Pemetrexed-free vs. Pemetrexed-based Immunochemotherapy in Metastatic TTF-1 Negative Lung Adenocarcinoma

Inclusion Criteria:

1. Patient has provided written informed consent

2. Patient* 18 years or older at time of signing the informed consent form

3. Histologically or cytologically confirmed metastatic stage IV non-squamous NSCLC

4. Negative local testing for TTF-1

5. Negative molecular testing for EGFR mutations and ALK rearrangements (testedlocally). Exception: In specific individual cases, treatment can be initiated priorto receiving molecular diagnostics after consulting with the sponsor, if the localprincipal investigator assesses the likelihood of an EGFR mutation or ALK fusion tobe negligible. However, this should only be done in exceptional cases if the patienthas particularly high demand for treatment. If it is subsequently found thatpatients are positive for EGFR mutations and/or ALK rearrangements, they must bewithdrawn from the study immediately and must not receive any further studymedication. Instead, patients should receive adequate SOC therapy outside the study. Awaiting results for molecular testing remains standard procedure for patientinclusion.

6. PD-L1 tumor proportion score (TPS) < 50%, tested locally by QUiP®-certifiedimmunohistochemistry

7. ECOG performance status ≤ 1

8. Measurable lesions according to RECIST v1.1

9. Life expectancy ≥ 12 weeks

10. Adequate hepatic, renal and bone marrow function

11. Hemoglobin ≥ 8.0 g/dL

12. Absolute neutrophil count ≥ 1.5 x 109/L

13. Platelets ≥ 100 x 109/L

14. Calculated creatine clearance ≥ 50 mL/min as determined by the Cockcroft-Gaultequation and/or creatinin ≤ 1,5x upper limit of normal (ULN)

15. Serum bilirubin ≤ 1.5 x institutional ULN

16. AST/ ALT and alkaline phosphatase ≤ 2.5 x ULN

17. International normalized ratio (INR)/ Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as longas PTT is within therapeutic range of intended use of anticoagulants

18. The patient is willing and able to comply with the protocol for the duration of thestudy, including hospital visits for treatment and scheduled follow-up visits andexaminations.

19. Female patients who are considered as woman of childbearing potential (WOCBP) mustuse any contraceptive method with a failure rate of less than 1% per year during thetreatment as well as up to 6 months after the last dose of study treatment. Malepatients who are sexually active with WOCBP must use any contraceptive method with afailure rate of less than 1% per year during the treatment as well as at least 6months after the last dose of IMP. Female patients who are not of childbearingpotential (i.e., who are postmenopausal or surgically sterile) as well asazoospermic male patients do not require contraception

Exclusion Criteria:

1. Mixed histologies (small-cell and non-small cell or non-squamous and squamous;patients exhibiting the latter expression pattern may be eligible if thenon-squamous part predominates)

2. Patients having received:

3. Systemic treatment for metastatic or locally advanced disease

4. prior PD-1/PD-L1 immunotherapies (prior treatment with CD137 agonists or immunecheckpoint blockade therapies, including, but not limited to, anti-cytotoxic Tlymphocyte associated protein 4 [anti-CTLA-4], anti T cell immunoreceptor withIg and tyrosine-based inhibition motif domains [anti-TIGIT], anti-PD-1 andanti-PD-L1 therapeutic antibodies)

5. Symptomatic, neurologically unstable CNS metastases or requiring increasing doses ofsteroids to manage CNS symptoms within 2 weeks prior to study entry (maximalacceptable dose must be ≤ 10 mg of prednisolone). Patients with asymptomatic,incidentally detected CNS metastases may be enrolled. Palliative radiotherapy forasymptomatic brain metastases (and any other, non-brain metastases, e.g. bonemetastases) may be conducted after study entry.

6. Leptomeningeal disease

7. History of interstitial lung disease

8. Severe infection within 2 weeks prior to study entry. Clinical signs must have beenresolved to CTCAE grade ≤ 1

9. Active infection with hepatitis B or C virus (HBV, HCV), human immunodeficiencyvirus (HIV) or Mycobacterium tuberculosis

10. Known additional malignancies other than NSCLC, either untreated or having requiredactive treatment within the past 3 years

11. Significant cardiovascular disease (≥ NYHA 3)

12. Active or prior documented autoimmune or inflammatory disorders (including but notlimited to diverticulitis [with the exception of diverticulosis], celiac disease,systemic lupus erythematosus, Sarcoidosis, or Wegener's syndrome [granulomatosiswith polyangiitis], Graves' disease, rheumatoid arthritis, hypophysitis, uveitis).The following are exceptions to this criterion:

13. Patients with vitiligo or alopecia

14. Patients with hypothyroidism (e.g., following Hashimoto's disease) stable onhormone replacement

15. Patients with controlled Type I diabetes mellitus on an insulin regimen

16. Any chronic skin condition that does not require systemic therapy

17. Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician

18. Current or prior use of immunosuppressive medication within 14 days before the firstdose of atezolizumab/pembrolizumab. The following are exceptions to this criterion:

19. Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intraarticular injection)

20. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day ofprednisone or its equivalent

21. Steroids as premedication for hypersensitivity reactions (e.g. CT scanpremedication)

22. Treatment with systemic immunostimulatory agents (including, but not limited to,interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever islonger) prior to initiation of study treatment

23. Live vaccine within 30 days prior to first dose of trial treatment

24. Known allergy or hypersensitivity to any component of the chemotherapy regimen or toatezolizumab or pembrolizumab or any constituents of the products

25. Any co-existing medical condition that in the investigator's judgement willsubstantially increase the risk associated with the patient's participation in thestudy.

26. Patient who has been incarcerated or involuntarily institutionalized by court orderor by the authorities.