ABC-lung: Atezolizumab, Bevacizumab and Chemotherapy in EGFR-mutant Non-small Cell Lung Carcinoma

Inclusion Criteria:

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

2. Chemotherapy naïve, non-squamous NSCLC, stage IIIB/C (not amenable to radicaltherapy) or IV. Patients who have received previous adjuvant or neoadjuvantchemotherapy are eligible if the date of last dose of treatment was at least 12months 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 priortreatment 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 tumourbiopsy taken >7 days prior to protocol treatment start or by recent ctDNAanalysis (informative ctDNA test, local test).

• T790M genotype is allowed If most recent line of treatment (1st or 2nd line) was a first- or second-generationEGFR TKI (e.g. afatinib, dacomitinib, erlotinib, gefitinib):

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

9. Adequate liver function:

• ALT and AST less or equal 2.5× ULN. If the patient has liver metastases, ALTand 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 acquiredresistance 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 periodin the last 2 years, must have a negative serum or urine pregnancy test within 7days before randomisation.

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

Exclusion Criteria:

1. Prior systemic cytotoxic chemotherapy for advanced stage NSCLC Patients who hadreceived previous adjuvant or neoadjuvant chemotherapy are eligible if the last doseof 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 (ifprogression biopsy has been performed locally).

6. Squamous cell histologic subtype

7. Known EGFR T790M positive genotype by tissue on most recent EGFR TKI progression orctDNA and have not received an approved EGFR TKI targeting T790M (e.g. athird-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 andsymptomatically stable with no ongoing requirement for corticosteroids astherapy 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 ofradiation within 4 weeks of randomization.

10. Presence or history of a malignant disease that has been diagnosed and/or requiredtherapy within the past 3 years. Exceptions to this exclusion include the following:completely resected basal cell and squamous cell skin cancers, and completelyresected 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, orresidual autoimmune-related hypothyroidism only requiring hormone replacement orpsoriasis 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, TNFblockers, anakinra, rituximab, abatacept, or tocilizumab) within 6 weeks prior totreatment start.

17. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-inducedpneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screeningchest computed tomography scan. History of radiation pneumonitis in the radiationfield (fibrosis) is permitted

18. Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHgand/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 orrecent 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 therapeuticanticoagulation)

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 agentsfor therapeutic purposes that has not been stable for >2 weeks prior torandomization

• The use of full-dose oral or parenteral anticoagulants is permitted as long asthe INR or aPTT is within therapeutic limits (according to the medical standardof the enrolling institution) and the patient has been on a stable dose ofanticoagulants for at least 2 weeks prior to randomization.

• Prophylactic anticoagulation for the patency of venous access devices isallowed, provided the activity of the agent results in an INR <1.5× ULN andaPTT 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 vascularaccess device, within 7 days prior to the first dose of bevacizumab

• Major surgery or significant traumatic injury 28 days prior to the first doseof bevacizumab.

• Minor surgical procedure within 7 days, or placement of a vascular accessdevice 2 days prior to the first dose of bevacizumab.

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

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

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

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-hoururine collection

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

31. Any unresolved toxicities from prior therapy greater than CTCAE v5.0 grade 1 at thetime 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 otherrecombinant human or humanised antibodies.

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

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 usean effective contraceptive method during the trial and up to 6 months afterdiscontinuing trial treatment

37. History of active diverticulitis