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 (tested locally). Exception: In specific individual cases, treatment can be initiated prior to receiving molecular diagnostics after consulting with the sponsor, if the local principal investigator assesses the likelihood of an EGFR mutation or ALK fusion to be negligible. However, this should only be done in exceptional cases if the patient has particularly high demand for treatment. If it is subsequently found that patients are positive for EGFR mutations and/or ALK rearrangements, they must be withdrawn from the study immediately and must not receive any further study medication. Instead, patients should receive adequate SOC therapy outside the study.

   Awaiting results for molecular testing remains standard procedure for patient inclusion.
6. PD-L1 tumor proportion score (TPS) \< 50%, tested locally by QUiP®-certified immunohistochemistry
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

    1. Hemoglobin ≥ 8.0 g/dL
    2. Absolute neutrophil count ≥ 1.5 x 109/L
    3. Platelets ≥ 100 x 109/L
    4. Calculated creatine clearance ≥ 50 mL/min as determined by the Cockcroft-Gault equation and/or creatinin ≤ 1,5x upper limit of normal (ULN)
    5. Serum bilirubin ≤ 1.5 x institutional ULN
    6. AST/ ALT and alkaline phosphatase ≤ 2.5 x ULN
    7. International normalized ratio (INR)/ Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PTT is within therapeutic range of intended use of anticoagulants
11. 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.
12. Female patients who are considered as woman of childbearing potential (WOCBP) must use any contraceptive method with a failure rate of less than 1% per year during the treatment as well as up to 6 months after the last dose of study treatment. 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 6 months after the last dose of IMP. Female patients who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) as well as azoospermic 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 the non-squamous part predominates)
2. Patients having received:

   1. Systemic treatment for metastatic or locally advanced disease
   2. prior PD-1/PD-L1 immunotherapies (prior treatment with CD137 agonists or immune checkpoint blockade therapies, including, but not limited to, anti-cytotoxic T lymphocyte associated protein 4 \[anti-CTLA-4\], anti T cell immunoreceptor with Ig and tyrosine-based inhibition motif domains \[anti-TIGIT\], anti-PD-1 and anti-PD-L1 therapeutic antibodies)
3. Symptomatic, neurologically unstable CNS metastases or requiring increasing doses of steroids to manage CNS symptoms within 2 weeks prior to study entry (maximal acceptable dose must be ≤ 10 mg of prednisolone). Patients with asymptomatic, incidentally detected CNS metastases may be enrolled. Palliative radiotherapy for asymptomatic brain metastases (and any other, non-brain metastases, e.g. bone metastases) may be conducted after study entry.
4. Leptomeningeal disease
5. History of interstitial lung disease
6. Severe infection within 2 weeks prior to study entry. Clinical signs must have been resolved to CTCAE grade ≤ 1
7. Active infection with hepatitis B or C virus (HBV, HCV), human immunodeficiency virus (HIV) or Mycobacterium tuberculosis
8. Known additional malignancies other than NSCLC, either untreated or having required active treatment within the past 3 years
9. Significant cardiovascular disease (≥ NYHA 3)
10. 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:

    1. Patients with vitiligo or alopecia
    2. Patients with hypothyroidism (e.g., following Hashimoto's disease) stable on hormone replacement
    3. Patients with controlled Type I diabetes mellitus on an insulin regimen
    4. Any chronic skin condition that does not require systemic therapy
    5. Patients without active disease in the last 5 years may be included but only after consultation with the study physician
11. Current or prior use of immunosuppressive medication within 14 days before the first dose of atezolizumab/pembrolizumab. The following are exceptions to this criterion:

    1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intra articular injection)
    2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
    3. Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication)
12. 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
13. Live vaccine within 30 days prior to first dose of trial treatment
14. Known allergy or hypersensitivity to any component of the chemotherapy regimen or to atezolizumab or pembrolizumab or any constituents of the products
15. 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.
16. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities.