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

Study Overview
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Brief Summary
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BOOSTER is a randomised, controlled, phase II trial comparing osimertinib and bevacizumab versus osimertinib alone as second-line treatment in patients with stage IIIb-IVb non-small cell lung carcinoma (NSCLC) harbouring activating EGFR (exon 19 deletion or L858R) and T790M resistance mutation.

Detailed Description
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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.

Official Title
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A Randomised Phase II Trial of Osimertinib and Bevacizumab Versus Osimertinib Alone as Second-line Treatment in Stage IIIb-IVb NSCLC With Confirmed EGFRm and T790M

Conditions
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Non Small Cell Lung Cancer Metastatic

Intervention / Treatment
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* Drug: Osimertinib
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients (male/female) must be >18 years of age. Patients diagnosed with NSCLC, stage IIIb/IIIc (not amenable to radical therapy) or IVa/IVb according to 8th TNM classification, after progression following prior EGFR TKI therapy (erlotinib, gefitinib, dacomitinib or afatinib) as the most recent treatment regimen; Pathological diagnosis of predominantly non-squamous NSCLC; Maximum one line of previous platinum based chemotherapy; Histological or cytological confirmation of EGFRm (exon 19 deletion or exon 21L858R); Locally confirmed T790M mutation determined from biopsy (preferred) or on circulating tumour DNA, documented in tissue, plasma or serum after disease progression on the most recent treatment regimen; Plasma, serum, and tumour (preferred) tissue or cytology (if biopsy was taken and FFPE tumor material is not yet fully depleted) after disease progression on the most recent EGFR TKI treatment available for central confirmation of T790M; Measurable or evaluable disease according to RECIST 1.1; Adequate haematological, renal and liver function; World Health Organization (WHO) performance status 0-2. Exclusion Criteria: Patients with mixed NSCLC with predominantly squamous cell cancer, or with any small cell lung cancer (SCLC) component; Symptomatic or active central nervous system metastases, as indicated by progressive growth or increasing need of steroids. Patients currently receiving medications or herbal supplements known to be potent CYP3A4 inducers; Patients with any unresolved toxicities from prior therapy greater than CTCAE V 4.0 grade 1 (exception: alopecia & grade 2, prior platinuma-therapy related neuropathy) Previous treatment with osimertinib and/or bevacizumab;

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Osimertinib plus Bevacizumab<br>Patients will receive treatment with osimertinib and bevacizumab until disease progression, lack of tolerability or the patient declines further treatment. Treatment may also continue beyond progression for as long as the patient may still derive benefit. | Drug: Osimertinib<br>* Osimertinib is administered orally at 80mg once daily. Doses should be taken approximately 24 hours apart at the same time point each day. The appropriate number of osimertinib tablets will be provided to patients to be self-administered at home. AstraZeneca will supply osimertinib as tablets for oral administration. AstraZeneca will supply osimertinib as tablets for oral administration.<br>* Other names: Tagrisso;Drug: Bevacizumab<br>* Bevacizumab is administered at 15mg/kg intravenously on day 1 of every 3-week cycle. Bevacizumab for intravenous administration will be supplied by Roche.<br>* Other names: Avastin;|
| Active Comparator: Osimertinib alone<br>Patients will receive treatment with osimertinib until disease progression, lack of tolerability or the patient declines further treatment. Treatment may also continue beyond progression for as long as the patient may still derive benefit. | Drug: Osimertinib<br>* Osimertinib is administered orally at 80mg once daily. Doses should be taken approximately 24 hours apart at the same time point each day. The appropriate number of osimertinib tablets will be provided to patients to be self-administered at home. AstraZeneca will supply osimertinib as tablets for oral administration. AstraZeneca will supply osimertinib as tablets for oral administration.<br>* Other names: Tagrisso;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS in patients with locally advanced or metastatic NSCLC will be assessed according to RECIST 1.1 criteria.The two treatment arms will be compared using the Kaplan-Meier method. | PFS will be measured from date of patient enrolment until documented progression, or death, if progression is not documented, evaluated up to 48 months from enrolment of the first patient and compared between treatment arms. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR, defined as the percentage of patients reaching a complete or partial response, based on evaluation using RECIST 1.1 criteria and disease control rate. | ORR will be evaluated from date of patient enrolment until termination of trial treatment across all assessment timepoints, evaluated up to 48 months from enrolment of the first patient and compared between treatment arms. | 
| Disease Control | Disease control, defined as complete or partial response, or disease stabilisation confirmed at subsequent radiological assessment. | Evaluated across all assessment timepoints from date of patient enrolment to termination of trial treatment, evaluated up to 48 months from enrolment of the first patient and compared between treatment arms. | 
| Adverse Events | Adverse events, graded by CTCAE 4.0, will be recorded from date of signature of informed consent until 30 days after all trial treatment discontinuation. | From date of signature of informed consent until 30 days after all trial treatment discontinuation, for a maximum of 48 months from enrolment of the first patient | 
| Overall Survival (OS) | Defined as the time from date of randomisation until death from any cause. | Evaluated from date of enrolment until death from any cause, assessed at 48 months from enrolment of the first patient. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TKI, NSCLC, EGFR, EGFRm, T790M