A Phase III Study With THIO + Cemiplimab vs Chemotherapy as 3rd Line Treatment in Advanced/Metastatic NSCLC

Inclusion criteria

• At least 18 years of age at the time of signing the Informed Consent Form (ICF) prior to initiation of any study specific activities/procedures.

Disease Characteristics

• Stage 3b or 4 histologically or cytologically confirmed NSCLC. Note: Stage is determined at the time of diagnosis.
• Two (2) prior lines of systemic treatment for advanced/metastatic disease, including an ICI (anti-PD-1/PD-L1) and a platinum-based chemotherapy (given in combination or in separate lines) for advanced/metastatic disease.

Note: The combination of primary therapy followed by maintenance is considered as one line of therapy. Prior treatment with docetaxel is preferred (but not mandated) and is a pre-specified stratification factor.

• Documented progression or intolerance following the most recent line of therapy.

• Stage 4 subjects - must have progressed or relapsed after first-line treatment.
• Stage 3b subjects - must have already failed, or be ineligible for, local, curative-intent therapy including surgery, and/or chemoradiation.

Note: Local, curative-intent therapy including surgery, and/or chemoradiation is not considered a treatment line in the advanced setting.

• Documented secondary resistance to the prior ICI treatment, as defined by the SITC IRTF (Kluger, 2020):

Resistance phenotype Drug exposure requirements Best response Confirmation scan for PD requirement Confirmation scan timeframe Secondary resistance ≥ 6 months CR, PR, SD for > 6 months Yes [1] At least 4 weeks after disease progression (per RECIST V1.1) [1] Other than when tumor growth is very rapid, and subjects are deteriorating clinically.

Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease

• No prior targeted therapy for driver mutations.
• At least one measurable target lesion that meets the definition of RECIST v1.1, with documented progression following the most recent line of therapy.
• An archival tissue sample (formalin fixed paraffin-embedded [FFPE] tissue block or unstained slides) is required if tissue is available at baseline.

Note: The sample does not need to be received by the central laboratory prior to Cycle 1, Day 1 (C1D1). Subjects without archival tissue available at baseline may be eligible with Medical Monitor approval.

Diagnostic Assessments

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Demonstrate adequate organ function as defined below. All screening laboratories should be performed up to 14 days before initiating IP:

Bone marrow function:

○ Neutrophil count ≥ 1500/mm3, hemoglobin ≥ 9.0 g/dL, platelet count ≥ 100,000/mm3

Liver function:

• Total bilirubin ≤ 1.5 x the upper limit of normal (ULN), up to ≤ 3 × ULN if due to Gilbert's syndrome
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 × ULN.

Note: For subjects with liver metastases present at baseline, ALT and/or AST ≤ 3 × ULN is permitted.

Renal function:

○ Creatinine clearance (CrCl) ≥ 60 mL/min calculated by the Cockcroft-Gault formula using actual body weight (see Table 18) or 24-hour urine collection.

Gender and Reproductive Requirements

• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 72 hours prior to receiving the first administration of IP.
• Contraception use:

In the THIO / cemiplimab arm:

• WOCBP must agree to use a highly effective birth control and refrain from oocyte donation during the study (prior to the first dose with THIO, for the duration of the treatment with THIO, and for six months after the last dose of study treatment, if conception is possible during this interval).
• Unless permanently sterile by bilateral orchidectomy, male subjects and WOCBP partners of male subjects should use a combination of the methods specified for female subjects in Appendix 4, Section 10.4 along with a male condom, from start of study treatment, for the duration of the treatment, and for six months after the last dose of study treatment. Male subjects should also refrain from sperm donation during this time.

In the single-agent chemotherapy arm: For WOCBP, male subjects and WOCBP partners of male subjects, contraception requirements should follow the relevant product's package labelling and standard of care.

Note: Contraception use by men or women in both treatment arms should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

Informed Consent 13. Capable and willing to give signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion criteria

• For subjects who have received prior treatment with a checkpoint inhibitor: primary resistance to prior checkpoint inhibitor, as defined by the SITC IRTF (Kluger, 2020):

Resistance phenotype Drug exposure requirements Best response Confirmation scan for PD requirement Confirmation scan timeframe Primary resistance ≥ 6 weeks PD; SD for < 6 months Yes [1] At least 4 weeks after initial disease progression (per RECIST v1.1) [1] Other than when tumor growth is very rapid, and subjects are deteriorating clinically.

Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease Note: Subjects with drug exposure > 6 weeks who achieved a partial or complete response then progressed before six months, would still be eligible.

• Untreated or symptomatic central nervous system (CNS) metastases. Note: Subjects with treated asymptomatic brain metastasis are eligible.
• Prior chemotherapy and/or non-biologic targeted therapy within 28 days, or biologic targeted therapy, immunotherapy, and/or radiation therapy within 42 days prior to start of study treatment.

Note: Subjects who receive targeted radiation therapy for localized palliative care may be eligible to start study treatment earlier than 42 days with Medical Monitor agreement.

• Prior treatment with cemiplimab.
• Prior treatment with a targeted therapy for an epidermal growth factor receptor (EGFR) mutation.
• Received blood, red blood cell or platelet transfusion within 14 days prior to start of study treatment.
• Any live, attenuated, inactivated or research vaccines within 30 days prior to start of study treatment.

Note: Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed.

• Prior allogeneic hematopoietic stem cell transplant or solid organ transplant.
• Undergone major surgery within 28 days prior to start of study treatment. Medical conditions
• Have not recovered to Grade ≤ 1 from adverse events due to prior anti-cancer treatment.
• Ongoing immune-related / stimulated adverse events (irAEs) from other agents or required permanent discontinuation of prior ICIs due to irAEs.

Note: Subjects with resolved irAE may be allowed to enroll following consultation with the Medical Monitor.

• Active gastrointestinal bleeding as evidenced by either hematemesis or melena.
• History of another concurrent malignancy other than the present condition (except nonmelanoma skin cancer or carcinoma in situ of the cervix), unless in complete remission and off all therapy for that disease for a minimum of three years.
• A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to start of study treatment.

Note: Inhaled or topical steroids, adrenal replacement doses 10 mg daily prednisone equivalents, and systemic corticosteroids to manage adverse events are permitted in the absence of active autoimmune disease.

• Active, uncontrolled bacterial, viral or fungal infections, requiring systemic therapy within 14 days of screening.
• Positive for Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), active hepatitis B or hepatitis C.
• Significant cardiovascular impairment (history of New York Heart Association Functional Classification System Class III or IV) or a history of myocardial infarction or unstable angina within the past six months prior to start of study treatment.
• QT interval corrected for heart rate (using Fridericia's correction formula; QTcF) > 480 msec at screening (based on average of triplicate electrocardiograms [ECGs] at baseline).

Note: If the QTc is prolonged in a subject with a pacemaker or bundle branch block, the subject may be enrolled in the study if confirmed by the Medical Monitor.

• Active autoimmune diseases or history of autoimmune diseases that may relapse, with the following exceptions:

• Controlled Type 1 diabetes
• Hypothyroidism (provided it is managed with hormone replacement therapy only)
• Controlled celiac disease
• Skin diseases not requiring systemic treatment (e.g., vitiligo, psoriasis, or alopecia)
• Any other disease that is not expected to recur in the absence of external triggering factors.
• Pregnancy or lactating.
• A serious nonmalignant disease (e.g., psychiatric, substance abuse, uncontrolled intercurrent illness, interstitial lung disease etc.) that could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor.
• Any other condition that, in the opinion of the Investigator, would prohibit the subject from participating in the study.

Prior / concurrent clinical study experience

• Currently enrolled in a clinical study involving another investigational product or nonapproved use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.

Other

• History of allergy to excipients of THIO, cemiplimab or any of the chemotherapies under study.