Overview

Cutaneous Squamous Cell Carcinoma (cSCC) is typically associated with a high tumour mutation burden, with the majority caused by Ultraviolet (UV) exposure (Pickering et al., 2014).

The use of this trial using neoadjuvant Pembrolizumab in patients with cSCC who will otherwise undergo highly morbid radical surgical resection has multiple potential advantages,

including

1. Reduction in surgical and radiotherapy morbidity by reducing tumour burden and allowing the appropriate selection of patients to undergo post-operative radiotherapy;
2. Provision of immediate information about pathological response and
3. Access to tissue to provide insight into resistance mechanisms and identification of biomarkers of response.

The Investigators hypothesized that the use of neoadjuvant Pembrolizumab could reduce tumour burden allowing appropriate selection of patients undergoing radical surgical resection and adjuvant radiotherapy.

Eligibility

Inclusion Criteria:

• Histologically confirmed diagnosis of invasive cSCC that is locally advanced (Stage II-IV on AJCC 8th edition) assessed preoperatively as sufficiently high risk that they will warrant post-operatively RT (as recommended by MDT) who is a candidate for a complete resection.

        Note: Participants with tumors arising on cutaneous non-glabrous (hair-bearing) lip with
        extension onto vermillion (dry red lip) may be eligible after communication and approval
        from the principal investigator. Participants for whom the primary site is the nose may be
        eligible after communication and approval from the MDT if the primary site is skin, not
        nasal mucosa with outward extension to skin. Participants who have squamous cell parotid
        metastases and have been treated previously for cSCC are permitted. cSCC that has recurred
        in the same location after 2 or more surgical procedures are not eligible.
          -  Participants must have measurable disease based on RECIST 1.1. Lesions situated in a
             previously irradiated area are considered measurable if progression has been
             demonstrated in such lesions.
          -  Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status
             of 0 to 1 within 10 days prior to the start of treatment.
          -  Participants must have adequate organ function
          -  Participants must have a tissue sample adequate for translational research. This
             tissue sample may be obtained from either a newly obtained core or excisional biopsy.
          -  Participants must have a life expectancy of greater than 6 months.
          -  Be at least 18 years of age on the day of signing the informed consent. 8. Female
             participants: Female participants of childbearing potential must have a negative urine
             or serum pregnancy test within 72 hours prior to receiving the first dose of trial
             medication. If the urine test is positive or cannot be confirmed as negative, a serum
             pregnancy test will be required.
        Note: In the event that 72 hours have elapsed between the screening pregnancy test and the
        first dose of study treatment, another pregnancy test (urine or serum) must be performed
        and must be negative in order for the participant to start receiving study medication.
        - A female participant is eligible to participate if she is not pregnant, not
        breastfeeding, and at least one of the following conditions applies: Not a woman of
        childbearing potential (WOCBP) as defined in Appendix 1 OR A WOCBP who agrees to use an
        adequate method of contraception during the treatment period and for at least 120 days
        after the last dose of study treatment. Note: Abstinence is acceptable if this is the usual
        lifestyle and preferred contraception for the participant.
        - The participant (or legally acceptable representative if applicable) must be willing and
        able to provide written informed consent for the trial. The participant may also provide
        consent for Future Biomedical Research. However the participant may participate in the main
        trial without participating in Future Biomedical Research.
        Exclusion Criteria:
          -  Participant has metastatic/unresectable cSCC that cannot be potentially cured with
             surgical resection, radiotherapy, or with a combination of surgery and radiotherapy.
          -  Participant has any other histologic type of skin cancer other than invasive squamous
             cell carcinoma as the primary disease under study, eg, basal cell carcinoma that has
             not been definitively treated with surgery or radiation, Bowen's disease, merkel cell
             carcinoma, melanoma.
          -  Participants with any prior allogeneic solid organ or hematopoietic stem cell
             transplantations are excluded.
          -  Participant has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2
             agent or with an agent directed to another stimulatory or co-inhibitory T-cell
             receptor (eg, CTLA-4, OX-40, CD137).
          -  Participant has received prior systemic anti-cancer therapy including investigational
             agents for cSCC.
          -  Participant has received prior radiotherapy to the target lesion.
          -  Participant has received a live vaccine within 30 days prior to the first dose of
             trial drug. Examples of live vaccines include, but are not limited to, the following:
             measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies,
             Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for
             injection are generally killed-virus vaccines and are allowed; however, intranasal
             influenza vaccines(eg, FluMist®) are live- attenuated vaccines and are not allowed.
          -  Participant is currently participating in or has participated in a trial of an
             investigational agent or has used an investigational device within 4 weeks prior to
             the first dose of trial treatment.
        Note: Participants who have entered the follow-up phase of an investigational trial may
        participate as long as it has been 4 weeks after the last dose of the previous
        investigational agent.
          -  Ongoing or recent (within 2 years) evidence of significant autoimmune disease that
             required treatment with systemic immunosuppressive treatments, which may suggest risk
             for immune-related adverse events (irAEs) or has a diagnosis of immunodeficiency
             disorders (such as HIV disease or organ transplantation or hematologic malignancies
             associated with immune suppression).
          -  The following are not exclusionary: vitiligo; asthma; type 1 diabetes; hypothyroidism
             that required only hormone replacement; or psoriasis that does not require systemic
             treatment.
          -  Participant has a diagnosis of immunodeficiency or is receiving systemic steroid
             therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form
             of immunosuppressive therapy within 7 days prior the first dose of trial drug.
          -  Participant has a diagnosis and/or has been treated for additional malignancy within
             the past 3 years prior to allocation.
        Note: Participants with cSCC of the skin that have undergone potentially curative therapy
        are not excluded if not related to current diagnosis.
        Note: Participants with basal cell carcinoma of the skin or carcinoma in situ (eg, breast
        carcinoma, cervical cancer or melanoma in situ) that have undergone potentially curative
        therapy are not excluded.
        Note: Participants with low-risk early-stage prostate cancer, defined as below are not
        excluded: Stage T1c or T2a with a Gleason score 6 and a prostate-specific antigen (PSA) (10
        ng/ml) either treated with definitive intent or untreated in active surveillance that has
        been stable for the past year prior to trial allocation.
          -  Participant has an active autoimmune disease that has required systemic treatment in
             the past 2 years (eg, with use of disease-modifying agents, anticoagulants,
             corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine,
             insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary
             insufficiency) is not considered a form of systemic treatment and is allowed.
          -  Participant has a history of (non-infectious) pneumonitis that required steroids or
             has current pneumonitis.
          -  Participant has an active infection requiring systemic therapy.
          -  Participant has a known history of Hepatitis B (defined as Hepatitis B surface antigen
             [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative]
             is detected) infection.
        Note: No testing for Hepatitis B or Hepatitis C is required unless mandated by a local
        health authority.
          -  Participant has a history or current evidence of any condition, therapy, or laboratory
             abnormality that might confound the results of the trial, interfere with the
             participant's participation for the full duration of the trial, or is not in the best
             interest of the participant to participate, in the opinion of the treating
             investigator.
          -  Participant has a known psychiatric or substance abuse disorder that would interfere
             with the participant's ability to cooperate with the requirements of the trial.
          -  Participant is pregnant or breastfeeding or expecting to conceive or father children
             within the projected duration of the trial, starting with the screening visit through
             120 days after the last dose of trial treatment.