Osimertinib and Bevacizumab Versus Osimertinib Alone as Second-line Treatment in Stage IIIb-IVb NSCLC With Confirmed EGFRm and T790M (BOOSTER)
- Conditions
- Non Small Cell Lung Cancer Metastatic
- Interventions
- Registration Number
- NCT03133546
- Lead Sponsor
- ETOP IBCSG Partners Foundation
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 155
- 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.
- 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;
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Osimertinib plus Bevacizumab Bevacizumab 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. Osimertinib plus Bevacizumab Osimertinib 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. Osimertinib alone Osimertinib 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.
- Primary Outcome Measures
Name Time Method Progression Free Survival (PFS) Evaluated up to approximately 45 months from the randomisation of the first patient. PFS is defined as the time from the date of randomisation until documented progression (based on RECIST 1.1 criteria) or death, if progression is not documented. Censoring (for patients without progression/death) will occur at the last tumour assessment if patient is lost to follow-up or refuses further documentation of follow-up.
- Secondary Outcome Measures
Name Time Method Disease Control Rate (DCR) Evaluated up to approximately 45 months from the randomisation of the first patient. DCR is defined as the percentage of patients reaching a complete or partial response, or disease stabilisation confirmed at subsequent radiological assessment, across all assessment time-points according to RECIST criteria v1.1, during the period from randomisation to termination of trial treatment.
Overall Survival (OS) Evaluated up to approximately 45 months from the randomisation of the first patient. OS is defined as time from the date of randomisation until death from any cause. Censoring will occur at the last follow-up date.
Objective Response Rate (ORR) Evaluated up to approximately 45 months from the randomisation of the first patient. ORR is defined as the percentage of patients reaching a complete or partial response, across all assessment time-points according to RECIST criteria v1.1, during the period from randomisation to termination of trial treatment.
Adverse Events Evaluated up to approximately 45 months from the randomisation of the first patient. Adverse events, graded by CTCAE version 4.0, will be recorded from date of signature of informed consent until 30 days after all trial treatment discontinuation.
Trial Locations
- Locations (25)
St. James Hospital
🇮🇪Dublin, Ireland
Mid Western Cancer Centre
🇮🇪Limerick, Ireland
VU University Medical Centre
🇳🇱Amsterdam, Netherlands
Geneva University Hospital (HUG)
🇨ðŸ‡Geneva, Switzerland
National Cancer Centre
🇰🇷Goyang, Korea, Republic of
Severance Hospital, Yonsei University Health System
🇰🇷Seoul, Korea, Republic of
ICO Badalona
🇪🇸Barcelona, Spain
National University Hospital
🇸🇬Singapore, Singapore
Tan Tock Seng Hospital
🇸🇬Singapore, Singapore
ICO Hospitalet
🇪🇸Barcelona, Spain
Hospital Virgen del Rocio
🇪🇸Sevilla, Spain
OSI Bilbao Basurto
🇪🇸Bilbao, Spain
Hospital Teresa Herrara
🇪🇸La Coruna, Spain
Fund. Jimenez Diaz
🇪🇸Madrid, Spain
Hospital de la Princesa
🇪🇸Madrid, Spain
Hospital General de Valencia
🇪🇸Valencia, Spain
Hospital la Paz
🇪🇸Madrid, Spain
Hospital Puerta de Hierro
🇪🇸Madrid, Spain
Hospital Sant Pau
🇪🇸Barcelona, Spain
Hospital General Alicante
🇪🇸Alicante, Spain
Hospital Arnau de Vilanova
🇪🇸Valencia, Spain
Centre Hospitalier Universitaire Vaudois
🇨ðŸ‡Lausanne, Switzerland
Kantonsspital Winterthur
🇨ðŸ‡Winterthur, Switzerland
UniversitatSpital Zurich
🇨ðŸ‡Zurich, Switzerland
Kantonsspital St. Gallen
🇨ðŸ‡St. Gallen, Switzerland