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

This is an open-label randomized, controlled, multicenter, phase II trial with two arms. Patients with metastatic TTF-1 negative, treatment-naive lung adenocarcinoma without actionable genomic alterations are randomized in a 1:1 manner to investigate the efficiency of atezolizumab, carboplatin and nab-paclitaxel (Arm A) versus pembrolizumab, cis-/carboplatin and pemetrexed (Arm B) as first-line treatment.

Inclusion Criteria:Patient has provided written informed consentPatient* 18 years or older at time of signing the informed consent formHistologically or cytologically confirmed metastatic stage IV non-squamous NSCLCNegative local testing for TTF-1Negative molecular testing for EGFR mutations and ALK rearrangements (tested locally)PD-L1 tumor proportion score (TPS) < 50%, tested locally by QUiP®-certified immunohistochemistryECOG performance status ≤ 1Measurable lesions according to RECIST v1.1Life expectancy ≥ 12 weeksAdequate hepatic, renal and bone marrow functionHemoglobin ≥ 8.0 g/dLAbsolute neutrophil count ≥ 1.5 x 109/LPlatelets ≥ 100 x 109/LCalculated creatine clearance ≥ 50 mL/min as determined by the Cockcroft-Gault equation and/or creatinin ≤ 1,5x upper limit of normal (ULN)Serum bilirubin ≤ 1.5 x institutional ULNAST/ ALT and alkaline phosphatase ≤ 2.5 x ULNInternational 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 anticoagulantsThe 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.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 contraceptionExclusion Criteria: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)Patients having received:Systemic treatment for metastatic or locally advanced diseaseprior 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)Symptomatic, neurologically unstable central nervous system (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)Leptomeningeal diseaseHistory of interstitial lung diseaseSevere infection within 2 weeks prior to study entry. Clinical signs must have been resolved to CTCAE grade ≤ 1Active infection with hepatitis B or C virus (HBV, HCV), human immunodeficiency virus (HIV) or Mycobacterium tuberculosisKnown additional malignancies other than NSCLC, either untreated or having required active treatment within the past 3 yearsSignificant cardiovascular disease (≥ NYHA 3)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 alopeciaPatients with hypothyroidism (e.g., following Hashimoto's disease) stable on hormone replacementPatients with controlled Type I diabetes mellitus on an insulin regimenAny chronic skin condition that does not require systemic therapyPatients without active disease in the last 5 years may be included but only after consultation with the study physicianCurrent or prior use of immunosuppressive medication within 14 days before the first dose of atezolizumab/pembrolizumab. 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 equivalentSteroids as premedication for hypersensitivity reactions (e.g. CT scan premedication)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 treatmentLive vaccine within 30 days prior to first dose of trial treatmentKnown allergy or hypersensitivity to any component of the chemotherapy regimen or to atezolizumab or pembrolizumab or any constituents of the productsAny co-existing medical condition that in the investigator's judgement will substantially increase the risk associated with the patient's participation in the study.Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities.