Osimertinib and Bevacizumab Versus Osimertinib Alone as Second-line Treatment in Stage IIIb-IVb NSCLC With Confirmed EGFRm and T790M

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.