Open label multicentric randomized phase II trial, using high throughput genome analysis as a therapeutic decision tool, aimed at comparing a targeted treatment administered according to the identified molecular anomalies of the tumor with a standard treatment (pemetrexed in Non-squamous patients and erlotinib in squamous cells, targeted substudy 1) as well as immunotherapy with maintenance therapy in patients without actionable genomic alterations or non eligible to substudy 1 (immune substudy 2).

Screening phase:

New frozen biopsy or an archived frozen sample or ctDNA sample will be sent to the genomic platforms for DNA extraction and genomic analysis (DNA microarrays and Next generation sequencing).

Patients can be considered as pre-eligible for the targeted substudy 1 randomisation phase when both following mandatory conditions have been met : stable or responding disease has been observed after 4 cycles of chemotherapy (investigator judgment) and targetable alteration has been identified by the Molecular tumor board (MTB).

If not eligible for the substudy 1 randomisation phase, patients can be considered as pre-eligible for the immune substudy 2 randomization phase when both following mandatory conditions are met: stable or responding disease (investigator judgment) is observed after 4 cycles of a platinum-based chemotherapy AND not eligible to randomization in the substudy 1 (because patient had no targetable alteration identified by the Molecular Tumor Board, or failed to have a genomic profile for the tumor [low tumor cells percentage, technical issue during genomic analysis, etc.], or a non-inclusion criteria that precluded entry into the substudy 1)

Randomization phase:

The mandatory post-chemotherapy 28-day wash-out period following cycle 4 of chemotherapy will provide time to achieve all the required tests and examinations.

The randomization program will allocate the following treatments with a 2:1 ratio in favor of Arm A of the considered substudy:

Substudy 1 : targeted therapies versus standard maintenance therapy

• Arm A1 / targeted arm: targeted maintenance from a list of 6 targeted drugs guided by the genomic analysis, or
• Arm B1 / standard arm : standard maintenance (pemetrexed in non-squamous and standard practice in squamous NSCLC).

Substudy 2 : immunotherapy versus standard maintenance therapy

• Arm A2 / immunotherapy maintenance arm: MEDI4736 or
• Arm B2 / standard arm : standard maintenance (pemetrexed in non-squamous and standard practice in squamous NSCLC).

Screening phase:

Inclusion Criteria:

• histologically proven NSCLC
• Metastatic relapse or stage IV at diagnosis, or stage IIIb not amenable to surgery or radiotherapy
• No EGFR-activating mutation or ALK translocation
• primary tumor or metastases that can be biopsied, excluding bone.
• Age >18 years
• WHO Performance Status 0/1
• Chemo-naïve patients eligible to a first line platinum-based chemotherapy
• No tumor progression observed with the current line of treatment
• measurable target lesion or evaluable diseases RECIST

Exclusion criteria

• Spinal cord compression and/or symptomatic or progressive brain metastases
• Abnormal coagulation contraindicating biopsy
• Inability to swallow
• Major problem with intestinal absorption
• Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG
• Any factors increasing the risk of QTc prolongation or arrhythmic events
• Experience of any of the following in the preceding 12 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, past or current uncontrolled angina pectoris, congestive heart failure NYHA Grade ≥2, torsades de pointes, current uncontrolled hypertension, cardiomyopathy
• Past medical history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis which requires steroid treatment or any evidence of clinically interstitial lung disease
• Previous or current malignancies of other histologies within the last 5 years,
• Evidence of severe or uncontrolled systemic disease (active bleeding diatheses, or active Hepatitis B, C and HIV)
• Diagnosis of diabetes mellitus type I or II
• diagnosis of acne rosacea, severe psoriasis and severe atopic eczema
• Prior exposure to anthracyclines or mitoxantrone with cumulative exposure in excess of 360 mg/m² for doxorubicin, 720 mg/m² for epirubicin, or 72 mg/m² for mitoxantrone
• History of retinal degenerative disease, eye injury or corneal surgery in the previous 3 months, past history of central serous retinopathy or retinal vein occlusion, intraocular pressure >21 mmHg, or uncontrolled glaucoma.
• History of hemorrhagic or thrombotic stroke, TIA or other CNS bleeds
• Renal disease including glomerulonephritis, nephritic syndrome, Fanconi syndrome, renal tubular acidosis
• Patients using drugs that are known potent inhibitors or potent inducers or substrates of cytochrome P450

Randomized phase:

Substudy 1:

Inclusion criteria

• Patients who received 4 cycles of an induction platinum-based chemotherapy and who have a SD or a PR at randomization
• presenting at least one genomic alteration from the predefined list
• Age > 25 years for patients planned to receive AZD4547
• 28-day washout period from chemo prior to randomization and grade ≤1 residual toxicities

Exclusion criteria

• Life expectancy <3 months
• Disease progression occuring at any time during chemotherapy and before randomization or toxicity that led to the discontinuation of the platinum-based chemotherapy before 4 full cycles have been delivered
• Less than 28 days from radiotherapy, less than 2 weeks from palliative radiation
• Patients previously treated with a targeted agent in the same class as agents tested in this study
• Toxicities of grade ≥2 from any previous anti-cancer therapy
• Altered haematopoietic or organ function
• Mean resting corrected QT interval (QTc) >480msec (or QTcF >450 msec) obtained from 3 consecutive ECGs
• Left ventricular ejection fraction (LVEF) <55% (MUGA scan or Echocardiogram),
• Altered ophthalmic conditions confirmed by an ophthalmology specialist for patients likely to be treated with AZD4547 orAZD8931 or Selumetinib
• Patients using non-substitutable drugs, that are known to prolong QT interval or induce Torsades de Pointes, when they are supposed to be treated with vandetanib, AZD5363 or AZD8931

Substudy 2:

Inclusion criteria

• Patients who received 4 cycles of an induction platinum-based chemotherapy and who have a SD or a PR at randomization
• Patients not eligible to substudy 1
• 28-day washout period from chemo prior to randomization and grade ≤1 residual toxicities

Exclusion criteria

• Life expectancy <3 months
• Disease progression occuring at any time during chemotherapy and before randomization or toxicity that led to the discontinuation of the platinum-based chemotherapy before 4 full cycles have been delivered
• Any previous treatment with a PD1 or PD-L1 inhibitor, including MEDI4736
• Toxicities of grade ≥2 from any previous anti-cancer therapy
• Altered haematopoietic or organ function
• Mean resting QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 consecutive ECGs using Bazett's Correction
• Current or prior use of immunosuppressive medication within 28 days before the first dose of MEDI4736, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
• Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded
• History of primary immunodeficiency