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

Inclusion Criteria

• Patients (male/female) must be ≥18 years of age.
• 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.
• 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.
• Measurable or evaluable disease by RECIST v1.1.
• 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)
• Treatment with an EGFR TKI therapy for at least 30 days
• 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
• Adequate renal function:
• Creatinine clearance greater or equal 45 mL/min (using the Cockcroft-Gault formula)
• 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.
• Willingness to provide any surplus tumour sample obtained at the time of acquired resistance to prior EGFR TKI
• Men and women of childbearing potential must agree to use adequate contraception
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Life expectancy greater or equal 12 weeks
• 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.
• 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

• 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.
• Prior therapy with bevacizumab or other anti-angiogenic agent
• Prior immune checkpoint inhibitor therapy
• More than two lines of EGFR TKI therapy
• Known small-cell lung carcinoma (SCLC) or high grade neuroendocrine carcinoma (if progression biopsy has been performed locally).
• Squamous cell histologic subtype
• 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).
• 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
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of randomization.
• Presence or history of a malignant disease that has been diagnosed and/or required therapy within the past 3 years. Exceptions to this exclusion in