This is an open-label, randomized study evaluating whether MRD-guided intermittent ICI therapy provides comparable survival to SOC continuous ICI therapy in subjects with histologically confirmed advanced / metastatic NSCLC, melanoma, MSI-High/dMMR CRC, RCC and other solid tumors. This study will be conducted in up to 100 sites.

This is a multi-center, open-label, randomized study evaluating whether MRD-guided intermittent ICI therapy provides non-inferior overall survival to SOC continuous ICI therapy in subjects with histologically confirmed advanced / metastatic NSCLC, melanoma, MSI-High/dMMR CRC, RCC and other solid tumors. Participants will be assigned to receive standard of care continuous ICI therapy, or molecular-residual disease (MRD)-guided intermittent immune-checkpoint inhibitor (ICI) therapy.

Participants meeting eligibility criteria are randomized into two arms:

Arm A (SOC Continuous ICI): Participants will continue current ICI therapy per standard of care (SOC). Standard infusion visits are maintained for the total of 2 years or until radiographic progression, unacceptable toxicity, other clinical indications for discontinuation or withdrawal of consent. Note: ICI therapy may be interrupted for toxicity and/or radiographic progression per SOC.

Arm B (MRD-Guided Intermittent ICI): Participants will interrupt ICI therapy upon randomization; reinitiate with the same ICI therapy (monotherapy or combination as documented at enrollment) if ctDNA(+) without evidence of radiographic progression per RECIST 1.1. Following reinitiation, ICI therapy may again be interrupted after achievement of ≥ 2 consecutive ctDNA-negative results (at least 6 weeks apart), and subsequently initiated upon recurrence of ctDNA positivity without evidence of radiographic progression. This cycle of MRD-guided interruption and reinitiation (maximum of 2 ICI interruptions) may continue until radiographic progression is documented. Upon radiographic progression, treatment will be determined by the treating physician in accordance with SOC.

Response assessments include imaging (CT/ MRI) (BICR review) and ctDNA testing performed at 12 weeks and then continued q12 weeks; PRO (QLQ-C30, FACT-ICM, PRO-CTCAE & EQ-5D-5L) data collection (q12 weeks); and continued AE assessment reviewed per CTCAE v6.0 at each visit and unscheduled contacts. Concomitant medications / new therapies data will be reviewed at each visit and updated continuously. Biospecimens (optional) will be banked at enrollment and at confirmed progression for future immune and molecular studies. Survival status will be assessed every 3 months until death, withdrawal of consent, or study discontinuation whichever comes first, for a maximum period of 5 years.

Inclusion Criteria:

General inclusion criteria includes the following selection criteria to be eligible for inclusion in any aspect of the study. Eligibility will be assessed by the investigator:

1. Signed Informed consent

2. Age ≥ 18 years

3. ECOG 0-2.

4. Histologically confirmed metastatic solid tumors including:

   Melanoma: Unresectable recurrent, advanced, or metastatic NSCLC: Advanced or Metastatic MSI-High/dMMR CRC: Metastatic RCC: Unresectable recurrent, advanced, or metastatic Other: Metastatic Solid tumors

5. Received First line ICI monotherapy or combo for a minimum of 12 months for NSCLC, RCC & other metastatic solid tumors, or for a minimum of 6 months for melanoma and MSI-High /dMMR CRC.

6. Radiographic CR/PR: Participants must have CR or PR at the last assessment performed within 6 weeks before randomization according to RECIST v1.1 using a diagnostic CT and/or MRI. Radiographic assessment will be confirmed by the BICR.

7. Known ctDNA negative with Signatera

   ≥ 2 consecutive ctDNA-negative results (from Natera's tissue-informed Signatera whole genome test) at least 6 wks apart; last test within 1 month of enrollment.

8. Adequate organ function:

   Hematology: ANC ≥1500/μL; Platelets ≥100000/μL;Hemoglobin ≥9.0g/dL; Renal: Serum Cr ≤1.5×ULN or calculated CrCl ≥60 mL/min (using Cock-Gault formula); Hepatic: Total bilirubin ≤1.5 ×ULN or, for subjects with total bilirubin levels >1.5×ULN, direct bilirubin within normal limits; AST (SGOT) and ALT (SGPT) ≤2.5×ULN; Coagulation: INR or PT, activated partial thromboplastin time (APTT) ≤1.5×ULN.

9. Recovery to baseline or ≤ Grade 1 common terminology criteria for adverse events (CTCAE) v6 from AE(s) related to any prior treatments unless AE(s) are deemed clinically non-significant by the Investigator and/or stable on supportive therapy.

10. No prior malignancy, with the exception of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, or in situ cancer, or has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since completion of definitive therapy.

    Subjects must be willing and able to comply with study visits, treatment plans, laboratory tests, and other study procedures.

11. WOCBP and male subjects partnering with WOCBP must agree to use highly effective contraception during the treatment phase and at least 180 days post last dose.

Exclusion Criteria:

1. Documented presence of a sensitizing EGFR, ALK, ROS-1, or BRAF V600E mutation or other genomic aberration for which an approved targeted therapy is available.
2. Available alternate treatment options with curative intent, e.g. surgery and / or RT with or without Chemotherapy.
3. Symptomatic or progressing CNS mets; or presence of leptomeningeal disease.
4. Patient has active autoimmune disease that required systemic treatment in the past 2 years, is immunocompromised in the opinion of the Investigator, or is receiving systemic immunosuppressive treatment. (Note: Participants with splenectomy are allowed.) Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment.
5. Patient is receiving systemic steroid therapy ≤3 days prior to enrollment or receiving any other form of immunosuppressive medication with the exception of daily steroid replacement therapy. Note: Use of inhaled corticosteroids, local steroid injection, or steroid eye drops is allowed.
6. Had allogeneic tissue/solid organ transplantation.
7. Interstitial lung disease or history of pneumonitis that has required oral or IV steroids. Note: Patients with lymphangitic carcinomatosis secondary to NSCLC can be considered as eligible.
8. Has received or will receive a live vaccine within 30 days prior to enrollment (seasonal flu vaccines that do not contain live vaccine are permitted).
9. Active infection requiring intravenous systemic therapy.
10. Known history of human immunodeficiency virus (HIV).
11. Known active Hepatitis B or C.
12. Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study.
13. Currently participating or has participated in a study of an investigational agent or using an investigational device within 4 weeks of enrollment.
14. Use of any commercial ctDNA or liquid biopsy monitoring outside of the study protocol during the primary 36-month monitoring period.