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Clinical Trial Results:
TIGER-2: A Phase 2, Open-label, Multicenter, Safety and Efficacy Study of Oral CO-1686 as 2nd Line EGFR-directed TKI in Patients with Mutant EGFR Non-small Cell Lung Cancer (NSCLC)

Summary
EudraCT number	2013-005532-23
Trial protocol	DE ES NL
Global end of trial date	27 Aug 2019

Results information
Results version number	v1(current)
This version publication date	06 Sep 2020
First version publication date	06 Sep 2020
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CO-1686-019

ISRCTN number

US NCT number

NCT02147990

WHO universal trial number (UTN)

Sponsor organisation name

Clovis Oncology UK Ltd

Sponsor organisation address

Granta Centre, Granta Park, Great Abington, Cambridge, United Kingdom, CB21 6GP

Public contact

Dr Lindsey Rolfe, Clovis Oncology UK Ltd, +44 12233645500, lrolfe@clovisoncology.com

Scientific contact

Dr Lindsey Rolfe, Clovis Oncology UK Ltd, +44 12233645500, lrolfe@clovisoncology.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

26 Jun 2020

Is this the analysis of the primary completion data?

Yes

Primary completion date

30 Jul 2019

Global end of trial reached?

Yes

Global end of trial date

27 Aug 2019

Was the trial ended prematurely?

Main objective of the trial

To evaluate the antitumor efficacy of oral (PO) single-agent rociletinib, as measured by objective response rate (ORR), when administered to patients with EGFR-mutated, centrally confirmed T790M-positive and T790M-negative advanced NSCLC after tumor progression on 1 previous EGFR-directed TKI

Protection of trial subjects

Safety assessments during treatment included monitoring for adverse events (AEs), laboratory tests (hematology, clinical chemistry including fasting glucose and glycated hemoglobin [HbA1c], and urinalysis), physical examinations, vital signs and body weight measurements, 12-lead ECG (triplicate recordings), concomitant medications/procedures, and ECOG performance status on Day 1 of each cycle.

Background therapy

Evidence for comparator

Actual start date of recruitment

16 Jun 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 23

Country: Number of subjects enrolled

Spain: 10

Country: Number of subjects enrolled

United Kingdom: 22

Country: Number of subjects enrolled

France: 16

Country: Number of subjects enrolled

Germany: 17

Country: Number of subjects enrolled

Australia: 23

Country: Number of subjects enrolled

Canada: 15

Country: Number of subjects enrolled

Hong Kong: 3

Country: Number of subjects enrolled

Korea, Republic of: 28

Country: Number of subjects enrolled

Switzerland: 5

Country: Number of subjects enrolled

Taiwan: 28

Country: Number of subjects enrolled

United States: 127

Worldwide total number of subjects

317

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

164

From 65 to 84 years

147

85 years and over

Subject disposition

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Recruitment details

318 patients were enrolled at 67 study sites in North America, Europe, Asia and Australia. One patient was not included in the Safety Population due to failure of the study site to provide any dosing data in electronic data capture (EDC) before the site was closed.

Screening details

All patients underwent screening assessments within 28 days prior to the first dose of rociletinib to establish study eligibility and document baseline measurements. Eligible NSCLC patients were required to have documented evidence of a tumor with an EGFR mutation known to be associated with sensitivity to rociletinib.

Period 1 title

Overall Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Rociletinib 625 mg BID T790M+

Arm description

Rociletinib 625 mg BID in patients with T790M-positive tumor status

Arm type

Experimental

Investigational medicinal product name

Rociletinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Starting dose of 625mg rociletinib, taken orally twice daily, with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Tablets should be swallowed whole. Treatment with rociletinib was continuous and each cycle was comprised of 28 days.

Rociletinib 500 mg BID T790M+

Arm description

Rociletinib 500 mg BID in patients with T790M-positive tumor status

Arm type

Experimental

Investigational medicinal product name

Rociletinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Starting dose of 500mg rociletinib, taken orally twice daily, with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Tablets should be swallowed whole. Treatment with rociletinib was continuous and each cycle was comprised of 28 days.

Rociletinib 500 mg BID T790M-

Arm description

Rociletinib 500 mg BID in patients with T790M-negative tumor status

Arm type

Experimental

Investigational medicinal product name

Rociletinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Started	154	100	63
Completed	154	100	63

Baseline characteristics

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Reporting group title

Rociletinib 625 mg BID T790M+

Reporting group description

Rociletinib 625 mg BID in patients with T790M-positive tumor status

Reporting group title

Rociletinib 500 mg BID T790M+

Reporting group description

Rociletinib 500 mg BID in patients with T790M-positive tumor status

Reporting group title

Rociletinib 500 mg BID T790M-

Reporting group description

Rociletinib 500 mg BID in patients with T790M-negative tumor status

Reporting group values	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-	Total
Number of subjects	154	100	63	317
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
arithmetic mean (standard deviation)	62.8 ± 10.67	65.3 ± 9.93	64.1 ± 10.01	-
Gender categorical
Units: Subjects
Female	105	69	41	215
Male	49	31	22	102
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	2	2	3	7
Not Hispanic or Latino	131	93	55	279
Unknown or Not Reported	21	5	5	31
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	1	0	0	1
Asian	59	34	32	125
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	6	5	2	13
White	74	58	23	155
More than one race	0	0	0	0
Unknown or Not Reported	14	3	6	23
T790M Status
Units: Subjects
T790M Negative	1	0	62	63
T790M Positive	153	100	0	253
Missing	0	0	1	1

Subject analysis set title

All T790M+

Subject analysis set type

Per protocol

Subject analysis set description

All Rociletinib 500 mg BID and 625 mg BID patients with T790M positive tumor status

Subject analysis sets values	All T790M+
Number of subjects	254
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Units: years
arithmetic mean (standard deviation)	63.8 ± 10.43
Gender categorical
Units: Subjects
Female	174
Male	80
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	4
Not Hispanic or Latino	224
Unknown or Not Reported	26
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	1
Asian	93
Native Hawaiian or Other Pacific Islander	0
Black or African American	11
White	132
More than one race	0
Unknown or Not Reported	17
T790M Status
Units: Subjects
T790M Negative	1
T790M Positive	253
Missing	0

End points

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Reporting group title

Rociletinib 625 mg BID T790M+

Reporting group description

Rociletinib 625 mg BID in patients with T790M-positive tumor status

Reporting group title

Rociletinib 500 mg BID T790M+

Reporting group description

Rociletinib 500 mg BID in patients with T790M-positive tumor status

Reporting group title

Rociletinib 500 mg BID T790M-

Reporting group description

Rociletinib 500 mg BID in patients with T790M-negative tumor status

Subject analysis set title

All T790M+

Subject analysis set type

Per protocol

Subject analysis set description

All Rociletinib 500 mg BID and 625 mg BID patients with T790M positive tumor status

Primary: Objective Response Rate (ORR) According to RECIST Version 1.1 as Determined by Investigator Assessment

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End point title

Objective Response Rate (ORR) According to RECIST Version 1.1 as Determined by Investigator Assessment ^[1]

End point description

ORR is defined as the percentage of patients with a best overall confirmed response of partial response (PR) or complete response (CR) recorded from the start of the treatment until disease progression. For patients who continued treatment post-progression, the first date of progression was used for the analysis. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter.

End point type

Primary

End point timeframe

Cycle 1 Day 1 to End of Treatment, up to approximately 57 months

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Per EMA feedback, the statistical analyses section can not accommodate the end point results for this study. Therefore, all statistical analyses details are provided in the End point values sections.

End point values	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Number of subjects analysed	153	97	61
Units: Percentage of Patients
number (confidence interval 95%)	34.6 (27.1 to 42.7)	34.0 (24.7 to 44.3)	18.0 (9.4 to 30.0)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) in T790M Positive Patients According to RECIST Version 1.1 as Determined by Investigator Assessment

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End point title

Duration of Response (DOR) in T790M Positive Patients According to RECIST Version 1.1 as Determined by Investigator Assessment ^[2]

End point description

DOR in patients with a T790M mutation (determined by central lab) with confirmed response per investigator. The DOR for complete response (CR) and partial response (PR) was measured from the date that any of these best responses is first recorded until the first date that progressive disease (PD) is objectively documented. For patients who continue treatment post-progression, the first date of progression was used for the analysis.

End point type

Secondary

End point timeframe

From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 54 months

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports results for T790M Positive Patients only.

End point values	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	All T790M+
Number of subjects analysed	53	33	86
Units: Months
median (confidence interval 95%)	7.4 (5.5 to 9.4)	9.1 (5.6 to 13.0)	7.6 (7.3 to 9.4)

No statistical analyses for this end point

Secondary: Disease Control Rate (DCR) by RECIST v1.1 as Determined by Investigator Assessment

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End point title

Disease Control Rate (DCR) by RECIST v1.1 as Determined by Investigator Assessment

End point description

DCR is defined as the percentage of patients who have achieved CR, PR, and SD lasting at least 12 weeks. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter since the treatment started.

End point type

Secondary

End point timeframe

From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 57 months

End point values	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Number of subjects analysed	153	97	61
Units: Percentage of Patients
number (confidence interval 95%)	67.3 (59.3 to 74.7)	76.3 (66.6 to 84.3)	59.0 (45.7 to 71.4)

No statistical analyses for this end point

Secondary: Progression-free Survival (PFS) in T790M Positive Patients by RECIST v1.1 as Determined by Investigator Assessment

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End point title

Progression-free Survival (PFS) in T790M Positive Patients by RECIST v1.1 as Determined by Investigator Assessment ^[3]

End point description

PFS was calculated as 1+ the number of days from the first dose of study drug to documented radiographic progression or death due to any cause, whichever occurs first. Patients without a documented event of radiographic progression were censored on the date of their last adequate tumor assessment (i.e., radiologic assessment) or date of first dose of study drug if no tumor assessments were performed. For patients who continued treatment post-progression, the first date of progression was used for the analysis of PFS. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of new lesions is also considered progression.

End point type

Secondary

End point timeframe

From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 57 months

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports results for T790M Positive Patients only.

End point values	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	All T790M+
Number of subjects analysed	154	100	254
Units: Months
median (confidence interval 95%)	5.5 (4.0 to 6.7)	5.9 (5.3 to 8.3)	5.5 (5.3 to 7.2)

No statistical analyses for this end point

Secondary: Overall Survival (OS) Determined by Investigator Assessment

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End point title

Overall Survival (OS) Determined by Investigator Assessment ^[4]

End point description

OS was calculated as 1+ the number of days from the first dose of study drug to death due to any cause. Patients without a documented date of death were censored on the date the patient was last known to be alive.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 to date of death, assessed up to 57 months

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports results for T790M Positive Patients only.

End point values	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	All T790M+
Number of subjects analysed	154 ^[5]	100 ^[6]	254
Units: Months
median (confidence interval 95%)	18.8 (15.2 to 57)	29.8 (26.2 to 47)	23.7 (17.7 to 40.6)

Notes
[5] - Upper confidence interval not available due to insufficient number of participants so max 57 noted.
[6] - Upper confidence interval not available due to insufficient number of participants so max 47 noted.

No statistical analyses for this end point

Secondary: EORTC QLQ-C30 Global Health Status

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End point title

EORTC QLQ-C30 Global Health Status

End point description

EORTC QLC-C30 is a 30-item questionnaire to assess the quality of life in cancer patients. EORTC QLQ-C30 includes functional scales (physical, role, cognitive, emotional, social), global health status, symptom scales (fatigue, pain, nausea/vomiting), and other (dyspnoea, appetite loss, insomnia, constipation/diarrhea, financial difficulties). Most questions used 4-point scale (1 'Not at All' to 4 'Very Much'); two used 7-point scale (1 'Very Poor' to 7'Excellent'). Scores are averaged, and transformed to 0-100 scale; higher score = better quality of life. Change from Baseline to Cycles 5, 10 and End of Treatment is reported.

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 5, 10 and EOT

End point values	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Number of subjects analysed	154 ^[7]	100 ^[8]	63 ^[9]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (Day 0)	62.18 ± 22.245	59.76 ± 22.495	54.63 ± 24.629
Cycle 5 (approximately month 5)	-2.48 ± 22.470	-0.56 ± 23.763	5.56 ± 28.842
Cycle 10 (approximately month 10)	-2.21 ± 22.294	-3.81 ± 21.422	3.57 ± 23.956
End of Treatment	-4.82 ± 23.381	-9.65 ± 18.481	-10.42 ± 35.158

Notes
[7] - Baseline = 154, Cycle 5 = 101, Cycle 10 = 49, EOT = 38
[8] - Baseline = 99, Cycle 5 = 60, Cycle 10 = 35, EOT = 19
[9] - Baseline = 63, Cycle 5 = 33, Cycle 10 = 14, EOT = 16

No statistical analyses for this end point

Secondary: Dermatology Life Quality Index (DLQI)

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End point title

Dermatology Life Quality Index (DLQI)

End point description

Dermatology Life Quality Index (DLQI) score is a participant-reported outcome consisting of a set of 10 questions regarding the degree to which the participant's skin has affected certain behaviors and quality of life over the last week. Responses to each are: very much (score of 3), a lot, a little, or not at all (score of 0). The DLQI score ranges from 0 (best) to 30 (worst); the higher the score, the more quality of life is impaired. Change from Baseline to Cycles 5, 10 and End of Treatment is reported.

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 5, 10 and EOT

End point values	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Number of subjects analysed	154 ^[10]	100 ^[11]	63 ^[12]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (Day 0)	2.10 ± 3.408	2.42 ± 4.706	2.74 ± 4.763
Cycle 5 (approximately month 5)	-0.82 ± 3.240	-1.29 ± 3.499	-1.63 ± 3.731
Cycle 10 (approximately month 10)	-1.02 ± 2.810	-1.64 ± 3.531	-0.79 ± 2.751
End of Treatment	-0.77 ± 3.191	-0.22 ± 2.157	-1.14 ± 4.204

Notes
[10] - Baseline = 152, Cycle 5 = 97, Cycle 10 = 49, EOT = 35
[11] - Baseline = 97, Cycle 5 = 58, Cycle 10 = 36, EOT = 18
[12] - Baseline = 62, Cycle 5 = 32, Cycle 10 = 14, EOT = 14

No statistical analyses for this end point

Secondary: EORTC QLQ-LC-13 Alopecia Scale

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End point title

EORTC QLQ-LC-13 Alopecia Scale

End point description

EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms. Change from Baseline to Cycles 5, 10 and End of Treatment is reported.

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 5, 10 and EOT

End point values	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Number of subjects analysed	154 ^[13]	100 ^[14]	63 ^[15]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (Day 0)	9.96 ± 21.264	9.43 ± 20.779	19.05 ± 29.154
Cycle 5 (approximately month 5)	-4.62 ± 27.499	-2.69 ± 27.855	-10.10 ± 19.516
Cycle 10 (approximately month 10)	-2.00 ± 21.728	-6.67 ± 25.309	-2.56 ± 21.350
End of Treatment	4.50 ± 33.483	3.51 ± 44.298	0.00 ± 39.841

Notes
[13] - Baseline = 154, Cycle 5 = 101, Cycle 10 = 50, EOT = 37
[14] - Baseline = 99, Cycle 5 = 62, Cycle 10 = 35, EOT = 19
[15] - Baseline = 63, Cycle 5 = 33, Cycle 10 = 13, EOT = 15

No statistical analyses for this end point

Secondary: EORTC QLQ-LC-13 Coughing Scale

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End point title

EORTC QLQ-LC-13 Coughing Scale

End point description

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 5, 10 and EOT

End point values	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Number of subjects analysed	154 ^[16]	100 ^[17]	63 ^[18]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (Day 0)	33.12 ± 26.540	29.97 ± 25.862	38.62 ± 23.346
Cycle 5 (approximately month 5)	-7.92 ± 26.728	-9.29 ± 26.619	-12.12 ± 27.409
Cycle 10 (approximately month 10)	-6.67 ± 23.328	-17.14 ± 30.648	2.56 ± 21.350
End of Treatment	-5.41 ± 27.793	0.00 ± 36.851	6.67 ± 25.820

Notes
[16] - Baseline = 154, Cycle 5 = 101, Cycle 10 = 50, EOT = 37
[17] - Baseline = 99, Cycle 5 = 61, Cycle 10 = 35, EOT = 19
[18] - Baseline = 63, Cycle 5 = 33, Cycle 10 = 13, EOT = 15

No statistical analyses for this end point

Secondary: EORTC QLQ-LC-13 Dysphagia Scale

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End point title

EORTC QLQ-LC-13 Dysphagia Scale

End point description

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 5, 10 and EOT

End point values	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Number of subjects analysed	154 ^[19]	100 ^[20]	63 ^[21]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (Day 0)	5.19 ± 15.306	7.41 ± 17.532	5.82 ± 17.495
Cycle 5 (approximately month 5)	1.65 ± 12.803	-0.54 ± 17.589	7.07 ± 21.663
Cycle 10 (approximately month 10)	-3.27 ± 13.752	-3.81 ± 15.700	2.56 ± 9.245
End of Treatment	3.60 ± 17.184	7.41 ± 31.427	6.67 ± 28.730

Notes
[19] - Baseline = 154, Cycle 5 = 101, Cycle 10 = 51, EOT = 37
[20] - Baseline = 99, Cycle 5 = 62, Cycle 10 = 35, EOT = 18
[21] - Baseline = 63, Cycle 5 = 33, Cycle 10 = 13, EOT = 15

No statistical analyses for this end point

Secondary: EORTC QLQ-LC-13 Dyspnoea Scale

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End point title

EORTC QLQ-LC-13 Dyspnoea Scale

End point description

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 5, 10 and EOT

End point values	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Number of subjects analysed	154 ^[22]	100 ^[23]	63 ^[24]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (Day 0)	21.79 ± 21.554	22.56 ± 21.441	30.34 ± 26.415
Cycle 5 (approximately month 5)	6.11 ± 21.681	-1.25 ± 18.777	-3.70 ± 23.516
Cycle 10 (approximately month 10)	2.83 ± 19.606	1.90 ± 14.879	6.84 ± 22.923
End of Treatment	8.41 ± 22.892	8.77 ± 18.362	0.00 ± 28.172

Notes
[22] - Baseline = 154, Cycle 5 = 101, Cycle 10 = 51, EOT = 37
[23] - Baseline = 99, Cycle 5 = 62, Cycle 10 = 35, EOT = 19
[24] - Baseline = 63, Cycle 5 = 33, Cycle 10 = 13, EOT = 15

No statistical analyses for this end point

Secondary: EORTC QLQ-LC-13 Haemoptysis Scale

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End point title

EORTC QLQ-LC-13 Haemoptysis Scale

End point description

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 5, 10 and EOT

End point values	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Number of subjects analysed	154 ^[25]	100 ^[26]	63 ^[27]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (Day 0)	2.38 ± 8.613	1.68 ± 11.039	4.76 ± 13.194
Cycle 5 (approximately month 5)	-1.98 ± 7.919	-1.61 ± 9.404	-5.21 ± 14.930
Cycle 10 (approximately month 10)	-0.65 ± 8.138	-0.95 ± 5.634	-5.13 ± 18.490
End of Treatment	-0.90 ± 12.389	0.00 ± 0.000	-2.22 ± 8.607

Notes
[25] - Baseline = 154, Cycle 5 = 101, Cycle 10 = 51, EOT = 37
[26] - Baseline = 99, Cycle 5 = 62, Cycle 10 = 35, EOT = 19
[27] - Baseline = 63, Cycle 5 = 32, Cycle 10 = 13, EOT = 15

No statistical analyses for this end point

Secondary: EORTC QLQ-LC-13 Pain in Arm or Shoulder Scale

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End point title

EORTC QLQ-LC-13 Pain in Arm or Shoulder Scale

End point description

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 5, 10 and EOT

End point values	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Number of subjects analysed	154 ^[28]	100 ^[29]	63 ^[30]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (Day 0)	19.91 ± 26.271	16.67 ± 26.325	28.42 ± 34.338
Cycle 5 (approximately month 5)	-5.94 ± 32.110	-2.69 ± 25.819	-7.29 ± 35.655
Cycle 10 (approximately month 10)	-1.31 ± 31.242	-2.86 ± 27.262	8.33 ± 28.868
End of Treatment	5.41 ± 29.932	0.00 ± 35.136	4.44 ± 33.014

Notes
[28] - Baseline = 154, Cycle 5 = 101, Cycle 10 = 51, EOT = 37
[29] - Baseline = 98, Cycle 5 = 62, Cycle 10 = 35, EOT = 19
[30] - Baseline = 61, Cycle 5 = 32, Cycle 10 = 12, EOT = 15

No statistical analyses for this end point

Secondary: EORTC QLQ-LC-13 Pain in Chest Scale

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End point title

EORTC QLQ-LC-13 Pain in Chest Scale

End point description

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 5, 10 and EOT

End point values	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Number of subjects analysed	154 ^[31]	100 ^[32]	63 ^[33]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (Day 0)	19.91 ± 25.429	12.79 ± 22.691	25.40 ± 32.635
Cycle 5 (approximately month 5)	-4.62 ± 25.399	-5.38 ± 20.194	-8.08 ± 28.904
Cycle 10 (approximately month 10)	-3.27 ± 24.272	-6.86 ± 19.728	2.56 ± 39.585
End of Treatment	1.80 ± 34.198	7.02 ± 13.962	-4.44 ± 30.516

Notes
[31] - Baseline = 154, Cycle 5 = 101, Cycle 10 = 51, EOT = 37
[32] - Baseline = 99, Cycle 5 = 62, Cycle 10 = 34, EOT = 19
[33] - Baseline = 63, Cycle 5 = 33, Cycle 10 = 13, EOT = 15

No statistical analyses for this end point

Secondary: EORTC QLQ-LC-13 Medicine for Pain Scale

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End point title

EORTC QLQ-LC-13 Medicine for Pain Scale

End point description

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 5, 10 and EOT

End point values	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Number of subjects analysed	154 ^[34]	100 ^[35]	63 ^[36]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (Day 0)	60.47 ± 27.302	66.67 ± 27.766	53.17 ± 23.350
Cycle 5 (approximately month 5)	6.67 ± 35.450	8.89 ± 23.458	-4.76 ± 36.648
Cycle 10 (approximately month 10)	4.76 ± 12.105	-4.17 ± 27.817	22.22 ± 19.245
End of Treatment	3.92 ± 20.008	0.00 ± 30.861	-5.56 ± 38.968

Notes
[34] - Baseline = 86, Cycle 5 = 30, Cycle 10 = 14, EOT = 17
[35] - Baseline = 50, Cycle 5 = 15, Cycle 10 = 8, EOT = 8
[36] - Baseline = 42, Cycle 5 = 14, Cycle 10 = 3, EOT = 6

No statistical analyses for this end point

Secondary: EORTC QLQ-LC-13 Pain in Other Parts Scale

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End point title

EORTC QLQ-LC-13 Pain in Other Parts Scale

End point description

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 5, 10 and EOT

End point values	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Number of subjects analysed	154 ^[37]	100 ^[38]	63 ^[39]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (Day 0)	28.41 ± 30.848	30.58 ± 33.219	31.69 ± 29.456
Cycle 5 (approximately month 5)	2.46 ± 34.464	-1.13 ± 29.664	-7.78 ± 33.543
Cycle 10 (approximately month 10)	-3.47 ± 28.550	-6.67 ± 31.102	-2.78 ± 22.285
End of Treatment	20.59 ± 31.798	0.00 ± 26.352	6.67 ± 44.006

Notes
[37] - Baseline = 149, Cycle 5 = 95, Cycle 10 = 48, EOT = 34
[38] - Baseline = 97, Cycle 5 = 59, Cycle 10 = 35, EOT = 17
[39] - Baseline = 61, Cycle 5 = 30, Cycle 10 = 12, EOT = 15

No statistical analyses for this end point

Secondary: EORTC QLQ-LC-13 Peripheral Neuropathy Scale

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End point title

EORTC QLQ-LC-13 Peripheral Neuropathy Scale

End point description

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 5, 10 and EOT

End point values	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Number of subjects analysed	154 ^[40]	100 ^[41]	63 ^[42]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (Day 0)	11.90 ± 22.117	6.40 ± 17.611	17.20 ± 29.409
Cycle 5 (approximately month 5)	0.00 ± 25.386	3.76 ± 23.458	4.17 ± 31.395
Cycle 10 (approximately month 10)	4.58 ± 25.837	2.86 ± 18.737	0.00 ± 20.101
End of Treatment	2.70 ± 21.341	7.02 ± 26.244	2.22 ± 15.258

Notes
[40] - Baseline = 154, Cycle 5 = 101, Cycle 10 = 51, EOT = 37
[41] - Baseline = 99, Cycle 5 = 62, Cycle 10 = 35, EOT = 19
[42] - Baseline = 62, Cycle 5 = 32, Cycle 10 = 12, EOT = 15

No statistical analyses for this end point

Secondary: EORTC QLQ-LC-13 Sore Mouth Scale

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End point title

EORTC QLQ-LC-13 Sore Mouth Scale

End point description

End point type

Secondary

End point timeframe

Baseline (Day 0), Months 5, 10 and EOT

End point values	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Number of subjects analysed	154 ^[43]	100 ^[44]	63 ^[45]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (Day 0)	5.19 ± 13.273	7.41 ± 17.532	10.58 ± 21.440
Cycle 5 (approximately month 5)	1.98 ± 18.149	-2.19 ± 21.832	-2.02 ± 27.562
Cycle 10 (approximately month 10)	0.65 ± 19.425	-1.90 ± 24.176	2.56 ± 21.350
End of Treatment	4.50 ± 21.026	12.28 ± 29.836	2.22 ± 36.659

Notes
[43] - Baseline = 154, Cycle 5 = 101, Cycle 10 = 51, EOT = 37
[44] - Baseline = 99, Cycle 5 = 61, Cycle 10 = 35, EOT = 19
[45] - Baseline = 63, Cycle 5 = 33, Cycle 10 = 13, EOT = 15

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were reported from the date of first dose of study drug and within 28 days after last dose of study drug, or up to approximately 62 months. In addition, study procedure-related AEs that occurred after signing of the informed consent form.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

Rociletinib 625 mg BID T790M+

Reporting group description

Rociletinib 625 mg BID in patients with T790M-positive tumor status

Reporting group title

Rociletinib 500 mg BID T790M+

Reporting group description

Rociletinib 500 mg BID in patients with T790M-positive tumor status

Reporting group title

Rociletinib 500 mg BID T790M-

Reporting group description

Rociletinib 500 mg BID in patients with T790M-negative tumor status

Serious adverse events	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Total subjects affected by serious adverse events
subjects affected / exposed	77 / 154 (50.00%)	48 / 100 (48.00%)	34 / 63 (53.97%)
number of deaths (all causes)	27	7	9
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression
subjects affected / exposed	23 / 154 (14.94%)	4 / 100 (4.00%)	7 / 63 (11.11%)
occurrences causally related to treatment / all	0 / 24	0 / 4	0 / 7
deaths causally related to treatment / all	0 / 23	0 / 3	0 / 7
Malignant pleural effusion
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to meninges
subjects affected / exposed	1 / 154 (0.65%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myelodysplastic syndrome
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Embolism
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Shock haemorrhagic
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	2 / 154 (1.30%)	2 / 100 (2.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Euthanasia
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Fatigue
subjects affected / exposed	0 / 154 (0.00%)	2 / 100 (2.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 154 (0.00%)	0 / 100 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oedema
subjects affected / exposed	0 / 154 (0.00%)	0 / 100 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 154 (0.00%)	0 / 100 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral swelling
subjects affected / exposed	0 / 154 (0.00%)	0 / 100 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 154 (0.65%)	3 / 100 (3.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 154 (0.00%)	0 / 100 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1
Respiratory, thoracic and mediastinal disorders
Chylothorax
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 154 (0.65%)	4 / 100 (4.00%)	3 / 63 (4.76%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Dyspnoea exertional
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Hypoxia
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	2 / 63 (3.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 154 (0.65%)	2 / 100 (2.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary artery thrombosis
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 154 (0.65%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	2 / 154 (1.30%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Blood creatinine increased
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	2 / 63 (3.17%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Electrocardiogram QT prolonged
subjects affected / exposed	2 / 154 (1.30%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemoglobin decreased
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Postoperative ileus
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Traumatic fracture
subjects affected / exposed	1 / 154 (0.65%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	2 / 63 (3.17%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	2 / 154 (1.30%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 154 (0.00%)	0 / 100 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	2 / 154 (1.30%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral infarction
subjects affected / exposed	0 / 154 (0.00%)	0 / 100 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cognitive disorder
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoaesthesia
subjects affected / exposed	0 / 154 (0.00%)	0 / 100 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Leukoencephalopathy
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Partial seizures
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	2 / 154 (1.30%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 154 (1.95%)	0 / 100 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymphadenitis
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	2 / 154 (1.30%)	0 / 100 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	3 / 3	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Angle closure glaucoma
subjects affected / exposed	0 / 154 (0.00%)	2 / 100 (2.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cataract
subjects affected / exposed	2 / 154 (1.30%)	2 / 100 (2.00%)	4 / 63 (6.35%)
occurrences causally related to treatment / all	1 / 2	2 / 2	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diplopia
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 154 (1.30%)	0 / 100 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	3 / 154 (1.95%)	2 / 100 (2.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	3 / 154 (1.95%)	4 / 100 (4.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 3	4 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	1 / 154 (0.65%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ileus paralytic
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 154 (0.00%)	0 / 100 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Melaena
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	6 / 154 (3.90%)	2 / 100 (2.00%)	2 / 63 (3.17%)
occurrences causally related to treatment / all	5 / 7	1 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	5 / 154 (3.25%)	0 / 100 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	4 / 5	0 / 0	1 / 1
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	4 / 154 (2.60%)	3 / 100 (3.00%)	3 / 63 (4.76%)
occurrences causally related to treatment / all	5 / 5	2 / 3	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct obstruction
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 154 (0.00%)	0 / 100 (0.00%)	2 / 63 (3.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	1 / 154 (0.65%)	2 / 100 (2.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gallbladder obstruction
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 154 (0.00%)	0 / 100 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder perforation
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cystitis interstitial
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 154 (0.00%)	0 / 100 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 154 (0.00%)	0 / 100 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	3 / 154 (1.95%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bursitis
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Flank pain
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 154 (0.00%)	2 / 100 (2.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteonecrosis of jaw
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	1 / 154 (0.65%)	1 / 100 (1.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal column stenosis
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal pain
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Biliary tract infection
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enterocolitis infectious
subjects affected / exposed	0 / 154 (0.00%)	0 / 100 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Listeria sepsis
subjects affected / exposed	0 / 154 (0.00%)	0 / 100 (0.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	2 / 63 (3.17%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Pneumonia
subjects affected / exposed	3 / 154 (1.95%)	5 / 100 (5.00%)	2 / 63 (3.17%)
occurrences causally related to treatment / all	0 / 3	1 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 154 (0.00%)	2 / 100 (2.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 154 (0.00%)	3 / 100 (3.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 154 (0.65%)	0 / 100 (0.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	4 / 154 (2.60%)	2 / 100 (2.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 4	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	10 / 154 (6.49%)	6 / 100 (6.00%)	1 / 63 (1.59%)
occurrences causally related to treatment / all	13 / 13	7 / 7	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 154 (0.00%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 154 (0.65%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 154 (0.65%)	1 / 100 (1.00%)	0 / 63 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Rociletinib 625 mg BID T790M+	Rociletinib 500 mg BID T790M+	Rociletinib 500 mg BID T790M-
Total subjects affected by non serious adverse events
subjects affected / exposed	153 / 154 (99.35%)	100 / 100 (100.00%)	63 / 63 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression
subjects affected / exposed	27 / 154 (17.53%)	7 / 100 (7.00%)	9 / 63 (14.29%)
occurrences all number	35	8	11
Vascular disorders
Hypertension
subjects affected / exposed	9 / 154 (5.84%)	4 / 100 (4.00%)	3 / 63 (4.76%)
occurrences all number	12	4	5
Hypotension
subjects affected / exposed	5 / 154 (3.25%)	5 / 100 (5.00%)	0 / 63 (0.00%)
occurrences all number	5	5	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	19 / 154 (12.34%)	6 / 100 (6.00%)	6 / 63 (9.52%)
occurrences all number	34	10	8
Chest pain
subjects affected / exposed	11 / 154 (7.14%)	13 / 100 (13.00%)	3 / 63 (4.76%)
occurrences all number	13	14	3
Fatigue
subjects affected / exposed	57 / 154 (37.01%)	48 / 100 (48.00%)	29 / 63 (46.03%)
occurrences all number	89	86	46
Influenza like illness
subjects affected / exposed	8 / 154 (5.19%)	5 / 100 (5.00%)	2 / 63 (3.17%)
occurrences all number	13	6	2
Malaise
subjects affected / exposed	4 / 154 (2.60%)	2 / 100 (2.00%)	4 / 63 (6.35%)
occurrences all number	4	2	4
Mucosal inflammation
subjects affected / exposed	6 / 154 (3.90%)	7 / 100 (7.00%)	3 / 63 (4.76%)
occurrences all number	6	11	3
Non-cardiac chest pain
subjects affected / exposed	8 / 154 (5.19%)	1 / 100 (1.00%)	2 / 63 (3.17%)
occurrences all number	9	1	2
Oedema peripheral
subjects affected / exposed	16 / 154 (10.39%)	6 / 100 (6.00%)	8 / 63 (12.70%)
occurrences all number	21	7	9
Pyrexia
subjects affected / exposed	21 / 154 (13.64%)	11 / 100 (11.00%)	5 / 63 (7.94%)
occurrences all number	25	15	7
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	35 / 154 (22.73%)	25 / 100 (25.00%)	18 / 63 (28.57%)
occurrences all number	43	25	18
Dysphonia
subjects affected / exposed	2 / 154 (1.30%)	6 / 100 (6.00%)	2 / 63 (3.17%)
occurrences all number	2	6	2
Dyspnoea
subjects affected / exposed	28 / 154 (18.18%)	24 / 100 (24.00%)	15 / 63 (23.81%)
occurrences all number	41	34	18
Dyspnoea exertional
subjects affected / exposed	5 / 154 (3.25%)	6 / 100 (6.00%)	1 / 63 (1.59%)
occurrences all number	6	7	1
Haemoptysis
subjects affected / exposed	4 / 154 (2.60%)	0 / 100 (0.00%)	4 / 63 (6.35%)
occurrences all number	4	0	4
Pleural effusion
subjects affected / exposed	7 / 154 (4.55%)	6 / 100 (6.00%)	6 / 63 (9.52%)
occurrences all number	7	7	10
Productive cough
subjects affected / exposed	8 / 154 (5.19%)	4 / 100 (4.00%)	4 / 63 (6.35%)
occurrences all number	9	7	5
Rhinorrhoea
subjects affected / exposed	2 / 154 (1.30%)	5 / 100 (5.00%)	0 / 63 (0.00%)
occurrences all number	2	5	0
Psychiatric disorders
Anxiety
subjects affected / exposed	7 / 154 (4.55%)	4 / 100 (4.00%)	4 / 63 (6.35%)
occurrences all number	7	4	4
Confusional state
subjects affected / exposed	8 / 154 (5.19%)	3 / 100 (3.00%)	2 / 63 (3.17%)
occurrences all number	10	4	3
Depression
subjects affected / exposed	5 / 154 (3.25%)	6 / 100 (6.00%)	3 / 63 (4.76%)
occurrences all number	5	6	3
Insomnia
subjects affected / exposed	13 / 154 (8.44%)	10 / 100 (10.00%)	6 / 63 (9.52%)
occurrences all number	16	11	6
Investigations
Alanine aminotransferase increased
subjects affected / exposed	21 / 154 (13.64%)	9 / 100 (9.00%)	6 / 63 (9.52%)
occurrences all number	35	14	10
Aspartate aminotransferase increased
subjects affected / exposed	18 / 154 (11.69%)	5 / 100 (5.00%)	5 / 63 (7.94%)
occurrences all number	29	10	8
Blood alkaline phosphatase increased
subjects affected / exposed	10 / 154 (6.49%)	6 / 100 (6.00%)	4 / 63 (6.35%)
occurrences all number	13	9	4
Blood bilirubin increased
subjects affected / exposed	15 / 154 (9.74%)	3 / 100 (3.00%)	2 / 63 (3.17%)
occurrences all number	32	4	2
Blood creatinine increased
subjects affected / exposed	12 / 154 (7.79%)	7 / 100 (7.00%)	5 / 63 (7.94%)
occurrences all number	18	9	10
Electrocardiogram QT prolonged
subjects affected / exposed	62 / 154 (40.26%)	29 / 100 (29.00%)	19 / 63 (30.16%)
occurrences all number	157	67	37
Platelet count decreased
subjects affected / exposed	6 / 154 (3.90%)	2 / 100 (2.00%)	4 / 63 (6.35%)
occurrences all number	17	2	6
Weight decreased
subjects affected / exposed	43 / 154 (27.92%)	28 / 100 (28.00%)	15 / 63 (23.81%)
occurrences all number	89	45	19
Nervous system disorders
Dizziness
subjects affected / exposed	21 / 154 (13.64%)	18 / 100 (18.00%)	7 / 63 (11.11%)
occurrences all number	24	19	8
Dysgeusia
subjects affected / exposed	10 / 154 (6.49%)	9 / 100 (9.00%)	5 / 63 (7.94%)
occurrences all number	13	13	5
Headache
subjects affected / exposed	45 / 154 (29.22%)	19 / 100 (19.00%)	14 / 63 (22.22%)
occurrences all number	58	27	20
Lethargy
subjects affected / exposed	3 / 154 (1.95%)	2 / 100 (2.00%)	4 / 63 (6.35%)
occurrences all number	3	2	6
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	32 / 154 (20.78%)	13 / 100 (13.00%)	10 / 63 (15.87%)
occurrences all number	72	23	21
Neutropenia
subjects affected / exposed	3 / 154 (1.95%)	5 / 100 (5.00%)	2 / 63 (3.17%)
occurrences all number	8	7	4
Thrombocytopenia
subjects affected / exposed	11 / 154 (7.14%)	1 / 100 (1.00%)	1 / 63 (1.59%)
occurrences all number	28	1	1
Eye disorders
Cataract
subjects affected / exposed	28 / 154 (18.18%)	18 / 100 (18.00%)	7 / 63 (11.11%)
occurrences all number	43	29	13
Vision blurred
subjects affected / exposed	7 / 154 (4.55%)	8 / 100 (8.00%)	2 / 63 (3.17%)
occurrences all number	9	8	3
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	6 / 154 (3.90%)	6 / 100 (6.00%)	0 / 63 (0.00%)
occurrences all number	7	6	0
Abdominal pain
subjects affected / exposed	24 / 154 (15.58%)	15 / 100 (15.00%)	6 / 63 (9.52%)
occurrences all number	34	21	7
Abdominal pain upper
subjects affected / exposed	18 / 154 (11.69%)	9 / 100 (9.00%)	1 / 63 (1.59%)
occurrences all number	26	14	2
Constipation
subjects affected / exposed	38 / 154 (24.68%)	35 / 100 (35.00%)	21 / 63 (33.33%)
occurrences all number	53	54	24
Diarrhoea
subjects affected / exposed	91 / 154 (59.09%)	59 / 100 (59.00%)	30 / 63 (47.62%)
occurrences all number	192	107	46
Dry mouth
subjects affected / exposed	18 / 154 (11.69%)	13 / 100 (13.00%)	2 / 63 (3.17%)
occurrences all number	19	14	2
Dyspepsia
subjects affected / exposed	13 / 154 (8.44%)	4 / 100 (4.00%)	7 / 63 (11.11%)
occurrences all number	15	5	8
Gastrooesophageal reflux disease
subjects affected / exposed	16 / 154 (10.39%)	8 / 100 (8.00%)	5 / 63 (7.94%)
occurrences all number	16	9	6
Mouth ulceration
subjects affected / exposed	2 / 154 (1.30%)	2 / 100 (2.00%)	5 / 63 (7.94%)
occurrences all number	2	2	6
Nausea
subjects affected / exposed	86 / 154 (55.84%)	58 / 100 (58.00%)	31 / 63 (49.21%)
occurrences all number	164	87	53
Stomatitis
subjects affected / exposed	9 / 154 (5.84%)	5 / 100 (5.00%)	1 / 63 (1.59%)
occurrences all number	9	9	2
Vomiting
subjects affected / exposed	62 / 154 (40.26%)	35 / 100 (35.00%)	21 / 63 (33.33%)
occurrences all number	101	45	36
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	11 / 154 (7.14%)	8 / 100 (8.00%)	2 / 63 (3.17%)
occurrences all number	11	10	2
Pruritus
subjects affected / exposed	8 / 154 (5.19%)	5 / 100 (5.00%)	7 / 63 (11.11%)
occurrences all number	13	5	9
Rash
subjects affected / exposed	9 / 154 (5.84%)	9 / 100 (9.00%)	2 / 63 (3.17%)
occurrences all number	9	11	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	22 / 154 (14.29%)	18 / 100 (18.00%)	5 / 63 (7.94%)
occurrences all number	26	21	7
Back pain
subjects affected / exposed	16 / 154 (10.39%)	19 / 100 (19.00%)	9 / 63 (14.29%)
occurrences all number	18	22	10
Muscle spasms
subjects affected / exposed	35 / 154 (22.73%)	23 / 100 (23.00%)	10 / 63 (15.87%)
occurrences all number	49	46	19
Musculoskeletal chest pain
subjects affected / exposed	11 / 154 (7.14%)	7 / 100 (7.00%)	4 / 63 (6.35%)
occurrences all number	15	9	4
Musculoskeletal pain
subjects affected / exposed	13 / 154 (8.44%)	7 / 100 (7.00%)	4 / 63 (6.35%)
occurrences all number	16	8	4
Myalgia
subjects affected / exposed	15 / 154 (9.74%)	4 / 100 (4.00%)	1 / 63 (1.59%)
occurrences all number	17	4	1
Neck pain
subjects affected / exposed	4 / 154 (2.60%)	5 / 100 (5.00%)	2 / 63 (3.17%)
occurrences all number	4	5	2
Pain in extremity
subjects affected / exposed	8 / 154 (5.19%)	7 / 100 (7.00%)	3 / 63 (4.76%)
occurrences all number	8	8	3
Infections and infestations
Paronychia
subjects affected / exposed	2 / 154 (1.30%)	5 / 100 (5.00%)	0 / 63 (0.00%)
occurrences all number	2	10	0
Pneumonia
subjects affected / exposed	7 / 154 (4.55%)	5 / 100 (5.00%)	5 / 63 (7.94%)
occurrences all number	7	5	5
Upper respiratory tract infection
subjects affected / exposed	13 / 154 (8.44%)	8 / 100 (8.00%)	4 / 63 (6.35%)
occurrences all number	13	8	4
Urinary tract infection
subjects affected / exposed	22 / 154 (14.29%)	15 / 100 (15.00%)	6 / 63 (9.52%)
occurrences all number	29	24	9
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	62 / 154 (40.26%)	42 / 100 (42.00%)	25 / 63 (39.68%)
occurrences all number	94	61	37
Dehydration
subjects affected / exposed	16 / 154 (10.39%)	5 / 100 (5.00%)	2 / 63 (3.17%)
occurrences all number	16	5	2
Hyperglycaemia
subjects affected / exposed	97 / 154 (62.99%)	64 / 100 (64.00%)	33 / 63 (52.38%)
occurrences all number	303	198	116
Hypoalbuminaemia
subjects affected / exposed	8 / 154 (5.19%)	3 / 100 (3.00%)	3 / 63 (4.76%)
occurrences all number	13	3	3
Hypokalaemia
subjects affected / exposed	18 / 154 (11.69%)	9 / 100 (9.00%)	8 / 63 (12.70%)
occurrences all number	24	12	10
Hypomagnesaemia
subjects affected / exposed	12 / 154 (7.79%)	7 / 100 (7.00%)	3 / 63 (4.76%)
occurrences all number	20	7	3
Hyponatraemia
subjects affected / exposed	8 / 154 (5.19%)	8 / 100 (8.00%)	3 / 63 (4.76%)
occurrences all number	9	11	4

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Were there any global substantial amendments to the protocol? Yes

09 May 2014

The starting rociletinib dose of 750 mg BID was adjusted to 625 mg BID, and dose modification steps were changed to reflect the reduction of starting dose to 625 mg BID. The addition of a C1D15 ECG safety assessment to identify patients that may be experiencing QTc prolongation resulting from treatment with rociletinib.

27 Oct 2014

Patients who discontinued treatment prior to progression were to continue to have tumor scans per protocol schedule of every 8 ± 1 weeks until progression; patients with clinical progression of disease were to have radiographic confirmation to document that radiographic progression had occurred.

13 Mar 2015

The rationale and study design were changed with the addition of a secondary goal to determine the effectiveness of rociletinib in patients with T790M-negative NSCLC, and the addition of a reduced dose level (500 mg BID).

16 Aug 2016

The Extension Phase was introduced following discontinuation of the rociletinib clinical development program.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: TIGER-2: A Phase 2, Open-label, Multicenter, Safety and Efficacy Study of Oral CO-1686 as 2nd Line EGFR-directed TKI in Patients with Mutant EGFR Non-small Cell Lung Cancer (NSCLC)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Objective Response Rate (ORR) According to RECIST Version 1.1 as Determined by Investigator Assessment

Primary: Objective Response Rate (ORR) According to RECIST Version 1.1 as Determined by Investigator Assessment

Secondary: Duration of Response (DOR) in T790M Positive Patients According to RECIST Version 1.1 as Determined by Investigator Assessment

Secondary: Duration of Response (DOR) in T790M Positive Patients According to RECIST Version 1.1 as Determined by Investigator Assessment

Secondary: Disease Control Rate (DCR) by RECIST v1.1 as Determined by Investigator Assessment

Secondary: Disease Control Rate (DCR) by RECIST v1.1 as Determined by Investigator Assessment

Secondary: Progression-free Survival (PFS) in T790M Positive Patients by RECIST v1.1 as Determined by Investigator Assessment

Secondary: Progression-free Survival (PFS) in T790M Positive Patients by RECIST v1.1 as Determined by Investigator Assessment

Secondary: Overall Survival (OS) Determined by Investigator Assessment

Secondary: Overall Survival (OS) Determined by Investigator Assessment

Secondary: EORTC QLQ-C30 Global Health Status

Secondary: EORTC QLQ-C30 Global Health Status

Secondary: Dermatology Life Quality Index (DLQI)

Secondary: Dermatology Life Quality Index (DLQI)

Secondary: EORTC QLQ-LC-13 Alopecia Scale

Secondary: EORTC QLQ-LC-13 Alopecia Scale

Secondary: EORTC QLQ-LC-13 Coughing Scale

Secondary: EORTC QLQ-LC-13 Coughing Scale

Secondary: EORTC QLQ-LC-13 Dysphagia Scale

Secondary: EORTC QLQ-LC-13 Dysphagia Scale

Secondary: EORTC QLQ-LC-13 Dyspnoea Scale

Secondary: EORTC QLQ-LC-13 Dyspnoea Scale

Secondary: EORTC QLQ-LC-13 Haemoptysis Scale

Secondary: EORTC QLQ-LC-13 Haemoptysis Scale

Secondary: EORTC QLQ-LC-13 Pain in Arm or Shoulder Scale

Secondary: EORTC QLQ-LC-13 Pain in Arm or Shoulder Scale

Secondary: EORTC QLQ-LC-13 Pain in Chest Scale

Secondary: EORTC QLQ-LC-13 Pain in Chest Scale

Secondary: EORTC QLQ-LC-13 Medicine for Pain Scale

Secondary: EORTC QLQ-LC-13 Medicine for Pain Scale

Secondary: EORTC QLQ-LC-13 Pain in Other Parts Scale

Secondary: EORTC QLQ-LC-13 Pain in Other Parts Scale

Secondary: EORTC QLQ-LC-13 Peripheral Neuropathy Scale

Secondary: EORTC QLQ-LC-13 Peripheral Neuropathy Scale

Secondary: EORTC QLQ-LC-13 Sore Mouth Scale

Secondary: EORTC QLQ-LC-13 Sore Mouth Scale

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
TIGER-2: A Phase 2, Open-label, Multicenter, Safety and Efficacy Study of Oral CO-1686 as 2nd Line EGFR-directed TKI in Patients with Mutant EGFR Non-small Cell Lung Cancer (NSCLC)