• 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.

• Type of Subject and Disease Characteristics

• Stage 3 or 4 histologically or cytologically confirmed NSCLC which has progressed or relapsed after treatment in the advanced setting

• ○ Stage 4 subjects: Part A and Part B: must have progressed or relapsed after first line treatment. Part C and Part D: must have progressed, discontinued due to toxicity, or relapsed after receiving (only) two prior lines of treatment for NSCLC in the advanced setting.

• ○ Stage 3 subjects - must have already failed, or be ineligible for, local, curative-intent therapy including surgery, and/or chemoradiation. Stage 3 subjects with documented relapse/progression after consolidation therapy with durvalumab following definitive chemoradiotherapy are eligible.

• Subjects must have secondary resistance to the prior ICI, as defined by the Society for Immunotherapy of Cancer (SITC) Immunotherapy Resistance Task Force (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) 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 PR or CR then progressed before 6 months, would still be eligible.

• Part A and Part B: Only one prior treatment for NSCLC in the advanced setting, which must have included one anti-PD-1/PD-L1 agent with documented radiographic disease progression on or after treatment.

‣ Prior treatment may have been with anti-PD-1/PD-L1 agent either alone or in combination with a non-anti-PD-1/PD-L1 treatment (e.g., chemotherapy)

⁃ Prior platinum-based chemotherapy is not required for eligibility.

⁃ Subjects receiving more than one ICI in the advanced setting (e.g., anti-PD-1/PD-L1 and anti-CTLA-4 compounds) will not be eligible.

• Part C and Part D: Only two prior treatments for NSCLC in the advanced setting, which must have included an anti-PD-1/PD-L1 agent, a platinum-based chemotherapy, and docetaxel, regardless of order or combination, with documented radiographic disease progression, intolerable toxicity, or relapse after treatment.

• ○ Combination of immune therapy is allowed (e.g., anti-PD-1/PD-L1 and anti-CTLA-4 compounds; anti-PD-1/PD-L1 and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT)-based immunotherapy).

• No prior targeted therapy for driver mutations.

• At least one measurable target lesion that meets the definition of RECIST v1.1.

• Part A and Part B: An archival tissue sample (formalin fixed paraffin-embedded \[FFPE\] tissue block or unstained slides) is required if tissue is available at baseline. Sample does not need to be received by central lab prior to Cycle 1, Day 1 (C1D1). Subjects without archival tissue available at baseline may be eligible with Medical Monitor approval.

• Part C and Part D: Archival tissue is not required. 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 due to Gilbert's syndrome

⁃ Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 × ULN. For subjects with liver metastases present at baseline, ALT and/or AST ≤ 3 × ULN is permitted.

• Renal function:

• ○ Creatinine clearance ≥ 60 mL/min calculated by the Cockcroft-Gault formula using actual body weight (see Table 15) or 24-hour urine collection.

• Gender and Reproductive Considerations

⁃ Women of childbearing potential (WOCBP) must have 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 by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Refer to Appendix 4, Section 10.4 for details and definitions of WOCBP, postmenopausal females and contraception guidance.

⁃ 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 plus 6 months after last dose of IP), if conception is possible during this interval.

⁃ Male subjects and WOCBP partners of male subjects should use a combination of the methods specified in Section 10.4 for the women along with a male condom from first dose of THIO (Cycle 1, Day 1), for the duration of the treatment with THIO plus 6 months after last dose of IP, unless permanently sterile by bilateral orchidectomy. Male subjects should also refrain from sperm donation during this time.

⁃ Informed Consent

⁃ Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol