Lung cancer has been the most common carcinoma in the world for several decades. Non-small
      cell lung carcinoma (NSCLC) represents approximately 80-85% of all lung cancers. At the time
      of diagnosis approximately 70% of NSCLC patients already have advanced or metastatic disease
      not amenable to surgical resection. A significant percentage of early stage NSCLC patients
      who have undergone surgery subsequently develop distant recurrence.

      First-generation EGFR tyrosine kinase inhibitors (TKIs) provide significant clinical benefit
      in patients with advanced EGFR-mutant (EGFRm) non-small cell lung carcinoma (NSCLC). However,
      all patients ultimately develop disease progression, driven - as the most prevalent
      identified biological mechanism - by the acquisition of a second T790M EGFR TKI resistance
      mutation.

      Osimertinib (AZD9291) is a novel oral, potent, and selective third-generation irreversible
      inhibitor of both EGFRm-sensitizing and T790M resistance mutants. This
      mono-anilino-pyrimidine compound is structurally distinct from other third-generation EGFR
      TKIs and offers a pharmacologically differentiated profile from earlier first and second
      generation EGFR TKIs.

      Osimertinib is being evaluated in several prospective clinical trials, notably in frontline
      treatment, in the adjuvant setting, and in combination with later lines in EGFRm positive
      advanced disease. Combination treatments that target both tumour cells and tumour
      microenvironment (such as angiogenesis) may be a promising strategy for further improving
      efficacy outcomes in patients with EGFRm NSCLC following progression on EGFR TKI therapy and
      other lines of therapy. There is thus a considerable unmet clinical need for novel
      therapeutic options that can further extend the efficacy of targeted agents such as EGFR
      TKIs, across all lines of therapy.

      Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits
      the interaction of VEGF-A to its receptors (Flt-1 and KDR) on the surface of endothelial
      cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and
      new blood vessel formation in in vitro models of angiogenesis. Neutralising the biological
      activity of VEGF regresses the vascularisation of tumours, normalises remaining tumour
      vasculature, and inhibits the formation of new tumour vasculature, thereby inhibiting tumour
      growth. Bevacizumab is indicated for the first-line treatment of unresectable, locally
      advanced, recurrent or metastatic non-squamous NSCLC in combination with carboplatin and
      paclitaxel.

      Osimertinib monotherapy, at the dose to be evaluated in this trial, has shown consistent and
      high objective response rates in the target patient population.

      Anti-angiogenic agents targeting the VEGF/VEGFR signalling pathway have been shown to provide
      additional efficacy when used in combination with first-line platinum-based chemotherapy in
      several trials in non-squamous NSCLC or in combination with erlotinib as first line therapy
      in EGFRm positive NSCLC patients. The combination of osimertinib plus an anti-angiogenic
      agent such as bevacizumab may provide a wider activity against tumours that have developed
      resistance to EGFR TKI agents by blocking the dual pathways of proliferative signalling and
      antigenic signalling. Preclinical studies suggested that patients on lower doses of EGFR TKI
      tend to develop treatment resistance earlier than those who receive higher doses. Therefore
      the combination may also delay the development of subsequent resistance as the preclinical
      studies suggested anti-angiogenic agents may increase intratumoural uptake of anti-cancer
      drugs by changing tumour vessel physiology.

      Efficacy and safety data from the osimertinib monotherapy studies have shown promising
      efficacy and an acceptable safety profile at the recommended dose of 80 mg once daily. The
      combination of osimertinib with bevacizumab may have the potential to provide additional
      clinical benefit in terms of increased and/or prolonged disease control and a delay in the
      emergence of resistance in patients with advanced EGFRm NSCLC who have progressed following a
      prior EGFR TKI agent, compared against the current standard of care (chemotherapy or another
      EGFR TKI) or monotherapy of any of the individual agents.