Trial Outcomes & Findings for Study Evaluating the Safety Of HKI-272 (Neratinib) In Subjects With Advanced Non-Small Cell Lung Cancer (NCT NCT00266877)

Last Updated: 2018-04-13

Results Overview

Objective response rate as reported by Independent Assessment (radiographic review by independent radiologists) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.0: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; and Non-PD for non-target lesions, and no new lesions.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

172 participants

Primary outcome timeframe

From first dose date to progression/death or last tumor assessment, up to three years.

Results posted on

2018-04-13

Participant Flow

Participant milestones

Participant milestones
Measure	Prior Tarceva or Iressa With EGFR Mutation Patients whose disease has progressed following \> or = 12 weeks of treatment with Tarceva or Iressa and who have a tumor with an EGFR mutation demonstrated at screening HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.	Prior Tarceva or Iressa w/o EGFR Mutation Patients whose disease has progressed following \> or = 12 weeks of treatment with Tarceva or Iressa and who have a tumor without an EGFR mutation demonstrated at screening HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.	No Prior EGFR Tyrosine Kinase Inhibitor Treatment Patients with no prior EGFR tyrosine kinase inhibitor treatment, adenocarcinoma, \< or = 20 pack-year smoking history, and current non-smoker (no requirement for EGFR mutation) HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.
Overall Study STARTED	91	48	28
Overall Study COMPLETED	0	0	0
Overall Study NOT COMPLETED	91	48	28

Reasons for withdrawal

Reasons for withdrawal
Measure	Prior Tarceva or Iressa With EGFR Mutation Patients whose disease has progressed following \> or = 12 weeks of treatment with Tarceva or Iressa and who have a tumor with an EGFR mutation demonstrated at screening HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.	Prior Tarceva or Iressa w/o EGFR Mutation Patients whose disease has progressed following \> or = 12 weeks of treatment with Tarceva or Iressa and who have a tumor without an EGFR mutation demonstrated at screening HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.	No Prior EGFR Tyrosine Kinase Inhibitor Treatment Patients with no prior EGFR tyrosine kinase inhibitor treatment, adenocarcinoma, \< or = 20 pack-year smoking history, and current non-smoker (no requirement for EGFR mutation) HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.
Overall Study Death	1	1	1
Overall Study Adverse Event	6	4	1
Overall Study Physician Decision	2	1	1
Overall Study Withdrawal by Subject	3	1	1
Overall Study Disease Progression	72	37	23
Overall Study Symptomatic Deterioration	6	3	1
Overall Study Hospitalization	1	0	0
Overall Study Concomitant Radiotherapy	0	1	0

Baseline Characteristics

Study Evaluating the Safety Of HKI-272 (Neratinib) In Subjects With Advanced Non-Small Cell Lung Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Prior Tarceva or Iressa With EGFR Mutation n=91 Participants Patients whose disease has progressed following \> or = 12 weeks of treatment with Tarceva or Iressa and who have a tumor with an EGFR mutation demonstrated at screening HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.	Prior Tarceva or Iressa w/o EGFR Mutation n=48 Participants Patients whose disease has progressed following \> or = 12 weeks of treatment with Tarceva or Iressa and who have a tumor without an EGFR mutation demonstrated at screening HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.	No Prior EGFR Tyrosine Kinase Inhibitor Treatment n=28 Participants Patients with no prior EGFR tyrosine kinase inhibitor treatment, adenocarcinoma, \< or = 20 pack-year smoking history, and current non-smoker (no requirement for EGFR mutation) HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.	Total n=167 Participants Total of all reporting groups
Age, Customized < 60 years	45 Participants n=5 Participants	24 Participants n=7 Participants	13 Participants n=5 Participants	82 Participants n=4 Participants
Age, Customized >= 60 years	46 Participants n=5 Participants	24 Participants n=7 Participants	15 Participants n=5 Participants	85 Participants n=4 Participants
Sex: Female, Male Female	74 Participants n=5 Participants	26 Participants n=7 Participants	18 Participants n=5 Participants	118 Participants n=4 Participants
Sex: Female, Male Male	17 Participants n=5 Participants	22 Participants n=7 Participants	10 Participants n=5 Participants	49 Participants n=4 Participants

PRIMARY outcome

Timeframe: From first dose date to progression/death or last tumor assessment, up to three years.

Population: modified ITT: Subjects who were randomized and who had taken at least 1 dose of neratinib; equivalent to the safety population

Outcome measures

Outcome measures
Measure	Prior Tarceva or Iressa With EGFR Mutation n=91 Participants Patients whose disease has progressed following \> or = 12 weeks of treatment with Tarceva or Iressa and who have a tumor with an EGFR mutation demonstrated at screening HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.	Prior Tarceva or Iressa w/o EGFR Mutation n=48 Participants Patients whose disease has progressed following \> or = 12 weeks of treatment with Tarceva or Iressa and who have a tumor without an EGFR mutation demonstrated at screening HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.	No Prior EGFR Tyrosine Kinase Inhibitor Treatment n=28 Participants Patients with no prior EGFR tyrosine kinase inhibitor treatment, adenocarcinoma, \< or = 20 pack-year smoking history, and current non-smoker (no requirement for EGFR mutation) HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.
Objective Response Rate for Neratinib in Patients With Non-small Cell Lung Cancer	3.3 percentage of participants Interval 0.9 to 8.3	0 percentage of participants Interval 0.0 to 6.05	3.6 percentage of participants Interval 0.18 to 15.85

SECONDARY outcome

Timeframe: From first dose date to progression/death or last tumor assessment, up to three years.

Clinical benefit rate is the percentage of patients with Partial or Complete Response, or with Stable Disease \>= 12 Weeks per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.0: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; and Non-PD for non-target lesions, and no new lesions; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Outcome measures

Outcome measures
Measure	Prior Tarceva or Iressa With EGFR Mutation n=91 Participants Patients whose disease has progressed following \> or = 12 weeks of treatment with Tarceva or Iressa and who have a tumor with an EGFR mutation demonstrated at screening HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.	Prior Tarceva or Iressa w/o EGFR Mutation n=48 Participants Patients whose disease has progressed following \> or = 12 weeks of treatment with Tarceva or Iressa and who have a tumor without an EGFR mutation demonstrated at screening HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.	No Prior EGFR Tyrosine Kinase Inhibitor Treatment n=28 Participants Patients with no prior EGFR tyrosine kinase inhibitor treatment, adenocarcinoma, \< or = 20 pack-year smoking history, and current non-smoker (no requirement for EGFR mutation) HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.
Clinical Benefit Rate for Neratinib in Patients With Non-small Cell Lung Cancer	9.9 percentage of participants Interval 5.26 to 16.62	6.3 percentage of participants Interval 1.73 to 15.37	10.7 percentage of participants Interval 2.98 to 25.42

SECONDARY outcome

Timeframe: From start date of response to first PD, assessed up to three years after the first randomization.

Population: Number of subjects with PR or higher response.

Measured from the time at which measurement criteria were first met for CR or PR (whichever status was recorded first), until the date of first recurrence, PD, or death was objectively documented, taking as a reference for PD the smallest measurements recorded since enrollment, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.0: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; and Non-PD for non-target lesions, and no new lesions.

Outcome measures

Outcome measures
Measure	Prior Tarceva or Iressa With EGFR Mutation n=3 Participants Patients whose disease has progressed following \> or = 12 weeks of treatment with Tarceva or Iressa and who have a tumor with an EGFR mutation demonstrated at screening HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.	Prior Tarceva or Iressa w/o EGFR Mutation Patients whose disease has progressed following \> or = 12 weeks of treatment with Tarceva or Iressa and who have a tumor without an EGFR mutation demonstrated at screening HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.	No Prior EGFR Tyrosine Kinase Inhibitor Treatment n=1 Participants Patients with no prior EGFR tyrosine kinase inhibitor treatment, adenocarcinoma, \< or = 20 pack-year smoking history, and current non-smoker (no requirement for EGFR mutation) HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.
Duration of Response for Neratinib in Patients With Non-small Cell Lung Cancer	54.1 weeks Interval 17.9 to 54.1	—	28.7 weeks Insufficient number of participants with events.

SECONDARY outcome

Timeframe: From first dose date to progression/death, assessed up to three years.

Defined as the interval from the date of randomization until the first date on which recurrence or progression, or death due to any cause, is documented, censored at the last assessable evaluation or at the initiation of new anticancer therapy. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v 1.0 as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Outcome measures

Outcome measures
Measure	Prior Tarceva or Iressa With EGFR Mutation n=91 Participants Patients whose disease has progressed following \> or = 12 weeks of treatment with Tarceva or Iressa and who have a tumor with an EGFR mutation demonstrated at screening HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.	Prior Tarceva or Iressa w/o EGFR Mutation n=48 Participants Patients whose disease has progressed following \> or = 12 weeks of treatment with Tarceva or Iressa and who have a tumor without an EGFR mutation demonstrated at screening HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.	No Prior EGFR Tyrosine Kinase Inhibitor Treatment n=28 Participants Patients with no prior EGFR tyrosine kinase inhibitor treatment, adenocarcinoma, \< or = 20 pack-year smoking history, and current non-smoker (no requirement for EGFR mutation) HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.
Progression Free Survival for Neratinib in Patients With Non-small Cell Lung Cancer	15.3 weeks Interval 11.9 to 15.7	16.1 weeks Interval 15.0 to 23.9	9.3 weeks Interval 6.4 to 18.9

Adverse Events

Prior Tarceva or Iressa With EGFR Mutation

Serious events: 33 serious events

Other events: 91 other events

Deaths: 0 deaths

Prior Tarceva or Iressa w/o EGFR Mutation

Serious events: 21 serious events

Other events: 46 other events

Deaths: 0 deaths

No Prior EGFR Tyrosine Kinase Inhibitor Treatment

Serious events: 14 serious events

Other events: 26 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Senior Director, Clinical Operations

Puma Biotechnology, Inc.

Phone: +1 (424) 248-6500

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Prior Tarceva or Iressa With EGFR Mutation n=91 participants at risk Patients whose disease has progressed following \> or = 12 weeks of treatment with Tarceva or Iressa and who have a tumor with an EGFR mutation demonstrated at screening HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.	Prior Tarceva or Iressa w/o EGFR Mutation n=48 participants at risk Patients whose disease has progressed following \> or = 12 weeks of treatment with Tarceva or Iressa and who have a tumor without an EGFR mutation demonstrated at screening HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.	No Prior EGFR Tyrosine Kinase Inhibitor Treatment n=28 participants at risk Patients with no prior EGFR tyrosine kinase inhibitor treatment, adenocarcinoma, \< or = 20 pack-year smoking history, and current non-smoker (no requirement for EGFR mutation) HKI-272: 320mg or 240mg daily by mouth. The starting dose was reduced from 320mg to 240mg per amendment #1 to the protocol for subject safety and tolerability.
Blood and lymphatic system disorders Anaemia	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	3.6% 1/28 • First dose through 28 days after last dose, assessed up to three years.
Blood and lymphatic system disorders Neutropenia	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	2.1% 1/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Cardiac disorders Pericardial effusion	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	2.1% 1/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Cardiac disorders Sinus tachycardia	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	2.1% 1/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Cardiac disorders Supraventricular tachycardia	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	2.1% 1/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Ear and labyrinth disorders Deafness unilateral	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Gastrointestinal disorders Abdominal pain	2.2% 2/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Gastrointestinal disorders Acute abdomen	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Gastrointestinal disorders Ascites	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Gastrointestinal disorders Diarrhoea	2.2% 2/91 • First dose through 28 days after last dose, assessed up to three years.	2.1% 1/48 • First dose through 28 days after last dose, assessed up to three years.	7.1% 2/28 • First dose through 28 days after last dose, assessed up to three years.
Gastrointestinal disorders Nausea	4.4% 4/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	3.6% 1/28 • First dose through 28 days after last dose, assessed up to three years.
Gastrointestinal disorders Vomiting	2.2% 2/91 • First dose through 28 days after last dose, assessed up to three years.	2.1% 1/48 • First dose through 28 days after last dose, assessed up to three years.	7.1% 2/28 • First dose through 28 days after last dose, assessed up to three years.
General disorders Fatigue	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	3.6% 1/28 • First dose through 28 days after last dose, assessed up to three years.
General disorders General physical health deterioration	5.5% 5/91 • First dose through 28 days after last dose, assessed up to three years.	6.2% 3/48 • First dose through 28 days after last dose, assessed up to three years.	10.7% 3/28 • First dose through 28 days after last dose, assessed up to three years.
General disorders Hyperthermia	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	3.6% 1/28 • First dose through 28 days after last dose, assessed up to three years.
General disorders Pyrexia	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	3.6% 1/28 • First dose through 28 days after last dose, assessed up to three years.
General disorders Unevaluable event	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Infections and infestations Bacteraemia	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Infections and infestations Bronchitis	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	3.6% 1/28 • First dose through 28 days after last dose, assessed up to three years.
Infections and infestations Escherichia urinary tract infection	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	3.6% 1/28 • First dose through 28 days after last dose, assessed up to three years.
Infections and infestations Infection	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Infections and infestations Lung infection	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	2.1% 1/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Infections and infestations Pneumonia	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	6.2% 3/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Injury, poisoning and procedural complications Accidental overdose	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	2.1% 1/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Injury, poisoning and procedural complications Overdose	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Injury, poisoning and procedural complications Spinal compression fracture	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Metabolism and nutrition disorders Dehydration	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	4.2% 2/48 • First dose through 28 days after last dose, assessed up to three years.	7.1% 2/28 • First dose through 28 days after last dose, assessed up to three years.
Musculoskeletal and connective tissue disorders Back pain	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	2.1% 1/48 • First dose through 28 days after last dose, assessed up to three years.	3.6% 1/28 • First dose through 28 days after last dose, assessed up to three years.
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	2.1% 1/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Musculoskeletal and connective tissue disorders Muscular weakness	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Musculoskeletal and connective tissue disorders Spinal pain	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	3.6% 1/28 • First dose through 28 days after last dose, assessed up to three years.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to meninges	2.2% 2/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-small cell lung cancer	4.4% 4/91 • First dose through 28 days after last dose, assessed up to three years.	6.2% 3/48 • First dose through 28 days after last dose, assessed up to three years.	3.6% 1/28 • First dose through 28 days after last dose, assessed up to three years.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	2.1% 1/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	3.6% 1/28 • First dose through 28 days after last dose, assessed up to three years.
Nervous system disorders Cerebral ischaemia	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Nervous system disorders Cerebral venous thrombosis	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Nervous system disorders Coma	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	3.6% 1/28 • First dose through 28 days after last dose, assessed up to three years.
Nervous system disorders Convulsion	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	2.1% 1/48 • First dose through 28 days after last dose, assessed up to three years.	3.6% 1/28 • First dose through 28 days after last dose, assessed up to three years.
Nervous system disorders Dizziness	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Nervous system disorders Headache	2.2% 2/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	3.6% 1/28 • First dose through 28 days after last dose, assessed up to three years.
Nervous system disorders Loss of consciousness	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Nervous system disorders Memory impairment	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Nervous system disorders Radicular syndrome	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Nervous system disorders Sciatica	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	2.1% 1/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Nervous system disorders Speech disorder	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Nervous system disorders Syncope	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	2.1% 1/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Psychiatric disorders Agitation	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	2.1% 1/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Psychiatric disorders Confusional state	2.2% 2/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Renal and urinary disorders Renal failure	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	3.6% 1/28 • First dose through 28 days after last dose, assessed up to three years.
Renal and urinary disorders Urinary retention	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	3.6% 1/28 • First dose through 28 days after last dose, assessed up to three years.
Respiratory, thoracic and mediastinal disorders Atelectasis	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	2.1% 1/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Respiratory, thoracic and mediastinal disorders Dyspnoea	4.4% 4/91 • First dose through 28 days after last dose, assessed up to three years.	2.1% 1/48 • First dose through 28 days after last dose, assessed up to three years.	10.7% 3/28 • First dose through 28 days after last dose, assessed up to three years.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	2.1% 1/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Respiratory, thoracic and mediastinal disorders Pleural effusion	7.7% 7/91 • First dose through 28 days after last dose, assessed up to three years.	8.3% 4/48 • First dose through 28 days after last dose, assessed up to three years.	3.6% 1/28 • First dose through 28 days after last dose, assessed up to three years.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	2.1% 1/48 • First dose through 28 days after last dose, assessed up to three years.	3.6% 1/28 • First dose through 28 days after last dose, assessed up to three years.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	2.1% 1/48 • First dose through 28 days after last dose, assessed up to three years.	3.6% 1/28 • First dose through 28 days after last dose, assessed up to three years.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	1.1% 1/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	3.6% 1/28 • First dose through 28 days after last dose, assessed up to three years.
Skin and subcutaneous tissue disorders Rash	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	2.1% 1/48 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/28 • First dose through 28 days after last dose, assessed up to three years.
Vascular disorders Superior vena cava syndrome	0.00% 0/91 • First dose through 28 days after last dose, assessed up to three years.	0.00% 0/48 • First dose through 28 days after last dose, assessed up to three years.	3.6% 1/28 • First dose through 28 days after last dose, assessed up to three years.