Clinical trial NCT03133546: Osimertinib and Bevacizumab Versus Osimertinib Alone as Second-line Treatment in Stage IIIb-IVb NSCLC With Confirmed EGFRm and T790M (BOOSTER)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non Small Cell Lung Cancer Metastatic
Keywords: NSCLC
EGFR
TKI
EGFRm
T790M
Lead sponsor: ETOP IBCSG Partners Foundation
Sponsor class: NETWORK
Collaborators: name: AstraZeneca
name: Hoffmann-La Roche
First posted: 2017-04-28
Enrollment: 155
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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;

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: Evaluated up to approximately 45 months from the randomisation of the first patient.
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Evaluated up to approximately 45 months from the randomisation of the first patient.
measure: Disease Control Rate (DCR)
timeFrame: Evaluated up to approximately 45 months from the randomisation of the first patient.
measure: Adverse Events
timeFrame: Evaluated up to approximately 45 months from the randomisation of the first patient.
measure: Overall Survival (OS)
timeFrame: Evaluated up to approximately 45 months from the randomisation of the first patient.
Other outcomes:
measure: T790M Evolution in Tissue and Plasma/Serum Between Baseline and Disease Progression (PD) on Trial Treatment.
timeFrame: Available for translational research, following completion of the primary trial research objectives.
Locations:
city: Dublin
country: Ireland
facility: St. James Hospital
city: Limerick
country: Ireland
facility: Mid Western Cancer Centre
city: Goyang
country: Korea, Republic of
facility: National Cancer Centre
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Amsterdam
country: Netherlands
facility: VU University Medical Centre
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: Tan Tock Seng Hospital
city: Alicante
country: Spain
facility: Hospital General Alicante
city: Barcelona
country: Spain
facility: Hospital Sant Pau
city: Barcelona
country: Spain
facility: ICO Badalona
city: Barcelona
country: Spain
facility: ICO Hospitalet
city: Bilbao
country: Spain
facility: OSI Bilbao Basurto
city: La Coruna
country: Spain
facility: Hospital Teresa Herrara
city: Madrid
country: Spain
facility: Fund. Jimenez Diaz
city: Madrid
country: Spain
facility: Hospital de la Princesa
city: Madrid
country: Spain
facility: Hospital la Paz
city: Madrid
country: Spain
facility: Hospital Puerta de Hierro
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocio
city: Valencia
country: Spain
facility: Hospital Arnau de Vilanova
city: Valencia
country: Spain
facility: Hospital General de Valencia
city: Geneva
country: Switzerland
facility: Geneva University Hospital (HUG)
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois
city: St. Gallen
country: Switzerland
facility: Kantonsspital St. Gallen
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
city: Zurich
country: Switzerland
facility: UniversitatSpital Zurich
Study officials:
affiliation: Centre Hospitalier Universitaire Vaudois
name: Solange Peters, MD
role: STUDY_CHAIR
affiliation: University Hospital Zuerich, Zurich, Switzerland
name: Rolf Stahel, MD
role: STUDY_CHAIR
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