Neo-DIANA: Neoadjuvant Treatment for EGFR Mutated Patients

Inclusion Criteria:

1. Previously untreated patients with histologically- or cytologically- documentedNSCLC who present stage IIIA disease (according to 8th version of theInternational Association for the Study of Lung Cancer Staging Manual inThoracic Oncology). PET/CT including IV contrast (CT of diagnostic quality)will be performed at baseline (28 days +10 before randomization).

2. Tumor should be considered resectable before study entry by a multidisciplinaryteam

3. Sensitizing EGFR mutation (Del Exon 19 and ins Exon 21).

4. ECOG (Performance status) 0-1

5. Screening laboratory values must meet the following criteria and should beobtained within 14 days prior to randomization i. Neutrophils ≥ 1500×109/L ii.Platelets ≥ 100 ×109/L iii. Hemoglobin > 9.0 g/dL iv. Serum creatinine ≤ 1.5 xULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gaultformula below): a. Female CrCl = (140 - age in years) x weight in kg x 0.85/ 72x serum creatinine in mg/dL b. Male CrCl = (140 - age in years) x weight in kgx 1.00/ 72 x serum creatinine in mg/dL v. AST/ALT ≤ 3 x ULN vi. Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have totalbilirubin < 3.0 mg/dL) vii. PT/APTT/INR within normal limits

6. Measurable or evaluable disease according to RECIST v1.1.

7. The patients need to have a forced expiratory volume (FEV1)≥ 1.2 liters or >40%p- predicted value.

8. All patients are notified of the investigational nature of this study andsigned a written informed consent in accordance with institutional and nationalguidelines, including the Declaration of Helsinki prior to any trial-relatedintervention.

9. Patients aged > 18 years.

10. Patient capable of proper therapeutic compliance and accessible for correctfollow-up.

11. For female patients of childbearing potential, agreement (by patient and/orpartner) to use a highly effective form(s) of contraception that results in alow failure rate (< 1% per year) when used consistently and correctly, and tocontinue its use for 5 months after the last dose of Atezolizumab and/or 6months after the last dose of Bevacizumab, whichever is later. Such methodsinclude: combined (estrogen and progestogen containing) hormonal contraception,progestogen-only hormonal contraception associated with inhibition of ovulationtogether with another additional barrier method always containing a spermicide,intrauterine device (IUD): intrauterine hormone-releasing system (IUS),bilateral tubal occlusion, vasectomized partner (on the understanding that thisis the only one partner during the whole study duration), and sexualabstinence.

12. For male patients with female partners of childbearing potential, agreement (bypatient and/or partner) to use a highly effective form(s) of contraception thatresults in a low failure rate [< 1% per year] when used consistently andcorrectly, and to continue its use for 6 months after the last dose ofBevacizumab. Male patients should not donate sperm during this study and for atleast 6 months after the last dose of Bevacizumab.

13. Oral contraception should always be combined with an additional contraceptivemethod because of a potential interaction with the study drugs. The same rulesare valid for male patients involved in this clinical study if they have apartner of childbirth potential. Male patients must always use a condom.

14. Women who are not postmenopausal (≥ 12 months of non-therapy-inducedamenorrhea) or surgically sterile must have a negative serum pregnancy testresult within 14 days prior to initiation of study drug

Exclusion Criteria:

1. All patients carrying other EGFR mutations.

2. Patients with known anaplastic lymphoma kinase (ALK) fusion oncogene, STK11ligand alteration or ROS1 translocations.

3. Clinically significant comorbidities that impaired administration ofplatinum-based chemotherapy.

4. Patients with a condition requiring systemic treatment with eithercorticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressivemedications within 14 days of randomization. Inhaled or topical steroids, andadrenal replacement steroid doses > 10 mg daily prednisone equivalent, arepermitted in the absence of active autoimmune disease.

5. Patients with a history of interstitial lung disease cannot be included if theyhave symptomatic ILD (Grade 3-4) and/or poor lung function. In case of doubtplease contact trial team.

6. Patients with other active malignancy requiring concurrent intervention and/orconcurrent treatment with other investigational drugs or anti-cancer therapy.

7. Patients with previous malignancies (except non-melanoma skin cancers, and thefollowing in situ cancers: bladder, gastric, colon, endometrial,cervical/dysplasia, melanoma, or breast) are excluded unless a completeremission was achieved at least 2 years prior to study entry AND no additionaltherapy is required during the study period.

8. Any medical, mental or psychological condition which in the opinion of theinvestigator would not permit the patient to complete the study or understandthe patient information.

9. Patients with positive test for hepatitis B virus surface antigen (HBV sAg) orhepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronicinfection.

10. Patients with known history of testing positive for human immunodeficiencyvirus (HIV) or known acquired immunodeficiency syndrome (AIDS).

11. Active tuberculosis.

12. Severe infections within 4 weeks prior to be included in the study, includingbut not limited to hospitalization for complications of infection, bacteremia,or severe pneumonia.

13. Patients with history of allergy to study drug components excipients.

14. History of severe allergic, anaphylactic, or other hypersensitivity reactionsto chimeric or humanized antibodies or fusion proteins.

15. Women who are pregnant or in the period of breastfeeding.

16. Sexually active men and women of childbearing potential who are not willing touse an effective contraceptive method during the study.

17.

• Patients with active, known or suspected autoimmune disease, including but notlimited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, vascularthrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis,Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, orglomerulonephritis.

• Patients with a history of autoimmune-related hypothyroidism on a stable doseof thyroid replacement hormone are eligible for this study.

• Patients with controlled Type 1 diabetes mellitus on a stable dose of insulinregimen are eligible for this study.

• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis wouldbe excluded) are permitted provided that they meet the following conditions:

• Rash must cover less than 10% of body surface area (BSA).

• Disease is well controlled at baseline and only requiring low-potencytopical steroids.

• No acute exacerbations of underlying condition within the previous 12months (not requiring PUVA [psoralen plus ultraviolet A radiation],methotrexate, retinoids, biologic agents, oral calcineurin inhibitors,high-potency or oral steroids).

18. Patients with any contraindication for bevacizumab administration.