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 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:

1. The patient has no history of intracranial haemorrhage, spinal cord haemorrhage or haemorrhagic intracranial lesions

2. 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

3. The patient is on a dose of corticosteroids ≤ 10 mg of oral prednisone or equivalent; anticonvulsant therapy at a stable dose is permitted

4. Metastases are limited to the cerebellum or the supratentorial region (i.e., no metastases to the midbrain, pons, medulla or spinal cord)

5. 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:

1. Patients with vitiligo or alopecia

2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement

3. 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

4. psoriasis that does not require systemic treatment.

5. 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:

1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)

2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent

3. 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.

What this study is about