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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2016-002029-12
    Trial protocol
    		 IE   ES   NL  
    Global end of trial date
    22 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Apr 2023
    First version publication date
    27 Apr 2023
    Other versions
    Summary report(s)
    		 Statistical analysis plan

    Trial information

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    Trial identification
    Sponsor protocol code
    ETOP10-16
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03133546
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Astra Zeneca: ESR-15-11666, Roche: MO39447
    Sponsors
    Sponsor organisation name
    ETOP IBCSG Partners Foundation
    Sponsor organisation address
    Effingerstrasse 33, Bern, Switzerland, 3008
    Public contact
    ETOP IBCSG Partners Foundation, ETOP IBCSG Partners Foundation, +41 31 511 94 00, etop-regulatory@etop.ibcsg.org
    Scientific contact
    ETOP IBCSG Partners Coordinating Center, ETOP IBCSG Partners Foundation, +41 31 511 94 00, etop-regulatory@etop.ibcsg.org
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Feb 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of the combination of osimertinib and bevacizumab versus osimertinib alone in terms of progression-free survival (PFS) assessed by RECIST 1.1.
    Protection of trial subjects
    The investigator will ensure that this trial is conducted in full conformance with the principles of the “Declaration of Helsinki” or with the laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual. The trial must fully adhere to the principles outlined in “Guideline for Good Clinical Practice (GCP)” ICH Tripartite Guideline (January 1997) or with local law if it affords greater protection to the patient. For studies conducted in the EU/EEA countries, the investigator will ensure compliance with the EU Clinical Trial Directive (2001/20/EC).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 May 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Spain: 78
    Country: Number of subjects enrolled
    Ireland: 10
    Country: Number of subjects enrolled
    Singapore: 31
    Country: Number of subjects enrolled
    Korea, Republic of: 28
    Country: Number of subjects enrolled
    Switzerland: 5
    Worldwide total number of subjects
    155
    EEA total number of subjects
    91
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    67
    From 65 to 84 years
    87
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between May 31, 2017 and February 21, 2019, 188 patients were captured in the iBiobank.

    Pre-assignment
    Screening details
    		 Out of the 188 patients, 155 coming from 22 centers (12 Spanish, 3 Swiss, 2 Irish, 2 in Singapore, 2 South Korean and 1 Dutch) were randomised. 33 patients were not randomized due to ‘Screening failure’ or ‘Error’ status.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Osimertinib Plus Bevacizumab
    Arm description
    		 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: 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avastin and Tagrisso
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Osimertinib, 80 mg p.o., once daily plus bevacizumab 15 mg/kg i.v. on day 1 of every 3-week cycle.

    Arm title
    		 Osimertinib Alone
    Arm description
    		 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. 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.
    Arm type
    		 Control

    Investigational medicinal product name
    Tagrisso
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Osimertinib, 80 mg p.o., once daily

    Number of subjects in period 1
    		Osimertinib Plus Bevacizumab Osimertinib Alone
    Started
    78
    77
    Received Treatment
    76
    77
    On Treatment
    1 [1]
    8 [2]
    Treatment Failures
    75
    69
    Never Started Treatment
    2 [3]
    0 [4]
    Completed
    27
    27
    Not completed
    51
    50
         Death
    46
    43
         Withdrawal/Lost to follow-up
    5
    7
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Osimertinib Plus Bevacizumab, among the 78 patients randomised, 76 received treatment (2 patients never started treatment). Out of the 76 who received treatment, 1 is still on treatment, while there are 75 patients with treatment failures (36 toxicities, 29 progressions, 4 other reasons, 3 patient decisions, 2 deaths, 1 investigator decision). In total, 27 patients are still on follow-up at final database cut-off, while 51 are lost to follow-up/withdrawal.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Osimertinib, among the 77 patients randomised, all patients received treatment, 8 are still on treatment, while there are 69 patients with treatment failures (3 toxicities, 53 progressions, 1 other reason, 4 patient decisions, 7 deaths, 1 investigator decision). In total, 27 patients are still on follow-up at final database cut-off, while 50 are lost to follow-up/withdrawal.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Osimertinib Plus Bevacizumab, among the 78 patients randomised, 76 received treatment (2 patients never started treatment). Out of the 76 who received treatment, 1 is still on treatment, while there are 75 patients with treatment failures (36 toxicities, 29 progressions, 4 other reasons, 3 patient decisions, 2 deaths, 1 investigator decision). In total, 27 patients are still on follow-up at final database cut-off, while 51 are lost to follow-up/withdrawal.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Osimertinib, among the 77 patients randomised, all patients received treatment, 8 are still on treatment, while there are 69 patients with treatment failures (3 toxicities, 53 progressions, 1 other reason, 4 patient decisions, 7 deaths, 1 investigator decision). In total, 27 patients are still on follow-up at final database cut-off, while 50 are lost to follow-up/withdrawal.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Osimertinib Plus Bevacizumab
    Reporting group description
    		 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: 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.

    Reporting group title
    Osimertinib Alone
    Reporting group description
    		 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. 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.

    Reporting group values
    		 Osimertinib Plus Bevacizumab Osimertinib Alone Total
    Number of subjects
    		 78 77 155
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    		 68 (34 to 85) 66 (41 to 83) -
    Gender categorical
    Units: Subjects
        Female
    		 47 49 96
        Male
    		 31 28 59
    Ethnicity
    Units: Subjects
        Asian
    		 32 31 63
        Non-Asian
    		 46 46 92
    ECOG Performance Status
    ECOG Performance status scaling: PS 0:Fully active, able to carry on all pre-disease performance without restriction. PS 1:Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work. PS 2:Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. PS 3:Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours. PS 4:Completely disabled. Cannot carry on any self-care. Totally confined to bed or cha
    Units: Subjects
        PS 0
    		 22 25 47
        PS 1
    		 51 48 99
        PS 2
    		 5 4 9
    Smoking status
    Current smoker: Still smokes cigarettes, Former smoker: Smoked at least 100 cigarettes in the past during the whole life, Never smoker: Smoked 0-99 cigarettes during the whole life.
    Units: Subjects
        Current smoker
    		 4 1 5
        Former smoker
    		 30 27 57
        Never smoked
    		 44 49 93
    Stage
    According to the American Joint Committee on Cancer 8th TNM classification.
    Units: Subjects
        IIIB/C
    		 2 0 2
        IVA/B
    		 76 76 152
        Missing
    		 0 1 1
    Use of prior platinum-based chemotherapy
    Units: Subjects
        Yes
    		 11 13 24
        No
    		 67 64 131
    Prior EGFR TKI
    TKI: tyrosine kinase inhibitors
    Units: Subjects
        Erlotinib/gefitinib
    		 57 57 114
        Afatinib/dacomitinib
    		 21 19 40
        Other
    		 0 1 1
    EGFR mutation type
    Units: Subjects
        Exon 19 deletion
    		 58 51 109
        Exon 21 L858R
    		 20 26 46
    T790M testing material
    Units: Subjects
        ctDNA
    		 38 37 75
        Tumour
    		 40 40 80
    Brain metastasis
    Units: Subjects
        Yes
    		 13 8 21
        No
    		 65 69 134
    Liver metastasis
    Units: Subjects
        Yes
    		 14 8 22
        No
    		 64 69 133
    Pleural effusion and ascites
    Units: Subjects
        Yes
    		 7 9 16
        No
    		 71 68 139

    End points

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    End points reporting groups
    Reporting group title
    Osimertinib Plus Bevacizumab
    Reporting group description
    		 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: 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.

    Reporting group title
    Osimertinib Alone
    Reporting group description
    		 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. 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.

    Primary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    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.
    End point type
    Primary
    End point timeframe
    Evaluated up to 48 months from randomisation of the first patient (expected follow-up for the required events, assuming an accrual of 29 months).
    End point values
    		 Osimertinib Plus Bevacizumab Osimertinib Alone
    Number of subjects analysed
    78
    77
    Units: months
        median (confidence interval 95%)
    15.4 (9.2 to 18)
    12.3 (6.2 to 17.2)
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    Assumption: Median PFS with osimertinib 11 months Target: Detect a 36% improvement in PFS (HR=0.64, corresponding to an increase in median PFS to 17.2 months) under osimertinib and bevacizumab (80% power, at one-sided significant level of 5%) 126 events required
    Comparison groups
    Osimertinib Alone v Osimertinib Plus Bevacizumab
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.84 [1]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.37
    Notes
    [1] - significance level: 5%

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Evaluated up to 48 months from randomisation of the first patient.
    End point values
    		 Osimertinib Plus Bevacizumab Osimertinib Alone
    Number of subjects analysed
    78
    77
    Units: percentage of participants
        number (confidence interval 95%)
    0.55 (0.43 to 0.66)
    0.55 (0.43 to 0.66)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Evaluated up to 48 months from enrolment of the first patient.
    End point values
    		 Osimertinib Plus Bevacizumab Osimertinib Alone
    Number of subjects analysed
    78
    77
    Units: percentage of participants
        number (confidence interval 95%)
    0.90 (0.81 to 0.95)
    0.82 (0.71 to 0.90)
    No statistical analyses for this end point

    Secondary: Adverse Events

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    End point title
    		 Adverse Events
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Evaluated up to 48 months from randomisation of the first patient.
    End point values
    		 Osimertinib Plus Bevacizumab Osimertinib Alone
    Number of subjects analysed
    76 [2]
    77
    Units: participants
        Experienced AE/SAE
    76
    76
        No AE/SAE
    0
    1
        Experienced SAE
    33
    27
    Notes
    [2] - Two patients never started treatment
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as time from the date of randomisation until death from any cause. Censoring will occur at the last follow-up date.
    End point type
    Secondary
    End point timeframe
    Evaluated up to 48 months from randomisation of the first patient.
    End point values
    		 Osimertinib Plus Bevacizumab Osimertinib Alone
    Number of subjects analysed
    78
    77
    Units: months
        median (confidence interval 95%)
    24.0 (17.8 to 32.1)
    24.3 (16.9 to 37.0)
    No statistical analyses for this end point

    Other pre-specified: T790M Evolution in Tissue and Plasma/Serum Between Baseline and Disease Progression (PD) on Trial Treatment.

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    End point title
    		 T790M Evolution in Tissue and Plasma/Serum Between Baseline and Disease Progression (PD) on Trial Treatment.
    End point description
    Tumour tissue blocks, plasma and serum samples will be collected at trial entry and at disease progression on trial treatment.
    End point type
    Other pre-specified
    End point timeframe
    Available for translational research, following completion of the primary trial research objectives.
    End point values
    		 Osimertinib Plus Bevacizumab Osimertinib Alone
    Number of subjects analysed
    76 [3]
    73 [4]
    Units: participants
        MD-MD
    8
    8
        MD-MND
    18
    13
        MND-MD
    0
    1
        MND-MND
    6
    8
        Missing
    22
    25
        Not applicable (No PD)
    22
    18
    Notes
    [3] - Patients with NGS plasma sample T790M base to PD MD: Mutation Detected MND: Mutation Not Detected
    [4] - Patients with NGS plasma sample T790M base to PD MD: Mutation Detected MND: Mutation Not Detected
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Continuously from date of Informed Consent signature to 30 days after all treatments discontinuation.
    Adverse event reporting additional description
    Adverse event (AE) is defined as any untoward medical occurrence that occurs from the date of signature of informed consent until 30 days after all trial treatment discontinuation, regardless of whether it is considered related to a medication. Adverse events are classified according to CTCAE version 4.0.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Osimertinib Plus Bevacizumab
    Reporting group description
    		 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: 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.

    Reporting group title
    Osimertinib Alone
    Reporting group description
    		 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. 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.

    Serious adverse events
    		 Osimertinib Plus Bevacizumab Osimertinib Alone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 76 (43.42%)
    27 / 77 (35.06%)
         number of deaths (all causes)
    46
    43
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastric carcinoma
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thromboembolic event
         subjects affected / exposed
    2 / 76 (2.63%)
    3 / 77 (3.90%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Pleurodesis of malignant pleural effusion
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug overdose
         subjects affected / exposed
    3 / 76 (3.95%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Autoimmune disorder
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary hemorrhage
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal hemorrhage
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic infection
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mania
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Lipase increased
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Heart failure
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 76 (3.95%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischemia cerebrovascular
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stroke
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis oral
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 76 (0.00%)
    3 / 77 (3.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Skin and subcutaneous tissue disorders
    Rash acneiform
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hematuria
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Upper respiratory infection
         subjects affected / exposed
    1 / 76 (1.32%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    4 / 76 (5.26%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pharyngitis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial infection
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 infection
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis caused by COVID-19 infection
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza A
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural infection
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatremia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalemia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycemia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Osimertinib Plus Bevacizumab Osimertinib Alone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    76 / 76 (100.00%)
    76 / 77 (98.70%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    32 / 76 (42.11%)
    7 / 77 (9.09%)
         occurrences all number
    32
    7
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    33 / 76 (43.42%)
    29 / 77 (37.66%)
         occurrences all number
    33
    29
    Pain
         subjects affected / exposed
    22 / 76 (28.95%)
    12 / 77 (15.58%)
         occurrences all number
    22
    12
    Fever
         subjects affected / exposed
    6 / 76 (7.89%)
    10 / 77 (12.99%)
         occurrences all number
    6
    10
    Edema limbs
         subjects affected / exposed
    10 / 76 (13.16%)
    4 / 77 (5.19%)
         occurrences all number
    10
    4
    Non-cardiac chest pain
         subjects affected / exposed
    9 / 76 (11.84%)
    1 / 77 (1.30%)
         occurrences all number
    9
    1
    Flu like symptoms
         subjects affected / exposed
    6 / 76 (7.89%)
    3 / 77 (3.90%)
         occurrences all number
    6
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    31 / 76 (40.79%)
    28 / 77 (36.36%)
         occurrences all number
    31
    28
    Dyspnea
         subjects affected / exposed
    13 / 76 (17.11%)
    17 / 77 (22.08%)
         occurrences all number
    13
    17
    Epistaxis
         subjects affected / exposed
    16 / 76 (21.05%)
    4 / 77 (5.19%)
         occurrences all number
    16
    4
    Sore throat
         subjects affected / exposed
    7 / 76 (9.21%)
    3 / 77 (3.90%)
         occurrences all number
    7
    3
    Pleural effusion
         subjects affected / exposed
    3 / 76 (3.95%)
    5 / 77 (6.49%)
         occurrences all number
    3
    5
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 76 (1.32%)
    7 / 77 (9.09%)
         occurrences all number
    1
    7
    Investigations
    Lipase increased
         subjects affected / exposed
    12 / 76 (15.79%)
    13 / 77 (16.88%)
         occurrences all number
    12
    13
    Serum amylase increased
         subjects affected / exposed
    12 / 76 (15.79%)
    13 / 77 (16.88%)
         occurrences all number
    12
    13
    Platelet count decreased
         subjects affected / exposed
    15 / 76 (19.74%)
    9 / 77 (11.69%)
         occurrences all number
    15
    9
    Neutrophil count decreased
         subjects affected / exposed
    7 / 76 (9.21%)
    10 / 77 (12.99%)
         occurrences all number
    7
    10
    Alanine aminotransferase increased
         subjects affected / exposed
    10 / 76 (13.16%)
    6 / 77 (7.79%)
         occurrences all number
    10
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    10 / 76 (13.16%)
    5 / 77 (6.49%)
         occurrences all number
    10
    5
    Electrocardiogram QT corrected interval prolonged
         subjects affected / exposed
    10 / 76 (13.16%)
    5 / 77 (6.49%)
         occurrences all number
    10
    5
    Ejection fraction decreased
         subjects affected / exposed
    9 / 76 (11.84%)
    1 / 77 (1.30%)
         occurrences all number
    9
    1
    Alkaline phosphatase increased
         subjects affected / exposed
    6 / 76 (7.89%)
    3 / 77 (3.90%)
         occurrences all number
    6
    3
    Creatinine increased
         subjects affected / exposed
    7 / 76 (9.21%)
    2 / 77 (2.60%)
         occurrences all number
    7
    2
    White blood cell decreased
         subjects affected / exposed
    5 / 76 (6.58%)
    4 / 77 (5.19%)
         occurrences all number
    5
    4
    GGT increased
         subjects affected / exposed
    6 / 76 (7.89%)
    2 / 77 (2.60%)
         occurrences all number
    6
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    18 / 76 (23.68%)
    9 / 77 (11.69%)
         occurrences all number
    18
    9
    Dizziness
         subjects affected / exposed
    9 / 76 (11.84%)
    11 / 77 (14.29%)
         occurrences all number
    9
    11
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    7 / 76 (9.21%)
    12 / 77 (15.58%)
         occurrences all number
    7
    12
    Eye disorders
    Dry eye
         subjects affected / exposed
    4 / 76 (5.26%)
    10 / 77 (12.99%)
         occurrences all number
    4
    10
    Blurred vision
         subjects affected / exposed
    4 / 76 (5.26%)
    5 / 77 (6.49%)
         occurrences all number
    4
    5
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    41 / 76 (53.95%)
    38 / 77 (49.35%)
         occurrences all number
    41
    38
    Constipation
         subjects affected / exposed
    19 / 76 (25.00%)
    16 / 77 (20.78%)
         occurrences all number
    19
    16
    Mucositis oral
         subjects affected / exposed
    19 / 76 (25.00%)
    10 / 77 (12.99%)
         occurrences all number
    19
    10
    Nausea
         subjects affected / exposed
    17 / 76 (22.37%)
    13 / 77 (16.88%)
         occurrences all number
    17
    13
    Vomiting
         subjects affected / exposed
    17 / 76 (22.37%)
    7 / 77 (9.09%)
         occurrences all number
    17
    7
    Abdominal pain
         subjects affected / exposed
    7 / 76 (9.21%)
    4 / 77 (5.19%)
         occurrences all number
    7
    4
    Dry mouth
         subjects affected / exposed
    2 / 76 (2.63%)
    8 / 77 (10.39%)
         occurrences all number
    2
    8
    Skin and subcutaneous tissue disorders
    Rash acneiform
         subjects affected / exposed
    27 / 76 (35.53%)
    19 / 77 (24.68%)
         occurrences all number
    27
    19
    Dry skin
         subjects affected / exposed
    16 / 76 (21.05%)
    15 / 77 (19.48%)
         occurrences all number
    16
    15
    Pruritus
         subjects affected / exposed
    8 / 76 (10.53%)
    15 / 77 (19.48%)
         occurrences all number
    8
    15
    Rash maculo-papular
         subjects affected / exposed
    6 / 76 (7.89%)
    5 / 77 (6.49%)
         occurrences all number
    6
    5
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    37 / 76 (48.68%)
    2 / 77 (2.60%)
         occurrences all number
    37
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    10 / 76 (13.16%)
    11 / 77 (14.29%)
         occurrences all number
    10
    11
    Pain in extremity
         subjects affected / exposed
    3 / 76 (3.95%)
    9 / 77 (11.69%)
         occurrences all number
    3
    9
    Myalgia
         subjects affected / exposed
    4 / 76 (5.26%)
    5 / 77 (6.49%)
         occurrences all number
    4
    5
    Arthralgia
         subjects affected / exposed
    5 / 76 (6.58%)
    3 / 77 (3.90%)
         occurrences all number
    5
    3
    Infections and infestations
    Upper respiratory infection
         subjects affected / exposed
    16 / 76 (21.05%)
    15 / 77 (19.48%)
         occurrences all number
    16
    15
    Paronychia
         subjects affected / exposed
    13 / 76 (17.11%)
    13 / 77 (16.88%)
         occurrences all number
    13
    13
    Urinary tract infection
         subjects affected / exposed
    6 / 76 (7.89%)
    6 / 77 (7.79%)
         occurrences all number
    6
    6
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    24 / 76 (31.58%)
    17 / 77 (22.08%)
         occurrences all number
    24
    17
    Hyponatremia
         subjects affected / exposed
    6 / 76 (7.89%)
    4 / 77 (5.19%)
         occurrences all number
    6
    4
    Hypokalemia
         subjects affected / exposed
    3 / 76 (3.95%)
    6 / 77 (7.79%)
         occurrences all number
    3
    6

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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