LUX-Lung 8: A Phase III Trial of Afatinib (BIBW 2992) Versus Erlotinib for the Treatment of Squamous Cell Lung Cancer After at Least One Prior Platinum Based Chemotherapy

• ClinicalTrials.gov Identifier: NCT01523587
• Recruitment Status: Completed
• First Posted: February 1, 2012
• Results First Posted: November 21, 2014
• Last Update Posted: February 15, 2019
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

Tracking Information

• First Submitted Date: January 30, 2012
• First Posted Date: February 1, 2012
• Results First Submitted Date: October 6, 2014
• Results First Posted Date: November 21, 2014
• Last Update Posted Date: February 15, 2019
• Actual Study Start Date: March 5, 2012
• Actual Primary Completion Date: October 21, 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 8, 2019)

Progression-free Survival, Based on Central Independent Review as Determined by Response Evaluation Criteria in Solid Tumours 1.1 [ Time Frame: First treatment administration up until cut off date of 02 March 2015 (up to 1058 days). ]

Progression Free Survival (PFS) was defined as the time from randomization to disease progression (or death if the patient died before progression) by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. RECIST is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize") or worsen ("progress") during treatment. Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

• Original Primary Outcome Measures (submitted: January 30, 2012): Progression-free survival, as determined by RECIST 1.1 [ Time Frame: 18 months ]

Current Secondary Outcome Measures (submitted: February 8, 2019)

• Overall Survival [ Time Frame: From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). ]
  Overall Survival is defined as the time from randomisation to death. It was a key secondary endpoint.
• Number of Participants With Objective Response According to RECIST 1.1 [ Time Frame: First treatment administration up until cut off date of 02 March 2015 (up to 1058 days). ]
  A patient with a best overall response of Complete Responder (CR) or Partial Responder (PR) was considered to show objective response to study medication. For patients with an objective response, time to objective response was defined as the time from randomization to the first objective response; duration of objective response was defined as the time from the first objective response to progression (or death if the patient died before progression). Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
• Number of Participants With Disease Control According to RECIST 1.1 [ Time Frame: First treatment administration up until cut off date of 02 March 2015 (up to 1058 days). ]
  Disease control was assessed based on Independent Radiologic Review (IRR) and investigator assessment. A patient with a best overall response of CR, PR, or Stable Disease (SD) was considered to have disease control. Patients with no baseline target lesions who had no evidence of disease progression in their non-target lesions and had no new lesions were considered to have disease control. Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
• Tumour Shrinkage [ Time Frame: First treatment administration up until cut off date of 02 March 2015 (up to 1058 days). ]
  Maximum percentage decrease from baseline in the sum of target lesion diameters following independent review. The change in the size (i.e. the sum of diameters (SOD)) of target lesions from baseline was derived. Tumour shrinkage for each patient was measured (based on Independent Radiologic Review (IRR)) as the minimum SOD of target lesions after randomisation. A negative percentage indicates decrease from baseline; positive numbers indicate an increase of tumour size. The mean maximum decrease from baseline of +5 and +9.4 reflect an average increase in tumour size. Post-baseline mean is adjusted for baseline sum of diameters and race.
• Number of Participants With Status Change in Cough, Dyspnoea and Pain Related Items Over Time in Health Related Quality of Life Questionnaire [ Time Frame: From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). ]
  Health-related quality of life (HRQoL) was measured with the following multi-dimensional questionnaires: the european organization for research and treatment of cancer (eortc) quality of life questionnaire (QLQ-C30) questionnaire and its lung cancer specific supplementary module EORTC QLQ-LC13 and the EQ-5D health status self-assessment questionnaire. The questionnaires were assessed at the first visit of each treatment course, at end of treatment (EOT) and follow up prior to clinical assessment. The results displayed show number of patients with improvement in the relevant criteria. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of: The number of patients that were improved: Change in cough; dyspnoea and pain scores over time.
• Summary of Time to Deterioration in Coughing, Dyspnoea and Pain. [ Time Frame: From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). ]
  Health-related quality of life (HRQoL) was measured with the following multi-dimensional questionnaires: the EORTC QLQ-C30. The questionnaires were assessed at the first visit of each treatment course. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of: Time to deterioration.
• Change in Score Over Time in Coughing,Dyspnoea and Pain [ Time Frame: From first drug administration from 9 April 2012 until study closure on 27 Dec 2017 (approximately 2089 days). ]
  Health related quality of life (HRQoL) was measured with the following multi dimensional questionnaires: the EORTC QLQ-C30. The questionnaires were assessed at the first visit of each treatment course. For each of the summary scales and items measuring cough, dyspnoea and pain, the two treatment arms were compared in terms of change in score over time, adjusted for baseline score and race. Questionnaires have items relating to Cough, Dyspnoea and Pain. Overall Scores are transformed to a standardised scale of 0 to 100 with the larger value indicating a worse outcome. A change of (+/-) 10 points is considered to be relevant. The change in cough, dyspnea and pain will be assessed using a mixed effects growth curve model with the average profile over time for each endpoint described by a piecewise linear model (presented as post baseline in data table). Post-baseline mean is adjusted for baseline and race.

• Original Secondary Outcome Measures (submitted: January 30, 2012): Overall Survival [ Time Frame: up to 3 years ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: LUX-Lung 8: A Phase III Trial of Afatinib (BIBW 2992) Versus Erlotinib for the Treatment of Squamous Cell Lung Cancer After at Least One Prior Platinum Based Chemotherapy
• Official Title: LUX-Lung 8: A Randomized, Open-label Phase III Trial of Afatinib Versus Erlotinib in Patients With Advanced Squamous Cell Carcinoma of the Lung as Second-line Therapy Following First-line Platinum-based Chemotherapy
• Brief Summary: This randomised, open-label phase III trial will be performed in patients with advanced squamous cell carcinoma of the lung requiring second-line treatment after receiving first-line platinum-based chemotherapy. The primary objective of this trial is to compare the efficacy of BIBW 2992 to erlotinib as second-line treatment in this group of patients.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Carcinoma, Non-Small-Cell Lung

Intervention

• Drug: afatinib
  Afatinib taken once daily, continuously until disease progression or unacceptable toxicity.
• Drug: erlotinib
  erlotinib taken once daily

Study Arms

• Experimental: Afatinib
  Patients receive afatinib tablets once daily
  Intervention: Drug: afatinib
• Active Comparator: Erlotinib
  Patients receive erlotinib tablets once daily
  Intervention: Drug: erlotinib

Publications *

• Lu S, Li W, Zhou C, Hu CP, Qin S, Cheng G, Feng J, Wang J, Cseh A, Peil B, Gibson N, Ehrnrooth E, Zhang L. Afatinib vs erlotinib for second-line treatment of Chinese patients with advanced squamous cell carcinoma of the lung. Onco Targets Ther. 2018 Nov 30;11:8565-8573. doi: 10.2147/OTT.S161506. eCollection 2018.
• Goss GD, Felip E, Cobo M, Lu S, Syrigos K, Lee KH, Goker E, Georgoulias V, Li W, Guclu S, Isla D, Min YJ, Morabito A, Ardizzoni A, Gadgeel SM, Fulop A, Buhnemann C, Gibson N, Kramer N, Solca F, Cseh A, Ehrnrooth E, Soria JC. Association of ERBB Mutations With Clinical Outcomes of Afatinib- or Erlotinib-Treated Patients With Lung Squamous Cell Carcinoma: Secondary Analysis of the LUX-Lung 8 Randomized Clinical Trial. JAMA Oncol. 2018 Sep 1;4(9):1189-1197. doi: 10.1001/jamaoncol.2018.0775.
• Gadgeel S, Goss G, Soria JC, Felip E, Georgoulias V, Lu S, Cobo M, Syrigos K, Lee KH, Goker E, Guclu SZ, Isla D, Morabito A, Dupuis N, Buhnemann C, Kramer N, Solca F, Ehrnrooth E, Ardizzoni A. Evaluation of the VeriStrat(R) serum protein test in patients with advanced squamous cell carcinoma of the lung treated with second-line afatinib or erlotinib in the phase III LUX-Lung 8 study. Lung Cancer. 2017 Jul;109:101-108. doi: 10.1016/j.lungcan.2017.05.010. Epub 2017 May 11.
• Soria JC, Felip E, Cobo M, Lu S, Syrigos K, Lee KH, Goker E, Georgoulias V, Li W, Isla D, Guclu SZ, Morabito A, Min YJ, Ardizzoni A, Gadgeel SM, Wang B, Chand VK, Goss GD; LUX-Lung 8 Investigators. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015 Aug;16(8):897-907. doi: 10.1016/S1470-2045(15)00006-6. Epub 2015 Jul 5.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 19, 2014): 795
• Original Estimated Enrollment (submitted: January 30, 2012): 800
• Actual Study Completion Date: December 27, 2017
• Actual Primary Completion Date: October 21, 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria:

1. Diagnosis of advanced stage NSCLC squamous histology.
2. Platinum-based doublet chemotherapy as 1st line treatment of Stage IIIB/IV NSCLC.
3. Eligible to receive 2nd line therapy in the opinion of the investigator.
4. Measurable disease according to RECIST 1.1.
5. Adequate Performance Status.
6. Availability of tumour tissue material for correlative studies. Archived tumour tissue is acceptable.
7. Adequate organ function.
8. Age = 18 years and above.
9. Written informed consent that is consistent with International Conference on Harmonisation (ICH)-Good Clinical Practice (GCP) guidelines.

Exclusion criteria:

1. Prior treatment with Epidermal Growth Factor Receptor (EGFR) directed small molecules or antibodies.
2. Radiotherapy within 4 weeks prior to randomization.
3. Active brain metastases .
4. Any other current malignancy or malignancy diagnosed within the past three (3) years (other than basal-cell carcinoma of the skin, in situ cervical cancer, in situ prostate cancer).
5. Known pre-existing interstitial lung disease.
6. Significant or recent acute gastrointestinal disorders with diarrhoea as a major symptom
7. Any other concomitant serious illness or organ system dysfunction which in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the test drug.
8. Women of child-bearing potential and men who are able to father a child, unwilling to be abstinent or use adequate contraception prior to study entry, for the duration of study participation and for at least 2 months after treatment has ended.

9. Female patients of childbearing potential (see Section 4.2.3.3) who:

   1. are nursing or
   2. are pregnant or
   3. are not using an acceptable method of birth control, or do not plan to continue using this method throughout the study and/or do not agree to submit to pregnancy testing required by this protocol.
10. Active hepatitis B infection (defined as presence of Hep B DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or known HIV carrier.
11. Known or suspected active drug or alcohol abuse in the opinion of the investigator.
12. Any contraindications for therapy with afatinib or erlotinib.
13. Known hypersensitivity to erlotinib, afatinib or the excipients of any of the trial drugs.
14. Major surgery within 4 weeks of starting study treatment.
15. Prior participation in an afatinib clinical study, even if not assigned to afatinib.
16. Use of any investigational drug within 4 weeks of randomisation (unless a longer time period is required by local regulations or by the guidelines for the investigational product).
17. Patients without Progression of their lung cancer.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Austria, Canada, Chile, China, Denmark, France, Germany, Greece, Hungary, India, Ireland, Italy, Korea, Republic of, Mexico, Netherlands, Portugal, Singapore, Spain, Taiwan, Turkey, United Kingdom, United States
• Removed Location Countries: Peru

Administrative Information

• NCT Number: NCT01523587
• Other Study ID Numbers: 1200.125; 2011-002380-24 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Boehringer Ingelheim
• Original Responsible Party: Same as current
• Current Study Sponsor: Boehringer Ingelheim
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Chair: Boehringer Ingelheim; Boehringer Ingelheim

• PRS Account: Boehringer Ingelheim
• Verification Date: February 2019