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A Global Study to Assess the Effects of MEDI4736 (Durvalumab) in Patients With Locally Advanced or Metastatic Non Small Cell Lung Cancer (ATLANTIC)

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ClinicalTrials.gov Identifier: NCT02087423
Recruitment Status : Active, not recruiting
First Posted : March 14, 2014
Results First Posted : January 3, 2018
Last Update Posted : March 1, 2019
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Non-Small Cell Lung Cancer
Intervention Drug: MEDI4736
Enrollment 446
Recruitment Details First patient in: 25 Feb 2014; Last patient in: 28 Dec 2015. Primary Analysis data cut-off (DCO): 03 Jun 2016; Final Analysis DCO: 7 Nov 2017. Patients were treated with durvalumab (10 milligrams [mg] / kilogram [kg] every 2 weeks [Q2W] intravenously [iv]). 101 sites in 16 countries treated patients in this study.
Pre-assignment Details Patients were enrolled in 3 cohorts. Cohort enrolment was dependent upon epidermal growth factor receptor (EGFR) / anaplastic lymphoma kinase (ALK) status and programmed cell death ligand-1 (PD-L1) expression level (percent of tumor cells [TC] with membrane staining).
Arm/Group Title Cohort 1 (EGFR/ALK+) Cohort 2 Cohort 3 (TC >= 90%)
Hide Arm/Group Description Consisted of patients who were EGFR/ALK positive and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown. Consisted of patients who were EGFR/ALK wild type/unknown and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown. Consisted of patients who were EGFR/ALK wild type/unknown and prospectively determined to be PD-L1 high (TC >=90%).
Period Title: Overall Study
Started 111 [1] 265 [1] 68 [1]
Completed 12 Months of Treatment 18 60 26
Completed 0 0 0
Not Completed 111 265 68
Reason Not Completed
Withdrawal by Subject             20             20             3
Death             68             207             40
Lost to Follow-up             0             2             0
Terminated from study at final DCO             23             36             25
[1]
Treated
Arm/Group Title Cohort 1 (EGFR/ALK+) Cohort 2 Cohort 3 (TC >= 90%) Total
Hide Arm/Group Description Consisted of patients who were EGFR/ALK positive and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown. Consisted of patients who were EGFR/ALK wild type/unknown and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown. Consisted of patients who were EGFR/ALK wild type/unknown and prospectively determined to be PD-L1 high (TC >=90%). Total of all reporting groups
Overall Number of Baseline Participants 111 265 68 444
Hide Baseline Analysis Population Description
Baseline analysis was based on the safety analysis set, defined as all patients who received at least 1 dose of durvalumab and for whom any postdose data were available.
Age, Categorical   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 111 participants 265 participants 68 participants 444 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
66
  59.5%
155
  58.5%
44
  64.7%
265
  59.7%
>=65 years
45
  40.5%
110
  41.5%
24
  35.3%
179
  40.3%
[1]
Measure Description: age groups of <=18, between 18 and 65, >=65,
Age, Continuous  
Median (Standard Deviation)
Unit of measure:  Years
Number Analyzed 111 participants 265 participants 68 participants 444 participants
61.0  (11.45) 62.0  (9.35) 61.0  (10.58) 62.0  (10.13)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 111 participants 265 participants 68 participants 444 participants
Female
70
  63.1%
103
  38.9%
29
  42.6%
202
  45.5%
Male
41
  36.9%
162
  61.1%
39
  57.4%
242
  54.5%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 111 participants 265 participants 68 participants 444 participants
White
44
  39.6%
212
  80.0%
42
  61.8%
298
  67.1%
Black or African American
1
   0.9%
2
   0.8%
2
   2.9%
5
   1.1%
Asian
66
  59.5%
51
  19.2%
24
  35.3%
141
  31.8%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 111 participants 265 participants 68 participants 444 participants
Hispanic or Latino
6
   5.4%
19
   7.2%
2
   2.9%
27
   6.1%
Not Hispanic or Latino
105
  94.6%
246
  92.8%
66
  97.1%
417
  93.9%
Weight  
Median (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 111 participants 265 participants 68 participants 444 participants
59  (14.15) 68  (14.52) 66  (15.79) 66  (14.93)
Weight group  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 111 participants 265 participants 68 participants 444 participants
<70 kg
81
  73.0%
146
  55.1%
40
  58.8%
267
  60.1%
Between 70 and 90 kg
27
  24.3%
97
  36.6%
21
  30.9%
145
  32.7%
>90 kg
3
   2.7%
22
   8.3%
7
  10.3%
32
   7.2%
WHO performance status  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 111 participants 265 participants 68 participants 444 participants
(0) Normal activity
45
  40.5%
86
  32.5%
19
  27.9%
150
  33.8%
(1) Restricted activity
65
  58.6%
178
  67.2%
49
  72.1%
292
  65.8%
(2) In bed <=50% of the time
1
   0.9%
1
   0.4%
0
   0.0%
2
   0.5%
(3) In bed >50% of the time
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
(4) 100% bed ridden
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Primary tumor location   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 111 participants 265 participants 68 participants 444 participants
111
 100.0%
265
 100.0%
68
 100.0%
444
 100.0%
[1]
Measure Description: Lung
Histology type  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 111 participants 265 participants 68 participants 444 participants
Squamous
1
   0.9%
55
  20.8%
20
  29.4%
76
  17.1%
Non-squamous
110
  99.1%
210
  79.2%
48
  70.6%
368
  82.9%
AJCC staging at initial diagnosis   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 111 participants 265 participants 68 participants 444 participants
Stage IA
2
   1.8%
3
   1.1%
0
   0.0%
5
   1.1%
Stage IB
0
   0.0%
4
   1.5%
0
   0.0%
4
   0.9%
Stage II
0
   0.0%
1
   0.4%
0
   0.0%
1
   0.2%
Stage IIA
1
   0.9%
1
   0.4%
1
   1.5%
3
   0.7%
Stage IIB
0
   0.0%
5
   1.9%
0
   0.0%
5
   1.1%
Stage III
0
   0.0%
1
   0.4%
0
   0.0%
1
   0.2%
Stage IIIA
9
   8.1%
13
   4.9%
5
   7.4%
27
   6.1%
Stage IIIB
8
   7.2%
28
  10.6%
9
  13.2%
45
  10.1%
Stage IV
90
  81.1%
208
  78.5%
53
  77.9%
351
  79.1%
Missing
1
   0.9%
1
   0.4%
0
   0.0%
2
   0.5%
[1]
Measure Description: Per tumor, node, metastasis (TNM) staging system as specified by American Joint Committee on Cancer (AJCC). The staging is determined by a number of different parameters and the higher the staging the worse the prognosis for survival.
Best response to previous therapy   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 111 participants 265 participants 68 participants 444 participants
complete response
0
   0.0%
1
   0.4%
0
   0.0%
1
   0.2%
partial response
31
  27.9%
39
  14.7%
18
  26.5%
88
  19.8%
stable disease
34
  30.6%
86
  32.5%
18
  26.5%
138
  31.1%
progression
38
  34.2%
114
  43.0%
26
  38.2%
178
  40.1%
non-evaluable
2
   1.8%
15
   5.7%
2
   2.9%
19
   4.3%
not applicable
6
   5.4%
10
   3.8%
4
   5.9%
20
   4.5%
[1]
Measure Description: based on the last therapy received prior to entering the study
Time from informed consent to first dose  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 111 participants 265 participants 68 participants 444 participants
<=14 days
21
  18.9%
68
  25.7%
7
  10.3%
96
  21.6%
Between 14 and 21 days
24
  21.6%
73
  27.5%
13
  19.1%
110
  24.8%
between 21 and 42 days
65
  58.6%
111
  41.9%
45
  66.2%
221
  49.8%
> 42 days
1
   0.9%
13
   4.9%
3
   4.4%
17
   3.8%
Overall disease classification   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 111 participants 265 participants 68 participants 444 participants
Metastatic
102
  91.9%
245
  92.5%
61
  89.7%
408
  91.9%
Locally advanced
9
   8.1%
20
   7.5%
7
  10.3%
36
   8.1%
[1]
Measure Description: either patient has any metastatic site of disease or has only locally advanced sites of disease
PD-L1 expression level   [1] 
Measure Type: Number
Unit of measure:  Number of patients (per PD-L1 category)
Number Analyzed 111 participants 265 participants 68 participants 444 participants
Positive (>=25%) 77 149 68 294
Negative (<25%) 30 95 0 125
Positive (>=90%) 47 72 67 186
<90% 33 122 0 155
Unknown 3 21 0 24
Missing 1 0 0 1
Total per cohort 111 265 68 444
[1]
Measure Description: % of tumor cells with membrane staining for PD-L1
Smoking history   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 111 participants 265 participants 68 participants 444 participants
Non-smoker
65
  58.6%
39
  14.7%
9
  13.2%
113
  25.5%
Smoker
46
  41.4%
225
  84.9%
59
  86.8%
330
  74.3%
Missing
0
   0.0%
1
   0.4%
0
   0.0%
1
   0.2%
[1]
Measure Description: Patients who checked options Cigarettes, Cigarillos, Cigars, Pipe Tobacco, or Tobacco for Smoking are considered smokers.
Number of regimens of previous anti-cancer therapy  
Median (Standard Deviation)
Unit of measure:  Number of regimens
Number Analyzed 111 participants 265 participants 68 participants 444 participants
3  (2.00) 3  (1.38) 2  (0.80) 3  (1.54)
1.Primary Outcome
Title Objective Response Rate (ORR)
Hide Description Patients commenced treatment with durvalumab on Day 1 and continued on a Q2W schedule for a maximum of 12 months. Tumor assessments using computed tomography / magnetic resonance imaging were performed every 8 weeks. Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) measurements as given by the Independent Central Review (ICR) were used to derive the primary variable of ORR .
Time Frame Responses recorded during initial 12 month treatment period (up to primary analysis DCO)
Hide Outcome Measure Data
Hide Analysis Population Description
The “Full analysis set [FAS] – evaluable for response per ICR” set, included all treated patients who had a baseline tumor assessment and had measurable disease at baseline according to the ICR.
Arm/Group Title Cohort 1 (EGFR/ALK+) PD-L1+ (>=25%) Cohort 1 (EGFR/ALK+) PD-L1+ (<25%) Cohort 2 PD-L1+ (>=25%) Cohort 2 PD-L1+ (<25%) Cohort 3 (TC>=90%)
Hide Arm/Group Description:
Consisted of patients who were EGFR/ALK positive and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown. patients with PD-L1 TC>=90% are included in this group.
Consisted of patients who were EGFR/ALK positive and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown.
Consisted of patients who were EGFR/ALK wild type/unknown and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown. Patients with PD-L1 TC>=90% are included within the PD-L1 high (TC>=25%) group.
Consisted of patients who were EGFR/ALK wild type/unknown and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown.
Consisted of patients who were EGFR/ALK wild type/unknown and prospectively determined to be PD-L1 high (TC>=90%).
Overall Number of Participants Analyzed 74 28 146 93 68
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: % of patients evaluable for response
12.2
(5.7 to 21.8)
3.6
(0.1 to 18.3)
16.4
(10.8 to 23.5)
7.5
(3.1 to 14.9)
30.9
(20.2 to 43.3)
2.Secondary Outcome
Title Time to Response (TTR)
Hide Description TTR (per RECIST 1.1 as assessed by the ICR) is defined as the time from the date of first dose until the date of first documented response (which is subsequently confirmed). TTR was only analyzed for Cohort 2.
Time Frame Responses recorded during initial 12 month treatment period (up to primary analysis DCO)
Hide Outcome Measure Data
Hide Analysis Population Description
The “FAS – evaluable for response per ICR” set for Cohort 2, included all treated patients in Cohort 2 who had a baseline tumor assessment and had measurable disease at baseline according to the ICR.
Arm/Group Title Cohort 1 (EGFR/ALK+) PD-L1+ (>=25%) Cohort 1 (EGFR/ALK+) PD-L1+ (<25%) Cohort 2 PD-L1+ (>=25%) Cohort 2 PD-L1+ (<25%) Cohort 3 (TC>=90%)
Hide Arm/Group Description:
Consisted of patients who were EGFR/ALK positive and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown. patients with PD-L1 TC>=90% are included in this group.
Consisted of patients who were EGFR/ALK positive and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown.
Consisted of patients who were EGFR/ALK wild type/unknown and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown. Patients with PD-L1 TC>=90% are included within the PD-L1 high (TC>=25%) group.
Consisted of patients who were EGFR/ALK wild type/unknown and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown.
Consisted of patients who were EGFR/ALK wild type/unknown and prospectively determined to be PD-L1 high (TC>=90%).
Overall Number of Participants Analyzed 0 0 24 7 0
Median (Full Range)
Unit of Measure: Months
1.9
(1.6 to 16.7)
2.1
(1.7 to 13.8)
3.Secondary Outcome
Title Duration of Response (DoR)
Hide Description DoR (per RECIST 1.1 as assessed by the ICR) was defined as the time from the date of first documented response (which was subsequently confirmed) until the first date of documented progression or death in the absence of disease progression (ie, date of PFS event or censoring – date of first response + 1). DoR was only analyzed for Cohort 2. Cohort 2: Median DoR was 12.3 months in the PD-L1 high (TC>=25%) group at DCO (Q3 was NR). Of the 7 evaluable patients, the median DoR was not reached in the PD-L1 low/neg group (TC <25%); therefore the DoR "number of participants analyzed" field has been entered as "0" and the DoR results field has been left blank.
Time Frame Time from response to progression, death, or last assessment (up to approximately 2 years 3 months for the primary analysis DCO)
Hide Outcome Measure Data
Hide Analysis Population Description
The “FAS – evaluable for response per ICR” set for Cohort 2, included all treated patients in Cohort 2 who had a baseline tumor assessment and had measurable disease at baseline according to the ICR.
Arm/Group Title Cohort 1 (EGFR/ALK+) PD-L1+ (>=25%) Cohort 1 (EGFR/ALK+) PD-L1+ (<25%) Cohort 2 PD-L1+ (>=25%) Cohort 2 PD-L1+ (<25%) Cohort 3 (TC>=90%)
Hide Arm/Group Description:
Consisted of patients who were EGFR/ALK positive and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown. patients with PD-L1 TC>=90% are included in this group.
Consisted of patients who were EGFR/ALK positive and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown.
Consisted of patients who were EGFR/ALK wild type/unknown and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown. Patients with PD-L1 TC>=90% are included within the PD-L1 high (TC>=25%) group.
Consisted of patients who were EGFR/ALK wild type/unknown and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown.
Consisted of patients who were EGFR/ALK wild type/unknown and prospectively determined to be PD-L1 high (TC>=90%).
Overall Number of Participants Analyzed 0 0 24 0 0
Median (Inter-Quartile Range)
Unit of Measure: Months
12.3 [1] 
(7.5 to NA)
[1]
75th percentile not reached (NR)
4.Secondary Outcome
Title Overall Survival (OS)
Hide Description OS was defined as the time from the date of first dose until death due to any cause (ie, date of death or censoring – date of first dose + 1). Results are reported as median OS, calculated using the Kaplan-Meier methodology.
Time Frame From date of first treatment until final DCO (up to approximately 3 years 8 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS included all treated patients who had a baseline tumor assessment and had measurable disease at baseline according to the Investigator site assessment.
Arm/Group Title Cohort 1 (EGFR/ALK+) PD-L1+ (>=25%) Cohort 1 (EGFR/ALK+) PD-L1+ (<25%) Cohort 2 PD-L1+ (>=25%) Cohort 2 PD-L1+ (<25%) Cohort 3 (TC>=90%)
Hide Arm/Group Description:
Consisted of patients who were EGFR/ALK positive and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown. patients with PD-L1 TC>=90% are included in this group.
Consisted of patients who were EGFR/ALK positive and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown.
Consisted of patients who were EGFR/ALK wild type/unknown and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown. Patients with PD-L1 TC>=90% are included within the PD-L1 high (TC>=25%) group.
Consisted of patients who were EGFR/ALK wild type/unknown and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown.
Consisted of patients who were EGFR/ALK wild type/unknown and prospectively determined to be PD-L1 high (TC>=90%).
Overall Number of Participants Analyzed 77 30 149 94 67
Median (95% Confidence Interval)
Unit of Measure: Months
13.3
(6.3 to 24.5)
9.9
(4.2 to 13.3)
10.9
(8.6 to 13.6)
9.3
(5.9 to 10.8)
13.2 [1] 
(5.9 to NA)
[1]
The upper limit of 95% confidence interval was not reached for patients in Cohort 3.
Time Frame Treatment-emergent adverse events (TEAEs) observed up until 90 days following discontinuation of durvalumab or until the initiation of the first subsequent anticancer therapy following discontinuation of durvalumab (whichever occurred first).
Adverse Event Reporting Description All-Cause Mortality is reported for the overall study period, up to the final DCO. Serious and Other (non-serious) TEAE data is reported for the initial treatment phase (maximum of 12 months of treatment).
 
Arm/Group Title Cohort 1 (EGFR/ALK+) Cohort 2 Cohort 3 (TC >=90%)
Hide Arm/Group Description Consisted of patients who were EGFR/ALK positive and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown. Consisted of patients who were EGFR/ALK wild type/unknown and retrospectively or prospectively determined to be PD-L1 high (TC >=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC <25%) or PD-L1 status unknown. Consisted of patients who were EGFR/ALK wild type/unknown and prospectively determined to be PD-L1 high (TC >=90%).
All-Cause Mortality
Cohort 1 (EGFR/ALK+) Cohort 2 Cohort 3 (TC >=90%)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   70/111 (63.06%)      217/265 (81.89%)      41/68 (60.29%)    
Show Serious Adverse Events Hide Serious Adverse Events
Cohort 1 (EGFR/ALK+) Cohort 2 Cohort 3 (TC >=90%)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   18/111 (16.22%)      77/265 (29.06%)      24/68 (35.29%)    
Blood and lymphatic system disorders       
Anaemia  1  0/111 (0.00%)  0 3/265 (1.13%)  7 2/68 (2.94%)  2
Haemolytic anaemia  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Cardiac disorders       
Acute coronary syndrome  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Atrial fibrillation  1  0/111 (0.00%)  0 2/265 (0.75%)  3 1/68 (1.47%)  1
Cardiac failure  1  1/111 (0.90%)  1 0/265 (0.00%)  0 1/68 (1.47%)  1
Cardio-respiratory arrest  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Pericardial effusion  1  1/111 (0.90%)  1 0/265 (0.00%)  0 0/68 (0.00%)  0
Bradycardia  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Endocrine disorders       
Hypopituitarism  1  0/111 (0.00%)  0 0/265 (0.00%)  0 1/68 (1.47%)  1
Adrenal insufficiency  1  0/111 (0.00%)  0 2/265 (0.75%)  2 1/68 (1.47%)  1
Diabetes insipidus  1  0/111 (0.00%)  0 0/265 (0.00%)  0 1/68 (1.47%)  1
Hypothyroidism  1  0/111 (0.00%)  0 0/265 (0.00%)  0 1/68 (1.47%)  1
Gastrointestinal disorders       
Dysphagia  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Gastrointestinal haemorrhage  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Gastrooesophageal reflux disease  1  0/111 (0.00%)  0 0/265 (0.00%)  0 1/68 (1.47%)  1
Subileus  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Abdominal pain  1  0/111 (0.00%)  0 3/265 (1.13%)  3 1/68 (1.47%)  1
Constipation  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Diarrhoea  1  0/111 (0.00%)  0 2/265 (0.75%)  2 1/68 (1.47%)  1
Enterocolitis  1  0/111 (0.00%)  0 0/265 (0.00%)  0 1/68 (1.47%)  1
Gastric haemorrhage  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Gastritis  1  0/111 (0.00%)  0 0/265 (0.00%)  0 1/68 (1.47%)  1
Gastrointestinal disorder  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Nausea  1  0/111 (0.00%)  0 1/265 (0.38%)  1 1/68 (1.47%)  1
Oesophageal rupture  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Oesophagitis  1  0/111 (0.00%)  0 0/265 (0.00%)  0 1/68 (1.47%)  1
Pancreatitis acute  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Vomiting  1  0/111 (0.00%)  0 1/265 (0.38%)  1 1/68 (1.47%)  1
General disorders       
Pain  1  0/111 (0.00%)  0 1/265 (0.38%)  3 1/68 (1.47%)  1
Sudden death  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Asthenia  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Fatigue  1  0/111 (0.00%)  0 3/265 (1.13%)  3 1/68 (1.47%)  1
General physical health deterioration  1  0/111 (0.00%)  0 2/265 (0.75%)  2 0/68 (0.00%)  0
Malaise  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Non-cardiac chest pain  1  0/111 (0.00%)  0 0/265 (0.00%)  0 1/68 (1.47%)  1
Pyrexia  1  0/111 (0.00%)  0 1/265 (0.38%)  1 2/68 (2.94%)  2
Hepatobiliary disorders       
Bile duct stone  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Hepatic atrophy  1  0/111 (0.00%)  0 0/265 (0.00%)  0 1/68 (1.47%)  1
Jaundice cholestatic  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Cholangitis  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Infections and infestations       
Meningitis  1  0/111 (0.00%)  0 0/265 (0.00%)  0 1/68 (1.47%)  1
Ophthalmic herpes zoster  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Pneumonia  1  0/111 (0.00%)  0 8/265 (3.02%)  9 1/68 (1.47%)  1
Sepsis  1  0/111 (0.00%)  0 3/265 (1.13%)  3 0/68 (0.00%)  0
Septic shock  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Urinary tract infection  1  1/111 (0.90%)  1 1/265 (0.38%)  1 0/68 (0.00%)  0
Bronchitis  1  1/111 (0.90%)  1 1/265 (0.38%)  1 0/68 (0.00%)  0
Bronchitis bacterial  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Campylobacter gastroenteritis  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Cellulitis  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Central nervous system infection  1  1/111 (0.90%)  1 0/265 (0.00%)  0 0/68 (0.00%)  0
Device related infection  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Diverticulitis  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Infection  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Infectious pleural effusion  1  0/111 (0.00%)  0 2/265 (0.75%)  2 0/68 (0.00%)  0
Lower respiratory tract infection  1  1/111 (0.90%)  1 1/265 (0.38%)  1 0/68 (0.00%)  0
Lung abscess  1  0/111 (0.00%)  0 1/265 (0.38%)  2 0/68 (0.00%)  0
Lung infection  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Pneumococcal sepsis  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Pulmonary sepsis  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Respiratory tract infection  1  0/111 (0.00%)  0 2/265 (0.75%)  4 0/68 (0.00%)  0
Staphylococcal infection  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Streptococcal abscess  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Injury, poisoning and procedural complications       
Hip fracture  1  0/111 (0.00%)  0 0/265 (0.00%)  0 1/68 (1.47%)  1
Infusion related reaction  1  1/111 (0.90%)  1 1/265 (0.38%)  1 1/68 (1.47%)  1
Investigations       
Alanine aminotransferase increased  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Hepatic enzyme increased  1  0/111 (0.00%)  0 1/265 (0.38%)  1 1/68 (1.47%)  1
Transaminases increased  1  0/111 (0.00%)  0 1/265 (0.38%)  1 1/68 (1.47%)  1
Urine output decreased  1  1/111 (0.90%)  1 0/265 (0.00%)  0 0/68 (0.00%)  0
Weight decreased  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Metabolism and nutrition disorders       
Decreased appetite  1  1/111 (0.90%)  1 1/265 (0.38%)  1 0/68 (0.00%)  0
Dehydration  1  0/111 (0.00%)  0 1/265 (0.38%)  1 1/68 (1.47%)  1
Hyperglycaemia  1  0/111 (0.00%)  0 0/265 (0.00%)  0 1/68 (1.47%)  1
Musculoskeletal and connective tissue disorders       
Back pain  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Musculoskeletal pain  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Basal cell carcinoma  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Colon cancer  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Metastases to central nervous system  1  2/111 (1.80%)  2 0/265 (0.00%)  0 0/68 (0.00%)  0
Tumour haemorrhage  1  1/111 (0.90%)  1 0/265 (0.00%)  0 0/68 (0.00%)  0
Nervous system disorders       
Intracranial pressure increased  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Seizure  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Somnolence  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Cerebral ischaemia  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Headache  1  0/111 (0.00%)  0 1/265 (0.38%)  1 1/68 (1.47%)  1
Memory impairment  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Spinal cord compression  1  1/111 (0.90%)  1 1/265 (0.38%)  1 0/68 (0.00%)  0
Psychiatric disorders       
Mental status changes  1  0/111 (0.00%)  0 0/265 (0.00%)  0 1/68 (1.47%)  1
Renal and urinary disorders       
Ureteric obstruction  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Hydronephrosis  1  1/111 (0.90%)  1 0/265 (0.00%)  0 0/68 (0.00%)  0
Nephritis  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Pulmonary embolism  1  1/111 (0.90%)  1 2/265 (0.75%)  2 2/68 (2.94%)  2
Chronic obstructive pulmonary disease  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Dyspnoea  1  3/111 (2.70%)  3 7/265 (2.64%)  7 0/68 (0.00%)  0
Haemoptysis  1  1/111 (0.90%)  2 1/265 (0.38%)  1 1/68 (1.47%)  1
Interstitial lung disease  1  0/111 (0.00%)  0 0/265 (0.00%)  0 1/68 (1.47%)  2
Organising pneumonia  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Pleural effusion  1  1/111 (0.90%)  1 5/265 (1.89%)  5 1/68 (1.47%)  1
Pneumonitis  1  1/111 (0.90%)  1 4/265 (1.51%)  4 0/68 (0.00%)  0
Pulmonary haemorrhage  1  1/111 (0.90%)  1 0/265 (0.00%)  0 0/68 (0.00%)  0
Respiratory failure  1  0/111 (0.00%)  0 2/265 (0.75%)  2 0/68 (0.00%)  0
Vascular disorders       
Vena cava thrombosis  1  1/111 (0.90%)  1 0/265 (0.00%)  0 0/68 (0.00%)  0
Hypertensive crisis  1  0/111 (0.00%)  0 0/265 (0.00%)  0 1/68 (1.47%)  1
Hypovolaemic shock  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
Superior vena cava syndrome  1  0/111 (0.00%)  0 1/265 (0.38%)  1 0/68 (0.00%)  0
1
Term from vocabulary, MedDRA 20.0
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Cohort 1 (EGFR/ALK+) Cohort 2 Cohort 3 (TC >=90%)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   96/111 (86.49%)      233/265 (87.92%)      60/68 (88.24%)    
Blood and lymphatic system disorders       
Anaemia  1  3/111 (2.70%)  3 43/265 (16.23%)  52 8/68 (11.76%)  8
Endocrine disorders       
Hyperthyroidism  1  11/111 (9.91%)  12 17/265 (6.42%)  18 7/68 (10.29%)  8
Hypothyroidism  1  11/111 (9.91%)  14 19/265 (7.17%)  24 8/68 (11.76%)  9
Gastrointestinal disorders       
Abdominal pain  1  5/111 (4.50%)  6 10/265 (3.77%)  10 4/68 (5.88%)  6
Abdominal pain upper  1  7/111 (6.31%)  8 12/265 (4.53%)  12 1/68 (1.47%)  1
Constipation  1  14/111 (12.61%)  15 37/265 (13.96%)  45 16/68 (23.53%)  19
Diarrhoea  1  11/111 (9.91%)  14 39/265 (14.72%)  53 9/68 (13.24%)  10
Nausea  1  14/111 (12.61%)  16 46/265 (17.36%)  57 12/68 (17.65%)  15
Vomiting  1  13/111 (11.71%)  15 27/265 (10.19%)  36 10/68 (14.71%)  13
General disorders       
Asthenia  1  14/111 (12.61%)  15 53/265 (20.00%)  76 4/68 (5.88%)  4
Fatigue  1  15/111 (13.51%)  16 69/265 (26.04%)  80 20/68 (29.41%)  31
Non-cardiac chest pain  1  3/111 (2.70%)  4 10/265 (3.77%)  15 4/68 (5.88%)  5
Oedema peripheral  1  7/111 (6.31%)  8 25/265 (9.43%)  25 9/68 (13.24%)  13
Pain  1  1/111 (0.90%)  1 8/265 (3.02%)  8 4/68 (5.88%)  4
Pyrexia  1  12/111 (10.81%)  14 53/265 (20.00%)  81 12/68 (17.65%)  16
Infections and infestations       
Pneumonia  1  2/111 (1.80%)  2 4/265 (1.51%)  4 4/68 (5.88%)  5
Upper respiratory tract infection  1  6/111 (5.41%)  9 8/265 (3.02%)  8 6/68 (8.82%)  6
Urinary tract infection  1  4/111 (3.60%)  4 15/265 (5.66%)  19 3/68 (4.41%)  4
Viral upper respiratory tract infection  1  5/111 (4.50%)  6 12/265 (4.53%)  13 11/68 (16.18%)  18
Investigations       
Alanine aminotransferase increased  1  5/111 (4.50%)  5 11/265 (4.15%)  13 5/68 (7.35%)  5
Aspartate aminotransferase increased  1  3/111 (2.70%)  3 12/265 (4.53%)  14 5/68 (7.35%)  5
Blood alkaline phosphatase increased  1  2/111 (1.80%)  2 14/265 (5.28%)  14 2/68 (2.94%)  2
Gamma-glutamyltransferase increased  1  4/111 (3.60%)  4 15/265 (5.66%)  15 0/68 (0.00%)  0
Weight decreased  1  3/111 (2.70%)  3 22/265 (8.30%)  22 13/68 (19.12%)  13
Metabolism and nutrition disorders       
Decreased appetite  1  15/111 (13.51%)  15 71/265 (26.79%)  77 12/68 (17.65%)  12
Hyponatraemia  1  2/111 (1.80%)  2 14/265 (5.28%)  20 4/68 (5.88%)  5
Musculoskeletal and connective tissue disorders       
Arthralgia  1  7/111 (6.31%)  7 21/265 (7.92%)  25 5/68 (7.35%)  6
Back pain  1  11/111 (9.91%)  11 23/265 (8.68%)  24 8/68 (11.76%)  10
Musculoskeletal pain  1  4/111 (3.60%)  4 16/265 (6.04%)  21 3/68 (4.41%)  4
Neck pain  1  3/111 (2.70%)  3 8/265 (3.02%)  8 7/68 (10.29%)  7
Pain in extremity  1  5/111 (4.50%)  5 18/265 (6.79%)  21 2/68 (2.94%)  2
Nervous system disorders       
Dizziness  1  6/111 (5.41%)  6 12/265 (4.53%)  18 4/68 (5.88%)  6
Headache  1  13/111 (11.71%)  15 26/265 (9.81%)  32 6/68 (8.82%)  6
Psychiatric disorders       
Anxiety  1  2/111 (1.80%)  2 16/265 (6.04%)  16 2/68 (2.94%)  2
Insomnia  1  10/111 (9.01%)  12 16/265 (6.04%)  19 5/68 (7.35%)  5
Respiratory, thoracic and mediastinal disorders       
Cough  1  26/111 (23.42%)  32 56/265 (21.13%)  67 13/68 (19.12%)  16
Dysphonia  1  0/111 (0.00%)  0 14/265 (5.28%)  15 1/68 (1.47%)  1
Dyspnoea  1  13/111 (11.71%)  14 43/265 (16.23%)  46 7/68 (10.29%)  10
Haemoptysis  1  3/111 (2.70%)  3 14/265 (5.28%)  20 4/68 (5.88%)  6
Productive cough  1  4/111 (3.60%)  4 20/265 (7.55%)  23 4/68 (5.88%)  4
Skin and subcutaneous tissue disorders       
Pruritus  1  9/111 (8.11%)  11 27/265 (10.19%)  39 13/68 (19.12%)  14
Rash  1  7/111 (6.31%)  9 19/265 (7.17%)  20 8/68 (11.76%)  8
1
Term from vocabulary, MedDRA 20.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Phillip Dennis, MD, PhD
Organization: AstraZeneca
Phone: +1 301 398-5549
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02087423     History of Changes
Other Study ID Numbers: D4191C00003
First Submitted: March 4, 2014
First Posted: March 14, 2014
Results First Submitted: June 3, 2017
Results First Posted: January 3, 2018
Last Update Posted: March 1, 2019