ETOP 15-19 ABC-lung is an international, multi-centre open-label, randomized phase II trial with two non-comparative parallel arms of atezolizumab plus bevacizumab with carboplatin-paclitaxel (Arm A) or atezolizumab, bevacizumab and pemetrexed (Arm B) in patients with stage IIIB-IV non-squamous non-small cell lung cancer (NSCLC) harbouring EGFR mutations after failure of standard EGFR tyrosine kinase inhibitors (TKIs).

Inclusion Criteria:

1. Patients (male/female) must be ≥18 years of age.

2. Chemotherapy naïve, non-squamous NSCLC, stage IIIB/C (not amenable to radical therapy) or IV. Patients who have received previous adjuvant or neoadjuvant chemotherapy are eligible if the date of last dose of treatment was at least 12 months before randomisation.

3. Known EGFR mutations genotypes by tissue or ctDNA, patients with common mutations (L858R or Del19) and other rare mutations (e.g. S768I, G719X) are eligible.

4. Measurable or evaluable disease by RECIST v1.1.

5. Disease progression (during or after) or unacceptable side effects from prior treatment with at least one EGFR TKI (washout period = 7 days).

   If most recent line of treatment (1st or 2nd line) was a third-generation EGFR TKI (e.g. osimertinib):

   • Patient must be known to be EGFR mutation positive, either on fresh tumour biopsy taken >7 days prior to protocol treatment start or by recent ctDNA analysis (informative ctDNA test, local test).
   • T790M genotype is allowed

   If most recent line of treatment (1st or 2nd line) was a first- or second-generation EGFR TKI (e.g. afatinib, dacomitinib, erlotinib, gefitinib):

   - Patient must be known to be tissue EGFR T790M wild type (local test) on most recent line of EGFR TKI or if no tissue re-biopsy, no evidence of T790M on ctDNA but identified L858R, del19, S768I or G719X genotypes (informative ctDNA test, local test)

6. Treatment with an EGFR TKI therapy for at least 30 days

7. Adequate haematological function:

   • Haemoglobin greater or equal 90 g/L
   • Absolute neutrophils count (ANC) greater or equal 1.5× 109/L
   • Platelet count greater or equal 100× 109/L

8. Adequate renal function:

   • Creatinine clearance greater or equal 45 mL/min (using the Cockcroft-Gault formula)

9. Adequate liver function:

   • ALT and AST less or equal 2.5× ULN. If the patient has liver metastases, ALT and AST must be less or equal 5× ULN
   • Total bilirubin less or equal 1.5x ULN.

10. Willingness to provide any surplus tumour sample obtained at the time of acquired resistance to prior EGFR TKI

11. Men and women of childbearing potential must agree to use adequate contraception

12. Eastern Cooperative Oncology Group (ECOG) performance status 0-1

13. Life expectancy greater or equal 12 weeks

14. Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 7 days before randomisation.

15. Patient is willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits and examinations including follow up.

Exclusion Criteria:

1. Prior systemic cytotoxic chemotherapy for advanced stage NSCLC Patients who had received previous adjuvant or neoadjuvant chemotherapy are eligible if the last dose of treatment was at least 12 months before randomisation.

2. Prior therapy with bevacizumab or other anti-angiogenic agent

3. Prior immune checkpoint inhibitor therapy

4. More than two lines of EGFR TKI therapy

5. Known small-cell lung carcinoma (SCLC) or high grade neuroendocrine carcinoma (if progression biopsy has been performed locally).

6. Squamous cell histologic subtype

7. Known EGFR T790M positive genotype by tissue on most recent EGFR TKI progression or ctDNA and have not received an approved EGFR TKI targeting T790M (e.g. a third-generation EGFR TKI such as osimertinib).

8. Active or untreated CNS metastases as determined by brain MRI

   - Patients with CNS metastases must be non-progressive by RECIST v1.1 and symptomatically stable with no ongoing requirement for corticosteroids as therapy for CNS disease; anticonvulsants at a stable dose allowed

9. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of randomization.

10. Presence or history of a malignant disease that has been diagnosed and/or required therapy within the past 3 years. Exceptions to this exclusion include the following: completely resected basal cell and squamous cell skin cancers, and completely resected carcinoma in situ of any type.

11. Clear tumour infiltration into the thoracic great vessels (seen on imaging)

12. QTc of grade ≥3 according to CTCAE v5.0

13. Active autoimmune disease that has required systemic treatment in past 2 years. Patients with vitiligo, controlled type I diabetes mellitus on stable insulin, or residual autoimmune-related hypothyroidism only requiring hormone replacement or psoriasis not requiring systemic treatment are permitted

14. Active or uncontrolled HIV, tuberculosis, hepatitis B or C infection

15. Live attenuated vaccination within 4 weeks prior to randomisation.

16. Subject receiving any biologic drugs targeting the immune system (for example, TNF blockers, anakinra, rituximab, abatacept, or tocilizumab) within 6 weeks prior to treatment start.

17. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted

18. Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg)

    - Anti-hypertensive therapy to achieve these parameters is allowable.

19. Prior history of hypertensive crisis or hypertensive encephalopathy

20. Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to randomization

21. History of haemoptysis (greater or equal 2.5mL of bright red blood per episode) within 1 month prior to randomization

22. Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation)

23. Current or recent (within 10 days before randomization) use of aspirin (>325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and clostazol

24. Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes that has not been stable for >2 weeks prior to randomization

    • The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to the medical standard of the enrolling institution) and the patient has been on a stable dose of anticoagulants for at least 2 weeks prior to randomization.
    • Prophylactic anticoagulation for the patency of venous access devices is allowed, provided the activity of the agent results in an INR <1.5× ULN and aPTT is within normal limits within 14 days prior to randomization.
    • Prophylactic use of low-molecular-weight heparin (i.e., enoxaparin 40 mg/day) is permitted.

25. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to the first dose of bevacizumab

    • Major surgery or significant traumatic injury 28 days prior to the first dose of bevacizumab.
    • Minor surgical procedure within 7 days, or placement of a vascular access device 2 days prior to the first dose of bevacizumab.

26. History of abdominal or tracheoesophageal fistula or gastrointestinal perforation within 6 months prior to randomization

27. Clinical signs of gastrointestinal obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding

28. Evidence of abdominal free air not explained by paracentesis or recent surgical procedure

29. Serious, non-healing wound, active ulcer, or untreated bone fracture

30. Proteinuria, as demonstrated by urine dipstick or >1.0 g of protein in a 24-hour urine collection

    - All patients with greater or equal 2+ protein on dipstick urine analysis at baseline must undergo a 24 hour urine collection and must demonstrate lesser or equal 1 g of protein in 24 hours.

31. Any unresolved toxicities from prior therapy greater than CTCAE v5.0 grade 1 at the time of starting trial treatment with the exception of alopecia

32. History of hypersensitivity to the known active substances (atezolizumab, bevacizumab and chemotherapy drugs) or to any of the excipients.

33. History of hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies.

34. Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.

35. Women who are pregnant or in the period of lactation.

36. Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the trial and up to 6 months after discontinuing trial treatment

37. History of active diverticulitis