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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Combining Afatinib and Concurrent Chemotherapy, Followed by Osimertinib and Concurrent Chemotherapy, in Untreated EGFR Positive NSCLC Tumors

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Afatinib, Osimertinib, Carboplatin and Pemetrexed


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with untreated EGFR positive NSCLC tumors<br>TKI-naïve advanced NSCLC patients, harboring a non-exon20insertion uncommon EGFR mutation, who are eligible for treatment with afatinib in 1st line | Drug: Afatinib, Osimertinib, Carboplatin and Pemetrexed<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | To assess long term efficacy | 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 | 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 | At 6 weeks | 
| Objective response rate according to RECIST v1.1 after start of afatinib | To assess short term efficacy | At 12 weeks | 
| Objective response rate according to RECIST v1.1 after start of osimertinib | To assess short term efficacy | At 6 weeks | 
| Objective response rate according to RECIST v1.1 after start of osimertinib | To assess short term efficacy | 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 | From start of therapy until disease progression or study drug toxicity assessed up to 100 days after part 1 and 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EGFR, EGFR mutation, Afatinib, Osimertinib, Chemotherapy, Combination strategy