Tiragolumab and Atezolizumab in Advanced Pan-cancer Patients

Inclusion Criteria:

1. Provision of written informed consent.

2. Aged ≥18 years old.

3. Histologically or cytologically confirmed locally advanced unresectable ormetastatic solid tumour.

4. Exhausted all available standard therapy or not suitable for standard therapy (including targeted therapies) for the tumour.

5. ECOG performance status score of 0-1.

6. Sufficient and accessible tumour tissue for panel sequencing, PD-L1 and TIL testing,and tertiary objectives.

7. Tumour biomarker criteria predictive of immune response defined by presence of oneor more of the following;

• Group 1: tumour mutation burden ≥ 10 mutations per megabase.

• Group 2: PD-L1 amplification >6 copy number alterations

• Group 3: tumour PD-L1 expression TAP score ≥ 5%

• Group 4: tumour infiltrating lymphocytes (TILs) (CD3+CD8+) ≥ 5%.

8. Patient is willing to provide tumour biopsy samples on treatment at Week 4.

9. Life expectancy >12 weeks.

10. Measurable disease as defined by iRECIST or RANO criteria.

11. Adequate haematological and biochemical indices as defined by:

• Absolute neutrophil count ≥1.0 x 10^9/L

• Haemoglobin ≥100 g/L

• Platelet count ≥100 x 10^9/L

• Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This willnot apply to patients with confirmed Gilbert's syndrome (persistent orrecurrent hyperbilirubinemia that is predominantly unconjugated in the absenceof haemolysis or hepatic pathology), who will be allowed only in consultationwith their physician.

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5x ULN;or ≤5.0x ULN if liver metastases are present.

• International normalised ratio (INR) <1.3 in the absence of anticoagulationtherapy.

• Serum creatinine clearance >40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance.

12. Negative HIV test at screening, with the following exception: patients with apositive HIV test at screening are eligible provided they are stable onantiretroviral therapy, have a CD4 count ≥ 200cells/mm3 , and have an undetectableviral load.

13. Negative hepatitis B surface antigen (HBsAg) test at screening.

14. Positive hepatitis B surface antibody (HBsAb) test at screening, or negative HBsAbat screening accompanied by either of the following:

• Negative total hepatitis B core antibody (HBcAb);

• Positive total HBcAb test followed by quantitative hepatitis B virus (HBV) DNA < 500 IU/mL. The HBV DNA test must be performed for patients who have a negative HBsAg test, anegative HBsAb test, and a positive total HBcAb test.

15. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCVantibody test followed by a negative HCV RNA test at screening. The HCV RNA testmust be performed for patients who have a positive HCV antibody test.

16. Women of childbearing potential must have a negative screening serum pregnancy testwithin 14 days prior to the first dose of study medication.

17. Women of childbearing potential and men must remain abstinent or use contraceptivemethods with a failure rate of <1% per year during the study and for at least 5months after the last dose of study medication.

18. Ability to adhere to the study visit schedule and understand and comply with allprotocol requirements and instructions from study staff.

Exclusion Criteria:

1. Involvement in the planning and/or conduct of the study (applies to both Roche staffand/or staff at the study site).

2. Patients with non-small cell lung cancer.

3. Participation in another clinical study with an investigational product during thelast 4 weeks prior to study enrolment.

4. Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy. Patientswith irreversible toxicity that is not reasonably expected to be exacerbated by theinvestigational product may be included (e.g., hearing loss, peripherallyneuropathy).

5. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3electrocardiograms (ECGs) using Fridericia's Correction.

6. Treatment with systemic immunosuppressive medication (including, but not limited to,corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, andanti-tumor necrosis factor-α [TNF-α] agents) within 2 weeks prior to initiation ofstudy treatment, or anticipation of need for systemic immunosuppressive medicationduring study treatment, with the following exceptions:

• topical, intranasal, or inhaled corticosteroids or systemic corticosteroids ator below physiological doses (eg. ≤10 mg/day of prednisone);

• use of dexamethasone up to 4mg/day within 14 days of initial treatment forpatients with brain tumours.

7. Symptomatic or actively progressing central nervous system (CNS) metastases. Asymptomatic patients with treated or untreated CNS lesions are eligible, providedthat all of the following criteria are met:

• Measurable disease, per RECIST v1.1, must be present outside the CNS.

• The patient has no history of intracranial haemorrhage or spinal cordhaemorrhage.

• The patient has not undergone stereotactic radiotherapy within 7 days prior toinitiation of study treatment, whole-brain radiotherapy within 14 days prior toinitiation of study treatment, or neurosurgical resection within 28 days priorto initiation of study treatment.

• The patient has no ongoing requirement for corticosteroids as therapy for CNSdisease.

• If the patient is receiving anti-convulsant therapy, the dose is consideredstable.

• Metastases are limited to the cerebellum or the supratentorial region (i.e., nometastases to the midbrain, pons, medulla, or spinal cord).

• There is no evidence of interim progression between completion of CNS directedtherapy (if administered) and initiation of study treatment. Asymptomatic patients with CNS metastases newly detected at screening are eligiblefor the study after receiving radiotherapy and/or surgery, with no need to repeatthe screening brain scan.

8. Prior use of approved or investigational anti-TIGIT therapy.

9. Prior treatment with CD137 agonists or immune checkpoint blockade therapies,including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies.

10. Treatment with systemic immunostimulatory agents within 4 weeks or 5drug-elimination half-lives prior to initiation of study treatment.

11. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previousimmunotherapy agent, or any unresolved irAE >Grade 1.

12. Active or history of autoimmune disease or immune deficiency, including, but notlimited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-phospholipidantibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barrésyndrome, or multiple sclerosis, with the following exceptions:

• Patients with a history of autoimmune-related hypothyroidism who are on thyroidreplacement hormone are eligible for the study.

• Patients with controlled Type 1 diabetes mellitus who are on an insulin regimenare eligible for the study.

• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis areexcluded) are eligible for the study provided all of following conditions aremet: i. Rash must cover < 10% of body surface area; ii. Disease is well controlledat baseline and requires only low-potency topical corticosteroids; and iii.There has been no occurrence of acute exacerbations of the underlying conditionrequiring psoralen plus ultraviolet A radiation, methotrexate, retinoids,biologic agents, oral calcineurin inhibitors, or high potency or oralcorticosteroids within the previous 12 months.

13. Active or prior documented inflammatory bowel disease requiring systemic treatmentwithin the past 2 years (e.g., Crohn's disease, ulcerative colitis).

14. History of primary immunodeficiency.

15. History of allogeneic organ transplant.

16. History of hypersensitivity to mAb to PD1/PD-L1 or any excipient.

17. Uncontrolled intercurrent illness including, but not limited to:

• Ongoing or active infection

• Symptomatic congestive heart failure

• Uncontrolled hypertension

• Unstable angina pectoris

• Cardiac arrhythmia

• Active peptic ulcer disease or gastritis

• Active bleeding diatheses

• Uncontrolled tumor-related pain. Patients requiring pain medication must be ona stable regimen at study entry. Symptomatic lesions (e.g., bone metastases ormetastases causing nerve impingement) amenable to palliative radiotherapyshould be treated prior to enrolment. Patients should be recovered from theeffects of radiation. There is no required minimum recovery period. Asymptomatic metastatic lesions that would likely cause functional deficits orintractable pain with further growth (e.g., epidural metastasis that is notcurrently associated with spinal cord compression) should be considered forloco-regional therapy, if appropriate, prior to enrolment.

• Uncontrolled pleural effusion, pericardial effusion, or ascites requiringrecurrent drainage procedures (once monthly or more frequently) Patients withindwelling catheters (e.g., PleurX®) are allowed.

• Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L,calcium > 12 mg/dL, or corrected calcium greater than ULN)

• Psychiatric illness/social situations that would limit compliance with studyrequirements or compromise the ability of the subject to give written informedconsent.

18. Active tuberculosis.

19. Positive EBV viral capsid antigen (VCA) IgM test during screening. An EBV polymerasechain reaction (PCR) test should be performed as clinically indicated to screen foracute infection or suspected chronic active infection. Patients with a positive EBVPCR test are excluded.

20. History of leptomeningeal carcinomatosis.

21. History of severe allergic, anaphylactic, or other hypersensitivity reactions tochimeric or humanized antibodies or fusion proteins; known hypersensitivity orallergy to biopharmaceuticals produced in Chinese hamster ovary cells or anycomponent of the atezolizumab formulation

22. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-inducedpneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screeningchest CT scan.

23. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving tiragolumab and atezolizumab.

24. Pregnant or breastfeeding.

25. Contraindication to study treatments as judged by the patient's responsibleclinician.