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
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
- 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
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
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
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
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
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
- 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
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
- 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
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
37. History of active diverticulitis