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A non-randomized two-cohort study of neoadjuvant Cemiplimab or neoadjuvant Cemiplimab plus Fianlimab (CF) in patients with basal cell carcinoma of the head and neck. Enrollment in the dual-therapy cohort will begin after completion of enrollment in the monotherapy cohort. Patients will undergo at least 2 and up to 6 infusions of immunotherapy prior to surgical resection. If patients have progression on neoadjuvant treatment, they may switch to standard of care surgical resection or hedgehog inhibitors prior to surgery. The primary endpoints are objective response rate and disease control rate. Safety and surgical benefit rate (de-escalation of surgery) with preservation of key anatomic structures are secondary endpoints. Correlative endpoints include analysis of pre and post treatment primary tumor and blood samples compared for histology, tumor genetics and immune cell composition.

The proposed study is a phase II trial of neoadjuvant Cemiplimab (cohort 1) or Cemiplimab plus Fianlimab (cohort 2) that will target patients with advanced BCCHN who have not been previously treated with anti-PD1 checkpoint therapy for this primary lesion. Patients will be assessed by the enrolling surgeon for response to therapy every 3 weeks (before initiating the next cycle) by clinical assessment, and by imaging assessment (every 6 weeks). Patients will undergo a minimum of 2 cycles of therapy over a 6-week window prior to surgery. Patients who demonstrate clinical or RECISTv1.1 response or stable disease with regression or up to 5% growth, will go on to the next cycle of treatment. Patients who demonstrate clinical or RECISTv1.1 radiographic progression or stable disease with >5%-20% growth will proceed directly to surgery or to other SOC therapy (after biopsies) (Fig 1). Patients who demonstrate a complete clinical response prior to at any assessment prior to completion of 6 cycles will proceed to appropriate surgery or biopsy of tumor site to ensure complete pathologic response at the time of CR.

PRIMARY OBJECTIVE:

I. Our primary objective is to assess treatment response of locally advanced BCC of the head and neck (BCCHN) in the neoadjuvant, presurgical setting.

SECONDARY OBJECTIVES:

I. To assess functional organ preservation with neoadjuvant Cemiplimab or Cemiplimab plus Fianlimab therapy.

II. To assess pathologic response. III. To assess safety of neoadjuvant therapy. IV. To assess changes in quality of life.

EXPLORATORY OBJECTIVE:

I. To assess treatment-related changes in the immune microenvironment related to functional changes in immune cell composition.

Inclusion Criteria:

-Individuals must meet all of the following inclusion criteria in order to be eligible to participate in the study:

1. Pathologically confirmed, locally-advanced BCC of the head and neck of any stage which is not resectable without major morbidity or unresectable, defined as requiring greater than 30% auriculectomy, rhinectomy, upper or lower lip resection, orbital exenteration (due to lid or orbital involvement), facial nerve sacrifice, or any Brigham and Women's stage 2b or 3 disease of head and neck (see Table 5).

2. Male or female, aged ≥18 years of age

3. Performance status 0-1.

4. Must have a life expectancy of at least 6 months as judged by the treating physician.

5. Adequate organ function:

   1. Absolute neutrophil count 1500/μl or more;
   2. Platelets 100,000/μl or more,
   3. Hemoglobin 9 g/dl or more;
   4. Bilirubin less than or equal to 1.5 x the upper limit of normal (except subjects with Gilbert syndrome, who can have total bilirubin <3 mg/dl);
   5. AST and ALT less than or equal to 2.5 x the upper limit of normal,
   6. GFR greater than or equal to 40 ml/min using the Cockcroft-Gault formula or measured creatinine clearance using 24 hours urine collection

6. Women of reproductive potential should have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG), which must also be confirmed as negative within 28 days of the start of study drugs.

7. Women of reproductive potential must use highly effective contraception methods to avoid pregnancy for 120 days after the last dose of study drugs. "Women of reproductive potential" is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL.

8. Men of reproductive potential who are sexually active with women of reproductive potential must use any contraceptive method with a failure rate of less than 1% per year. Men who are receiving the study medications will be instructed to adhere to contraception for 120 days after the last dose of study drugs. Men who are azoospermic do not require contraception.

9. Informed Consent: All subjects must be able to comprehend and sign a written informed consent document.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Prior radiation therapy within the past 6 months for this target cancer documented by surgeon at Visit 1, Day 0 initial assessment. (Prior surgical resection to area/tumor is acceptable.)
2. Any history of allergy to the study drug components.
3. Any concurrent malignancies: exceptions include- basal cell carcinoma of the skin at another site, chronic lymphocytic leukemia, melanoma in situ, squamous cell carcinoma of the skin of a secondary location, superficial bladder cancer or in situ cervical cancer that has undergone potentially curative therapy. Patients with a history of other prior malignancy must have been treated with curative intent and must have remained disease-free for 2 years post-diagnosis.
4. Any unresolved toxicity NCI CTCAE v 5.0 Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with anti-PD1 therapy may be included only after consultation with the Study Physician.
5. Any Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 28 days of study drug administration., or a prior history of allogenic organ transplantation.
6. Any diagnosis of a significant connective tissue disorder as determined by the treating surgeon or medical team.
7. Patients must not be receiving any other investigational agents.
8. Receipt of a live attenuated vaccine within 30 days prior to the first dose of drug on trial.
9. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
10. Patients must not be pregnant or breastfeeding.
11. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc]and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV)antibody are eligible only if polymerase chain reaction is negative for HCVRNA.
12. Any patient with prior immunotherapy or HHI for malignancy treatment.
13. Any untreated metastasis(es) to the brain that may be considered active.
14. History of pneumonitis with the past 5 years.