A Value-Driven Study on Reducing Immune Checkpoint Inhibitor Dosing Frequency in Advanced Cancers

Inclusion Criteria:

1. Provision of informed consent prior to any study-specific procedure

2. Patients with one of the following:

• Cohort A: Previously untreated locally advanced/metastatic HER2 -vegastric/gastroesophageal junction/esophageal (PDL1 CPS ≥5% adenocarcinomas notamenable to curative surgery or radiotherapy who are above to begin platinumdouble and nivolumab.

• Cohort B: Previously untreated locally advanced/metastatic Child's Ahepatocellular carcinoma not amenable to curative surgery or radiotherapy whoare above to begin atezolizumab and bevacizumab.

• Cohort C: Previously untreated locally advanced/metastatic lung adenocarcinoma (PDL1 TPS≥50%, EGFR/ALK wildtype) not amenable to curative surgery orradiotherapy who are above to begin pembrolizumab monotherapy

3. Measurable disease per RECIST 1.1 criteria

4. ECOG Performance status is 0-2

5. Normal organ and bone marrow function measured within 28 days before the study asdefined below:

• Haemoglobin ≥ 8.0 g/dL and no blood transfusions in the 28 days prior to entry

• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L

• No features suggestive of MDS/AML on peripheral blood smear

• White blood cells (WBC) > 3x10^9/L

• Platelet count ≥ 100 x 10^9/L

• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)

• AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless livermetastases are present in which case it must be ≤ 5x ULN

• Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN)

6. A life expectancy ≥ 12 weeks in all patients.

7. Females in childbearing age should be using adequate contraceptive measures, shouldnot be breastfeeding and their pregnancy test prior to the start of treatment mustbe negative. Evidence of non-child-bearing potential is fulfilled by one of thefollowing criteria at screening:

8. The post-menopausal period defined as age ≥50 years and amenorrheic for at least 12months following cessation of all exogenous hormonal treatments

9. Women <50 years old they have been amenorrheic for 12 months or more followingcessation of exogenous hormonal treatments and with LH and FSH levels in thepost-menopausal range.

10. Documentation of irreversible surgical sterilisation by hysterectomy, bilateraloophorectomy or bilateral salpingectomy but not a tubal ligatio

11. Male patients should be willing to use barrier contraception

12. The patient is willing to comply with the protocol during the study includingundergoing treatment and scheduled visits and examinations including follow up.

13. At least one lesion, not previously irradiated, that can be accurately measured atbaseline as ≥ 10 mm in the longest diameter (except lymph nodes which must haveshort axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and is considered suitable for accurate repeated measurements

Exclusion Criteria:

1. Patients who have previously received immune checkpoint inhibitors orinvestigational monoclonal antibody therapy.

2. Patients with second primary cancer, except: adequately treated non-melanoma skincancer, curatively treated in-situ cancer of the cervix, or other solid tumourscuratively treated with no evidence of disease for ≥ 5 years

3. Unstable spinal cord compression/brain metastases unless asymptomatic and notrequiring steroids for at least 2 weeks prior to the start of study treatment. Forpatients with brain metastases, gamma knife or stereotactic brain surgery is allowedprior to study treatment.

4. Major surgery within 4 weeks of starting study treatment and patients must haverecovered from any effects of any major surgery. Minor surgery is allowed.

5. Severe or uncontrolled systemic diseases, including uncontrolled hypertension andactive bleeding diatheses, which based on investigator's opinion makes itundesirable for the patient to participate in the trial or which would jeopardisecompliance with the protocol, or having active infection including hepatitis B,hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditionsis not required.

6. Autoimmune disorders

7. Males and females of reproductive potential who are not using an effective method ofcontraception and females who are pregnant or breastfeeding or have a positive serumpregnancy test prior to study entry

8. Judgment by the Investigator that the patient should not participate in the study ifthe patient is unlikely to comply with study procedures, restrictions andrequirements

9. Previous allogeneic bone marrow transplant.