An Open-label, Randomized, Phase I/II Trial Investigating the Safety and Efficacy of IO102 in Combination with Pembrolizumab, with or without Chemotherapy, as First-line Treatment for Patients with Metastatic Non-Small Cell Lung Cancer

1. Patients with histologically or cytologically confirmed metastatic NSCLC (Cohort A) or non squamous NSCLC (Cohort B), who have not received prior systemic treatment for their metastatic disease.
a. No known sensitizing EGFR or ALK mutations.
b. Solitary metastases must be biopsied to confirm the diagnosis metastasis from NSCLC
2. PD-L1 tumor expression of greater than or equal to 50% (Cohort A) or below 50% (Cohort B). PD-L1 tumour expression should be confirmed prior to randomization using the DAKO 22C3 assay, using local/central services.
3. A male participant able to father a child must agree to use contraception starting with the screening visit and through 120 days after last dose of pembrolizumab or 180 days after last dose of chemotherapy.
Note: See section 6.7.2 of the protocol for details on contraception
4. A female participant is eligible to participate if she is not pregnant not breastfeeding, and at least one of the following conditions applies:
a. Not a woman of childbearing potential (WOCBP)
b. A WOCBP who agrees to follow contraceptive guidance starting with the screening visit and through 120 days after last dose of pembrolizumab or 180 days after last dose of chemotherapy.
Note: A WOCBP i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Tubal ligation is NOT a method of permanent sterilisation. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
Note: See section 6.7.2 of the protocol for details on contraception.
5. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial in accordance with ICH-GCP and local legislation prior to admission to the trial.
6. Be equal to or over 18 years of age on day of signing informed consent.
7. Have measurable disease per RECIST 1.1 as assessed by local site investigator/radiologist. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
8. Have provided a blood sample and archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded tissue blocks are preferred to slides.
Note: If archival tissue is available, it is preferred this is obtained within 90 days prior to randomization. If using unstained cut slides, newly cut slides should be used for the testing, within 14 days from the date slides are cut.
9. Have an ECOG performance status of 0 to 1.
10. Have adequate organ function as defined in the following Table 3. Specimens must be collected within 10 days prior to the start of trial treatment.

1. A WOCBP who has a positive urine pregnancy test (e.g., within 72 hours) prior to treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
2. 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 and was discontinued from that treatment due to a Grade 3 or higher immune-related AE (irAE).
3. Has received prior systemic anti-cancer therapy in the first line setting for the participant's metastatic disease.
Note: Participants must have recovered from all AEs due to previous therapies to *Grade 1 or baseline. Participants with *Grade 2 neuropathy may be eligible.
Note: If participant received major surgery, they must have recovered adequately from the adverse events and/or complications from the intervention prior to starting trial treatment.
4. Has received prior radiotherapy to the lung >30 Gy within 6 months of start of trial treatment. Participants must have recovered from all radiation-related adverse events, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (*2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
5. Has received a live vaccine within 30 days prior to the first dose of trial treatment. Seasonal influenza vaccines for
injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
6. Is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 6 months 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 6 months after the last dose of the previous investigational agent.
7. Has a diagnosis of immunodeficiency or is receiving chronic 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 treatment.
8. Has a known additional malignancy that is progressing or has required active treatment within the past 2 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
9. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during trial screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of trial treatment.
10. Has severe hypersensitivity (*Grade 3) to IO102, pembrolizumab, carboplatin, pemetrexed and/or any of its excipients.
11. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of
systemic treatment and is allowed.
12. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
13. Has an active infection requiring systemic therapy.
14. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority.
15. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (HCV) (defined as HCV ribonucleic acid *RNA* [qualitative] is detected) infection.
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
17. Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the trial.
18. 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 for cohort A and 180 days for cohort B after last dose of trial treatment.
19. Has had an allogenic tissue/solid organ transplant.