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

August 23, 2022 updated by: ETOP IBCSG Partners Foundation

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

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.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

155

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Ireland
      • Dublin, Ireland
        • St. James Hospital
      • Limerick, Ireland
        • Mid Western Cancer Centre
  • Korea, Republic of
      • Goyang, Korea, Republic of
        • National Cancer Centre
      • Seoul, Korea, Republic of
        • Severance Hospital, Yonsei University Health System
  • Netherlands
      • Amsterdam, Netherlands
        • VU University Medical Centre
  • Singapore
      • Singapore, Singapore
        • National University Hospital
      • Singapore, Singapore
        • Tan Tock Seng Hospital
  • Spain
      • Alicante, Spain
        • Hospital General Alicante
      • Barcelona, Spain
        • Hospital Sant Pau
      • Barcelona, Spain
        • ICO Hospitalet
      • Barcelona, Spain
        • ICO Badalona
      • Bilbao, Spain
        • OSI Bilbao Basurto
      • La Coruna, Spain
        • Hospital Teresa Herrara
      • Madrid, Spain
        • Hospital La Paz
      • Madrid, Spain
        • Hospital de La Princesa
      • Madrid, Spain
        • Hospital Puerta de Hierro
      • Madrid, Spain
        • Fund. Jimenez Diaz
      • Sevilla, Spain
        • Hospital Virgen del Rocio
      • Valencia, Spain
        • Hospital Arnau de Vilanova
      • Valencia, Spain
        • Hospital General de Valencia
  • Switzerland
      • Geneva, Switzerland
        • Geneva University Hospital (HUG)
      • Lausanne, Switzerland
        • Centre Hospitalier Universitaire Vaudois
      • St. Gallen, Switzerland
        • Kantonsspital St. Gallen
      • Winterthur, Switzerland
        • Kantonsspital Winterthur
      • Zurich, Switzerland
        • UniversitätSpital Zürich

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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;

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Osimertinib plus 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.
Drug: Osimertinib

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.

Other Names:
  • Tagrisso
Drug: Bevacizumab
Bevacizumab is administered at 15mg/kg intravenously on day 1 of every 3-week cycle. Bevacizumab for intravenous administration will be supplied by Roche.
Other Names:
  • Avastin
ACTIVE_COMPARATOR: Osimertinib alone
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

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.

Other Names:
  • Tagrisso

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression Free Survival (PFS)
Time Frame: 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.
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)
Time Frame: 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.
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
Time Frame: 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.
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
Time Frame: 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
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)
Time Frame: Evaluated from date of enrolment until death from any cause, assessed at 48 months from enrolment of the first patient.
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.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
T790M evolution in tissue and plasma/serum between baseline and disease progression on trial treatment
Time Frame: Assessed at baseline and disease progression on trial treatment (maximum 48 months)
For this correlative studie tumour tissue blocks, plasma and serum samples will be collected at trial entry and at disease progression on trial treatment.
Assessed at baseline and disease progression on trial treatment (maximum 48 months)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

ETOP IBCSG Partners Foundation

Collaborators

Hoffmann-La Roche
AstraZeneca

Investigators

  • Study Chair: Solange Peters, MD, Centre Hospitalier Universitaire Vaudois
  • Study Chair: Rolf Stahel, MD, University Hospital Zuerich, Zurich, Switzerland

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

May 31, 2017

Primary Completion (ANTICIPATED)

May 1, 2023

Study Completion (ANTICIPATED)

May 1, 2023

Study Registration Dates

First Submitted

April 20, 2017

First Submitted That Met QC Criteria

April 25, 2017

First Posted (ACTUAL)

April 28, 2017

Study Record Updates

Last Update Posted (ACTUAL)

August 24, 2022

Last Update Submitted That Met QC Criteria

August 23, 2022

Last Verified

August 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ETOP 10-16
  • 2016-002029-12 (EUDRACT_NUMBER)
  • ESR-15-11666 (OTHER: AstraZeneca)
  • MO39447 (OTHER: Roche)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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