor other than those outlined in the protocol, per the study’s specified dosing regimens. Patients must not receive live vaccines during the study. Any other medication which is considered necessary for the patient’s welfare, and which is not expected to interfere with the evaluation of the study drug, may be given at the discretion of the Investigator.

[0115] Patients using immunosuppressive doses (>10 mg per day of prednisone or equivalent) of systemic corticosteroids, other than for corticosteroid replacement, will not be eligible for the study. It is recommended that patients do not receive systemic corticosteroids such as hydrocortisone, prednisone, prednisolone (Solu-Medrol®), or dexamethasone (Decadron®) at any time throughout the study except in the case of a life-threatening emergency and / or to treat an imAE. Similarly, it is recommended that patients do not receive other immunosuppressive medications (e.g., methotrexate) at any time throughout the study except in the case of a lifethreatening emergency and / or to treat an imAE. Other immunosuppressive medications required to treat imAEs, infusion-related reactions, or life-threatening emergencies may be used at the Investigator’s discretion. Investigators are allowed to treat adverse events requiring immunosuppressive medication using their institutional standard, which may involve medications not specifically mentioned in the protocol.

[0116] Permitted Medications and Procedures: Standard antiemetics and preparative medications will be used for all patients receiving chemotherapy as per institutional SOC. Physiologic replacement doses of systemic corticosteroids are permitted, even if >10 mg / day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted.

[0117] Efficacy Procedures: For tumor assessments, a CT or MRI for tumor assessment will be performed at indicated time points. The choice of performing imaging by CT or MRI is an Investigator decision. The same radiological method should be used consistently at screening and throughout the study. Pre-surgical imaging and other indicated assessments are to be performed within 10 days prior to surgery. Imaging in the post-surgical period should be performed at intervals consistent with standard of care from surgery for up to 5 years following surgery. Tumor response assessments will be performed according to RECIST 1.1 criteria (RECIST 1.1 without the requirement for confirmation of responses [PR / CR] as this is not feasible within the neoadjuvant period) (Eisenhauer, 2009).

[0118] For tumor biopsies and surgical samples, during the screening period, after patients have given informed consent, they will be asked to provide on-study tumor biopsies. Up to 4 core needle biopsies will be obtained at indicated time points. For HCC lesions, the biopsy must be performed by an interventional radiologist with imaging guidance and the biopsy needle must first traverse at least 1 cm of normal hepatic parenchyma in order to mitigate potential bleeding complications. Patients receiving anti-coagulation or anti-platelet therapy must be candidates for safe interruption of this therapy prior to biopsy as determined by the investigator, and coagulation parameters (aPTT / INR) must have normalized at the time of biopsy to <1.5 ULN. Tumor biopsiesare mandatory during screening and expected but remain optional upon progression. The resulting biopsy samples will be collected according to directions in the laboratory manual.

[0119] Adverse Events: The neoadjuvant treatment period is defined as the time from the day of first dose of neoadjuvant treatment to the day of the last dose of neoadjuvant treatment plus 90 days or to 1 day before patients receive their first dose of adjuvant cemiplimab or another anticancer systemic therapy, whichever is earlier. Neoadjuvant treatment-emergent AEs (TEAEs) are defined as AEs that developed or worsened during the neoadjuvant treatment period and any treatment-related AEs that occur after neoadjuvant treatment period but prior to patients receiving their first dose of cemiplimab as adjuvant therapy or another anticancer systemic therapy.

[0120] The adjuvant treatment period is defined as the time from the day of first dose of adjuvant cemiplimab to the day of the last dose of adjuvant cemiplimab plus 90 days or to 1 day before patients receive another anticancer systemic therapy, whichever is earlier. Adjuvant TEAEs are defined as AEs that developed or worsened during the adjuvant treatment period and any treatment-related AEs that occur after adjuvant treatment period but prior to patients receiving another anticancer systemic therapy.

[0121] It is expected that neoadjuvant therapy with cemiplimab with or without SBRT or fianlimab will result in measurable, pathologic responses in NSCLC, HCC, and HNSCC.Example 2: Low-dose Stereotactic Body Radiotherapy (SBRT) Prior To Pre-operative Cemiplimab For Patients With Resectable Hepatocellular Carcinoma (HCC)

[0122] Background - Radiation and Immunotherapy: SBRT induces immunogenic cell death and may augment immune checkpoint inhibitor (ICI) activity. 8 Gy x 3 fractions is one of the optimal doses established pre-clinically to induce immunogenic cell death. (Vanpouille-Box C et al, Nature Comm 2017). ICIs administered following concurrent chemoradiation have imparted progression-free and overall survival benefit in patients with NSCLC (Antonia SJ et al, NEJM 2018). To date, concurrent use of ICIs concurrent with chemoradiation has not improved outcomes, likely due to lymphotoxicity (Machiels JP et al, ESMO 2022). Pre-clinical modeling suggests that radiation should be administered prior to immunotherapy (Wei J et al, Science Immunology 2021). Prior studies have demonstrated safety and potentially synergistic efficacy when SBRT 8 Gy x3 is administered prior to immunotherapy in the pre-operative / neoadjuvant setting for NSCLC (Altorki NK et al Lancet Oncology 2021). Small trials in locally advanced HCC, as well as many other tumour types, have evaluated the addition of SBRT to induce immunogenic cell death and augment ICI activity. In lung cancer patients, neoadjuvant 8Gy x 3 has been used prior to immunotherapy, however, no study to date has evaluated this approach in HCC though small studies have looked at the combination in more advanced HCC

[0123] ICI have shown activity in early-stage HCC: ICIs are the standard of care for advanced HCC. Early-stage HCC is often surgically resected, but recurrence occurs in -70% of patients at five years (Galle PR et al. J Hepatol 2018). The first study of perioperative ICI using cemiplimab in resectable HCC showed >50% necrosis in 35% of patients after 2 doses of cemiplimab (Marron TU et al. Lancet Gastroenterol Hepatol 2022; Magen A et al. Nature Medicine 2023). Brief windows of opportunity enable the in vivo study of MOA of novel ICI combinations. Here, the first trial to investigate low-dose SBRT prior to ICIs in patients with early-stage HCC is presented.

[0124] This is a single-arm, open-label phase 2 trial (NCT03916627). Adult treatment- naive patients with resectable HCC received SBRT (8Gy x 3 fractions) and neoadjuvant cemiplimab (350 mg IV Q3W for 2 cycles) prior to surgical resection with collection of tumors for analysis of necrosis and immune correlatives. Patients subsequently received cemiplimab (350 mg IV Q3W for 8 cycles). Pre-treatment biopsies and serial blood collection for exploratory analyses (i.e., multiplex immunohistochemistry, and single-cell proteomic and transcriptomic analysis). Inclusion criteria included: histologically confirmed diagnosis of HCC; ECOG performance status of 0 or 1 ; patient is a surgical candidate for resection of their tumour; and adequate organ and bone marrow function. Exclusion criteria included: any systemic anti-cancer therapy or radiotherapy within 6 months prior to entering the study; and ongoing or recent (<1 year) autoimmune disease requiring systemic immunosuppression. Primary endpoint was significant tumour necrosis (STN): >70% necrosis of resected tumour. Secondary endpoints included: delay to surgery; overall response rate; incidence of AEs; and change in lymphocyte infiltration.

[0125] Demographics and baseline characteristics are provided in Table 3. 20 patients were enrolled. 50% were Asian and nearly all had a history of viral hepatitis.Table 3 Characteristic, n (%) unless otherwise indicated All patients (N=20)Age, yearsMedian (SD) 65 (58-69)> 65 years 10 (50)Male 16 (80)Asian 10 (50)History of viral hepatitis 17 (85)ECOG performance status0 18 (90)1 2 (10)Cancer stage at screeningStage lb 15 (75)Stage Illa 4 (20)Stage I lib 1 (5)

[0126] Safety during the neoadjuvant phase is summarized in Table 4. No Grade >3 treatment-related AEs occurred during neoadjuvant therapy. There were no TEAEs or treatment- related AEs that resulted in death. SBRT followed by neoadjuvant cemiplimab was generally well tolerated.Table 4 n (%) All patients (N=20)Any TEAE 20 (100)Grade >3 TEAE 5 (25)TEAEs that occurred in >10% of patientsAnaemia 7 (35)Increased alanine aminotransferase 6 (30)Increased aspartate aminotransferase 6 (30)Hyperglyceamia 6 (30)Decreased white blood cell count 5 (25)Decreased lymphocyte count 4 (20)Procedural pain 4 (20)Constipation 4 (20)Increased blood alkaline phosphatase 3 (15)Increased blood lactate dehydrogenase 3 (15)TEAEs that occurred in >10% of patientsDiarrhoea 3 (15)Paraesthesia 3 (15)Fatigue 3 (15)Cough 3 (15)Increased blood creatinine 2 (10)Decreased platelet count 2 (10)Infusion-related reaction 2 (10)Hypophosphataemia 2 (10)Abdominal pain 2 (10)Thrombocytopenia 2 (10)Insomnia 2 (10)

[0127] Patient Outcomes: 20 patients were enrolled and completed neoadjuvant treatment. 16 patients underwent surgical resection (one after data cut-off). Median time to surgery was 32 weeks (95% Cl: 28-38). 4 patients completed neoadjuvant ICI therapy but came off trial prior to surgical resection (not due to toxicity): one patient not cleared by pulmonologist for surgery; one patient not cleared by cardiologist for surgery; one patient found on pre-operative imaging to have spinal metastasis; one patient with concern for inadequate hepatic reserve following ICI, and administered pre-op Y90. When including the patient who underwent surgery after the cut-off date, 3 of 16 patients had significant tumor necrosis, including 2 patients with a complete pathologic response and the third with 90% necrosis; and 6 of the 16 patients, or 38%, had 50% or more tumor necrosis.

[0128] Tumor Response is summarized in Table 5. Additionally, surgical results were obtained from one patient who underwent surgery after the data cut-off date. This patient experienced STN, with 90% tumour necrosis.Table 5Patients who successfully completed surgery as of data cut-offEndpoint (N=15)STN (>70%)2 (13%) ** both pCR** Primary endpointT umour necrosis >50%5 (33%) Exploratory endpoint

[0129] Conclusions: This is the first clinical trial to report efficacy of neoadjuvant SBRT + ICIs in patients with resectable HCC. Of 16 patients who completed surgical resection (including 1 patient who had surgery after the data cut-off): 6 (38%) had >50% tumour necrosis; 3 (19%) patients achieved STN (>70% necrosis); 2 (13%) patients had complete (100%) tumor necrosis; pathologic response rates were similar to those observed with cemiplimab alone (Marron TU et al.Lancet Gastroenterol Hepatol. 2022). Planned deep tissue and blood analyses will be used to define the immunodynamic effects of SBRT + cemiplimab compared to cemiplimab alone.REFERENCES

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[0201] The present disclosure is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those describedherein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

Claims

We claim:

1. A method of treating or inhibiting the growth of a tumor, comprising:(a) selecting a patient with cancer;(b) administering to the patient a therapeutically effective amount of a neoadjuvant programmed death-1 (PD-1) inhibitor, wherein the neoadjuvant PD-1 inhibitor is an antibody that binds specifically to PD-1 and comprises three heavy chain complementarity determining regions (CDRs) (HCDR1 , HCDR2 and HCDR3) contained in a heavy chain variable region (HCVR) of SEQ ID NO: 1 and three light chain CDRs (LCDR1 , LCDR2 and LCDR3) contained in a light chain variable region (LCVR) of SEQ ID NO: 2 in combination with radiation therapy; and(c) after step (b), surgically resecting the cancer tumor.

2. The method of claim 1 , wherein the cancer is hepatocellular carcinoma (HCC).

3. The method of claim 1 or 2, wherein the radiation is stereotactic body radiotherapy (SBRT).

4. A method of treating or inhibiting the growth of a tumor, comprising:(a) selecting a patient with cancer;(b) administering to the patient a therapeutically effective amount of a neoadjuvant programmed death-1 (PD-1) inhibitor, wherein the neoadjuvant PD-1 inhibitor is an antibody that binds specifically to PD-1 and comprises three heavy chain complementarity determining regions (CDRs) (HCDR1 , HCDR2 and HCDR3) contained in a heavy chain variable region (HCVR) of SEQ ID NO: 1 and three light chain CDRs (LCDR1 , LCDR2 and LCDR3) contained in a light chain variable region (LCVR) of SEQ ID NO: 2 in combination with an antibody that binds specifically to LAG-3; and(c) after step (b), surgically resecting the cancer tumor.

5. The method of claim 4, wherein the cancer is hepatocellular carcinoma (HCC).

6. The method of claim 4 or 5, wherein the anti-LAG-3 antibody is fianlimab.

7. The method of any one of claims 1-6, wherein the administered neoadjuvant anti-PD-1 antibody comprises a HCDR1 having an amino acid sequence of SEQ ID NO: 3; a HCDR2 having an amino acid sequence of SEQ ID NO: 4; a HCDR3 having an amino acid sequence of SEQ ID NO: 5; a LCDR1 having an amino acid sequence of SEQ ID NO: 6; a LCDR2 having an amino acid sequence of SEQ ID NO: 7; and a LCDR3 having an amino acid sequence of SEQ ID NO: 8.

8. The method of any one of claims 1-7, wherein the administered neoadjuvant anti-PD-1 antibody comprises a HCVR comprising an amino acid sequence of SEQ ID NO: 1 .

9. The method of any one of claims 1-7, wherein the administered neoadjuvant anti-PD-1 antibody comprises a LCVR comprising an amino acid sequence of SEQ ID NO: 2.

10. The method of any one of claims 1-7, wherein the administered neoadjuvant anti-PD-1 antibody comprises a HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 / 2.

11. The method of any one of claims 1-7, wherein the administered neoadjuvant anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain has an amino acid sequence of SEQ ID NO: 9.

12. The method of any one of claims 1-10, wherein the administered neoadjuvant anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the light chain has an amino acid sequence of SEQ ID NO: 10.

13. The method of any one of claims 1-10, wherein the administered neoadjuvant anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain has an amino acid sequence of SEQ ID NO: 9 and the light chain has an amino acid sequence of SEQ ID NO: 10.

14. The method of any one of claims 1-13, wherein the administered neoadjuvant anti-PD-1 antibody is cemiplimab.

15. The method of any one of claims 1-10, wherein the administered neoadjuvant PD-1 inhibitor is an anti-PD-1 antibody comprising a HCVR with 90%, 95%, 97%, or 98% sequence identity to SEQ ID NO: 1.

16. The method of any one of claims 1-10, wherein the administered neoadjuvant PD-1 inhibitor is an anti-PD-1 antibody comprising a LCVR with 90%, 95%, 97%, or 98% sequence identity to SEQ ID NO: 2.

17. The method of any one of claims 1-10, wherein the administered neoadjuvant PD-1 inhibitor is an anti-PD-1 antibody comprising a HCVR with 90%, 95%, 97%, or 98% sequence identity to SEQ ID NO: 1 , and a LCVR with 90%, 95%, 97%, or 98% sequence identity to SEQ ID NO: 2.

18. The method of any one of claims 1-17, further comprising:(d) after step (c), administering to the patient a therapeutically effective amount of an adjuvant programmed death-1 (PD-1) inhibitor, wherein the adjuvant PD-1 inhibitor is an antibodythat binds specifically to PD-1 and comprises three heavy chain complementarity determining regions (CDRs) (HCDR1 , HCDR2 and HCDR3) contained in a heavy chain variable region (HCVR) of SEQ ID NO: 1 and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in a light chain variable region (LCVR) of SEQ ID NO: 2.

19. The method of claim 18, wherein the administered adjuvant anti-PD-1 antibody comprises HCDR1 having an amino acid sequence of SEQ ID NO: 3; HCDR2 having an amino acid sequence of SEQ ID NO: 4; HCDR3 having an amino acid sequence of SEQ ID NO: 5; LCDR1 having an amino acid sequence of SEQ ID NO: 6; LCDR2 having an amino acid sequence of SEQ ID NO: 7; and LCDR3 having an amino acid sequence of SEQ ID NO: 8.

20. The method of claim 18 or 19, wherein the administered adjuvant anti-PD-1 antibody comprises a HCVR comprising an amino acid sequence of SEQ ID NO: 1 .

21. The method of claim 18 or 19, wherein the administered adjuvant anti-PD-1 antibody comprises a LCVR comprising an amino acid sequence of SEQ ID NO: 2.

22. The method of claim 18 or 19, wherein the administered adjuvant anti-PD-1 antibody comprises a HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 / 2.

23. The method of any one of claims 18-22, wherein the administered adjuvant anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain has an amino acid sequence of SEQ ID NO: 9.

24. The method of any one of claims 18-22, wherein the administered adjuvant anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the light chain has an amino acid sequence of SEQ ID NO: 10.

25. The method of any one of claims 18-22, wherein the administered adjuvant anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain has an amino acid sequence of SEQ ID NO: 9 and the light chain has an amino acid sequence of SEQ ID NO: 10.

26. The method of claim 19, wherein the administered adjuvant PD-1 inhibitor is an anti-PD-1 antibody comprising a HCVR with 90%, 95%, 97%, or 98% sequence identity to SEQ ID NO: 1.

27. The method of claim 19, wherein the administered adjuvant PD-1 inhibitor is an anti-PD-1 antibody comprising a LCVR with 90%, 95%, 97%, or 98% sequence identity to SEQ ID NO: 2.

28. The method of claim 19, wherein the administered adjuvant PD-1 inhibitor is an anti-PD-1 antibody comprising a HCVR with 90%, 95%, 97%, or 98% sequence identity to SEQ ID NO: 1, and a LCVR with 90%, 95%, 97%, or 98% sequence identity to SEQ ID NO: 2.

29. The method of any one of claims 1-28, further comprising administering to the patient an additional therapeutic agent or therapy selected from one or more of: an anti-viral therapy, photodynamic therapy, a programmed death ligand 1 (PD-L1) inhibitor, a lymphocyte activation gene 3 (LAG3) inhibitor, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, a glucocorticoid-induced tumor necrosis factor receptor (GITR) agonist, a T-cell immunoglobulin and mucin containing -3 (TIM3) inhibitor, a B- and T-lymphocyte attenuator (BTLA) inhibitor, a T-cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor, a CD38 inhibitor, a CD47 inhibitor, an antagonist of another T-cell co-inhibitor or ligand, a CD20 inhibitor, an indoleamine-2,3- dioxygenase (IDO) inhibitor, a CD28 activator, a vascular endothelial growth factor (VEGF) antagonist, an angiopoietin-2 (Ang2) inhibitor, a transforming growth factor beta (TGFP) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an agonist to a co-stimulatory receptor, an antibody to a tumor-specific antigen, a vaccine, an adjuvant to increase antigen presentation, an oncolytic virus, a cytotoxin, a chemotherapeutic agent, platinum-based chemotherapy, a tyrosine kinase inhibitor, an IL-6R inhibitor, an IL-4R inhibitor, an IL-10 inhibitor, a cytokine, an antibody drug conjugate (ADC), chimeric antigen receptor T cells, an anti-inflammatory drug, and a dietary supplement.

30. The method of any one of claims 1-29, wherein the neoadjuvant PD-1 inhibitor is administered as one or more doses, wherein each dose is administered every two weeks, three weeks, four weeks, five weeks or six weeks.

31. The method of any one of claims 1-30, wherein the neoadjuvant PD-1 inhibitor is administered as two or more doses, wherein each dose is administered every three weeks.

32. The method of any one of claims 1-31 , wherein the neoadjuvant PD-1 inhibitor is administered at a dose of 5 mg to 1000 mg.

33. The method of any one of claims 1-32, wherein the neoadjuvant PD-1 inhibitor is administered at a dose of 200 mg, 250 mg, 350 mg, 400 mg, 500 mg, 600 mg, 750 mg, 800 mg, or 1000 mg.

34. The method of any one of claims 1-33, wherein the neoadjuvant PD-1 inhibitor is administered at a dose of 1 mg / kg to 20 mg / kg of the patient’s body weight.

35. The method of any one of claims 1-34, wherein the neoadjuvant PD-1 inhibitor is administered at a dose of 1 mg / kg, 3 mg / kg or 10 mg / kg of the patient’s body weight.

36. The method of any one of claims 1-35, wherein the neoadjuvant PD-1 inhibitor and / or the adjuvant PD-1 inhibitor is administered intravenously, or subcutaneously.

37. The method of any one of claims 1-3 or 7-36, wherein the radiation therapy is administered prior to the PD-1 inhibitor.

38. The method of claim 38, wherein the radiation therapy is SBRT.

39. The method of claim 38 or 39, wherein the radiation therapy is low-dose SBRT.

40. The method of any one of claims 37-39, wherein the radiation therapy is administered one week prior to the PD-1 inhibitor.