Trial Outcomes & Findings for LUX-Head&Neck 2: A Phase III Trial of Afatinib (BIBW 2992) Versus Placebo for the Treatment of Head and Neck Squamous Cell Cancer After Treatment With Chemo-radiotherapy (NCT NCT01345669)

Last Updated: 2017-12-07

Results Overview

Disease Free Survival defined as the time from randomisation until documented tumour recurrence/ second primary tumour (SPT) or death from any cause, whichever occurred first.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

617 participants

Primary outcome timeframe

Up to 5 years

Results posted on

2017-12-07

Participant Flow

This was a randomised, placebo-controlled, double-blind, parallel arms, multinational phase III trial in which patients were randomised 2:1 to Afatinib or Placebo.

Participant milestones

Participant milestones
Measure	Afatinib (BIBW 2992) Patient received Afatinib film-coated tablets with starting dose 40 mg (milligram)/day and escalation to 50 mg/day and/or reduction to 40, 30 or 20 mg/day according to absence or presence of drug-related adverse events (AEs), orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.	Placebo Patient received placebo matching Afatinib film-coated tablets with matching Afatinib dosage regimen, orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.
Overall Study STARTED	411	206
Overall Study COMPLETED	124	87
Overall Study NOT COMPLETED	287	119

Reasons for withdrawal

Reasons for withdrawal
Measure	Afatinib (BIBW 2992) Patient received Afatinib film-coated tablets with starting dose 40 mg (milligram)/day and escalation to 50 mg/day and/or reduction to 40, 30 or 20 mg/day according to absence or presence of drug-related adverse events (AEs), orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.	Placebo Patient received placebo matching Afatinib film-coated tablets with matching Afatinib dosage regimen, orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.
Overall Study Primary tumour recurrence	53	32
Overall Study Second primary tumour	4	3
Overall Study Adverse Event	63	9
Overall Study Protocol Violation	3	1
Overall Study Lost to Follow-up	1	1
Overall Study Withdrawal by Subject	52	13
Overall Study Other Reasons	111	60

Baseline Characteristics

LUX-Head&Neck 2: A Phase III Trial of Afatinib (BIBW 2992) Versus Placebo for the Treatment of Head and Neck Squamous Cell Cancer After Treatment With Chemo-radiotherapy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Afatinib (BIBW 2992) n=411 Participants Patient received Afatinib film-coated tablets with starting dose 40 mg (milligram)/day and escalation to 50 mg/day and/or reduction to 40, 30 or 20 mg/day according to absence or presence of drug-related adverse events (AEs), orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.	Placebo n=206 Participants Patient received placebo matching Afatinib film-coated tablets with matching Afatinib dosage regimen, orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.	Total n=617 Participants Total of all reporting groups
Age, Continuous	58.3 Years STANDARD_DEVIATION 8.23 • n=5 Participants	57.3 Years STANDARD_DEVIATION 8.64 • n=7 Participants	58.0 Years STANDARD_DEVIATION 8.38 • n=5 Participants
Sex: Female, Male Female	61 Participants n=5 Participants	28 Participants n=7 Participants	89 Participants n=5 Participants
Sex: Female, Male Male	350 Participants n=5 Participants	178 Participants n=7 Participants	528 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 5 years

Population: Randomised Set (RS): Included all patients who were randomised, regardless of taking investigational treatment (as randomised)

Disease Free Survival defined as the time from randomisation until documented tumour recurrence/ second primary tumour (SPT) or death from any cause, whichever occurred first.

Outcome measures

Outcome measures
Measure	Afatinib (BIBW 2992) n=411 Participants Patient received Afatinib film-coated tablets with starting dose 40 mg (milligram)/day and escalation to 50 mg/day and/or reduction to 40, 30 or 20 mg/day according to absence or presence of drug-related adverse events (AEs), orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.	Placebo n=206 Participants Patient received placebo matching Afatinib film-coated tablets with matching Afatinib dosage regimen, orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.
Disease Free Survival (DFS)	43.40 Months Interval 16.82 to Non calculable because the 75th percentile hasn't been reached	NA Months Interval 16.69 to Non calculable because the median hasn't been reached

SECONDARY outcome

Timeframe: Up to 2 years

Population: Randomised Set, the number of patients from the randomized set those are disease free (or DFS) at 2 years.

Disease Free Survival (DFS) rate at 2 years. Probability of being disease free at 2 years in percentage is provided based on Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Afatinib (BIBW 2992) n=117 Participants Patient received Afatinib film-coated tablets with starting dose 40 mg (milligram)/day and escalation to 50 mg/day and/or reduction to 40, 30 or 20 mg/day according to absence or presence of drug-related adverse events (AEs), orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.	Placebo n=76 Participants Patient received placebo matching Afatinib film-coated tablets with matching Afatinib dosage regimen, orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.
Disease Free Survival (DFS) Rate at 2 Years	67.2 Probability (%) Interval 61.2 to 72.5	73.5 Probability (%) Interval 66.0 to 79.5

SECONDARY outcome

Timeframe: Up to 5 years

Population: Randomised Set (RS): Included all patients who were randomised, regardless of taking investigational treatment (as randomised)

Overall survival (OS), defined as the time from randomisation until death (regardless of cause). Due to the small event rate in both treatment arms caused by the early termination of the trial, the hazard estimate is not interpretable. Hence presented the total randomized and the percentage of patients died.

Outcome measures

Outcome measures
Measure	Afatinib (BIBW 2992) n=411 Participants Patient received Afatinib film-coated tablets with starting dose 40 mg (milligram)/day and escalation to 50 mg/day and/or reduction to 40, 30 or 20 mg/day according to absence or presence of drug-related adverse events (AEs), orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.	Placebo n=206 Participants Patient received placebo matching Afatinib film-coated tablets with matching Afatinib dosage regimen, orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.
Percentage of Patient Deaths (Overall Survival (OS))	15.1 Percentage of patients Interval 16.82 to	11.2 Percentage of patients Interval 16.69 to

SECONDARY outcome

Timeframe: Up to 5 years

Population: Randomised Set (RS): Included all patients who were randomised, regardless of taking investigational treatment (as randomised)

HRQoL questionnaires focused on 3 scales: Pain scale from H\&N35, Swallowing scale from H\&N35 and Global health status/QoL scale from C30. Improvement was defined as a score that improved from baseline by at least 10 points (on the 0-100 point scale) at any time during the study. If a patient had not improved, worsening was defined as a 10-point worsening at any time during the study. Patients who had neither improved nor worsened were considered as stable. Percentages of patients with improvement in HRQoL are presented.

Outcome measures

Outcome measures
Measure	Afatinib (BIBW 2992) n=411 Participants Patient received Afatinib film-coated tablets with starting dose 40 mg (milligram)/day and escalation to 50 mg/day and/or reduction to 40, 30 or 20 mg/day according to absence or presence of drug-related adverse events (AEs), orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.	Placebo n=206 Participants Patient received placebo matching Afatinib film-coated tablets with matching Afatinib dosage regimen, orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.
Patients With Improved Health Related Quality of Life (HRQOL) Swallowing (Q5-Q8 from QLQ-HN35)	34.8 Percentage of Patients Interval 16.82 to	27.2 Percentage of Patients Interval 16.69 to
Patients With Improved Health Related Quality of Life (HRQOL) Pain HN35 (Q1-Q4 from QLQ-HN35)	33.8 Percentage of Patients	26.2 Percentage of Patients
Patients With Improved Health Related Quality of Life (HRQOL) Global health status/QoL(Q29-Q30 from QLQ-C30)	33.6 Percentage of Patients	38.3 Percentage of Patients

SECONDARY outcome

Timeframe: Up to 5 years

Population: Randomised Set (RS): Included all patients who were randomised, regardless of taking investigational treatment (as randomised)

HRQoL questionnaires focused on 3 scales: Pain scale from H\&N35, Swallowing scale from H\&N35 and Global health status/QoL scale from C30. Time to deterioration was defined as the time from randomisation to the first 10-point worsening on the 0-100 point scale. Patients with no deterioration (including those with disease recurrence/SPT) were censored at the last available HRQoL assessment date. Patients with no post-baseline assessments were censored on the day of randomisation.

Outcome measures

Outcome measures
Measure	Afatinib (BIBW 2992) n=411 Participants Patient received Afatinib film-coated tablets with starting dose 40 mg (milligram)/day and escalation to 50 mg/day and/or reduction to 40, 30 or 20 mg/day according to absence or presence of drug-related adverse events (AEs), orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.	Placebo n=206 Participants Patient received placebo matching Afatinib film-coated tablets with matching Afatinib dosage regimen, orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.
Time to Deterioration in Health Related Quality of Life (HRQOL) Swallowing	18.43 Months Interval 3.68 to Non calculable because the 75th percentile hasn't been reached	31.44 Months Interval 3.78 to Non calculable because the 75th percentile hasn't been reached
Time to Deterioration in Health Related Quality of Life (HRQOL) Pain HN35	12.06 Months Interval 1.91 to Non calculable because the 75th percentile hasn't been reached	31.08 Months Interval 3.78 to Non calculable because the 75th percentile hasn't been reached
Time to Deterioration in Health Related Quality of Life (HRQOL) Global health status/QoL	7.59 Months Interval 1.87 to Non calculable because the 75th percentile hasn't been reached	25.79 Months Interval 6.21 to Non calculable because the 75th percentile hasn't been reached

SECONDARY outcome

Timeframe: Baseline and 5 years

Population: Randomised Set (RS): Included all patients who were randomised, regardless of taking investigational treatment (as randomised)

HRQoL questionnaires focused on 3 scales: Pain scale from H\&N35, Swallowing scale from H\&N35 and Global health status/QoL scale from C30. Scoring of the symptom scales/items followed the European Organisation for Research and Treatment of Cancer (EORTC) scoring manual and a linear transformation of the scores to a 0-100 point scale. Higher values are better.

Outcome measures

Outcome measures
Measure	Afatinib (BIBW 2992) n=411 Participants Patient received Afatinib film-coated tablets with starting dose 40 mg (milligram)/day and escalation to 50 mg/day and/or reduction to 40, 30 or 20 mg/day according to absence or presence of drug-related adverse events (AEs), orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.	Placebo n=206 Participants Patient received placebo matching Afatinib film-coated tablets with matching Afatinib dosage regimen, orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.
Health Related Quality of Life (HRQOL) Scores Over Time Global health status/QoL	29.6 Unit on Scale Standard Error 2.23 • Interval 1.87 to	33.0 Unit on Scale Standard Error 2.28 • Interval 6.21 to
Health Related Quality of Life (HRQOL) Scores Over Time Swallowing	10.1 Unit on Scale Standard Error 1.00 • Interval 3.68 to	8.8 Unit on Scale Standard Error 1.12 • Interval 3.78 to
Health Related Quality of Life (HRQOL) Scores Over Time Pain HN35	13.1 Unit on Scale Standard Error 0.98 • Interval 1.91 to	9.9 Unit on Scale Standard Error 1.10 • Interval 3.78 to

Adverse Events

Afatinib (BIBW 2992)

Serious events: 80 serious events

Other events: 407 other events

Deaths: 0 deaths

Placebo

Serious events: 51 serious events

Other events: 169 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Boehringer Ingelheim, Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Afatinib (BIBW 2992) n=411 participants at risk Patient received Afatinib film-coated tablets with starting dose 40 mg (milligram)/day and escalation to 50 mg/day and/or reduction to 40, 30 or 20 mg/day according to absence or presence of drug-related adverse events (AEs), orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.	Placebo n=206 participants at risk Patient received placebo matching Afatinib film-coated tablets with matching Afatinib dosage regimen, orally, once daily for up to 80 weeks or until recurrence / occurrence of second primary tumour, unacceptable side effects, or other reason necessitating withdrawal.
Blood and lymphatic system disorders Anaemia	5.6% 23/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	3.4% 7/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Gastrointestinal disorders Abdominal pain	5.1% 21/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	2.9% 6/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Gastrointestinal disorders Cheilitis	5.4% 22/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	0.49% 1/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Gastrointestinal disorders Constipation	8.0% 33/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	9.7% 20/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Gastrointestinal disorders Diarrhoea	81.5% 335/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	19.9% 41/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Gastrointestinal disorders Dry mouth	13.4% 55/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	12.1% 25/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Gastrointestinal disorders Dyspepsia	10.2% 42/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	4.9% 10/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Gastrointestinal disorders Dysphagia	11.7% 48/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	10.2% 21/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Gastrointestinal disorders Gastrooesophageal reflux disease	5.6% 23/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	0.97% 2/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Gastrointestinal disorders Nausea	10.5% 43/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	11.7% 24/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Gastrointestinal disorders Oral pain	5.6% 23/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	2.9% 6/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Gastrointestinal disorders Stomatitis	26.0% 107/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	5.8% 12/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Gastrointestinal disorders Vomiting	9.7% 40/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	9.7% 20/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
General disorders Asthenia	10.5% 43/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	11.2% 23/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
General disorders Fatigue	14.8% 61/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	10.2% 21/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
General disorders Mucosal inflammation	30.7% 126/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	8.3% 17/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
General disorders Pyrexia	7.1% 29/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	3.4% 7/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Infections and infestations Conjunctivitis	5.1% 21/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	0.97% 2/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Infections and infestations Nasopharyngitis	5.4% 22/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	8.7% 18/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Infections and infestations Paronychia	20.7% 85/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	1.9% 4/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Infections and infestations Upper respiratory tract infection	4.6% 19/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	7.3% 15/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Investigations Weight decreased	16.3% 67/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	9.2% 19/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Metabolism and nutrition disorders Decreased appetite	18.0% 74/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	11.2% 23/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Musculoskeletal and connective tissue disorders Back pain	3.2% 13/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	8.3% 17/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Musculoskeletal and connective tissue disorders Muscle spasms	6.3% 26/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	4.4% 9/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Musculoskeletal and connective tissue disorders Neck pain	2.7% 11/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	5.3% 11/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Nervous system disorders Dizziness	2.7% 11/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	6.3% 13/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Nervous system disorders Dysgeusia	8.3% 34/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	4.9% 10/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Nervous system disorders Headache	4.4% 18/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	5.8% 12/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Psychiatric disorders Anxiety	2.4% 10/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	5.8% 12/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Respiratory, thoracic and mediastinal disorders Cough	8.5% 35/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	14.6% 30/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Respiratory, thoracic and mediastinal disorders Dysphonia	5.4% 22/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	8.3% 17/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Respiratory, thoracic and mediastinal disorders Epistaxis	13.1% 54/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	1.5% 3/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	6.6% 27/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	6.8% 14/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Skin and subcutaneous tissue disorders Acne	5.4% 22/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	0.97% 2/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Skin and subcutaneous tissue disorders Dermatitis acneiform	27.3% 112/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	2.9% 6/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Skin and subcutaneous tissue disorders Dry skin	18.5% 76/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	7.8% 16/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Skin and subcutaneous tissue disorders Erythema	6.8% 28/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	2.4% 5/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	7.3% 30/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	0.00% 0/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Skin and subcutaneous tissue disorders Pruritus	14.1% 58/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	6.3% 13/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Skin and subcutaneous tissue disorders Rash	45.7% 188/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	16.5% 34/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Skin and subcutaneous tissue disorders Skin fissures	9.7% 40/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	0.49% 1/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks
Vascular disorders Hypertension	4.4% 18/411 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks	5.8% 12/206 • From first drug administration until 4 weeks after the last drug administration, up to 84 weeks