NeoTRACK - Dissection of IO Efficacy in NSCLC by Longitudinal tracKing

Inclusion Criteria:

1. Has provided written informed consent
2. Patient\* 18 years or older at time of signing informed consent form
3. Histologically confirmed NSCLC of squamous or non-squamous histology
4. Resectable clinical stage II, IIIA and IIIB (T3N2 only) NSCLC (according to UICC 8)
5. Adequate disease staging by PET and/or CT as per SOC (performed ≤ 42 days prior initiation of the study treatment)
6. At least 1 measurable lesion according to RECIST v1.1
7. ECOG performance status ≤ 1
8. Adequate lung and cardiac function for curative intend lung resection (R0) according to German S3 guideline
9. Eligibility to receive a platinum-based neoadjuvant chemotherapy
10. The patient is willing and able to comply with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations.
11. The patient is willing and able to provide liquid and tissue samples for the accompanying translation project.
12. Adequate bone marrow and renal function including the following:

    * Hemoglobin ≥ 9.0 g/dL
    * Absolute neutrophil count ≥ 1.0 x 109/L
    * Platelets ≥ 75 x 109/L
    * Calculated creatinine clearance ≥ 30 mL/min as determined by the Cockcroft-Gault equation
13. Adequate hepatic function (with stenting for any obstruction, if required) including the following:

    * Serum bilirubin ≤ 3 x institutional upper limit of normal (ULN)
    * AST (SGOT) / ALT (SGPT) and alkaline phosphatase ≤ 2.5x ULN
14. Female patients who are considered as women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test within 7 days prior to start of trial.
15. Female patients who are considered as WOCBP must use any contraceptive method with a failure rate of less than 1% per year during the treatment as well as up to 5 months after the last dose of IMP. Male patients who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year during the treatment as well as at least 5 months after the last dose of IMP. Female patients who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile, see section 5.1.5) as well as azoospermic male patients do not require contraception.

Exclusion Criteria:

1. Treatment in any other clinical trial with an investigational product within 30 days before screening
2. Clinical stage I, IIIB (T4N2), IIIC, nodal NSCLC stage cN3 and stage IV NSCLC
3. Positive testing of activating (TKI-responsive) EGFR-mutation, ROS1-mutation or known ALK fusion oncogene
4. Expected pneumonectomy at baseline to achieve curative intend resection
5. Any concurrent chemotherapy, investigational product (IMP), biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer related conditions (e.g. hormone replacement therapy) is acceptable.
6. Malignancies other than NSCLC within 3 years prior to study inclusion with the exception of malignancies with a negligible risk of metastases or death (5-year OS \> 90%) like localized prostate cancer, ductal carcinoma in situ, adequately treated carcinoma in situ of the cervix, Stage I uterine cancer, in-situ bladder cancer treated by BCG-Instillation, or non-melanoma skin carcinoma
7. History of allogeneic tissue / solid organ transplant or allogeneic stem cell transplantation
8. History of active primary immunodeficiency.
9. Clinical diagnosis of active tuberculosis.
10. Positive testing for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus (HCV) RNA indicating acute or chronic infection. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
11. Positive testing for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
12. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 5 months after the last dose of atezolizumab/tiragolumab.
13. Active or prior documented autoimmune or inflammatory disorders (including but not limited to diverticulitis \[with the exception of diverticulosis\], celiac disease, systemic lupus erythematosus, Sarcoidosis, or Wegener's syndrome \[granulomatosis with polyangiitis\], Graves' disease, rheumatoid arthritis, hypophysitis, uveitis). The following are exceptions to this criterion:

    * Patients with vitiligo or alopecia
    * Patients with hypothyroidism (e.g., following Hashimoto's disease) stable on hormone replacement
    * Patients with controlled Type I diabetes mellitus on an insulin regimen
    * Any chronic skin condition that does not require systemic therapy
    * Patients without active disease in the last 5 years may be included but only after consultation with the study physician.
14. Active, uncontrolled inflammatory bowel disease \[e.g. ulcerative colitis or Crohn's disease\]. Patients in stable remission for more than 1 year may be included.
15. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, interstitial lung disease, gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
16. Current or prior use of immunosuppressive medication within 14 days before the first dose of atezolizumab/tiragolumab. The following are exceptions to this criterion:

    * Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intra articular injection)
    * Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
    * Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication)
17. Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment
18. History of idiopathic pulmonary fibrosis, interstitial lung disease, organizing pneumonia, drug-induced pneumonitis, or evidence of active pneumonitis on screening chest Computed Tomography (CT) scan.
19. Prior treatment with CD137 agonist or immune checkpoint blockade therapies, such as anti-TIGIT, anti-PD-1 and anti-PD-L1 therapeutic antibody
20. Live vaccine within 30 days prior to first dose of trial treatment
21. Known allergy or hypersensitivity to any component of the chemotherapy regimen or to the IMP or any constituents of the products
22. Any co-existing medical condition that in the investigator's judgement will substantially increase the risk associated with the patient's participation in the study.
23. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities.
24. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts