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    Clinical Trial Results:
    A randomised non-comparative open label phase II trial of atezolizumab plus bevacizumab, with carboplatin-paclitaxel or pemetrexed, in EGFR mutant non-small cell lung carcinoma with acquired resistance

    Summary
    EudraCT number
    		 2019-001687-30
    Trial protocol
    		 ES   DE  
    Global end of trial date
    22 Jul 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Mar 2026
    First version publication date
    06 Mar 2026
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ETOP 15-19
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04245085
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Roche Number: MO40586
    Sponsors
    Sponsor organisation name
    ETOP IBCSG Partners Foundation
    Sponsor organisation address
    Effingerstrasse 33, Bern, Switzerland, 3008
    Public contact
    ETOP IBCSG Partners Coordinating Center, ETOP IBCSG Partners Foundation, +41 315119400, etop-regulatory@etop.ibcsg.org
    Scientific contact
    ETOP IBCSG Partners Coordinating Center, ETOP IBCSG Partners Foundation, +41 315119400, 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
    01 Dec 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Sep 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jul 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to explore the clinical efficacy of atezolizumab and bevacizumab combined with chemotherapy in EGFR mutated patients after failure of standard EGFR targeted therapies.
    Protection of trial subjects
    Participating institutions’ ethics committees or Institutional Review Boards approved the trial according to local laws and regulations. All patients gave written informed consent, and the trial was performed in compliance with the Helsinki Declaration. The Data Safety and Monitoring Board reviewed the data from this research throughout the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Sep 2020
    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
    Korea, Democratic People's Republic of: 41
    Country: Number of subjects enrolled
    Switzerland: 11
    Country: Number of subjects enrolled
    Singapore: 10
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Spain: 32
    Worldwide total number of subjects
    95
    EEA total number of subjects
    33
    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)
    58
    From 65 to 84 years
    36
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Overall, 95 patients were registered and randomized in iBiobank from September 29, 2020 until September 12, 2022 (randomization date of the last patient). Randomized patients come from ten centers in Spain, three in Switzerland, two in South Korea, one in Singapore and one in Germany.

    Pre-assignment
    Screening details
    		 There were 25 screening failures.

    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
    		 Arm A
    Arm description
    		 Atezolizumab: Patients in both treatment arms will receive atezolizumab at a fixed dose of 1200 mg i.v. on day one of every 3-week (3 days) cycle, until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment. Treatment beyond RECIST-defined progression will be allowed if patient is continuing to derive clinical benefit. Bevacizumab: Patients in both treatment arms will receive bevacizumab at a dose of 15 mg/kg i.v. on day one of every 3-week (+/- 3 days) cycle, until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment. Carboplatin: Patients in treatment Arm A will receive carboplatin, AUC5 every 3 weeks for 4-6 cycles. Paclitaxel: Patients in treatment Arm A will receive paclitaxel, 175-200 mg/m2 (at the investigators' discretion), every 3 weeks for 4-6 cycles.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Tecentriq
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1200 mg i.v. on day one of every 3-week (+/-3 days) cycle, until PD1, refusal or unacceptable toxicity

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    15mg/kg i.v. on day one of every 3-week (+/-3 days) cycle, until PD, refusal or unacceptable toxicity

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients in treatment Arm A will receive carboplatin, AUC5 plus paclitaxel, 175-200 mg/m2, at the investigator’s discretion, every 3 weeks for 4-6 cycles.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients in treatment Arm A will receive carboplatin, AUC5 plus paclitaxel, 175-200 mg/m2, at the investigator’s discretion, every 3 weeks for 4-6 cycles.

    Arm title
    		 Arm B
    Arm description
    		 Atezolizumab: Patients in both treatment arms will receive atezolizumab at a fixed dose of 1200 mg i.v. on day one of every 3-week (3 days) cycle, until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment. Treatment beyond RECIST-defined progression will be allowed if patient is continuing to derive clinical benefit. Bevacizumab: Patients in both treatment arms will receive bevacizumab at a dose of 15 mg/kg i.v. on day one of every 3-week (+/- 3 days) cycle, until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment. Pemetrexed: Patients in treatment Arm B will receive Pemetrexed, 500 mg/m2 every 3 weeks until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Tecentriq
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1200 mg i.v. on day one of every 3-week (+/-3 days) cycle, until PD1, refusal or unacceptable toxicity

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    15mg/kg i.v. on day one of every 3-week (+/-3 days) cycle, until PD, refusal or unacceptable toxicity

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg/m2, Q3W, until PD

    Number of subjects in period 1
    		Arm A Arm B
    Started
    45
    50
    Completed
    16
    20
    Not completed
    29
    30
         Death
    26
    27
         Withdrawal/Lost to follow-up
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Atezolizumab: Patients in both treatment arms will receive atezolizumab at a fixed dose of 1200 mg i.v. on day one of every 3-week (3 days) cycle, until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment. Treatment beyond RECIST-defined progression will be allowed if patient is continuing to derive clinical benefit. Bevacizumab: Patients in both treatment arms will receive bevacizumab at a dose of 15 mg/kg i.v. on day one of every 3-week (+/- 3 days) cycle, until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment. Carboplatin: Patients in treatment Arm A will receive carboplatin, AUC5 every 3 weeks for 4-6 cycles. Paclitaxel: Patients in treatment Arm A will receive paclitaxel, 175-200 mg/m2 (at the investigators' discretion), every 3 weeks for 4-6 cycles.

    Reporting group title
    Arm B
    Reporting group description
    		 Atezolizumab: Patients in both treatment arms will receive atezolizumab at a fixed dose of 1200 mg i.v. on day one of every 3-week (3 days) cycle, until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment. Treatment beyond RECIST-defined progression will be allowed if patient is continuing to derive clinical benefit. Bevacizumab: Patients in both treatment arms will receive bevacizumab at a dose of 15 mg/kg i.v. on day one of every 3-week (+/- 3 days) cycle, until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment. Pemetrexed: Patients in treatment Arm B will receive Pemetrexed, 500 mg/m2 every 3 weeks until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment

    Reporting group values
    		 Arm A Arm B Total
    Number of subjects
    		 45 50 95
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 61 (32 to 93) 63 (45 to 75) -
    Gender categorical
    Units: Subjects
        Female
    		 27 17 44
        Male
    		 18 33 51
    Race/Ethnicity
    Units: Subjects
        Asian
    		 25 27 52
        White
    		 20 21 41
        Black
    		 0 1 1
        Other
    		 0 1 1
    ECOG Performance Status
    0: Fully active, able to carry on all pre-disease performance without restriction; 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work;
    Units: Subjects
        Status 0
    		 16 8 24
        Status 1
    		 29 42 71
    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
    		 3 4 7
        Former smoker
    		 17 14 31
        Never smoked
    		 25 32 57
    Stage
    Stage is based on the 8th TNM classification for NSCLC (American Joint Committee on Cancer). Stage IIIB/C: the tumor is 5 cm or smaller (IIIB) or any size (IIIC) and cancer has spread to lymph nodes above the collarbone on the same side of the chest as the primary tumor or to any lymph nodes on the opposite side of the chest as the primary tumor. Stage IVA: cancer has spread within the chest and/or has spread to 1 area outside of the chest. Stage IVB: cancer has spread outside of the chest to more than 1 place in 1 organ or to more than 1 organ.
    Units: Subjects
        IIIB
    		 1 0 1
        IVA
    		 10 21 31
        IVB
    		 34 29 63
    EGFR mutation type
    Histologically or cytologically confirmed exon 19 deletion or exon 21 L858R mutation by a certified local laboratory
    Units: Subjects
        Exon 19 deletion
    		 28 29 57
        Exon 21 L858R
    		 16 19 35
        Other
    		 1 2 3
    Prior TKI treatment
    TKI: tyrosine kinase inhibitors
    Units: Subjects
        Afatinib
    		 9 8 17
        Erlotinib
    		 2 3 5
        Gefitinib
    		 4 5 9
        Lazertinib
    		 1 5 6
        Nazartinib
    		 1 0 1
        Osimertinib
    		 28 27 55
        Osimertinib or Lazertinib
    		 0 1 1
        Osimertinib or Savolitinib
    		 0 1 1
    Brain metastasis
    Units: Subjects
        Yes
    		 15 16 31
        No
    		 30 34 64

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Atezolizumab: Patients in both treatment arms will receive atezolizumab at a fixed dose of 1200 mg i.v. on day one of every 3-week (3 days) cycle, until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment. Treatment beyond RECIST-defined progression will be allowed if patient is continuing to derive clinical benefit. Bevacizumab: Patients in both treatment arms will receive bevacizumab at a dose of 15 mg/kg i.v. on day one of every 3-week (+/- 3 days) cycle, until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment. Carboplatin: Patients in treatment Arm A will receive carboplatin, AUC5 every 3 weeks for 4-6 cycles. Paclitaxel: Patients in treatment Arm A will receive paclitaxel, 175-200 mg/m2 (at the investigators' discretion), every 3 weeks for 4-6 cycles.

    Reporting group title
    Arm B
    Reporting group description
    		 Atezolizumab: Patients in both treatment arms will receive atezolizumab at a fixed dose of 1200 mg i.v. on day one of every 3-week (3 days) cycle, until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment. Treatment beyond RECIST-defined progression will be allowed if patient is continuing to derive clinical benefit. Bevacizumab: Patients in both treatment arms will receive bevacizumab at a dose of 15 mg/kg i.v. on day one of every 3-week (+/- 3 days) cycle, until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment. Pemetrexed: Patients in treatment Arm B will receive Pemetrexed, 500 mg/m2 every 3 weeks until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment

    Primary: Progression-free rate at 12 months

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    End point title
    		 Progression-free rate at 12 months
    End point description
    Progression-Free Survival (PFS) rate at 12-months is defined as the rate of patients without a PFS event at 12 months from randomisation. PFS is defined as the time from the date of randomisation until documented progression (according to RECIST v1.1) or death, if progression is not documented. Censoring (for patients without a PFS/death event) will occur at the last tumour assessment if the patient is lost to follow-up or refuses further documentation of follow-up.
    End point type
    Primary
    End point timeframe
    Evaluated up to approximately 36 months from the randomisation of the first patient.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    43 [1]
    45 [2]
    Units: Patients
    9
    21
    Notes
    [1] - Primary efficacy cohort, rando pts who are not lost from FU before a PFS event or earlier than 1y FU
    [2] - Primary efficacy cohort, rando pts who are not lost from FU before a PFS event or earlier than 1y FU
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm B v Arm A
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.367 [3]
    Method
    		 Exact binomial one-sample
    Parameter type
    		 proportion
    Point estimate
    20.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10
         upper limit
    		 36
    Notes
    [3] - 1-sided significance level of 2.5%
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The study was design to test the primary efficacy hypothesis that 14 or more patients among the 45 evaluable in each treatment arm should be progression-free in the 12-month timepoint in order to reject the null hypothesis H0: 12-month PFS rate (π0) ≤0.18, versus the alternative hypothesis H1: 12-month PFS rate (π1) >0.18, evaluated at π1=0.37. The rate of progression-free patients at 12 months will be accompanied by 2-sided 95% exact binomial CI.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.174 [4]
    Method
    		 Exact binomial one-sample
    Parameter type
    		 proportion
    Point estimate
    24.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 12.9
         upper limit
    		 39.5
    Notes
    [4] - 1-sided significance level of 2.5%

    Secondary: Objective response (OR)

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    End point title
    		 Objective response (OR)
    End point description
    Objective response is defined as best overall response (CR or PR) across all assessment time-points according to RECIST v1.1, from randomisation until either the end of protocol treatment or the end of follow-up.
    End point type
    Secondary
    End point timeframe
    Evaluated up to approximately 36 months from the randomisation of the first patient.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    45 [5]
    50 [6]
    Units: Participant
    21
    16
    Notes
    [5] - Intention-To-Treat cohort of all randomised patients
    [6] - Intention-To-Treat cohort of all randomised patients
    No statistical analyses for this end point

    Secondary: Extra-cranial Progression-free survival (ecPFS)

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    End point title
    		 Extra-cranial Progression-free survival (ecPFS)
    End point description
    Extra-cranial progression-free-survival is the time from randomisation to documentation of disease progression outside the central nervous system (CNS) as per RECIST v1.1 or death, whichever occurred first.
    End point type
    Secondary
    End point timeframe
    Evaluated up to approximately 36 months from the randomisation of the first patient.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    45
    50
    Units: Molarnth
        median (confidence interval 95%)
    7.8 (5.5 to 9.7)
    9.2 (4.9 to 9.8)
    No statistical analyses for this end point

    Secondary: Intra-cranial Progression-free survival (icPFS)

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    End point title
    		 Intra-cranial Progression-free survival (icPFS)
    End point description
    Intracranial progression-free-survival is defined as the time from randomisation to first documented radiographic evidence of CNS progression. CNS progression is defined as progression due to newly developed CNS lesions and/or progression of pre-existing baseline CNS lesions.
    End point type
    Secondary
    End point timeframe
    Evaluated up to approximately 36 months from the randomisation of the first patient.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    45 [7]
    50 [8]
    Units: Month
        median (confidence interval 95%)
    8.3 (5.7 to 15.4)
    12.3 (9.8 to 15.8)
    Notes
    [7] - Intention-To-Treat cohort of all randomised patients
    [8] - Intention-To-Treat cohort of all randomised patients
    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 the time from the date of randomisation until death from any cause. Censoring will occur at the last follow-up date. BECAUSE THE SYSTEM DOES NOT ALLOW EMPTY VALUES IN THE RESULTS SECTION, THEY ARE ADDED BELOW INSTEAD: Arm B Median: 15.6, 95%CI: 11.8 to NA, the upper 95% confidence limit is not estimable.
    End point type
    Secondary
    End point timeframe
    Evaluated up to approximately 36 months from the randomisation of the first patient.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    45 [9]
    50 [10]
    Units: Month
        median (confidence interval 95%)
    15.4 (9.4 to 23.9)
    0 (0 to 0)
    Notes
    [9] - Intention-To-Treat cohort of all randomised patients
    [10] - Intention-To-Treat cohort of all randomised patients
    No statistical analyses for this end point

    Secondary: Time to deterioration (TTD) assessed by the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30)

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    End point title
    		 Time to deterioration (TTD) assessed by the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30)
    End point description
    Deterioration is defined as the first time that patient's score for Global health status/QoL shows a ≥10-point decrease from baseline. Deterioration must be held for at least two consecutive assessments or be followed by PD and/or death within the next 3 weeks. BECAUSE THE SYSTEM DOES NOT ALLOW EMPTY VALUES IN THE RESULTS SECTION, THEY ARE ADDED BELOW INSTEAD: Results Arm A Median: 7.2, 95%CI 2.7 to NA, the upper 95% confidence limit is not estimable. Results Arm B Median: NA, 95%CI 3.5 to NA, median deterioration time and upper 95% confidence limit are not estimable.
    End point type
    Secondary
    End point timeframe
    Evaluated up to approximately 36 months from the randomisation of the first patient.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    40 [11]
    48 [12]
    Units: months
        median (confidence interval 95%)
    0 (0 to 0)
    0 (0 to 0)
    Notes
    [11] - QoL cohort (at least 1 dose of treatment, with baseline QoL assessment and post-baseline QoL forms)
    [12] - QoL cohort (at least 1 dose of treatment, with baseline QoL assessment and post-baseline QoL forms)
    No statistical analyses for this end point

    Secondary: Time to deterioration (TTD) assessed by the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire lung cancer-specific module (QLQ-LC13)

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    End point title
    		 Time to deterioration (TTD) assessed by the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire lung cancer-specific module (QLQ-LC13)
    End point description
    Deterioration is defined as the first time that patient's score for Cough QLQ-LC13 symptom shows a ≥10-point decrease from baseline. Deterioration must be held for at least two consecutive assessments or be followed by PD and/or death within the next 3 weeks. BECAUSE THE SYSTEM DOES NOT ALLOW EMPTY VALUES IN THE RESULTS SECTION, THEY ARE ADDED BELOW INSTEAD: Arm A Median: NA, 95%CI: 8.6 to NA, median deterioration time and upper 95% confidence limit are not estimable. Arm B Median: NA, 95%CI: NA to NA, median deterioration time and lower and upper 95% confidence limit are not estimable.
    End point type
    Secondary
    End point timeframe
    Evaluated up to approximately 36 months from the randomisation of the first patient.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    40 [13]
    48 [14]
    Units: Month
        median (confidence interval 95%)
    0 (0 to 0)
    0 (0 to 0)
    Notes
    [13] - QoL cohort (at least 1 dose of treatment, with baseline QoL assessment and post-baseline QoL forms)
    [14] - QoL cohort (at least 1 dose of treatment, with baseline QoL assessment and post-baseline QoL forms)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival

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    End point title
    		 Progression-Free Survival
    End point description
    PFS is defined as the time from the date of randomisation until documented progression (according to RECIST v1.1) or death, if progression is not documented. Censoring (for patients without a PFS/death event) will occur at the last tumour assessment if the patient is lost to follow-up or refuses further documentation of follow-up.
    End point type
    Secondary
    End point timeframe
    Evaluated up to approximately 36 months from the randomisation of the first patient.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    45 [15]
    50 [16]
    Units: Month
        median (confidence interval 95%)
    6.4 (5.3 to 8.3)
    7.6 (4.1 to 9.7)
    Notes
    [15] - Intention-To-Treat cohort of all randomised patients
    [16] - Intention-To-Treat cohort of all randomised patients
    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 5.0, will be recorded from date of signature of informed consent until 90 days after all trial treatment discontinuation.
    End point type
    Secondary
    End point timeframe
    Evaluated up to approximately 36 months from the randomisation of the first patient.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    44 [17]
    50 [18]
    Units: Participant
        Experienced AE/SAE
    43
    49
        No AE/SAE
    1
    1
        Experienced SAE
    19
    23
    Notes
    [17] - Safety population (all patients who received at least 1 dose of trial treatment).
    [18] - Safety population (all patients who received at least 1 dose of trial treatment).
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs were reported from the date randomisation until 90 days after the last dose of protocol treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    5.0
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Atezolizumab: Patients in both treatment arms will receive atezolizumab at a fixed dose of 1200 mg i.v. on day one of every 3-week (3 days) cycle, until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment. Treatment beyond RECIST-defined progression will be allowed if patient is continuing to derive clinical benefit. Bevacizumab: Patients in both treatment arms will receive bevacizumab at a dose of 15 mg/kg i.v. on day one of every 3-week (+/- 3 days) cycle, until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment. Carboplatin: Patients in treatment Arm A will receive carboplatin, AUC5 every 3 weeks for 4-6 cycles. Paclitaxel: Patients in treatment Arm A will receive paclitaxel, 175-200 mg/m2 (at the investigators' discretion), every 3 weeks for 4-6 cycles.

    Reporting group title
    Arm B
    Reporting group description
    		 Atezolizumab: Patients in both treatment arms will receive atezolizumab at a fixed dose of 1200 mg i.v. on day one of every 3-week (3 days) cycle, until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment. Treatment beyond RECIST-defined progression will be allowed if patient is continuing to derive clinical benefit. Bevacizumab: Patients in both treatment arms will receive bevacizumab at a dose of 15 mg/kg i.v. on day one of every 3-week (+/- 3 days) cycle, until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment. Pemetrexed: Patients in treatment Arm B will receive Pemetrexed, 500 mg/m2 every 3 weeks until progression of disease determined according to RECIST v1.1 or lack of tolerability, or patient declines further treatment.

    Serious adverse events
    		 Arm A Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 44 (43.18%)
    23 / 50 (46.00%)
         number of deaths (all causes)
    3
    3
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Synchronous urothelial carcinoma
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thromboembolic event
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    0 / 44 (0.00%)
    4 / 50 (8.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medically assisted suicide
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease (COPD)
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnea
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxemic respiratory failure
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalitis
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paresthesia
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (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
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Transient ischemic attacks
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis oral
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pressure ulcers
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (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
    Acute kidney injury
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (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
    Arthritis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anorectal infection
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         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
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 infection
         subjects affected / exposed
    0 / 44 (0.00%)
    4 / 50 (8.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic infection
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    3 / 44 (6.82%)
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Meningitis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shingles
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperuricemia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatremia
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    		 Arm A Arm B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 44 (97.73%)
    49 / 50 (98.00%)
    Vascular disorders
    Arterial thromboembolism
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Hot flashes
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    10 / 44 (22.73%)
    17 / 50 (34.00%)
         occurrences all number
    10
    17
    Hypotension
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Thromboembolic event
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Surgical and medical procedures
    Prophylactic femoral intramedullary nailing
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Chills
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    Edema face
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    Edema limbs
         subjects affected / exposed
    2 / 44 (4.55%)
    6 / 50 (12.00%)
         occurrences all number
    2
    6
    Fatigue
         subjects affected / exposed
    13 / 44 (29.55%)
    16 / 50 (32.00%)
         occurrences all number
    13
    16
    Fever
         subjects affected / exposed
    6 / 44 (13.64%)
    3 / 50 (6.00%)
         occurrences all number
    6
    3
    Flu like symptoms
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    General deterioration
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    General discomfort
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    General weakness
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 50 (2.00%)
         occurrences all number
    2
    1
    Generalited edema
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    Infusion site extravasation
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Localized edema
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Malaise
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    Night sweat
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Non cardiac chest pain
         subjects affected / exposed
    3 / 44 (6.82%)
    5 / 50 (10.00%)
         occurrences all number
    3
    5
    Pain
         subjects affected / exposed
    4 / 44 (9.09%)
    9 / 50 (18.00%)
         occurrences all number
    4
    9
    Poor general condition
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Poor oral intake
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Acute bronchitis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Aspiration
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Blood tinged sputum
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Chronic obstructive pulmonary disease (COPD)
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    6 / 44 (13.64%)
    6 / 50 (12.00%)
         occurrences all number
    6
    6
    Dysphonia
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Dyspnea
         subjects affected / exposed
    5 / 44 (11.36%)
    11 / 50 (22.00%)
         occurrences all number
    5
    11
    Epistaxis
         subjects affected / exposed
    3 / 44 (6.82%)
    4 / 50 (8.00%)
         occurrences all number
    3
    4
    Hiccups
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Hoarseness
         subjects affected / exposed
    2 / 44 (4.55%)
    2 / 50 (4.00%)
         occurrences all number
    2
    2
    Laryngeal hemorrhage
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Pleural effusion
         subjects affected / exposed
    2 / 44 (4.55%)
    4 / 50 (8.00%)
         occurrences all number
    2
    4
    Pneumonitis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Productive cough
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Pulmonary edema
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    Retrosternal pain
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Rhinorrhea
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 50 (4.00%)
         occurrences all number
    1
    2
    Sputum
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Anxiety
         subjects affected / exposed
    2 / 44 (4.55%)
    3 / 50 (6.00%)
         occurrences all number
    2
    3
    Confusion
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Depression
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Insomnia
         subjects affected / exposed
    3 / 44 (6.82%)
    5 / 50 (10.00%)
         occurrences all number
    3
    5
    Low mood
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 44 (13.64%)
    13 / 50 (26.00%)
         occurrences all number
    6
    13
    Alkaline phosphatase increased
         subjects affected / exposed
    1 / 44 (2.27%)
    5 / 50 (10.00%)
         occurrences all number
    1
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    7 / 44 (15.91%)
    19 / 50 (38.00%)
         occurrences all number
    7
    19
    BUN increased
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 44 (0.00%)
    4 / 50 (8.00%)
         occurrences all number
    0
    4
    Cholesterol high
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Creatinine increased
         subjects affected / exposed
    1 / 44 (2.27%)
    5 / 50 (10.00%)
         occurrences all number
    1
    5
    GGT increased
         subjects affected / exposed
    1 / 44 (2.27%)
    9 / 50 (18.00%)
         occurrences all number
    1
    9
    Leukocytes count decreased
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Lipase increased
         subjects affected / exposed
    5 / 44 (11.36%)
    3 / 50 (6.00%)
         occurrences all number
    5
    3
    Neutrophil count decreased
         subjects affected / exposed
    12 / 44 (27.27%)
    4 / 50 (8.00%)
         occurrences all number
    12
    4
    Platelet count decreased
         subjects affected / exposed
    3 / 44 (6.82%)
    1 / 50 (2.00%)
         occurrences all number
    3
    1
    Serum amylase increased
         subjects affected / exposed
    8 / 44 (18.18%)
    8 / 50 (16.00%)
         occurrences all number
    8
    8
    Transaminitis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Weight loss
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 50 (4.00%)
         occurrences all number
    1
    2
    White blood cell decreased
         subjects affected / exposed
    4 / 44 (9.09%)
    0 / 50 (0.00%)
         occurrences all number
    4
    0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    Infusion related reaction
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 50 (2.00%)
         occurrences all number
    2
    1
    Seroma
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Vaccination complication
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Wound dehiscence
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Chest pain cardiac
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Palpitations
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Pericardial effusion
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Sinus tachycardia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 44 (0.00%)
    4 / 50 (8.00%)
         occurrences all number
    0
    4
    Dysgeusia
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 50 (4.00%)
         occurrences all number
    1
    2
    Dysphasia
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    6 / 44 (13.64%)
    10 / 50 (20.00%)
         occurrences all number
    6
    10
    Hydrocephalus
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Memory impairment
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Neurotoxicity
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Neurotoxicity in hands
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Paresthesia
         subjects affected / exposed
    4 / 44 (9.09%)
    1 / 50 (2.00%)
         occurrences all number
    4
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    15 / 44 (34.09%)
    3 / 50 (6.00%)
         occurrences all number
    15
    3
    Recurrent laryngeal nerve palsy
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Seizure
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Syncope
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    11 / 44 (25.00%)
    7 / 50 (14.00%)
         occurrences all number
    11
    7
    Febrile neutropenia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Nose bleeding
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Thrombotic microangiopathy
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Vertigo
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Eye disorders
    Blepharitis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Blurred vision
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    Cataract
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Dry eye
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 50 (2.00%)
         occurrences all number
    2
    1
    Periorbital oedema
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Vision decreased
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Watering eyes
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 44 (9.09%)
    5 / 50 (10.00%)
         occurrences all number
    4
    5
    Anal fissure
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Anal hemorrhage
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Ascites
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Bloating
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Bowel rhythm change
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Colitis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Colonic hemorrhage
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    12 / 44 (27.27%)
    15 / 50 (30.00%)
         occurrences all number
    12
    15
    Dental caries
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Diarrhea
         subjects affected / exposed
    3 / 44 (6.82%)
    8 / 50 (16.00%)
         occurrences all number
    3
    8
    Diverticulitis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    Dyspepsia
         subjects affected / exposed
    3 / 44 (6.82%)
    4 / 50 (8.00%)
         occurrences all number
    3
    4
    Epigastric pain
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Esophagal spasm
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Esophagitis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Gastroesophagal reflux disease
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    Gastrointestinal pain
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Gum inflammation
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Hemorrhoids
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 50 (2.00%)
         occurrences all number
    3
    1
    Ileus
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Mucositis oral
         subjects affected / exposed
    4 / 44 (9.09%)
    3 / 50 (6.00%)
         occurrences all number
    4
    3
    Nausea
         subjects affected / exposed
    13 / 44 (29.55%)
    18 / 50 (36.00%)
         occurrences all number
    13
    18
    Periodontal disease
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Pyrosis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Toothache
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    3 / 44 (6.82%)
    6 / 50 (12.00%)
         occurrences all number
    3
    6
    Hepatobiliary disorders
    Cholangiohepatitis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Hepatic cytolysis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    9 / 44 (20.45%)
    1 / 50 (2.00%)
         occurrences all number
    9
    1
    Dry skin
         subjects affected / exposed
    5 / 44 (11.36%)
    2 / 50 (4.00%)
         occurrences all number
    5
    2
    Eczema
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Mucositis in hands
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Palmar plantar erythrodysesthesia syndrome
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    7 / 44 (15.91%)
    5 / 50 (10.00%)
         occurrences all number
    7
    5
    Pustules
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Rash acneiform
         subjects affected / exposed
    1 / 44 (2.27%)
    3 / 50 (6.00%)
         occurrences all number
    1
    3
    Rash eczematiform
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Rash maculo papular
         subjects affected / exposed
    4 / 44 (9.09%)
    5 / 50 (10.00%)
         occurrences all number
    4
    5
    Skin induration
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Skin rash
         subjects affected / exposed
    2 / 44 (4.55%)
    3 / 50 (6.00%)
         occurrences all number
    2
    3
    Toxicoderma
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Umbilical hernia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Urticaria
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    2 / 44 (4.55%)
    4 / 50 (8.00%)
         occurrences all number
    2
    4
    Proteinuria
         subjects affected / exposed
    12 / 44 (27.27%)
    9 / 50 (18.00%)
         occurrences all number
    12
    9
    Urinary frequency
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Urinary retention
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    Hypothyroidism
         subjects affected / exposed
    4 / 44 (9.09%)
    4 / 50 (8.00%)
         occurrences all number
    4
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 44 (15.91%)
    4 / 50 (8.00%)
         occurrences all number
    7
    4
    Back pain
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    Bone pain
         subjects affected / exposed
    2 / 44 (4.55%)
    4 / 50 (8.00%)
         occurrences all number
    2
    4
    Flank pain
         subjects affected / exposed
    1 / 44 (2.27%)
    3 / 50 (6.00%)
         occurrences all number
    1
    3
    Generalized muscle weakness
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Hip pain
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Joint range of motion decreased
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Lumbar pain
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    3 / 44 (6.82%)
    2 / 50 (4.00%)
         occurrences all number
    3
    2
    Neck pain
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Other
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 50 (2.00%)
         occurrences all number
    2
    1
    Shoulder and pelvic girdle pain
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Tingling (fingers, toes)
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Belly button infection
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    C reactive protein increased
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    COVID 19 infection
         subjects affected / exposed
    9 / 44 (20.45%)
    7 / 50 (14.00%)
         occurrences all number
    9
    7
    Conjunctivitis
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Gum infection
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Hepatitis viral
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Herpes simplex reactivation
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Lung infection
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 50 (4.00%)
         occurrences all number
    1
    2
    Mucosal infection
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Pneumonia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Sepsis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Shingles
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Skin infection
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 50 (4.00%)
         occurrences all number
    1
    2
    Upper respiratory infection
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 44 (2.27%)
    4 / 50 (8.00%)
         occurrences all number
    1
    4
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    5 / 44 (11.36%)
    11 / 50 (22.00%)
         occurrences all number
    5
    11
    Dehydration
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Hypercalcemia
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Hyperkalemia
         subjects affected / exposed
    0 / 44 (0.00%)
    4 / 50 (8.00%)
         occurrences all number
    0
    4
    Hypoglycemia
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Hypokalemia
         subjects affected / exposed
    2 / 44 (4.55%)
    3 / 50 (6.00%)
         occurrences all number
    2
    3
    Hypomagnesemia
         subjects affected / exposed
    3 / 44 (6.82%)
    1 / 50 (2.00%)
         occurrences all number
    3
    1
    Hyponatremia
         subjects affected / exposed
    3 / 44 (6.82%)
    2 / 50 (4.00%)
         occurrences all number
    3
    2
    Hyporeflexia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Hypovitaminose D
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Iron deficiency
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Jun 2021
    During the submission process of the first protocol version ETOP received several requests for protocol changes from authorities in various countries. Main change requests concerned recommendations for the paclitaxel dosing, in particular for the Asian population, and some clarification regarding the eligibility criteria for the liver and renal function, as well as for EGFR status. Furthermore, the amendment accounts for the new safety information for atezolizumab, including the addition of the newly identified risks of Severe Cutaneous Adverse Reactions (SCARs). The management of atezolizumab-related toxicities has been updated based on the latest version of the atezolizumab IB Version 15, July 2019, the Addendum 2, December 2019 to the IB V15. The diagnostic criteria and management guidelines for haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), replacing systemic immune activation (SIS), were updated according to a separate Safety Memorandum from Roche. In addition, the list of AESIs has been updated to reflect the new safety information and history of active diverticulitis has been added to the exclusion criteria. Furthermore, some minor protocol clarifications have been added and ambiguities and typos eliminated.

    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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