Non-Small Cell Lung CancerPhase 2COMBINATIONNCT05298176
Combining Afatinib and Concurrent Chemotherapy, Followed by Osimertinib and Concurrent Chemotherapy, in Untreated EGFR Positive NSCLC Tumors
A Phase 2 study testing Afatinib, Osimertinib, Carboplatin and Pemetrexed in people with Non-Small Cell Lung Cancer, run by Amsterdam UMC, location VUmc at 1 site in Netherlands.
Trial summary
The aim of the COMBINATION trial is to prospectively study the sequential approach of using afatinib combined with a short course of chemotherapy, followed by osimertinib, upon progression and acquisition of a T790M mutation, also combined with a short course of chemotherapy. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Non-Small Cell Lung Cancer
- What is being tested?
- Afatinib, Osimertinib, Carboplatin and Pemetrexed
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 5 participants
- Where
- 1 siteNetherlands
- Study dates
- 4 Jan 2022to 1 Apr 2024
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically confirmed NSCLC, positive for non-exon20insertion uncommon EGFR mutations that are eligible for afatinib therapy in first line
- WHO PS 0-2
- Be willing and able to provide written informed consent for the trial.
- Be above 18 years of age on day of signing informed consent.
- Patients must have radiological measurable disease
- Demonstrate adequate organ function, as deemed acceptable by the treating physician in the context of metastatic NSCLC.
Who cannot join
- Inability to provide informed consent
- Inability to take study medications
- Patients with symptomatic or unstable CNS metastases
- Prior EGFR TKI or platinum-doublet therapy for advanced stage NSCLC. Prior (neo)adjuvant treatments are allowed when the last administration is one year or more.
- Evidence of interstitial lung disease or active, non-infectious pneumonitis.
- Active infection requiring systemic therapy.
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- Active Hepatitis B or C.
- Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- Patient is pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial, starting with the screening visit.
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Amsterdam UMC, location VUmc
Amsterdam, North Holland, 1081 HV
About this study
The aim of the COMBINATION trial is to prospectively study the sequential approach of using afatinib combined with a short course of chemotherapy, followed by osimertinib, upon progression and acquisition of a T790M mutation, also combined with a short course of chemotherapy.
Read the detailed description
The investigators hypothesized that treating advanced stage EGFR mutation positive NSCLC in first line with afatinib and osimertinib in second line (in T790M positive tumors) will cause an apoptotic cell death in a large part of TKI-sensitive cancer cells, resulting in a large reduction of the tumor bulk. Adding cytotoxic chemotherapy after 6 weeks of EGFR-TKI will destroy remaining TKI-resistant subclones at an early stage, when the TKI-resistance tumor volume is the smallest and most vulnerable. The investigators will administer only 2 cycles of chemotherapy to limit toxicity, while maintaining a substantial anti-cancer effect. After progression on afatinib-chemotherapy combination, some participants will develop T790M and will be able treated by osimertinib-chemotherapy combination.
So, this strategy will allow the investigators to timely sequence the most appropriate drugs (afatinib and osimertinib with chemotherapy) to get the highest anti-cancer efficiency. In this way, the investigators will avoid long periods of maintenance treatments with chemotherapy or anti-VEGFR treatments that are associated with toxicity, costs, and necessitate the participants to come into the ward for intravenous medication. The limited cycles of chemotherapy also allows the treating physician to again treat the participant with the same chemotherapy regimen once progression occurs after all sensible targeted therapy options have been used.
Therefore, the investigators hypothesize that this sequential combination strategy will be more effective than other available strategies and will improve the quality of patient care as compared to current general practice.
- Conditions
- Non-Small Cell Lung Cancer
- Being tested
- Afatinib, Osimertinib, Carboplatin and Pemetrexed
- Keywords
- EGFR, EGFR mutation, Afatinib, Osimertinib, Chemotherapy, Combination strategy
- Medical subject headings
- Carcinoma, Non-Small-Cell Lung
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Afatinib, Osimertinib, Carboplatin and PemetrexedDrug
This study consists of 2 parts. Part 1 is defined as a first line treatment with afatinib orally (30 mg once a day) for the first 6 weeks, followed by concurrent use of afatinib (20mg once a day, part 1B) plus 2 cycles of carboplatin and pemetrexed (21 days per cycle); followed by afatinib monotherapy (30mg once a day). Part 2 comprises a 2nd line treatment with osimertinib (80 mg once daily) after failure of part 1, only in T790M positive patients for the first 6 weeks, followed by concurrent use of osimertinib (80mg once a day) plus 2 cycles of carboplatin and pemetrexed (21 days per cycle); followed by osimertinib monotherapy (80mg once a day).
| Study group | Role | What they receive |
|---|---|---|
| Patients with untreated EGFR positive NSCLC tumors | Experimental | TKI-naïve advanced NSCLC patients, harboring a non-exon20insertion uncommon EGFR mutation, who are eligible for treatment with afatinib in 1st line Receives: Drug: Afatinib, Osimertinib, Carboplatin and Pemetrexed |
What is being measured
The primary outcome is the main question the study is designed to answer.
Disease control rate (DCR)
To assess the efficacy of the sequential strategy of front-line afatinib-chemo, followed by a treatment with osimertinib-chemo in those patients that develop a T790M mutation as a mechanism of resistance
Measured: 18 months
Secondary outcomes (7)
Progression Free Survival (PFS)
To assess long term efficacy
Measured: From start of therapy until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 50 months
Overall Survival (OS)
To assess long term efficacy
Measured: From start of therapy until the date of death from any cause, assessed up to 50 months
Objective response rate according to RECIST v1.1 after start of afatinib
To assess short term efficacy
Measured: At 6 weeks
Objective response rate according to RECIST v1.1 after start of afatinib
To assess short term efficacy
Measured: At 12 weeks
Objective response rate according to RECIST v1.1 after start of osimertinib
To assess short term efficacy
Measured: At 6 weeks
Objective response rate according to RECIST v1.1 after start of osimertinib
To assess short term efficacy
Measured: At 12 weeks
Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)
To assess the safety of afatinib and osimertinib intercalated with 2 cycles of carboplatin-pemetrexed
Measured: From start of therapy until disease progression or study drug toxicity assessed up to 100 days after part 1 and 2
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Mar 2022
- Study start4 Jan 2022
- Primary completion1 Apr 2024
- Study completion1 Apr 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Non-Small Cell Lung CancerStudies of the same condition, open and under way.
- More trials run by Amsterdam UMC, location VUmcThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 5 participants (actual)
Sponsor and investigators
- Lead sponsor
- Amsterdam UMC, location VUmc
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Idris Bahce, Amsterdam UMC, location VUmc
- Investigators
- Idris Bahce, MD, PhD, Principal investigator, Amsterdam UMC, location VUmc
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05298176
- Sponsor's protocol ID
- NL74383.029.20
- Other IDs
- 2020-003025-37
- Acronym
- COMBINATION
- Status last verified
- Mar 2025
- First submitted
- 15 Jan 2022
- Last updated
- 28 Mar 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 28 Mar 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Combining Afatinib and Concurrent Chemotherapy, Followed by Osimertinib and Concurrent Chemotherapy, in Untreated EGFR Positive NSCLC Tumors
- ClinicalTrials.gov ID
- NCT05298176
- Acronym / sponsor ID
- COMBINATION / NL74383.029.20
- Conditions
- Non-Small Cell Lung Cancer
- Keywords
- EGFR, EGFR mutation, Afatinib, Osimertinib, Chemotherapy, Combination strategy
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 5 participants (actual)
- Lead sponsor
- Amsterdam UMC, location VUmcUniversity, hospital or other
- Study start
- 4 Jan 2022 (actual)
- Primary completion
- 1 Apr 2024 (actual)
- Study completion
- 1 Apr 2024 (actual)
- First posted
- 28 Mar 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The aim of the COMBINATION trial is to prospectively study the sequential approach of using afatinib combined with a short course of chemotherapy, followed by osimertinib, upon progression and acquisition of a T790M mutation, also combined with a short course of chemotherapy.
Detailed description
The investigators hypothesized that treating advanced stage EGFR mutation positive NSCLC in first line with afatinib and osimertinib in second line (in T790M positive tumors) will cause an apoptotic cell death in a large part of TKI-sensitive cancer cells, resulting in a large reduction of the tumor bulk. Adding cytotoxic chemotherapy after 6 weeks of EGFR-TKI will destroy remaining TKI-resistant subclones at an early stage, when the TKI-resistance tumor volume is the smallest and most vulnerable. The investigators will administer only 2 cycles of chemotherapy to limit toxicity, while maintaining a substantial anti-cancer effect. After progression on afatinib-chemotherapy combination, some participants will develop T790M and will be able treated by osimertinib-chemotherapy combination.
So, this strategy will allow the investigators to timely sequence the most appropriate drugs (afatinib and osimertinib with chemotherapy) to get the highest anti-cancer efficiency. In this way, the investigators will avoid long periods of maintenance treatments with chemotherapy or anti-VEGFR treatments that are associated with toxicity, costs, and necessitate the participants to come into the ward for intravenous medication. The limited cycles of chemotherapy also allows the treating physician to again treat the participant with the same chemotherapy regimen once progression occurs after all sensible targeted therapy options have been used.
Therefore, the investigators hypothesize that this sequential combination strategy will be more effective than other available strategies and will improve the quality of patient care as compared to current general practice.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Patients with untreated EGFR positive NSCLC tumors | Experimental | Drug: Afatinib, Osimertinib, Carboplatin and PemetrexedTKI-naïve advanced NSCLC patients, harboring a non-exon20insertion uncommon EGFR mutation, who are eligible for treatment with afatinib in 1st line |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Histologically confirmed NSCLC, positive for non-exon20insertion uncommon EGFR mutations that are eligible for afatinib therapy in first line
- WHO PS 0-2
- Be willing and able to provide written informed consent for the trial.
- Be above 18 years of age on day of signing informed consent.
- Patients must have radiological measurable disease
Key exclusion criteria (9 listed)
- Inability to provide informed consent
- Inability to take study medications
- Patients with symptomatic or unstable CNS metastases
- Prior EGFR TKI or platinum-doublet therapy for advanced stage NSCLC. Prior (neo)adjuvant treatments are allowed when the last administration is one year or more.
- Evidence of interstitial lung disease or active, non-infectious pneumonitis.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Afatinib, Osimertinib, Carboplatin and PemetrexedThis study consists of 2 parts. Part 1 is defined as a first line treatment with afatinib orally (30 mg once a day) for the first 6 weeks, followed by concurrent use of afatinib (20mg once a day, part 1B) plus 2 cycles of carboplatin and pemetrexed (21 days per cycle); followed by afatinib monotherapy (30mg once a day). Part 2 comprises a 2nd line treatment with osimertinib (80 mg once daily) after failure of part 1, only in T790M positive patients for the first 6 weeks, followed by concurrent use of osimertinib (80mg once a day) plus 2 cycles of carboplatin and pemetrexed (21 days per cycle); followed by osimertinib monotherapy (80mg once a day). | Drug | Patients with untreated EGFR positive NSCLC tumors |
Primary outcome
Disease control rate (DCR)
Time frame: 18 months
To assess the efficacy of the sequential strategy of front-line afatinib-chemo, followed by a treatment with osimertinib-chemo in those patients that develop a T790M mutation as a mechanism of resistance
7 secondary outcomes
Progression Free Survival (PFS)
Time frame: From start of therapy until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 50 months
Overall Survival (OS)
Time frame: From start of therapy until the date of death from any cause, assessed up to 50 months
Objective response rate according to RECIST v1.1 after start of afatinib
Time frame: At 6 weeks
Objective response rate according to RECIST v1.1 after start of afatinib
Time frame: At 12 weeks
Objective response rate according to RECIST v1.1 after start of osimertinib
Time frame: At 6 weeks
Objective response rate according to RECIST v1.1 after start of osimertinib
Time frame: At 12 weeks
Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: From start of therapy until disease progression or study drug toxicity assessed up to 100 days after part 1 and 2
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Mar 2025.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Idris Bahce, MD, PhD principal investigator
Amsterdam UMC, location VUmc
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Afatinib, Osimertinib, Carboplatin and Pemetrexed in people with Non-Small Cell Lung Cancer, run by Amsterdam UMC, location VUmc at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Mar 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Disease control rate (DCR) (time frame: 18 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Mar 2025.