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

Non Small Cell Lung Cancer Metastatic Clinical Trial

— 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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03133546
• Other study ID #: ETOP 10-16
• Secondary ID: 2016-002029-12ES
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: May 31, 2017
• Est. completion date: May 2023

Study information

• Verified date: August 2022
• Source: ETOP IBCSG Partners Foundation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 155
• Est. completion date: May 2023
• Est. primary completion date: May 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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;

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Non Small Cell Lung Cancer Metastatic

Intervention

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.
• 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.

Locations

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

Sponsors (3)

Lead Sponsor	Collaborator
ETOP IBCSG Partners Foundation	AstraZeneca, Hoffmann-La Roche

Countries where clinical trial is conducted

Ireland,  Korea, Republic of,  Netherlands,  Singapore,  Spain,  Switzerland, 

References & Publications (6)

Bonomi PD. Implications of key trials in advanced nonsmall cell lung cancer. Cancer. 2010 Mar 1;116(5):1155-64. doi: 10.1002/cncr.24815. Review. — View Citation

Camidge DR, Pao W, Sequist LV. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol. 2014 Aug;11(8):473-81. doi: 10.1038/nrclinonc.2014.104. Epub 2014 Jul 1. Review. — View Citation

Finlay MR, Anderton M, Ashton S, Ballard P, Bethel PA, Box MR, Bradbury RH, Brown SJ, Butterworth S, Campbell A, Chorley C, Colclough N, Cross DA, Currie GS, Grist M, Hassall L, Hill GB, James D, James M, Kemmitt P, Klinowska T, Lamont G, Lamont SG, Martin N, McFarland HL, Mellor MJ, Orme JP, Perkins D, Perkins P, Richmond G, Smith P, Ward RA, Waring MJ, Whittaker D, Wells S, Wrigley GL. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem. 2014 Oct 23;57(20):8249-67. doi: 10.1021/jm500973a. Epub 2014 Oct 1. — View Citation

Jackman DM, Miller VA, Cioffredi LA, Yeap BY, Jänne PA, Riely GJ, Ruiz MG, Giaccone G, Sequist LV, Johnson BE. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin Cancer Res. 2009 Aug 15;15(16):5267-73. doi: 10.1158/1078-0432.CCR-09-0888. Epub 2009 Aug 11. — View Citation

Oxnard GR, Arcila ME, Sima CS, Riely GJ, Chmielecki J, Kris MG, Pao W, Ladanyi M, Miller VA. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res. 2011 Mar 15;17(6):1616-22. doi: 10.1158/1078-0432.CCR-10-2692. Epub 2010 Dec 6. — View Citation

Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Muñoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L; Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239-46. doi: 10.1016/S1470-2045(11)70393-X. Epub 2012 Jan 26. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	T790M evolution in tissue and plasma/serum between baseline and disease progression on trial treatment	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)
Primary	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	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.
Secondary	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.
Secondary	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
Secondary	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.