A Multicenter Open-label Phase II Study of Cemiplimab Plus Chemotherapy, Selected on the Basis of Baseline Cytidine Deaminase Activity, in Advanced Squamous Non-small Cell Lung Cancer

Patients will receive chemotherapy plus Cemiplimab according to the baseline CDA enzymatic activity measured baseline in plasma samples by spectrophotometric assay: Patients with low CDA activity (< 7.2 U/mg) will receive: Cisplatin 80 mg/sqm on day 1 + Gemcitabine 1200 mg/sqm on days 1 and 8 and Cemiplimab 350 mg on day 1 administered every 3 weeks for 4 cycles followed by Cemiplimab 350 mg every 3 weeks until disease progression or unacceptable toxicity or a maximum of 108 weeks; or of investigator's choice: Carboplatin AUC 5 day 1 + Gemcitabine 1000 mg/sqm on days 1 and 8 and Cemiplimab 350 mg on day 1 administered every 21 days for 4 cycles followed by Cemiplimab 350 mg every 3 weeks until disease progression or unacceptable toxicity or a maximum of 108 weeks Patients with high CDA activity (≥ 7.2 U/mg) will receive carboplatin at an area under the concentration-time curve of 6 mg/mL/min IV (day 1) + paclitaxel 200 mg/sqm on days 1 and Cemiplimab 350 mg on day 1 administered every 21 days for 4 cycles followed by Cemiplimab 350 mg every 3 weeks until disease progression or unacceptable toxicity or a maximum of 108 weeks.

Inclusion criteria

• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
• Written informed consent and any locally required authorization obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
• Age > 18 years at the time of study entry.
• Histologically or cytologically (cell blocks only; smears are not acceptable) documented pulmonary squamous carcinoma.
• Stage IV or recurrent disease according to the AJCC 8th edition Cancer Staging Manual.
• Body weight > 30 kg
• No prior chemotherapy or treatment with another systemic anti-cancer agent for the metastatic disease.
• Patients who have received prior neo-adjuvant, adjuvant chemotherapy or chemoradiotherapy with curative intent for non-metastatic disease must have experienced a treatment- free interval of at least 6 months from enrolment since the last chemotherapy or completion of chemoradiotherapy.
• Patients who received prior anti-PD-(L)1 as adjuvant or neoadjuvant therapy at stage 3B /3C disease will be allowed if have experienced a treatment-free interval of at least 6 months from enrolment since the last immunotherapy dose.
• Known PD-L1 tumor status as determined by an IHC assay performed by local laboratory on previously obtained archival tumor tissue or tissue obtained from a biopsy at screening.
• No need for concomitant chest irradiation.
• ECOG perforance status 0-1.
• Life expectancy ≥12 weeks.
• At least one lesion measurable according to RECIST v 1.1 outside of the CNS, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis > 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements.
• Adequate hematologic function as evidenced by absolute neutrophil count (ANC) ≥1,500/μL, hemoglobin ≥ 9.0 g/dL (5.58 mmol/L), and platelet count ≥ 100,000/μl.
• Adequate hepatic and renal function:

• Total bilirubin ≤ 1.5 times the upper limit of normal (ULN).
• ALT (SGPT), AST (SGOT) ≤ 2.5 x institutional upper limit of normal (< 5 x ULN if the liver has tumor involvment).
• Serum creatinine ≤ 1.5 times the ULN or creatinine clearance ≥ 60 mL/min, calculated according to the standard Cockcroft and Gault formula.
• The patient has adequate coagulation function as defined by International Normalized Ratio (INR) ≤ 1.5 and a partial thromboplastin time (PTT) (PTT/aPTT) < 1.5 x ULN.
• Patients on full-dose anticoagulation must be on a stable dose (minimum duration 14 days) of oral anticoagulant or low molecular weight heparin (LMWH). If receiving warfarin, the patient must have an INR ≤ 3.0.
• Female patients must have a negative pregnancy test and not be breast feeding prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:

• Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments.
• Women under 50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments and with LH and FSH levels in the post- menopausal range for the institution.
• Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
• For female patients of childbearing potential, agreement (by patient and/or partner) to use a highly effective form of contraception that results in a low failure rate (< 1% per year) when used consistently and correctly, and to continue its use for 6 months after the last dose of chemotherapy or at least 4 months after the last dose of cemiplimab, whichever occurs last. Such methods include: combined (estrogen and progestogen containing) hormonal contraception, progestogen-only hormonal contraception associated with inhibition of ovulation together with another additional barrier method always containing a spermicide, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, and vasectomized partner (on the understanding that this is the only one partner during the whole study duration).
• Male patients who are sexually active must be willing to use barrier contraceptives (i.e.; by use of condoms) during sex with all partners during treatment with chemotherapy and for at least 6 months after the last dose of chemotherapy or at least 4 months after the last dose of cemiplimab, whichever occurs last. Patients should refrain from donating sperm from the start of dosing until 6 months after discontinuing study treatment.
• Ability to comply with the study protocol, in the investigator's judgment.

Exclusion criteria

• Patients with a sensitizing mutation in the epidermal growth factor receptor (EGFR) gene, or with anaplastic lymphoma kinase (EML4-ALK) translocations or with ROS1 proto-oncogene receptor tyrosine kinase (ROS1) translocations. EGFR mutations, ALK and ROS1 translocations will be assessed in never- smoker patients
• Symptomatic brain metastases or spinal cord compression (CT or MRI of the head is required within 4 weeks prior to registration) requiring immediate radiotherapy for palliation. Patients with asymptomatic CNS lesions are eligible, provided that all of the following criteria are met:

• The patient has no history of intracranial haemorrhage, spinal cord haemorrhage or haemorrhagic intracranial lesions
• At least 14 days between the end of stereotactic radiotherapy or whole brain radiotherapy and initiation of study treatment, or at least 28 days between neurosurgical resection and initiation of study treatment
• The patient is on a dose of corticosteroids ≤ 10 mg of oral prednisone or equivalent; anticonvulsant therapy at a stable dose is permitted
• Metastases are limited to the cerebellum or the supratentorial region (i.e., no metastases to the midbrain, pons, medulla or spinal cord)
• There is no evidence of interim progression between completion of CNS directed therapy (if administered) and initiation of study treatment.
• History of leptomeningeal disease.
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures. Patients with indwelling catheters (e.g., Pleura-Cath) are allowed.
• Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected calcium > ULN).
• History of cardiac disease: congestive heart failure >NYHA class 2; active CAD (MI or acute coronary syndrome more than 12 months prior to study entry is allowed); cardiac arrythmias requiring anti-arrythmic therapy (beta blockers or digoxin are permitted) or uncontrolled hypertension.
• Transient ischemic attack or stroke within 1 year
• Active SARS- COV-2 infection.
• 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.
• Participants with HBsAg positive who have controlled infection (serum HBV DNA PCR that is below the limit of detection and receiving anti-viral therapy for hepatitis B) are eligible. Participants with controlled infections must undergo periodic monitoring of HBV DNA. Participants must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study medication.
• Participants with HBsAg negative but total HBcAb positive are permitted with the following requirements: If serum HBV DNA PCR is above the limit of detection at screening, initiate HBV antiviral therapy before study entry. If serum HBV DNA PCR is below the limit of detection, periodic monitoring of HBsAg must be performed.
• Participants who are 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 eligible.
• Known positive serology for HIV. Participants with known controlled HIV infection (undetectable viral load on HIV RNA PCR) and CD4 count above 350 either spontaneously or on a stable antiviral regimen are eligible. For these participants monitoring will be performed per local standards.
• Any infection requiring hospitalization or treatment with IV anti-infectives within 2 weeks of first dose of study medication
• Significant traumatic injury or radiotherapy involving an extensive field within the last 4 weeks prior to first dose of study treatment or anticipation of the need for major surgery during study treatment. Palliative radiotherapy to a limited field is allowed if concluded at least 2 weeks prior enrolment.
• Other malignancies (previous or current), except for adequately treated in situ carcinoma of the uterine cervix, basal or squamous cell carcinoma of the skin, localized prostate cancer surgically treated with curative intent or ductal carcinoma in situ treated surgically treated with curative intent or if previous malignancy was more than 5 years prior and there are no signs or symptoms of recurrence.
• Major surgery (including open biopsy) within 28 days prior to first dose of protocol therapy.
• Prior allogeneic stem cell or solid organ transplantation.
• Patients with any underlying medical condition that might be aggravated by treatment or which cannot be controlled i.e. patients with active serious infection, uncontrolled diabetes mellitus, pericardial effusion.
• Any concurrent chemotherapy, Investigational Product, biologic, or hormonal therapy for cancer treatment other than those in the present study. Concurrent use of hormonal therapy for non-cancer- related conditions (e.g., hormone replacement therapy) is acceptable.
• Treatment with any other investigational agent within 30 days prior to starting study treatment, or concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
• Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contra- indicates the use of an investigational drug or puts the patient at high risk for treatment- related complications
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:

• Patients with vitiligo or alopecia
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
• Any chronic skin condition that does not require systemic therapy. Patients without active disease in the last 5 years may be included but only after consultation with the study physician
• psoriasis that does not require systemic treatment.
• Patients with celiac disease controlled by diet alone.
• History or active autoimmune neurologic paraneoplastic syndrome (e.g. non infectious encephalitis, Lambert- Eaton syndrome etc.) or any other immune-mediated paraneoplastic syndrome.

Patients with SIADH or ectopic ATCH production are allowed on the study.

• Patient has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP. Receipt of COVID-19 vaccination within 1 week of planned start of study medication or for which the planned COVID-19 vaccinations would not be completed 1 week prior to start of study medication
• History of idiopathic pulmonary fibrosis, including pneumonitis, drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• Prior therapy for metastatic disease with any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent and anti-CTL-A4 agent.
• Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug elimination half-lives (whichever is longer) prior to initiation of study treatment.
• Any condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of randomization. The following are exceptions to this criterion:

• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
• Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
• History of allergies or hypersensitivity to any study drugs or study drug components or excipient.
• Any unresolved toxicity NCI CTCAE 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 carboplatin, paclitaxel, gemcitabine or cemiplimab may be included only after consultation with the Study Physician.
• Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.

• Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 6 months after last chemotherapy dose or at least 4 months after the last dose of cemiplimab, whichever occurs last. WOCBP and men 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 4 months after the last dose. Highly effective contraceptive measures include:
• 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;
• Intrauterine device; intrauterine hormone-releasing system;
• Bilateral tubal occlusion/ligation;
• Vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the WOCBP study participant and that the vasectomized partner has obtained medical assessment of surgical success for the procedure); and/or Sexual abstinence
• Patients should refrain from donating sperm from the start of dosing until 6 months after discontinuing study treatment.
• Patients should not donate blood whilst on this study.