Combining Afatinib and Concurrent Chemotherapy, Followed by Osimertinib and Concurrent Chemotherapy, in Untreated EGFR Positive NSCLC Tumors (COMBINATION)

  • End date
    Jan 11, 2025
  • participants needed
  • sponsor
    Amsterdam UMC, location VUmc
Updated on 11 April 2022
measurable disease
cancer chemotherapy


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.


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.

Condition Non-Small Cell Lung Cancer
Treatment Afatinib, Osimertinib, Carboplatin and Pemetrexed
Clinical Study IdentifierNCT05298176
SponsorAmsterdam UMC, location VUmc
Last Modified on11 April 2022


Yes No Not Sure

Inclusion Criteria

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

Exclusion Criteria

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
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
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