Xentuzumab (BI 836845) Plus Afatinib in Patients With Epidermal Growth Factor Receptor (EGFR) Mutant Non-small Cell Lung Cancer (NSCLC)

A Phase Ib Open-label Clinical Trial of Once Daily Oral Treatment of Afatinib Plus Weekly Intravenous Infusion of Xentuzumab (BI 836845) in Patients With EGFR Mutant Non-small Cell Lung Cancer With Progression Following Prior EGFR Tyrosine Kinase Inhibitors

Part A: To determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of Xentuzumab (BI 836845) in combination with afatinib in patients with non-small cell lung cancer with progression following prior treatment (EGFR TKI or platinum-based chemotherapy).

Part B: To evaluate the early anti-tumour activity of Xentuzumab (BI 836845) in combination with afatinib in patients with EGFR mutant non-small cell lung cancer with progression following prior irreversible EGFR TKIs.

Part A and B: To evaluate the safety and pharmacokinetics of BI 836845 in combination with afatinib in patients with non-small cell lung cancer

Study Overview

• Status: Completed
• Conditions: Carcinoma, Non-Small-Cell Lung
• Intervention / Treatment: Drug: Xentuzumab; Drug: Afatinib

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Fukuoka, Fukuoka, Japan, 811-1395
    • National Hospital Organization Kyushu Cancer Center
• Korea, Republic of
  • Cheongju, Korea, Republic of, 361-771
    • Chungbuk National University Hospital
  • Seoul, Korea, Republic of, 135-710
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 138-736
    • Asan Medical Center
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital
• Singapore
  • Singapore, Singapore, 169610
    • National Cancer Centre Singapore
• Taiwan
  • Chiayi, Taiwan, 613
    • Chang Gung Memorial Hospital Chiayi
  • Kaohsiung, Taiwan, 83301
    • Kaohsiung Chang Gung Memorial Hospital
  • Tainan, Taiwan, 704
    • NCKUH
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

• Aged 18 years or older
• Pathologically confirmed of advanced and/or metastatic stage IIIb/IV non-small cell carcinoma of lung
• Activating EGFR mutation (exon 19 deletion, L858R, G719X, L861X)
• Presence of EGFR activating mutation and absence of EGFR T790M in the tumour associated with the latest disease progression. Only applicable in Part B
• Must have adequate fresh or archival tumour tissue at the late disease progression immediately prior to the study entry
• Part A: Progression of disease (RECIST 1.1) while on continuous treatment with single EGFR TKI or for histology other than adenocarcinoma and without prior EGFR TKI treatment: progression of disease (RECIST v1.1) on platinum-based chemotherapy. Part B: Progression of disease (RECIST v1.1) while on continuous treatment with single agent of the second generation irreversible EGFR TKI (e.g. afatinib or dacomitinib)
• No intervening systemic therapy between cessation of EGFR TKI and study treatment
• Patient must have measurable disease per RECIST 1.1 presented after tumour biopsy for the late disease progression
• Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1
• Life expectancy of >= 3 months
• Fasting plasma glucose < 8.9 mmol/L (< 160mg/dL) and HbA1C < 8%
• Adequate organ function
• Recovered from any previous therapy related toxicity to <= Grade 1 at study entry (except for stable sensory neuropathy <= Grade 2 and alopecia)
• Written informed consent that is consistent with ICH-GCP guidelines and local regulations
• No known potentially targetable mutation other than IGF signaling pathway or EGFR or no available treatment for potentially targetable mutation

Exclusion criteria:

• Part A only: For patient who has been treated with afatinib: last treatment at reduced dose below the assigned dose level
• Patient whose disease progressed on insufficient dose of EGFR TKI immediately prior to study in the opinion of the investigator
• More than 2 prior EGFR TKI treatment regimens for Part B
• Chemotherapy, biological therapy or investigational agents (except EGFR TKIs) within 4 weeks
• Use of previous EGFR TKIs except afatinib within 3 days
• Radiotherapy within 4 weeks prior to the start of study treatment
• Active brain or subdural metastases
• Meningeal carcinomatosis.
• Major surgery (as judged by the investigator) within 4 weeks
• Known hypersensitivity to afatinib, monoclonal antibody
• Prior severe infusion-related reaction to a monoclonal antibody
• History or presence of clinically relevant cardiovascular abnormalities
• Female patients of childbearing potential (see Section 4.2.2.3) and male who are able to father a child
• Any history of or concomitant condition that, in the opinion of the investigator not to comply with the study or interfere with the evaluation of the efficacy and safety of the test drug
• Previous or concomitant malignancies at other sites, except effectively treated non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ or effectively treated malignancy that has been in remission for more than 3 years and is considered to be cured.
• Disease that is considered by the investigator to be rapidly progressing or life threatening such as extensive symptomatic visceral disease including hepatic involvement and pulmonary lymphangitic spread of tumour (subjects who are intended for urgent chemotherapy)
• Requiring treatment with any of the prohibited concomitant medications
• Known pre-existing interstitial lung disease (ILD)
• Any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of the study drug
• Active hepatitis B infection active hepatitis C infection and/or known HIV carrier.
• Previous treatment with agents targeting the insulin like growth factor (IGF) signalling pathway.
• Previous treatment with EGFR TKI which cannot be documented as either reversible or irreversible (Part B only)
• Part B only: Prior treatment with third generation irreversible EGFR TKI (e.g. AZD9291 or CO-1686)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Xentuzumab + Afatinib 30 milligram (mg) - Part A; Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 30 mg film-coated tablet. Dose confirmation part (Part A).	Drug: Xentuzumab; Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib film-coated tablet.; Other Names: BI 836845; Drug: Afatinib; Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib film-coated tablet.
Experimental: Xentuzumab + Afatinib 40 mg - Part A; Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 40 mg film-coated tablet. Dose confirmation part (Part A).	Drug: Xentuzumab; Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib film-coated tablet.; Other Names: BI 836845; Drug: Afatinib; Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib film-coated tablet.
Experimental: Xentuzumab + Afatinib 20 mg - Part B; Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 20 mg film-coated tablet. Expansion part (Part B).	Drug: Xentuzumab; Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib film-coated tablet.; Other Names: BI 836845; Drug: Afatinib; Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib film-coated tablet.
Experimental: Xentuzumab + Afatinib 30 mg - Part B; Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 30 mg film-coated tablet. Expansion part (Part B).	Drug: Xentuzumab; Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib film-coated tablet.; Other Names: BI 836845; Drug: Afatinib; Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib film-coated tablet.
Experimental: Xentuzumab + Afatinib 40 mg - Part B; Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 40 mg film-coated tablet. Expansion part (Part B).	Drug: Xentuzumab; Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib film-coated tablet.; Other Names: BI 836845; Drug: Afatinib; Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib film-coated tablet.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Dose Limiting Toxicities (DLT) - Part A	DLT Criteria: Common Terminology Criteria for Adverse Events(CTCAE) CTCAE Grade (G) 4 neutropenia lasting ≥7 days; Febrile neutropenia with a single/sustained temperature of ≥38.3°C for >1 hour; Documented infection with absolute neutrophil count (ANC) <1.0 x 109/L; G 3/4 thrombocytopenia associated with bleeding requiring platelet transfusion; G 2/higher decrease in cardiac left ventricular function; G 2 diarrhea lasting for ≥7 days; G ≥3 diarrhea; G≥3 nausea/vomiting; G≥3 skin rash; aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >5 x Upper limit of normal (ULN)/>baseline value +4 x ULN; G≥3 fatigue/asthenia lasting for >7 days; G≥3 hyperglycemia lasting >48 hours; All other non-hematologic adverse events(AEs) of G≥3 (except alopecia, infusion reaction, and allergic reaction) that led to an interruption of afatinib/xentuzumab for >14 days until recovery to baseline/G 1; Any other study drug-related toxicity considered significant enough to qualify as DLT.	During the first treatment course, up to 28 days.
Maximum Tolerated Dose (MTD) - Part A	Maximum tolerated dose (MTD) of Xentuzumab in combination with Afatinib, in patients with non-small cell lung cancer with progression following prior treatment, based on the occurrence of dose limiting toxicity (DLT) during the first treatment course. MTD was defined as the highest dose level examined of trial medication, at which no more than 1 out of 6 patients experienced a DLT during the MTD evaluation period.	During the first treatment course, up to 28 days.
Number of Participants With Objective Response (OR) - Part B	OR was defined as best overall response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, where best overall response was defined according to RECIST v1.1 from first administration of trial medication until the earliest of disease progression, death or last evaluable tumour assessment before start of subsequent anti-cancer therapy.	Tumour assessment was performed every 4 weeks after the start of treatment for first 8 weeks, in 8-week intervals thereafter and in 12-week interval after Course 16 until disease progression or the start of further anti-cancer treatment, up to 1200 days.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Disease Control (DC) - Part B	DC was defined as best overall response of complete response (CR) or partial response (PR) or stable disease (SD) according to RECIST v1.1, where best overall response was defined according to RECIST v1.1 from first administration of trial medication until the earliest of disease progression, death or last evaluable tumour assessment before start of subsequent anti-cancer therapy.	Tumour assessment was performed every 4 weeks after the start of treatment for first 8 weeks, in 8-week intervals thereafter and in 12-week interval after Course 16 until disease progression or the start of further anti-cancer treatment, up to 1200 days.
Time to OR - Part B	Time to OR, defined as the time from first treatment administration until first documented CR or PR. For patients with OR, time to OR was summarised on a patient level.	Tumour assessment was performed every 4 weeks after the start of treatment for first 8 weeks, in 8-week intervals thereafter and in 12-week interval after Course 16 until disease progression or the start of further anti-cancer treatment, up to 1200 days.
Duration of OR - Part B	Duration of OR, defined as the time from first documented CR or PR until the earliest of disease progression or death among patients with OR - Part B. For patients with OR, duration of OR was summarised on a patient level.	Tumour assessment was performed every 4 weeks after the start of treatment for first 8 weeks, in 8-week intervals thereafter and in 12-week interval after Course 16 until disease progression or the start of further anti-cancer treatment, up to 1200 days.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim
• Investigators: Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): October 21, 2014
• Primary Completion (Actual): April 18, 2018
• Study Completion (Actual): April 18, 2018

Study Registration Dates

• First Submitted: July 14, 2014
• First Submitted That Met QC Criteria: July 14, 2014
• First Posted (Estimated): July 16, 2014

Study Record Updates

• Last Update Posted (Estimated): June 25, 2025
• Last Update Submitted That Met QC Criteria: June 6, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; Tyrosine Kinase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Afatinib
• Other Study ID Numbers: 1280.16

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Once the criteria in section "Time Frame" are fulfilled, researchers can use the following link https://www.mystudywindow.com/msw/datasharing to request access to the clinical study documents regarding this study, and upon a signed "Document Sharing Agreement".

Furthermore, researchers can request access to the clinical study data, for this and other listed studies, after the submission of a research proposal and according to the terms outlined in the website.

• IPD Sharing Time Frame: One year after the approval has been granted by major Regulatory Authorities and after the primary manuscript has been accepted for publication, or after termination of the development program.

IPD Sharing Access Criteria

For study documents - upon signing of a 'Document Sharing Agreement'.

For study data - 1. after the submission and approval of the research proposal (checks will be performed by the sponsor and/or the independent review panel, including checking that the planned analysis does not compete with sponsor's publication plan); 2. and upon signing of a legal agreement.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR