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

Sponsor

ETOP IBCSG Partners Foundation (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03133546

Collaborator

AstraZeneca (Industry), Hoffmann-La Roche (Industry)

155

Enrollment

Locations

Arms

Anticipated Duration (Months)

6.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Non Small Cell Lung Cancer Metastatic	Drug: Osimertinib Drug: Bevacizumab	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

155 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

May 31, 2017

Anticipated Primary Completion Date :

May 1, 2022

Anticipated Study Completion Date :

May 1, 2022

Arms and Interventions

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

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

Other Names:

Tagrisso

Outcome Measures

Primary Outcome Measures

Progression Free Survival (PFS) [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.

Secondary Outcome Measures

Objective Response Rate (ORR) [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.
Disease Control [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.
Adverse Events [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.
Overall Survival (OS) [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.

Other Outcome Measures

T790M evolution in tissue and plasma/serum between baseline and disease progression on trial treatment [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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;

Contacts and Locations

Locations

	Site	City	Country
1	St. James Hospital	Dublin	Ireland
2	Mid Western Cancer Centre	Limerick	Ireland
3	National Cancer Centre	Goyang	Korea, Republic of
4	Severance Hospital, Yonsei University Health System	Seoul	Korea, Republic of
5	VU University Medical Centre	Amsterdam	Netherlands
6	National University Hospital	Singapore	Singapore
7	Tan Tock Seng Hospital	Singapore	Singapore
8	Hospital General Alicante	Alicante	Spain
9	Hospital Sant Pau	Barcelona	Spain
10	ICO Badalona	Barcelona	Spain
11	ICO Hospitalet	Barcelona	Spain
12	OSI Bilbao Basurto	Bilbao	Spain
13	Hospital Teresa Herrara	La Coruna	Spain
14	Fund. Jimenez Diaz	Madrid	Spain
15	Hospital de la Princesa	Madrid	Spain
16	Hospital la Paz	Madrid	Spain
17	Hospital Puerta de Hierro	Madrid	Spain
18	Hospital Virgen del Rocio	Sevilla	Spain
19	Hospital Arnau de Vilanova	Valencia	Spain
20	Hospital General de Valencia	Valencia	Spain
21	Geneva University Hospital (HUG)	Geneva	Switzerland
22	Centre Hospitalier Universitaire Vaudois	Lausanne	Switzerland
23	Kantonsspital St. Gallen	St. Gallen	Switzerland
24	Kantonsspital Winterthur	Winterthur	Switzerland
25	UniversitatSpital Zurich	Zurich	Switzerland