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RU-2861651-C2 - ADMINISTRATION OF PD-1 INHIBITORS FOR TREATMENT OF SKIN CANCER

RU2861651C2RU 2861651 C2RU2861651 C2RU 2861651C2RU-2861651-C2

Abstract

FIELD: oncology. SUBSTANCE: method for reducing the risk of recurrence of cutaneous squamous cell carcinoma (CSCC) is proposed. Selecting a patient with CSCC having a high risk of CSCC recurrence, completed resective surgery and postoperative radiotherapy is carried out. The patient is subjected to adjuvant therapy with an effective amount of an antibody or antigen-binding fragment thereof that specifically binds to PD-1, 2-6 weeks after completion of radiotherapy. The method provides a reduction in the risk of CSCC recurrence or at least a 10% lower rate of CSCC recurrence compared to a patient after completion of surgical resection and radiotherapy without adjuvant therapy. EFFECT: enhanced tumour regression and improved disease control. 17 cl, 2 dwg, 6 tbl, 3 ex

Inventors

  • FURY, MATTHEW G.
  • LOWY, ISRAEL

Dates

Publication Date
20260506
Application Date
20200227
Priority Date
20190228

Claims (20)

  1. 1. A method for reducing the risk of recurrence of cutaneous squamous cell carcinoma (CSCC), including:
  2. (a) selection of a patient with CSCC where the patient has a high risk of recurrence of CSCC and has completed resection surgery and postoperative radiotherapy for the treatment of CSCC; and
  3. (b) subjecting the patient to adjuvant therapy 2-6 weeks after completion of radiation therapy, wherein the adjuvant therapy comprises a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to programmed death protein 1 (PD-1),
  4. wherein the antibody or antigen-binding fragment thereof comprises three complementarity-determining regions (CDRs) (HCDR1, HCDR2, and HCDR3) contained within a heavy chain variable region (HCVR) and three CDRs (LCDR1, LCDR2, and LCDR3) contained within a light chain variable region (LCVR), wherein HCDR1 has the amino acid sequence of SEQ ID NO: 3; HCDR2 has the amino acid sequence of SEQ ID NO: 4; HCDR3 has the amino acid sequence of SEQ ID NO: 5; LCDR1 has the amino acid sequence of SEQ ID NO: 6; LCDR2 has the amino acid sequence of SEQ ID NO: 7; and LCDR3 has the amino acid sequence of SEQ ID NO: 8; and
  5. wherein the administration of the antibody or antigen-binding fragment thereof results in a reduction in the risk of CSCC recurrence or at least a 10% lower rate of CSCC recurrence compared to the patient after completion of surgical resection and radiation therapy without adjuvant therapy for CSCC.
  6. 2. The method according to claim 1, wherein the CSCC has at least one of the following high-risk features:
  7. (i) lymph node involvement with extracapsular extension and at least 1 node >20 mm;
  8. (ii) in-transit metastases (ITM);
  9. (iii) T4 lesion;
  10. (iv) perineural invasion (PNI); and
  11. (v) recurrent CSCC, and at least one of the following additional features: disease ≥N2b associated with the recurrent lesion; nominal ≥T3; and recurrent lesion diameter ≥20 mm.
  12. 3. The method according to claim 1 or 2, wherein the therapeutically effective amount of the antibody is in the range of 5 mg to 500 mg.
  13. 4. The method according to any one of claims 1 to 3, wherein the therapeutically effective amount of the antibody is 350 mg.
  14. 5. The method according to any one of claims 1 to 4, wherein the antibody or antigen-binding fragment thereof is administered in the form of one or more doses.
  15. 6. The method of claim 5, wherein each dose of the antibody is administered 2-12 weeks after the immediately preceding dose.
  16. 7. The method of claim 5, wherein each dose of the antibody is administered 3 weeks after the immediately preceding dose.
  17. 8. The method according to any one of claims 5 to 7, wherein each dose of antibody is in the range of 5 mg to 500 mg.
  18. 9. The method according to any one of claims 6 to 8, wherein each dose is 350 mg.
  19. 10. The method according to any one of claims 1 to 9, wherein the antibody or antigen-binding fragment thereof is administered intravenously.
  20. 11. The method according to any one of claims 1 to 10, wherein administration of the antibody or antigen-binding fragment thereof results in a zero rate of subsequent recurrence of CSCC.

Description

FIELD OF INVENTION [0001] The present invention relates to methods of treating or inhibiting tumor growth, comprising selecting a patient with skin cancer and administering to the patient a therapeutically effective amount of a programmed death protein 1 (PD-1) inhibitor. LEVEL OF TECHNOLOGY [0002] Skin cancer is the most common malignancy in the United States (Guy et al., Am. J. Prev. Med . 48:183–87, 2015). In 2012, approximately 5.4 million cases of nonmelanoma skin cancer, including basal cell carcinoma and squamous cell carcinoma, were diagnosed in the United States (Rogers et al., JAMA Dermatol ., 151(10):1081–86, 2015). Cutaneous squamous cell carcinoma (CSCC) is the second most common malignancy in the United States after basal cell carcinoma (BCC) (Karia et al., J. Am. Acad. Dermatol . 68:957–66, 2013). Chronic sunlight exposure is the predominant risk factor for nonmelanoma skin cancer. [0003] CSCC is a malignant proliferation of epidermal keratinocytes with dermal invasion and is distinct from noninvasive precursor lesions such as actinic keratosis (Fernandez et al., Immunol Allergy Clin North Am 37(2):315–27, 2017). Its incidence varies considerably worldwide, with the highest incidence in Australia and the lowest incidence in parts of Africa (Lomas et al., Br J Dermatol , 166(5):1069–80, 2012). The exact incidence of CSCC is unknown because it is not included in most malignancy registries. However, the incidence of CSCC has increased in recent decades according to various estimates that do not include patients with only noninvasive precursor lesions (Lomas et al., Br J Dermatol , 166(5):1069–80, 2012; Que et al., J Am Acad Dermatol , 78(2):237–47, 2018; Rogers et al., ArchDermatol , 146(3):283–87, 2010). [0004] Risk factors for CSCC include UV exposure, older age, and immunosuppression (Alam et al., New Engl. J. Med . 344:975-83, 2001; Madan, Lancet 375:673-85, 2010). Although the vast majority of individuals diagnosed with CSCC or BCC have a very favorable prognosis, CSCC has a higher tendency to aggressive recurrence than BCC. Furthermore, individuals diagnosed with CSCC, unlike individuals diagnosed with BCC, have increased mortality compared to age-matched controls (Rees et al., Int. J. Cancer 137:878-84, 2015). [0005] Surgical resection is the central element of the clinical treatment of CSCC or BCC. The primary goal is complete resection of the malignancy, and an acceptable cosmetic outcome is a secondary goal. Factors associated with an unfavorable prognosis in CSCC include tumor size >2 cm, tumor invasion depth >2 mm, perineural invasion, host immunosuppression, and recurrent sites. However, some patients who develop advanced-stage CSCC, including both locally advanced and metastatic CSCC, are not candidates for surgery. Some such patients may be treated with postoperative radiation therapy or chemotherapy, but these may not be attractive options due to concerns about safety and tolerability. [0006] Field cancerization, defined as multiple malignant lesions in UV-exposed areas, is common in many patients with CSCC. Furthermore, recurrent CSCC increases the risk of subsequent recurrences. In a single-center retrospective study of 212 patients, recurrent CSCCs were twice as likely to recur after excisional surgery compared to primary CSCCs (Harris et al., Otolaryngol Head Neck Surg , 156(5):863-69, 2017). Multiple surgeries over a period of time can be disfiguring and lead to surgical fatigue, which is the physical and emotional exhaustion that results from consecutive surgeries. Furthermore, CSCC in head and neck sites such as the ear, temple, and lip is associated with poorer clinical outcomes (Brantsch et al., Lancet Oncol 9(8):713–20, 2008; Harris et al., Otolaryngol Head Neck Surg , 156(5):863–69, 2017; Thompson et al., JAMA Dermatol 2016; 152(4):419–28, 2016). [0007] The most common clinical subtype of BCC is nodular BCC. Less common clinical subtypes include superficial, morphoic (fibrosing), and fibroepithelial. Most patients are cured with surgery, but a small proportion of patients experience recurrent lesions or develop unresectable locally advanced or metastatic disease. Understanding the oncogenic role of the G protein-coupled receptor Smoothened (SMO) in BCC led to the development of vismodegib and sonidegib, orally administered SMO inhibitors, commonly referred to as hedgehog inhibitors (HHIs). In addition to the undesirable side effects of HHI, it was found that in patients who progressed during treatment with one HHI (vismodegib), subsequent treatment with another HHI (sonidegib) did not result in tumor inhibition (Danial et al., Clin. Cancer Res .22:1325-29, 2016). [0008] Thus, there remains a need for safe and effective therapy for skin cancers such as CSCC and BCC, particularly skin cancers that recur despite previous surgical interventions. [0009] Additionally, a small proportion of patients with CSCC are considered to be at high risk for CSCC, assessed using a number